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Management of Chronic Left Ventricular Systolic Heart Failure – Adult – Inpatient/Ambulatory

Management of Chronic Left Ventricular Systolic Heart Failure – Adult – Inpatient/Ambulatory - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Cardiovascular


1
Management of Chronic Left Ventricular
Systolic Heart Failure – Adult –
Inpatient/Ambulatory
Clinical Practice Guideline
Note: Active Table of Contents – Click to follow link
Table of Contents
EXECUTIVE SUMMARY ........................................................................................................... 3
Management of Risk Factors .............................................................................................................. 3
Non-Pharmacological Management .................................................................................................... 3
Medications ......................................................................................................................................... 7
Laboratory Tests ............................................................................................................................... 10
Referral to Electrophysiology ............................................................................................................ 10
Referral to Cardiology ....................................................................................................................... 10
SCOPE .....................................................................................................................................12
METHODOLOGY .....................................................................................................................13
INTRODUCTION ......................................................................................................................14
RECOMMENDATIONS .............................................................................................................14
UW HEALTH IMPLEMENTATION ............................................................................................15
APPENDIX A. BETA BLOCKER EQUIVALENCY DOSING FOR PATIENTS WITH HEART
FAILURE5-14 ..............................................................................................................................18
REFERENCES .........................................................................................................................19
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 12/2015CCKM@uwhealth.org

2
CPG Contact for Content:
Name: Maryl Johnson, MD- Medicine- Cardiology
Phone Number: (608) 263-0080
Email Address: mrj@medicine.wisc.edu
CPG Contact for Changes:
Name: Lindsey Spencer, MS- Center for Clinical Knowledge Management (CCKM)
Phone Number: (608) 890-6403
Email Address: lspencer2@uwhealth.org
Guideline Author(s):
American College of Cardiology Foundation/American Heart Association (ACCF/AHA)
Coordinating Team Members:
Peter Rahko, MD- Medicine- Cardiology
Shahab Akhter, MD- Surgery- Cardiothoracic
Lucian Lozonschi, MD- Surgery- Cardiothoracic
Nicole Bonk, MD- Urgent Care- Family Medicine- General
Irene Hamrick, MD- Family Medicine- General
Michael Thom, MD- Medicine- Internal Medicine- General
Peter Gill, MD- Medicine- Hospitalist
Margaret Murray, DNP- Surgery- Cardiothoracic
Cindy Gaston, PharmD, BCPS- Drug Policy Program
Anne Rose, PharmD, BCPS- Pharmacy- Inpatient Services
Jennifer Schauer, PharmD- Pharmacy- Unity Pharmacy Program
Peter Rusch, RT- Respiratory Therapy
Vonda R. Shaw, MS, MPH- Preventive Cardiology and Heart Station Manager
Deana Jansa, MBA/HCM, BSN, RN-BC- Clinics- Administration
Jill Lindwall, MSN, RN- Clinic Management- General
Kristen Sipsma, MPH- Center for Clinical Knowledge Management (CCKM)
Jennifer Grice, PharmD, BCPS- Center for Clinical Knowledge Management (CCKM)
Review Individuals/Bodies:
Mark Micek, MD- Medicine- Internal Medicine- General
Teresa Darcy, MD- Pathology- General
Committee Approvals/Dates:
Clinical Knowledge Management (CKM) Council (12/17/2015)
Release Date: December 2015 | Next Review Date: December 2017
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 12/2015CCKM@uwhealth.org

3
Executive Summary
Guideline Overview
UW Health has agreed to endorse and adopt the 2013 ACCF/AHA Guidelines for the
Diagnosis and Management of Heart Failure in Adults.1
Key Revisions (2016 Periodic Review)
1. Added criteria for cardiac rehabilitation referral (page 3).
2. Adapted algorithm for guideline-directed medical therapy (page 6).
3. Added recommendations for sacubitril/valsartran and ivabradine (pages 7-8, 14).
4. Added beta blocker dosing equivalency table (Appendix A).
Key Practice Recommendations
MANAGEMENT OF RISK FACTORS
1. Control hypertension and lipid disorders according to current guidelines.1 (AHA Class I,
Level of Evidence A)
2. Avoid tobacco use or exposure.1 (AHA Class I, Level of Evidence C)
3. Control or avoid obesity, diabetes mellitus, and use of known cardiotoxic agents.1
(AHA Class I, Level of Evidence C)
NON-PHARMACOLOGICAL MANAGEMENT
1. Patients with HFrEF should receive education to facilitate self-care.1 (AHA Class I,
Level of Evidence B)
2. Exercise training (or regular physical activity) is recommended in patients who are
able to participate.1 (AHA Class I, Level of Evidence A)
3. Cardiac rehabilitation can be useful in clinically stable heart failure patients.1 (AHA
Class IIa, Level of Evidence B) Non-Medicare insurers may cover the service based upon
medical necessity and will be evaluated by staff upon referral.
The following enrollment criteria are required prior to participation:
ξ Ventricular ejection fraction < 35% (measured within the last 12 months)
ξ New York Heart Association (NYHA) Class II-III symptoms despite being on
optimal medical therapy for at least 6 weeks
ξ Clinical stability, defined as not having a recent (< 6 weeks) or planned (< 6
months) major cardiovascular hospitalization or procedure
ξ Referral by a cardiologist directly involved with the patient’s care. Direct
referrals from non-cardiology physicians will be reviewed by the Preventive
Cardiology Medical Director.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
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4
4. Sodium restriction is reasonable to reduce congestive symptoms in patients who are
symptomatic.1 (AHA Class IIa, Level of Evidence C)
5. Fluid restriction (1.5-2 L/day) is reasonable in stage D, especially in patients with
hyponatremia, to reduce congestive symptoms.1 (AHA Class IIa, Level of Evidence C) As a
patient's heart failure starts to decompensate, thirst is stimulated and fluid restriction
may be provided to reduce the risk of fluid overload.
6. Effective systems of care coordination, with special attention to care transitions,
should be deployed for every patient with chronic HFrEF that facilitate and ensure
effective care that is designed to achieve guideline-directed medical and device
therapy (GDMT) and prevent hospitalization.1 (AHA Class I, Level of Evidence B)
7. Palliative care should be considered for patients with advanced HF, especially those
who are not candidates for heart transplantation or mechanical circulatory support.1
(AHA Class I, Level of Evidence B)
Stages of heart failure (HF) and recommended treatment are shown in Figures 1- 2.
Copyright © 2015 University of Wisconsin Hospitals and Clinics Authority
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5
FIGURE 1. Stages in the Development of HF and Recommended Therapy by Stage1
ACEI indicates angiotensin-converting enzyme inhibi-tor; AF, atrial ἀbrillation; ARB, angiotensin-receptor blocker; CAD, coronary artery disease; CRT, cardiac resynchronization therapy; DM, diabetes mellitus;
EF, ejection fraction; GDMT, guideline-directed medical therapy; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HRQOL, health-
related quality of life; HTN, hypertension; ICD, implantable cardioverter-defibrillator; LV, left ventricular; LVH, left ventricular hypertrophy; MCS, mechanical circulatory support; and MI, myocardial infarction.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: CCKM@uwhealth.org 12/2015

6
FIGURE 2. Stage C HFrEF Guideline-Directed Medical Therapy
HFrEF Stage C NYHA Class I-IV
Treatment:
AHA Class I, LOE A
ACEI or ARB AND
Beta Blocker
For persistently
symptomatic African
Americans,
NYHA Class III-IV
For NYHA class II-IV
patients. Provided
estimated creatinine
clearance > 30 mL/min
and K+ < 5.0 mEq/dL
For all volume
overload, NYHA Class
II-IV patients
For NYHA Class II-III
patients with NSR,
HR > 70 bpm
For NYHA Class II-IV
patients
Transition from
ACEI/ARB
UW Health Class IIa, LOE B
Sacubitril/valsartan
Add
AHA Class I, LOE A
Aldosterone
Antagonist
ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin-receptor blocker; AHA, American Heart Association; HFrEF, heart failure with reduced ejection
fraction; Hydral-Nitrates, hydralazine and isosorbide dinitrate; LOE, Level of Evidence; NSR, normal sinus rhythm; NYHA, New York Association
AHA Class I, LOE A
Hydral-Nitrates
AHA Class I, LOE C
Loop Diuretics
UW Health Class IIa, LOE B
Ivabradine
AddAddAdd
Figure adapted from the 2013 ACCF/AHA Guideline.1-3
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
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MEDICATIONS
In patients requiring hospitalization during chronic maintenance guideline directed
medical therapy for HFrEF, the medical therapy should be continued during the
hospitalization in the absence of hemodynamic instability or contraindications. If the
therapy requires a decrease or discontinuation during the hospital stay, the therapy
should be resumed at or following hospital discharge as the patient's condition allows.
1. Angiotensin-converting enzyme inhibitors (ACEI) should be prescribed unless
contraindicated.1 (AHA Class I, Level of Evidence A) However, sacubitril/valsartan could
be prescribed in preference to ACEI (see below).
2. An angiotensin-receptor blocker (ARB), preferably candesartan or valsartan, should
be prescribed in ACEI intolerant patients, unless contraindicated.1 (AHA Class I, Level of
Evidence A)
3. Contraindications to BOTH ACEIs and ARBs must be documented individually. Such
a patient should be prescribed the combination of hydralazine/nitrates.
4. One of the beta blockers proven to reduce mortality in HFrEF (carvedilol, metoprolol
succinate, or bisoprolol) should be prescribed to patients with HFrEF.1 (AHA Class I,
Level of Evidence A) If a beta blocker is not prescribed, a contraindication must be
documented.
5. Sacubitril/valsartan has demonstrated a survival benefit compared to enalapril in
patients on GDMT to reduce the risk of cardiovascular death and hospitalization for
heart failure in patients with chronic heart failure (NYHA Class II-IV) and reduced
ejection fraction. It is recommended in patients on guideline-directed medications at
a dose equivalent to at least 10 mg of enalapril daily and NYHA Class II-IV and heart
failure hospitalization within the last year.3 (UW Health Class IIa, Level of Evidence B)
Patients on GMDT should be transitioned off of the ACE-I (at least 36 hour washout)
prior to initiation, as this medication should not be used in conjunction with ACE-I or
additional ARBs. Beta blocker therapy should be continued on the maximum
tolerated dose. The most common side effects are hyperkalemia, hypotension, renal
impairment, dizziness. Additional valsartan should not be prescribed.
6. An aldosterone receptor antagonist (ARA) should be prescribed, unless
contraindicated, in high risk patients with New York Heart Association (NYHA) Class
II HF (prior hospitalization or elevated natriuretic peptide levels) and in all patients
with NYHA Class III or IV HF, if the creatinine is < 2.5 mg/dL in men or < 2.0 mg/dL
in women and potassium < 5.0 mEq/L.1 (AHA Class I, Level of Evidence A) When ARAs
are prescribed, renal function and potassium levels must be checked weekly until
stable, then every three months.
7. The combination of hydralazine and isosorbide dinitrate is recommended to reduce
mortality in African Americans with NYHA Class III-IV heart failure on optimal ACEI
and beta-blocker therapy.1 (AHA Class I, Level of Evidence A)
8. Ivabradine is reasonable in patients with stable, symptomatic heart failure in normal
sinus rhythm on guideline-directed medications (e.g., ACE, ARB, beta blocker) at the
guideline-directed or highest tolerated dose, yet with resting heart rate > 70 bpm.2
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
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8
(UW Health Class IIa, Level of Evidence B) The most common side effects include
bradycardia, hypertension, atrial fibrillation, and temporary vision disturbances
(flashes of light). Hospital admission for heart failure and heart failure deaths are
significantly reduced by use of ivabradine in those patients described above.
9. Loop diuretics are recommended for treatment of volume overload to improve
symptoms.1 (AHA Class I, Level of Evidence C) Appropriate dosing should result in a
compensated patient with no signs and symptoms of volume overload.
10. Digoxin should be reserved for patients with persistent symptoms and
hospitalizations due to heart failure.1 (AHA Class IIa, Level of Evidence B) Low doses
should be prescribed, and the blood concentration should not exceed 1.0 ng/mL.
11. Medications to AVOID1:
ξ Nonsteroidal anti-inflammatory drugs (NSAIDs) (AHA Class III, Level of Evidence B)
ξ Most antiarrhythmics, except amiodarone (AHA Class III, Level of Evidence B)
ξ Nondihydropyridine calcium channel blockers with negative inotropic effects,
such as diltiazem or verapamil. The dihydropyridine calcium channel blocker
amlodipine has been shown to be safe, but not beneficial, in patients with
heart failure and EF < 30%. (AHA Class III, Level of Evidence C)
ξ Thiazolidinediones (e.g., rosiglitazone, pioglitazone) (AHA Class III, Level of
Evidence B)
ξ Alpha blocking drugs used to treat hypertension (e.g., prazosin, doxazosin)
are associated with increased mortality in heart failure with LV systolic
dysfunction, and alternative therapy should be sought.
A summary of drugs commonly used for Stage C HFrEF are shown in Table 1 below1,4:
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
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TABLE 1. Drugs Used in Stage C HFrEF
Drug Initial Daily Dose(s) Maximum Dose(s) Mean Dose Achieved in Clinical Trials1
ACE inhibitors
Captopril 6.25 mg 3 times 50 mg 3 times 122.7 mg/day
Enalapril 2.5 mg twice 10 to 20 mg twice 16.6 mg/day
Lisinopril 2.5 to 5 mg 20 to 40 mg once 32.5 to 35 mg/day
Fosinopril 5 to 10 mg once 40 mg once N/A
Perindopril 2 mg once 8 to 16 mg once N/A
Quinapril 5 mg twice 20 mg twice N/A
Ramipril 1.25 to 2.5 mg once 10 mg once N/A
Trandolapril 1 mg once 4 mg once N/A
ARBs
Candesartan 4 to 8 mg once 32 mg once 24 mg/day
Losartan 25 to 50 mg once 50 to 150 mg once 129 mg/day
Valsartan 20 to 40 mg twice 160 mg twice 254 mg/day
Beta Blockers
Bisoprolol 1.25 mg once 10 mg once 8.6 mg/day
Carvedilol 3.125 mg twice 50 mg twice 37 mg//day
Carvedilol CR 10 mg once 80 mg once N/A
Metoprolol succinate
ER (metoprolol CR/XL) 12.5 to 25 mg once 200 mg once 159 mg/day
Aldosterone antagonists
Spironolactone 12.5 to 25 mg once 25 mg once or twice 26 mg/day
Eplerenone 25 mg once 50 mg once 42.6 mg/day
Hydralazine and isosorbide dinitrate
Fixed-dose
combination
37.5 mg hydralazine/20 mg
isosorbide dinitrate 3 times
daily
75 mg hydralazine/40 mg
isosorbide dinitrate 3 times
daily
~175 mg hydralazine/90
mg isosorbide dinitrate
daily
Hydralazine and
isosorbide dinitrate
Hydralazine: 25 to 50 mg, 3
or 4 times daily and
isosorbide dinitrate: 20 to 30
mg 3 or 4 times daily
Hydralazine: 300 mg daily
in divided doses and
isosorbide dinitrate: 120
mg daily in divided doses
N/A
Miscellaneous
Ivabradine2 5 mg twice 7.5 mg twice 12.9 mg/day
Sacubitril/valsartan3 49/51 mg twice 97/103 mg twice 375 mg
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LABORATORY TESTS
1. Initial laboratory evaluation of patients presenting with heart failure should include
complete blood count, urinalysis, serum electrolytes (including calcium and
magnesium), BUN, serum creatinine, glucose, fasting lipid profile, liver function
tests, and TSH.1 (AHA Class I, Level of Evidence C)
2. Serial monitoring, when indicated, should include serum electrolytes and renal
function.1 (AHA Class I, Level of Evidence C) Patients with heart failure should have BUN,
serum creatinine and potassium monitored on a regular basis (at least every 6
months or more frequently if clinically unstable).
REFERRAL TO ELECTROPHYSIOLOGY
(For Consideration of Device Therapy [AICD &/or Cardiac Resynchronization Therapy] if LVEF ≤ 35%)
1. Implantable cardiac defibrillator (ICD) implantation
ξ ICD therapy for primary prevention of sudden cardiac death is recommended
in patients with nonischemic dilated cardiomyopathy or ischemic heart
disease at least 40 days post-MI with LVEF < 35% and NYHA class II or III
symptoms on guideline directed medical therapy who have reasonable
expectation of meaningful survival for > 1 year.1 (AHA Class I, Level of Evidence A)
ξ ICD therapy is recommended for primary prevention of sudden cardiac death
in patients at least 40 days post-MI, with LVEF < 30%, and NYHA class I
symptoms while receiving guideline directed medical therapy who have
reasonable expectation of meaningful survival for > 1 year.1 (AHA Class I, Level
of Evidence B)
2. ICD implantation is of uncertain benefit in patients with a high risk of non sudden
death as predicted by frequent hospitalizations, advanced frailty, dementia, or
comorbidities such as systemic malignancy or severe renal dysfunction.1 (AHA Class
IIb, Level of Evidence B) Cardiac resynchronization therapy (CRT) – see Figure 3.4
REFERRAL TO CARDIOLOGY
1. Failure to tolerate guideline-directed medical therapy (GDMT).
2. Persistent volume overload despite therapy with diuretics, leading to repeated
hospitalizations.
Companion Documents
1. Beta Blocker Equivalency Dosing Table
Related UW Health Clinical Practice Guidelines
1. Atrial Fibrillation Management – Adult – Inpatient/Ambulatory
2. Management of Non-ST Elevation Acute Coronary Syndromes – Adult –
Inpatient
3. Mechanical Circulatory Device (MCD) – Adult – Inpatient/Ambulatory
4. Hypertension – Adult – Inpatient/Ambulatory
5. Secondary Prevention of ASCVD – Adult – Inpatient/Ambulatory
6. Standards of Medical Care in Diabetes – Pediatric/Adult – Inpatient/Ambulatory
7. Obesity – Adult - Ambulatory
8. Tobacco Cessation – Adult/Pediatric – Inpatient/Ambulatory
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
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11
FIGURE 3. Indications for CRT therapy algorithm
CRT indicates cardiac resynchronization therapy; CRT-D, cardiac resynchronization therapy-defibrillator; GDMT, guideline-directed medical therapy; HF, heart failure; ICD, implantable
cardioverter-defibrillator; LBBB, left bundle-branch block; LVEF, left ventricular ejection fraction; MI, myocardial infarction; and NYHA, New York Heart Association.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
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Scope
Disease/Condition(s): Heart Failure
Clinical Specialty: Cardiology, Primary Care, Cardiothoracic Surgery, Pharmacy,
Laboratory, Nursing
Intended Users: Physicians, Advance Practice Providers, Nurses (RN Care
Coordinators, RN, LPN, MA), Pharmacists
Objective(s): To assist clinicians in clinical decision making by describing a range of
generally acceptable approaches to the diagnosis, management and prevention of heart
failure.
Target Population: Patients age 18 years or older with reduced left ventricular heart
function. This guideline does not include recommendations for congenital heart lesions
in adults.
Interventions and Practices Considered:
ξ Guideline-directed medical and device therapy (GDMT)
ξ Management of comorbidities
ξ Patient/family education
ξ Physical activity/cardiac rehabilitation
ξ Mechanical circulatory support
ξ Coronary artery revascularization via coronary artery bypass graft (CABG) or
percutaneous/transcatheter intervention
Major Outcomes Considered:
ξ Reduced mortality
ξ Increased quality of life
Guideline Metrics:
1. Number of deaths per 100 discharges with principal diagnosis code of CHF (AHRQ – IQI 16)
2. All discharges of age 18 years and older with ICD-9-CM principal diagnosis code for heart
failure (AHRQ – IQI 8)
3. Percentage of patients aged 18 years or older with a diagnosis of heart failure with a current
or prior left ventricular ejection fraction (LVEF) < 40% who were prescribed beta-blocker
therapy either within a 12 month period when seen in the outpatient setting OR at each
hospital discharge (ACO-MSSP)
4. Percentage of patients aged 18 years or older with a diagnosis of heart failure with a current
or prior left ventricular ejection fraction (LVEF) < 40% who were prescribed a ACE-I/ARB
either within a 12 month period when seen in the outpatient setting OR at each hospital
discharge (CPG Workgroup-derived)
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13
Methodology
Methods Used to Collect/Select the Evidence:
Electronic database searches were conducted to collect evidence for review, in addition
to review of the 2013 ACC/AHA guideline. Expert opinion and clinical experience were
also considered during review of the evidence.
Methods Used to Formulate the Recommendations:
The workgroup members agreed to adopt recommendations developed by the
ACC/AHA and/or arrived at a consensus through discussion of the literature and expert
experience. All recommendations endorsed or developed by the guideline workgroup
were reviewed and approved by other stakeholders or committees (as appropriate).
Methods Used to Assess the Quality and Strength of the
Evidence/Recommendations:
Recommendations developed by external organizations (e.g., ACC/AHA) maintained
the evidence grade assigned within the original source document and were adopted for
use at UW Health. Internally developed recommendations were evaluated by the
guideline workgroup using the ACC/AHA grading scheme.
Rating Scheme for the Strength of the Evidence/Recommendations:
A modified Grading of Recommendations, Assessment, Development and Evaluation
(GRADE) scheme developed by the American Heart Association and American College
of Cardiology
(see Figure 4)
was used to
grade each
recommendation.
Figure 4.
ACC/AHA
Grading Scheme
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Introduction
Despite improvements in medicine, the absolute mortality rates for heart failure remain
at approximately 50% within five years of initial diagnosis.1 In addition, the primary
diagnosis for over 1 million inpatient admissions annually is heart failure.1 The 2013
ACCF/AHA Guidelines are intended to provide clinicians with generally acceptable
approaches to the diagnosis, management, and prevention of heart failure.
Recommendations
UW Health endorses the recommendations outlined within the 2013 ACCF/AHA
Guidelines for the Diagnosis and Management of Heart Failure in Adults located online
at http://circ.ahajournals.org/content/128/16/e240.extract.1 These recommendations are
for heart failure with reduced ejection fraction (HFrEF) defined as a left ventricular
ejection fraction (LVEF) of < 40%. If clinically appropriate, these guidelines can be used
with patients who have an LVEF between 41 to 50%.
In addition to those recommendations found within the ACCF/AHA Guideline, the
following supplementary statements were developed by UW Health as a result of the
recent FDA approval of two medications:
 Sacubitril/valsartan has demonstrated a survival benefit compared to enalapril in
patients on guideline-directed medical therapy (GDMT) to reduce the risk of
cardiovascular death and hospitalization for heart failure in patients with chronic
heart failure (NYHA Class II-IV) and reduced ejection fraction. It is recommended
in patients on guideline-directed medications at a dose equivalent to at least 10
mg of enalapril daily and NYHA Class II-IV and heart failure hospitalization within
the last year.3 (UW Health Class IIa, Level of Evidence B) Patients on GMDT should be
transitioned off of the ACE-I (at least 36 hour washout) prior to initiation, as this
medication should not be used in conjunction with ACE-I or additional ARBs.
Beta blocker therapy should be continued on the maximum tolerated dose. The
most common side effects are hyperkalemia, hypotension, renal impairment,
dizziness. Additional valsartan should not be prescribed.
 Ivabradine is reasonable in patients with stable, symptomatic heart failure in
normal sinus rhythm on guideline-directed medications (e.g., ACE, ARB, beta
blocker) at the guideline-directed or highest tolerated dose, yet with resting heart
rate > 70 bpm.2 (UW Health Class IIa, Level of Evidence B) The most common side
effects include bradycardia, hypertension, atrial fibrillation, and temporary vision
disturbances (flashes of light). Hospital admission for heart failure and heart
failure deaths are significantly reduced by use of ivabradine in those patients
described above.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 12/2015CCKM@uwhealth.org

15
UW Health Implementation
Potential Benefits:
ξ Improved patient outcomes, including reduced mortality and increased quality of life
ξ Decreased hospital readmissions
Potential Harms:
ξ Medications such as NSAIDs, most antiarrhythmic drugs, and most calcium channel
blocking drugs could be indicated for other conditions, while contraindicated for heart
failure.
Pertinent UW Health Policies & Procedures
None.
Patient Resources
1. Health Factors for You #3072- Heart Failure Packet
a. Health Facts for You #6087- Congestive Heart Failure
b. Health Facts for You #5817- Your Risk of Heart and Vascular Disease
c. Health Facts for You #5818- About Plaque
d. Health Facts for You #6094- Weight and Vital Signs Log
e. Health Facts for You #180- Sodium
f. Health Facts for You #203- Tips for Healthy Eating Out
g. Health Facts for You #302- How to Read Food Labels
2. Health Facts for You #3199- Heart Failure (KAB) Packet
a. Health Facts for You #6087- Congestive Heart Failure
b. Health Facts for You #7810- Heart Failure Zones
c. Health Facts for You #180- Sodium
d. Health Facts for You #5528- Sodium Content of Common Foods
e. Health Facts for You #302- How to Read Food Labels
f. Health Facts for You #203- Tips for Healthy Eating Out
3. Health Facts for You #6154- Congestive Heart Failure for VAD Patients
4. Health Facts for You #6885- Heart Failure and Depression
5. Health Facts for You #7727- Cardiac Rehabilitation for Heart Failure
6. Health Facts for You #4951- The Heart Transplant Process
7. Health Facts for You #6546- Waiting for your Heart Transplant
8. Healthwise: ACE Inhibitors
9. Healthwise: ACE Inhibitors: General Info
10. Healthwise: ACE Inhibitors: Heart Failure: General Info
11. Healthwise: ARBs: General Info
12. Healthwise: Beta-Blockers
13. Healthwise: Heart Failure
14. Healthwise: Heart Failure: General Info
15. Healthwise: Heart Failure Zones: General Info
16. Healthwise: Heart Failure: Advance Care Planning
17. Healthwise: Heart Failure: Arrhythmias
18. Healthwise: Heart Failure: Avoiding Triggers
19. Healthwise: Heart Failure: Limiting Sodium and Fluids
20. Healthwise: Heart Failure: Managing Other Conditions
21. Healthwise: Heart Failure: Medicines
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16
22. Healthwise: Heart Failure: Medicines to Avoid
23. Healthwise: Heart Failure: Oxygen Therapy
24. Healthwise: Heart Failure: Self-Care: General Info
25. Healthwise: Heart Failure: Sleep Apnea
26. Health Information: Heart Failure
27. Health Information: Heart Failure and Sexual Activity
28. Health Information: Heart Failure and Sleep Problems
29. Health Information: Heart Failure Complications
30. Health Information: Heart Failure Stages
31. Health Information: Heart Failure Symptoms
32. Health Information: Heart Failure Types
33. Health Information: Heart Failure: Activity and Exercise
34. Health Information: Heart Failure: Avoiding Colds and Flu
35. Health Information: Heart Failure: Avoiding Medications That Make Symptoms Worse
36. Health Information: Heart Failure: Avoiding Triggers for Sudden Heart Failure
37. Health Information: Heart Failure: Checking Your Weight
38. Health Information: Heart Failure: Compensation by the Heart and Body
39. Health Information: Heart Failure: Disease Management Programs
40. Health Information: Heart Failure: Eating a Healthy Diet
41. Health Information: Heart Failure: Eating Out on a Low Salt Diet
42. Health Information: Heart Failure: Less Common Symptoms
43. Health Information: Heart Failure: Should I Get a Pacemaker (Cardiac Resynchronization
Therapy)?
44. Health Information: Heart Failure: Should I Get an Implantable Cardioverter-Defibrillator
(ICD)?
45. Health Information: Heart Failure: Taking Medicines Properly
46. Health Information: Heart Failure: Tips for Caregivers
47. Health Information: Heart Failure: Tips for Easier Breathing
48. Health Information: Heart Failure: Watching Your Fluids
Implementation Plan/Tools
1. Guideline will be housed on U-Connect in a dedicated folder for CPGs.
2. Release of the guideline will be advertised in the Clinical Knowledge Management
Corner within the Best Practice newsletter.
3. Links to this guideline will be updated and/or added in appropriate Health Link or
equivalent tools, including:
Order Sets/Smart Sets
CHF Office Visit [3148]
IP – Heart Failure – Adult – Admission [688]
IP – Heart Failure – Adult – Discharge [1411]
IP – Cardiology – Adult – Discharge [3328]
IP – Cardiac Surgery – Adult – Preoperative [2701]
IP – Pre Ventricular Assist Device – Adult – Admission [5851]
IP – Contrast Induced Nephropathy Prophylaxis – Heart Failure/Fluid Volume Overload [1342]
Best Practice Alerts
UWIP BPA Heart Failure ACE-I/ARB [2586; 3000583; 1896]
UWIP BPA Heart Failure ACE-I/ARB/BB [3000575; 3000584; 1897; 1898]
UWIP BPA Heart Failure Beta Blocker [2413; 3000585; 3000586; 1899; 1900]
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 12/2015CCKM@uwhealth.org

17
UWOP BPA Heart Failure ACE-I/ARB [2328]
UWOP BPA Heart Failure BB [2334]
Delegation Protocols
Heart Failure Lab Ordering – Adult – Ambulatory [77]
Heart Failure Medication Titration – Adult – Ambulatory [82]
e-Consults
eConsult to Cardiology- Heart Failure [5625]
Care Plans
Heart Failure- Adult IPOC [508]
Heart Failure- Geriatric IPOC [509]
Coping, Ineffective – Heart Failure – Adult [505]
Knowledge, Deficient – Heart Failure – Adult [504]
Fluid/Electrolyte Imbalance – Heart Failure – Adult [506]
Gas Exchange, Impaired – Heart Failure – Adult [507]
Miscellaneous
Standard Order Group for All Discharge Order Sets [OSQ 190359]
Problem List Smart Form (Documentation of contraindications to GDMT)
Heart Failure Registry
Disclaimer
CPGs are described to assist clinicians by providing a framework for the evaluation and
treatment of patients. This Clinical Practice Guideline outlines the preferred approach
for most patients. It is not intended to replace a clinician’s judgment or to establish a
protocol for all patients. It is understood that some patients will not fit the clinical
condition contemplated by a guideline and that a guideline will rarely establish the only
appropriate approach to a problem.
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 12/2015CCKM@uwhealth.org

18
Appendix A. Beta Blocker Equivalency Dosing for Patients
with Heart Failure5-14
NOTE: Conversion carvedilol or metoprolol succinate should be made in patients with HFrEF, as these are the
medications most commonly used in the U.S. that have been found to be effective in the treatment of HFrEF.
Current Prescription* CONVERSION
Carvedilol
Metoprolol
succinate ER
Atenolol 50 mg daily 12.5 mg BID 100 mg daily
100 mg daily 25 mg BID+ 200 mg daily
Labetalol
100 mg BID 12.5 mg BID 100 mg daily
200-400 mg BID 25 mg BID+ 200 mg daily
Metoprolol
tartrate
25-50 mg BID 12.5 mg BID 100 mg daily
100-200 mg BID 25 mg BID+ 200 mg daily
Nadolol
40 mg daily 3.125 mg - 6.25 mg BID 25 mg daily
80 mg daily 12.5 mg BID 100 mg daily
240-320 mg daily 25 mg BID+ 200 mg daily
Propranolol
40 mg BID or 80 mg of ER
daily
12.5 mg BID 100 mg daily
60-120 mg BID or 120-160
mg of ER daily 25 mg BID+ 200 mg daily
Timolol 10 mg BID 12.5 mg BID 100 mg daily
10-30 mg BID 25 mg BID+ 200 mg daily
Acebutolol 200 mg BID or 400 mg daily 12.5 mg BID 100 mg daily
200-400 mg BID 25 mg BID+ 200 mg daily
Pindolol 5 mg BID 12.5 mg BID 100 mg daily
30 mg BID 25 mg BID+ 200 mg daily
*Doses provided are approximate. Lower initial doses may be chosen at the provider’s discretion; +Carvedilol 50 mg
BID if ≥ 85 kg; BID: twice daily; ER: extended release
Both carvedilol and metoprolol succinate are off-patent and available in generic form. Because
of manufacturing issues with generic metoprolol succinate, carvedilol tends to be lower in cost
at this time.
Once the conversion is made to a guidelines-approved beta blocker, attempts should be made
to uptitrate to the goal doses shown to have mortality benefit in trials of heart failure patients
with reduced ejection fraction. For carvedilol, this dose is 25 mg bid if < 85 kg, 50 mg BID if ≥
85 kg. For metoprolol succinate, this dose is 200 mg daily.
Please be advised that beta blockers, due to varying properties, are not fully equivalent. In
general, when switching to a beta blocker with CHF benefit, consider a dose that is an
equivalent percentage (or less) of the maximum dose of the beta blockers being selected for
conversion. Some patients may require doses different from the ones provided in this table as
being more or less equivalent.
References found within the UW Health Heart Failure – Adult – Inpatient/Ambulatory Clinical Practice Guideline.
Last reviewed/revised: 12/2015
Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 12/2015CCKM@uwhealth.org

19
References
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of heart failure: a report of the American College of Cardiology Foundation/American
Heart Association Task Force on practice guidelines. Circulation. Oct
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2. Swedberg K, Komajda M, Böhm M, et al. Ivabradine and outcomes in chronic heart
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enalapril in heart failure. N Engl J Med. Sep 2014;371(11):993-1004.
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American College of Cardiology/American Heart Association Task Force on Practice
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Copyright © 2015 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 12/2015CCKM@uwhealth.org

Stevenson, W.H. Wilson Tang, Emily J. Tsai and Bruce L. Wilkoff
J.V. McMurray, Judith E. Mitchell, Pamela N. Peterson, Barbara Riegel, Flora Sam, Lynne W.
Johnson, Edward K. Kasper, Wayne C. Levy, Frederick A. Masoudi, Patrick E. McBride, John
Drazner, Gregg C. Fonarow, Stephen A. Geraci, Tamara Horwich, James L. Januzzi, Maryl R.
Clyde W. Yancy, Mariell Jessup, Biykem Bozkurt, Javed Butler, Donald E. Casey, Jr, Mark H.
Practice Guidelines
American College of Cardiology Foundation/American Heart Association Task Force on
2013 ACCF/AHA Guideline for the Management of Heart Failure: A Report of the
Print ISSN: 0009-7322. Online ISSN: 1524-4539
Copyright ' 2013 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231Circulation
doi: 10.1161/CIR.0b013e31829e8776
2013;128:e240-e327; originally published online June 5, 2013;Circulation.
http://circ.ahajournals.org/content/128/16/e240
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e240
(Circulation. 2013;128:e240-e327.)
2013 by the American College of Cardiology Foundation and the American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org DOI: 10.1161/CIR.0b013e31829e8776
*Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other
entities may apply; see Appendix 1 for recusal information.
†ACCF/AHA representative.
‡ACCF/AHA Task Force on Practice Guidelines liaison.
§American College of Physicians representative.
�American College of Chest Physicians representative.
¶International Society for Heart and Lung Transplantation representative.
#ACCF/AHA Task Force on Performance Measures liaison.
**American Academy of Family Physicians representative.
††Heart Rhythm Society representative.
‡‡Former Task Force member during this writing effort.
This document was approved by the American College of Cardiology Foundation Board of Trustees and the American Heart Association Science
Advisory and Coordinating Committee in May 2013.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/CIR.0b013e31829e8776/-/DC1.
The online-only Comprehensive Relationships Table is available with this article at http://circ.ahajournals.org/lookup/suppl/doi:10.1161/
CIR.0b013e31829e8776/-/DC2.
The American Heart Association requests that this document be cited as follows: Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH,
Fonarow GC, Geraci SA, Horwich T, Januzzi JL, Johnson MR, Kasper EK, Levy WC, Masoudi FA, McBride PE, McMurray JJV, Mitchell JE, Peterson
PN, Riegel B, Sam F, Stevenson LW, Tang WHW, Tsai EJ, Wilkoff BL. 2013 ACCF/AHA guideline for the management of heart failure: a report of the
American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation. 2013;128:e240–e327.
This article has been copublished in the Journal of the American College of Cardiology.
Copies: This document is available on the World Wide Web sites of the American College of Cardiology (www.cardiosource.org) and the American Heart
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2013 ACCF/AHA Guideline for the
Management of Heart Failure
A Report of the American College of Cardiology Foundation/American
Heart Association Task Force on Practice Guidelines
Developed in Collaboration With the American College of Chest Physicians, Heart Rhythm Society and
International Society for Heart and Lung Transplantation
Endorsed by the American Association of Cardiovascular and Pulmonary Rehabilitation
WRITING COMMITTEE MEMBERS*
Clyde W. Yancy, MD, MSc, FACC, FAHA, Chair†‡;
Mariell Jessup, MD, FACC, FAHA, Vice Chair*†; Biykem Bozkurt, MD, PhD, FACC, FAHA†;
Javed Butler, MBBS, FACC, FAHA*†; Donald E. Casey, Jr, MD, MPH, MBA, FACP, FAHA§;
Mark H. Drazner, MD, MSc, FACC, FAHA*†; Gregg C. Fonarow, MD, FACC, FAHA*†;
Stephen A. Geraci, MD, FACC, FAHA, FCCP�; Tamara Horwich, MD, FACC†;
James L. Januzzi, MD, FACC*†; Maryl R. Johnson, MD, FACC, FAHA¶;
Edward K. Kasper, MD, FACC, FAHA†; Wayne C. Levy, MD, FACC*†;
Frederick A. Masoudi, MD, MSPH, FACC, FAHA†#; Patrick E. McBride, MD, MPH, FACC**;
John J.V. McMurray, MD, FACC*†; Judith E. Mitchell, MD, FACC, FAHA†;
Pamela N. Peterson, MD, MSPH, FACC, FAHA†; Barbara Riegel, DNSc, RN, FAHA†;
Flora Sam, MD, FACC, FAHA†; Lynne W. Stevenson, MD, FACC*†;
W.H. Wilson Tang, MD, FACC*†; Emily J. Tsai, MD, FACC†;
Bruce L. Wilkoff, MD, FACC, FHRS*††
ACCF/AHA Practice Guideline
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e241
Table of Contents
Preamble .....................................e242
1. Introduction .................................e245
1.1. Methodology and Evidence Review . . . . . . . . . . . e245
1.2. Organization of the Writing Committee ........e245
1.3. Document Review and Approval..............e245
1.4. Scope of This Guideline With Reference to
Other Relevant Guidelines or Statements .......e245
2. Definition of HF..............................e246
2.1. HF With Reduced EF (HFrEF) ...............e247
2.2. HF With Preserved EF (HFpEF) ..............e247
3. HF Classifications ............................e247
4. Epidemiology................................e248
4.1. Mortality ................................e248
4.2. Hospitalizations...........................e248
4.3. Asymptomatic LV Dysfunction...............e248
4.4. Health-Related Quality of Life and
Functional Status..........................e249
4.5. Economic Burden of HF ....................e249
4.6. Important Risk Factors for HF (Hypertension,
Diabetes Mellitus, Metabolic Syndrome, and
Atherosclerotic Disease) ....................e249
5. Cardiac Structural Abnormalities and Other
Causes of HF ................................e249
5.1. Dilated Cardiomyopathies...................e249
5.1.1. Definition and Classification of Dilated
Cardiomyopathies....................e249
5.1.2. Epidemiology and Natural History
of DCM............................e250
5.2. Familial Cardiomyopathies ..................e250
5.3. Endocrine and Metabolic Causes of
Cardiomyopathy ..........................e250
5.3.1. Obesity ............................e250
5.3.2. Diabetic Cardiomyopathy..............e250
5.3.3. Thyroid Disease .....................e250
5.3.4. Acromegaly and Growth Hormone
Deficiency ..........................e250
5.4. Toxic Cardiomyopathy .....................e251
5.4.1. Alcoholic Cardiomyopathy.............e251
5.4.2. Cocaine Cardiomyopathy ..............e251
5.4.3. Cardiotoxicity Related to Cancer
Therapies ..........................e251
5.4.4. Other Myocardial Toxins and Nutritional
Causes of Cardiomyopathy.............e251
5.5. Tachycardia-Induced Cardiomyopathy ........e251
5.6. Myocarditis and Cardiomyopathies Due to
Inflammation ............................e251
5.6.1. Myocarditis ........................e251
5.6.2. Acquired Immunodeficiency Syndrome ..e252
5.6.3. Chagas Disease .....................e252
5.7. Inflammation-Induced Cardiomyopathy:
Noninfectious Causes .....................e252
5.7.1. Hypersensitivity Myocarditis ..........e252
5.7.2. Rheumatological/Connective Tissue
Disorders..........................e252
5.8. Peripartum Cardiomyopathy................e252
5.9. Cardiomyopathy Caused By Iron Overload ....e252
5.10. Amyloidosis.............................e252
5.11. Cardiac Sarcoidosis.......................e253
5.12. Stress (Takotsubo) Cardiomyopathy ..........e253
6. Initial and Serial Evaluation of the HF Patient ......e253
6.1. Clinical Evaluation .......................e253
6.1.1. History and Physical Examination:
Recommendations...................e253
6.1.2. Risk Scoring: Recommendation ........e253
6.2. Diagnostic Tests: Recommendations .........e253
6.3. Biomarkers: Recommendations .............e255
6.3.1. Natriuretic Peptides: BNP or NT-proBNP . e256
6.3.2. Biomarkers of Myocardial Injury:
Cardiac Troponin T or I ..............e256
6.3.3. Other Emerging Biomarkers ...........e256
6.4. Noninvasive Cardiac Imaging:
Recommendations........................e256
6.5. Invasive Evaluation: Recommendations .......e258
6.5.1. Right-Heart Catheterization ...........e259
6.5.2. Left-Heart Catheterization ............e259
6.5.3. Endomyocardial Biopsy ..............e260
7. Treatment of Stages A to D .....................e260
7.1. Stage A: Recommendations ................e260
7.1.1. Recognition and Treatment of Elevated
Blood Pressure .....................e260
7.1.2. Treatment of Dyslipidemia and
Vascular Risk ......................e260
7.1.3. Obesity and Diabetes Mellitus .........e260
7.1.4. Recognition and Control of Other
Conditions That May Lead to HF .......e260
7.2. Stage B: Recommendations ................e261
7.2.1. Management Strategies for Stage B .....e262
7.3. Stage C ................................e262
ACCF/AHA TASK FORCE MEMBERS
Jeffrey L. Anderson, MD, FACC, FAHA, Chair;
Alice K. Jacobs, MD, FACC, FAHA, Immediate Past Chair‡‡;
Jonathan L. Halperin, MD, FACC, FAHA, Chair-Elect;
Nancy M. Albert, PhD, CCNS, CCRN, FAHA; Biykem Bozkurt, MD, PhD, FACC, FAHA;
Ralph G. Brindis, MD, MPH, MACC; Mark A. Creager, MD, FACC, FAHA‡‡;
Lesley H. Curtis, PhD; David DeMets, PhD; Robert A. Guyton, MD, FACC;
Judith S. Hochman, MD, FACC, FAHA; Richard J. Kovacs, MD, FACC, FAHA;
Frederick G. Kushner, MD, FACC, FAHA‡‡; E. Magnus Ohman, MD, FACC;
Susan J. Pressler, PhD, RN, FAAN, FAHA; Frank W. Sellke, MD, FACC, FAHA;
Win-Kuang Shen, MD, FACC, FAHA; William G. Stevenson, MD, FACC, FAHA‡‡;
Clyde W. Yancy, MD, MSc, FACC, FAHA‡‡
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e242 Circulation October 15, 2013
7.3.1. Nonpharmacological Interventions.......e262
7.3.1.1. Education: Recommendation ....e262
7.3.1.2. Social Support................e263
7.3.1.3. Sodium Restriction:
Recommendation .............e263
7.3.1.4. Treatment of Sleep Disorders:
Recommendation .............e263
7.3.1.5. Weight Loss..................e263
7.3.1.6. Activity, Exercise Prescription,
and Cardiac Rehabilitation:
Recommendations .............e264
7.3.2. Pharmacological Treatment for Stage C
HFrEF: Recommendations.............e264
7.3.2.1. Diuretics: Recommendation .....e265
7.3.2.2. ACE Inhibitors: Recommendation e265
7.3.2.3. ARBs: Recommendations .......e267
7.3.2.4. Beta Blockers: Recommendation . e267
7.3.2.5. Aldosterone Receptor Antagonists:
Recommendations .............e268
7.3.2.6. Hydralazine and Isosorbide
Dinitrate: Recommendations.....e270
7.3.2.7. Digoxin: Recommendation ......e271
7.3.2.8. Other Drug Treatment ..........e271
7.3.2.8.1. Anticoagulation:
Recommendations ....e271
7.3.2.8.2. Statins:
Recommendation . . . . . e272
7.3.2.8.3. Omega-3 Fatty Acids:
Recommendation . . . . . e272
7.3.2.9. Drugs of Unproven Value
or That May Worsen HF:
Recommendations.............e273
7.3.2.9.1. Nutritional Supplements
and Hormonal
Therapies ...........e273
7.3.2.9.2. Antiarrhythmic Agents e273
7.3.2.9.3. Calcium Channel Blockers:
Recommendation . . . . . e273
7.3.2.9.4. Nonsteroidal Anti-
Inflammatory Drugs ...e274
7.3.2.9.5. Thiazolidinediones ....e274
7.3.3. Pharmacological Treatment for Stage
C HFpEF: Recommendations...........e274
7.3.4. Device Therapy for Stage C HFrEF:
Recommendations ...................e274
7.3.4.1. Implantable Cardioverter-
Defibrillator..................e278
7.3.4.2. Cardiac Resynchronization
Therapy .....................e279
7.4. Stage D .................................e280
7.4.1. Definition of Advanced HF.............e280
7.4.2. Important Considerations in Determining
If the Patient Is Refractory .............e280
7.4.3. Water Restriction: Recommendation .....e280
7.4.4. Inotropic Support: Recommendations ....e281
7.4.5. Mechanical Circulatory Support:
Recommendations ...................e282
7.4.6. Cardiac Transplantation: Recommendation..e283
8. The Hospitalized Patient .......................e284
8.1. Classification of Acute Decompensated HF .....e284
8.2. Precipitating Causes of Decompensated HF:
Recommendations.........................e285
8.3. Maintenance of GDMT During Hospitalization:
Recommendations.........................e286
8.4. Diuretics in Hospitalized Patients:
Recommendations.........................e286
8.5. Renal Replacement Therapy—Ultrafiltration:
Recommendations.........................e287
8.6. Parenteral Therapy in Hospitalized HF:
Recommendation..........................e287
8.7. Venous Thromboembolism Prophylaxis in
Hospitalized Patients: Recommendation........e288
8.8. Arginine Vasopressin Antagonists:
Recommendation..........................e288
8.9. Inpatient and Transitions of Care:
Recommendations.........................e288
9. Important Comorbidities in HF .................e290
9.1. Atrial Fibrillation.........................e290
9.2. Anemia ................................e293
9.3. Depression..............................e293
9.4. Other Multiple Comorbidities...............e293
10. Surgical/Percutaneous/Transcatheter Interventional
Treatments of HF: Recommendations ............e293
11. Coordinating Care for Patients With Chronic HF ...e295
11.1. Coordinating Care for Patients With
Chronic HF: Recommendations ............e295
11.2. Systems of Care to Promote Care Coordination
for Patients With Chronic HF ..............e296
11.3. Palliative Care for Patients With HF .........e296
12. Quality Metrics/Performance Measures:
Recommendations ...........................e296
13. Evidence Gaps and Future Research Directions ....e299
References ....................................e299
Appendix 1. Author Relationships With Industry
and Other Entities (Relevant) ...........e320
Appendix 2. Reviewer Relationships With Industry
and Other Entities (Relevant) ...........e323
Appendix 3. Abbreviations .......................e327
Preamble
The medical profession should play a central role in evaluating
the evidence related to drugs, devices, and procedures for the
detection, management, and prevention of disease. When prop-
erly applied, expert analysis of available data on the benefits
and risks of these therapies and procedures can improve the
quality of care, optimize patient outcomes, and favorably affect
costs by focusing resources on the most effective strategies. An
organized and directed approach to a thorough review of evi-
dence has resulted in the production of clinical practice guide-
lines that assist clinicians in selecting the best management
strategy for an individual patient. Moreover, clinical practice
guidelines can provide a foundation for other applications,
such as performance measures, appropriate use criteria, and
both quality improvement and clinical decision support tools.
The American College of Cardiology Foundation (ACCF)
and the American Heart Association (AHA) have jointly pro-
duced guidelines in the area of cardiovascular disease since
1980. The ACCF/AHA Task Force on Practice Guidelines
(Task Force), charged with developing, updating, and revis-
ing practice guidelines for cardiovascular diseases and proce-
dures, directs and oversees this effort. Writing committees are
charged with regularly reviewing and evaluating all available
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e243
evidence to develop balanced, patient-centric recommenda-
tions for clinical practice.
Experts in the subject under consideration are selected by
the ACCF and AHA to examine subject-specific data and write
guidelines in partnership with representatives from other med-
ical organizations and specialty groups. Writing committees
are asked to perform a literature review; weigh the strength
of evidence for or against particular tests, treatments, or pro-
cedures; and include estimates of expected outcomes where
such data exist. Patient-specific modifiers, comorbidities, and
issues of patient preference that may influence the choice of
tests or therapies are considered. When available, information
from studies on cost is considered, but data on efficacy and
outcomes constitute the primary basis for the recommenda-
tions contained herein.
In analyzing the data and developing recommendations and
supporting text, the writing committee uses evidence-based
methodologies developed by the Task Force.
1
The Class of
Recommendation (COR) is an estimate of the size of the treat-
ment effect considering risks versus benefits in addition to evi-
dence and/or agreement that a given treatment or procedure is
or is not useful/effective or in some situations may cause harm.
The Level of Evidence (LOE) is an estimate of the certainty
or precision of the treatment effect. The writing committee
reviews and ranks evidence supporting each recommenda-
tion with the weight of evidence ranked as LOE A, B, or C
according to specific definitions that are included in Table 1.
Studies are identified as observational, retrospective, prospec-
tive, or randomized where appropriate. For certain conditions
for which inadequate data are available, recommendations
Table 1. Applying Classification of Recommendation and Level of Evidence
A recommendation with Level of Evidence B or C does not imply that the recommendation is weak. Many important clinical questions addressed in the guidelines do
not lend themselves to clinical trials. Although randomized trials are unavailable, there may be a very clear clinical consensus that a particular test or therapy is useful
or effective.
*Data available from clinical trials or registries about the usefulness/efficacy in different subpopulations, such as sex, age, history of diabetes, history of prior
myocardial infarction, history of heart failure, and prior aspirin use.
†For comparative effectiveness recommendations (Class I and IIa; Level of Evidence A and B only), studies that support the use of comparator verbs should involve
direct comparisons of the treatments or strategies being evaluated.
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e244 Circulation October 15, 2013
are based on expert consensus and clinical experience and
are ranked as LOE C. When recommendations at LOE C are
supported by historical clinical data, appropriate references
(including clinical reviews) are cited if available. For issues
for which sparse data are available, a survey of current prac-
tice among the clinicians on the writing committee is the basis
for LOE C recommendations and no references are cited. The
schema for COR and LOE are summarized in Table 1, which
also provides suggested phrases for writing recommendations
within each COR. A new addition to this methodology is sepa-
ration of the Class III recommendations to delineate whether
the recommendation is determined to be of “no benefit” or is
associated with “harm” to the patient. In addition, in view of
the increasing number of comparative effectiveness studies,
comparator verbs and suggested phrases for writing recom-
mendations for the comparative effectiveness of one treatment
or strategy versus another have been added for COR I and IIa,
LOE A or B only.
In view of the advances in medical therapy across the spec-
trum of cardiovascular diseases, the Task Force has desig-
nated the term guideline-directed medical therapy (GDMT)
to represent optimal medical therapy as defined by ACCF/
AHA guideline–recommended therapies (primarily Class I).
This new term, GDMT, will be used herein and throughout all
future guidelines.
Because the ACCF/AHA practice guidelines address patient
populations (and clinicians) residing in North America, drugs
that are not currently available in North America are discussed
in the text without a specific COR. For studies performed in
large numbers of subjects outside North America, each writ-
ing committee reviews the potential influence of different
practice patterns and patient populations on the treatment
effect and relevance to the ACCF/AHA target population
to determine whether the findings should inform a specific
recommendation.
The ACCF/AHA practice guidelines are intended to assist
clinicians in clinical decision making by describing a range
of generally acceptable approaches to the diagnosis, manage-
ment, and prevention of specific diseases or conditions. The
guidelines attempt to define practices that meet the needs of
most patients in most circumstances. The ultimate judgment
regarding care of a particular patient must be made by the cli-
nician and patient in light of all the circumstances presented
by that patient. As a result, situations may arise for which
deviations from these guidelines may be appropriate. Clinical
decision making should involve consideration of the quality
and availability of expertise in the area where care is provided.
When these guidelines are used as the basis for regulatory or
payer decisions, the goal should be improvement in quality of
care. The Task Force recognizes that situations arise in which
additional data are needed to inform patient care more effec-
tively; these areas will be identified within each respective
guideline when appropriate.
Prescribed courses of treatment in accordance with these
recommendations are effective only if followed. Because lack
of patient understanding and adherence may adversely affect
outcomes, clinicians should make every effort to engage the
patient’s active participation in prescribed medical regimens
and lifestyles. In addition, patients should be informed of the
risks, benefits, and alternatives to a particular treatment and
be involved in shared decision making whenever feasible,
particularly for COR IIa and IIb, for which the benefit-to-risk
ratio may be lower.
The Task Force makes every effort to avoid actual, potential,
or perceived conflicts of interest that may arise as a result of
industry relationships or personal interests among the mem-
bers of the writing committee. All writing committee members
and peer reviewers of the guideline are required to disclose
all current healthcare-related relationships, including those
existing 12 months before initiation of the writing effort. In
December 2009, the ACCF and AHA implemented a new pol-
icy for relationship with industry and other entities (RWI) that
requires the writing committee chair plus a minimum of 50%
of the writing committee to have no relevant RWI (Appendix 1
includes the ACCF/AHA definition of relevance). These state-
ments are reviewed by the Task Force and all members during
each conference call and/or meeting of the writing committee
and are updated as changes occur. All guideline recommen-
dations require a confidential vote by the writing committee
and must be approved by a consensus of the voting members.
Members are not permitted to draft or vote on any text or rec-
ommendations pertaining to their RWI. Members who recused
themselves from voting are indicated in the list of writing
committee members, and specific section recusals are noted
in Appendix 1. Authors’ and peer reviewers’ RWI pertinent
to this guideline are disclosed in Appendixes 1 and 2, respec-
tively. Additionally, to ensure complete transparency, writing
committee members’ comprehensive disclosure information—
including RWI not pertinent to this document—is available
as an online supplement. Comprehensive disclosure infor-
mation for the Task Force is also available online at http://
www.cardiosource.org/en/ACC/About-ACC/Who-We-Are/
Leadership/Guidelines-and-Documents-Task-Forces.aspx.
The work of writing committees is supported exclusively by
the ACCF and AHA without commercial support. Writing
committee members volunteered their time for this activity.
In an effort to maintain relevance at the point of care for
practicing clinicians, the Task Force continues to oversee
an ongoing process improvement initiative. As a result, in
response to pilot projects, several changes to these guidelines
will be apparent, including limited narrative text, a focus
on summary and evidence tables (with references linked to
abstracts in PubMed), and more liberal use of summary rec-
ommendation tables (with references that support LOE) to
serve as a quick reference.
In April 2011, the Institute of Medicine released 2 reports:
Clinical Practice Guidelines We Can Trust and Finding What
Works in Health Care: Standards for Systematic Reviews.
2,3

It is noteworthy that the ACCF/AHA practice guidelines are
cited as being compliant with many of the proposed standards.
A thorough review of these reports and of our current meth-
odology is under way, with further enhancements anticipated.
The recommendations in this guideline are considered cur-
rent until they are superseded by a focused update or the full-
text guideline is revised. Guidelines are official policy of both
the ACCF and AHA.
Jeffrey L. Anderson, MD, FACC, FAHA
Chair, ACCF/AHA Task Force on Practice Guidelines
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e245
1. Introduction
1.1. Methodology and Evidence Review
The recommendations listed in this document are, when-
ever possible, evidence based. An extensive evidence review
was conducted through October 2011 and includes selected
other references through April 2013. Searches were extended
to studies, reviews, and other evidence conducted in human
subjects and that were published in English from PubMed,
EMBASE, Cochrane, Agency for Healthcare Research and
Quality Reports, and other selected databases relevant to this
guideline. Key search words included but were not limited to
the following: heart failure, cardiomyopathy, quality of life,
mortality, hospitalizations, prevention, biomarkers, hyperten-
sion, dyslipidemia, imaging, cardiac catheterization, endo-
myocardial biopsy, angiotensin-converting enzyme inhibitors,
angiotensin-receptor antagonists/blockers, beta blockers, car-
diac, cardiac resynchronization therapy, defibrillator, device-
based therapy, implantable cardioverter-defibrillator, device
implantation, medical therapy, acute decompensated heart
failure, preserved ejection fraction, terminal care and trans-
plantation, quality measures, and performance measures.
Additionally, the committee reviewed documents related to
the subject matter previously published by the ACCF and
AHA. References selected and published in this document are
representative and not all-inclusive.
To provide clinicians with a representative evidence base,
whenever deemed appropriate or when published, the absolute
risk difference and number needed to treat or harm are provided
in the guideline (within tables), along with confidence intervals
and data related to the relative treatment effects such as odds
ratio, relative risk, hazard ratio, and incidence rate ratio.
1.2. Organization of the Writing Committee
The committee was composed of physicians and a nurse with
broad expertise in the evaluation, care, and management of
patients with heart failure (HF). The authors included general
cardiologists, HF and transplant specialists, electrophysiolo-
gists, general internists, and physicians with methodologi-
cal expertise. The committee included representatives from
the ACCF, AHA, American Academy of Family Physicians,
American College of Chest Physicians, American College of
Physicians, Heart Rhythm Society, and International Society
for Heart and Lung Transplantation.
1.3. Document Review and Approval
This document was reviewed by 2 official reviewers each
nominated by both the ACCF and the AHA, as well as 1 to
2 reviewers each from the American Academy of Family
Physicians, American College of Chest Physicians, Heart
Rhythm Society, and International Society for Heart and Lung
Transplantation, as well as 32 individual content review-
ers (including members of the ACCF Adult Congenital and
Pediatric Cardiology Council, ACCF Cardiovascular Team
Council, ACCF Council on Cardiovascular Care for Older
Adults, ACCF Electrophysiology Committee, ACCF Heart
Failure and Transplant Council, ACCF Imaging Council,
ACCF Prevention Committee, ACCF Surgeons’ Scientific
Council, and ACCF Task Force on Appropriate Use Criteria).
All information on reviewers’ RWI was distributed to the writ-
ing committee and is published in this document (Appendix 2).
This document was approved for publication by the govern-
ing bodies of the ACCF and AHA and endorsed by the American
Association of Cardiovascular and Pulmonary Rehabilitation,
American College of Chest Physicians, Heart Rhythm Society,
and International Society for Heart and Lung Transplantation.
1.4. Scope of This Guideline With Reference to
Other Relevant Guidelines or Statements
This guideline covers multiple management issues for the
adult patient with HF. Although there is an abundance of
evidence addressing HF, for many important clinical consid-
erations, this writing committee was unable to identify suf-
ficient data to properly inform a recommendation. The writing
committee actively worked to reduce the number of LOE “C”
recommendations, especially for Class I−recommended thera-
pies. Despite these limitations, it is apparent that much can
be done for HF. Adherence to the clinical practice guidelines
herein reproduced should lead to improved patient outcomes.
Although of increasing importance, HF in children and con-
genital heart lesions in adults are not specifically addressed in
this guideline. The reader is referred to publically available
resources to address questions in these areas. However, this
guideline does address HF with preserved ejection fraction (EF)
in more detail and similarly revisits hospitalized HF. Additional
areas of renewed interest are in stage D HF, palliative care, tran-
sition of care, and quality of care for HF. Certain management
strategies appropriate for the patient at risk for HF or already
affected by HF are also reviewed in numerous relevant clinical
practice guidelines and scientific statements published by the
ACCF/AHA Task Force on Practice Guidelines, AHA, ACCF
Task Force on Appropriate Use Criteria, European Society of
Cardiology, Heart Failure Society of America, and the National
Heart, Lung, and Blood Institute. The writing committee saw
no need to reiterate the recommendations contained in those
guidelines and chose to harmonize recommendations when
appropriate and eliminate discrepancies. This is especially the
case for device-based therapeutics, where complete alignment
between the HF guideline and the device-based therapy guide-
line was deemed imperative.
4
Some recommendations from
earlier guidelines have been updated as warranted by new evi-
dence or a better understanding of earlier evidence, whereas
others that were no longer accurate or relevant or which were
overlapping were modified; recommendations from previous
guidelines that were similar or redundant were eliminated or
consolidated when possible.
The present document recommends a combination of life-
style modifications and medications that constitute GDMT.
GDMT is specifically referenced in the recommendations for
the treatment of HF (Section 7.3.2). Both for GDMT and other
recommended drug treatment regimens, the reader is advised
to confirm dosages with product insert material and to evalu-
ate carefully for contraindications and drug-drug interactions.
Table 2 is a list of documents deemed pertinent to this effort
and is intended for use as a resource; it obviates the need to
repeat already extant guideline recommendations. Additional
other HF guideline statements are highlighted as well for the
purpose of comparison and completeness.
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e246 Circulation October 15, 2013
2. Definition of HF
HF is a complex clinical syndrome that results from any
structural or functional impairment of ventricular filling or
ejection of blood. The cardinal manifestations of HF are
dyspnea and fatigue, which may limit exercise tolerance,
and fluid retention, which may lead to pulmonary and/
or splanchnic congestion and/or peripheral edema. Some
patients have exercise intolerance but little evidence of fluid
retention, whereas others complain primarily of edema,
dyspnea, or fatigue. Because some patients present without
signs or symptoms of volume overload, the term “heart
failure” is preferred over “congestive heart failure.” There
is no single diagnostic test for HF because it is largely a
clinical diagnosis based on a careful history and physical
examination.
The clinical syndrome of HF may result from disorders
of the pericardium, myocardium, endocardium, heart valves,
or great vessels or from certain metabolic abnormalities, but
most patients with HF have symptoms due to impaired left
ventricular (LV) myocardial function. It should be emphasized
Table 2. Associated Guidelines and Statements
Title Organization
Publication
Year
(Reference)
Guidelines
Guidelines for the Management of Adults With Congenital Heart Disease ACCF/AHA 2008
5
Guidelines for the Management of Patients With Atrial Fibrillation ACCF/AHA/HRS 2011
6–8
Guideline for Assessment of Cardiovascular Risk in Asymptomatic Adults ACCF/AHA 2010
9
Guideline for Coronary Artery Bypass Graft Surgery ACCF/AHA 2011
10
Guidelines for Device-Based Therapy of Cardiac Rhythm Abnormalities ACCF/AHA/HRS 2013
4
Guideline for the Diagnosis and Treatment of Hypertrophic Cardiomyopathy ACCF/AHA 2011
11
Guideline for Percutaneous Coronary Intervention ACCF/AHA/SCAI 2011
12
Secondary Prevention and Risk Reduction Therapy for Patients With Coronary and Other Atherosclerotic
Vascular Disease: 2011 Update
AHA/ACCF 2011
13
Guideline for the Diagnosis and Management of Patients With Stable Ischemic Heart Disease ACCF/AHA/ACP/AATS/PCNA/SCAI/STS 2012
14
Guideline for the Management of ST-Elevation Myocardial Infarction ACCF/AHA 2013
15
Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction ACCF/AHA 2013
16
Guidelines for the Management of Patients With Valvular Heart Disease ACCF/AHA 2008
17
Comprehensive Heart Failure Practice Guideline HFSA 2010
18
Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure ESC 2012
19
Chronic Heart Failure: Management of Chronic Heart Failure in Adults in Primary and Secondary Care NICE 2010
20
Antithrombotic Therapy and Prevention of Thrombosis ACCP 2012
21
Guidelines for the Care of Heart Transplant Recipients ISHLT 2010
22
Statements
Contemporary Definitions and Classification of the Cardiomyopathies AHA 2006
23
Genetics and Cardiovascular Disease AHA 2012
24
Appropriate Utilization of Cardiovascular Imaging in Heart Failure ACCF 2013
25
Appropriate Use Criteria for Coronary Revascularization Focused Update ACCF 2012
26
Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of
High Blood Pressure
NHLBI 2003
27
Implications of Recent Clinical Trials for the National Cholesterol Education Program Adult Treatment Panel
III Guidelines
NHLBI 2002
28
Referral, Enrollment, and Delivery of Cardiac Rehabilitation/Secondary Prevention Programs at Clinical
Centers and Beyond
AHA/AACVPR 2011
29
Decision Making in Advanced Heart Failure AHA 2012
30
Recommendations for the Use of Mechanical Circulatory Support: Device Strategies and Patient Selection AHA 2012
31
Advanced Chronic Heart Failure ESC 2007
32
Oral Antithrombotic Agents for the Prevention of Stroke in Nonvalvular Atrial Fibrillation AHA/ASA 2012
33
Third Universal Definition of Myocardial Infarction ESC/ACCF/AHA/WHF 2012
34
AACVPR indicates American Association of Cardiovascular and Pulmonary Rehabilitation; AATS, American Association for Thoracic Surgery; ACCF, American College
of Cardiology Foundation; ACCP, American College of Chest Physicians; ACP, American College of Physicians; AHA, American Heart Association; ASA, American Stroke
Association; ESC, European Society of Cardiology; HFSA, Heart Failure Society of America; HRS, Heart Rhythm Society; ISHLT, International Society for Heart and Lung
Transplantation; NHLBI, National Heart, Lung, and Blood Institute; NICE, National Institute for Health and Clinical Excellence; PCNA, Preventive Cardiovascular Nurses
Association; SCAI, Society for Cardiovascular Angiography and Interventions; STS, Society of Thoracic Surgeons; and WHF, World Heart Federation.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e247
that HF is not synonymous with either cardiomyopathy or LV
dysfunction; these latter terms describe possible structural
or functional reasons for the development of HF. HF may be
associated with a wide spectrum of LV functional abnormali-
ties, which may range from patients with normal LV size and
preserved EF to those with severe dilatation and/or markedly
reduced EF. In most patients, abnormalities of systolic and
diastolic dysfunction coexist, irrespective of EF. EF is consid-
ered important in classification of patients with HF because
of differing patient demographics, comorbid conditions, prog-
nosis, and response to therapies
35
and because most clinical
trials selected patients based on EF. EF values are dependent
on the imaging technique used, method of analysis, and opera-
tor. Because other techniques may indicate abnormalities in
systolic function among patients with a preserved EF, it is
preferable to use the terms preserved or reduced EF over pre-
served or reduced systolic function. For the remainder of this
guideline, we will consistently refer to HF with preserved EF
and HF with reduced EF as HFpEF and HFrEF, respectively
(Table 3).
2.1. HF With Reduced EF (HFrEF)
In approximately half of patients with HFrEF, variable
degrees of LV enlargement may accompany HFrEF.
36,37

The definition of HFrEF has varied, with guidelines of left
ventricular ejection fraction (LVEF) ≤35%, <40%, and
≤40%.
18,19,38
Randomized controlled trials (RCTs) in patients
with HF have mainly enrolled patients with HFrEF with an
EF ≤35% or ≤40%, and it is only in these patients that effi-
cacious therapies have been demonstrated to date. For the
present guideline, HFrEF is defined as the clinical diagnosis
of HF and EF ≤40%. Those with LV systolic dysfunction
commonly have elements of diastolic dysfunction as well.
39

Although coronary artery disease (CAD) with antecedent
myocardial infarction (MI) is a major cause of HFrEF, many
other risk factors (Section 4.6) may lead to LV enlargement
and HFrEF.
2.2. HF With Preserved EF (HFpEF)
In patients with clinical HF, studies estimate that the preva-
lence of HFpEF is approximately 50% (range 40% to 71%).
40

These estimates vary largely because of the differing EF cut-
off criteria and challenges in diagnostic criteria for HFpEF.
HFpEF has been variably classified as EF >40%, >45%,
>50%, and ≥55%. Because some of these patients do not
have entirely normal EF but also do not have major reduc-
tion in systolic function, the term preserved EF has been used.
Patients with an EF in the range of 40% to 50% represent an
intermediate group. These patients are often treated for under-
lying risk factors and comorbidities and with GDMT similar
to that used in patients with HFrEF. Several criteria have been
proposed to define the syndrome of HFpEF. These include a)
clinical signs or symptoms of HF; b) evidence of preserved
or normal LVEF; and c) evidence of abnormal LV diastolic
dysfunction that can be determined by Doppler echocardiog-
raphy or cardiac catheterization.
41
The diagnosis of HFpEF is
more challenging than the diagnosis of HFrEF because it is
largely one of excluding other potential noncardiac causes of
symptoms suggestive of HF. Studies have suggested that the
incidence of HFpEF is increasing and that a greater portion
of patients hospitalized with HF have HFpEF.
42
In the gen-
eral population, patients with HFpEF are usually older women
with a history of hypertension. Obesity, CAD, diabetes melli-
tus, atrial fibrillation (AF), and hyperlipidemia are also highly
prevalent in HFpEF in population-based studies and regis-
tries.
40,43
Despite these associated cardiovascular risk factors,
hypertension remains the most important cause of HFpEF,
with a prevalence of 60% to 89% from large controlled tri-
als, epidemiological studies, and HF registries.
44
It has been
recognized that a subset of patients with HFpEF previously
had HFrEF.
45
These patients with improvement or recovery
in EF may be clinically distinct from those with persistently
preserved or reduced EF. Further research is needed to better
characterize these patients.
See Online Data Supplement 1 for additional data on
HFpEF.
3. HF Classifications
Both the ACCF/AHA stages of HF
38
and the New York Heart
Association (NYHA) functional classification
38,46
provide use-
ful and complementary information about the presence and
severity of HF. The ACCF/AHA stages of HF emphasize the
development and progression of disease and can be used to
describe individuals and populations, whereas the NYHA
classes focus on exercise capacity and the symptomatic status
of the disease (Table 4).
Table 3. Definitions of HFrEF and HFpEF
Classification EF (%) Description
I. Heart failure with reduced
ejection fraction
(HFrEF)
≤40 Also referred to as systolic HF. Randomized controlled trials have mainly enrolled patients with HFrEF, and it is only in
these patients that efficacious therapies have been demonstrated to date.
II. Heart failure with
preserved ejection
fraction (HFpEF)
≥50 Also referred to as diastolic HF. Several different criteria have been used to further define HFpEF. The diagnosis of HFpEF
is challenging because it is largely one of excluding other potential noncardiac causes of symptoms suggestive of HF.
To date, efficacious therapies have not been identified.
a. HFpEF, borderline 41 to 49 These patients fall into a borderline or intermediate group. Their characteristics, treatment patterns, and outcomes
appear similar to those of patients with HFpEF.
b. HFpEF, improved >40 It has been recognized that a subset of patients with HFpEF previously had HFrEF. These patients with improvement or
recovery in EF may be clinically distinct from those with persistently preserved or reduced EF. Further research is
needed to better characterize these patients.
EF indicates ejection fraction; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; and HFrEF, heart failure with reduced ejection fraction.
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e248 Circulation October 15, 2013
The ACCF/AHA stages of HF recognize that both risk fac-
tors and abnormalities of cardiac structure are associated with
HF. The stages are progressive and inviolate; once a patient
moves to a higher stage, regression to an earlier stage of HF
is not observed. Progression in HF stages is associated with
reduced 5-year survival and increased plasma natriuretic pep-
tide concentrations.
47
Therapeutic interventions in each stage
aimed at modifying risk factors (stage A), treating structural
heart disease (stage B), and reducing morbidity and mortality
(stages C and D) (covered in detail in Section 7) are reviewed
in this document. The NYHA functional classification gauges
the severity of symptoms in those with structural heart dis-
ease, primarily stages C and D. It is a subjective assessment
by a clinician and can change frequently over short periods of
time. Although reproducibility and validity may be problem-
atic,
48
the NYHA functional classification is an independent
predictor of mortality.
49
It is widely used in clinical practice
and research and for determining the eligibility of patients for
certain healthcare services.
See Online Data Supplement 2 for additional data on
ACCF/AHA stages of HF and NYHA functional classifications.
4. Epidemiology
The lifetime risk of developing HF is 20% for Americans ≥40
years of age.
50
In the United States, HF incidence has largely
remained stable over the past several decades, with >650 000
new HF cases diagnosed annually.
51–53
HF incidence increases
with age, rising from approximately 20 per 1000 individuals
65 to 69 years of age to >80 per 1000 individuals among those
≥85 years of age.
52
Approximately 5.1 million persons in the
United States have clinically manifest HF, and the prevalence
continues to rise.
51
In the Medicare-eligible population, HF
prevalence increased from 90 to 121 per 1000 beneficiaries
from 1994 to 2003.
52
HFrEF and HFpEF each make up about
half of the overall HF burden.
54
One in 5 Americans will be
>65 years of age by 2050.
55
Because HF prevalence is highest
in this group, the number of Americans with HF is expected to
significantly worsen in the future. Disparities in the epidemi-
ology of HF have been identified. Blacks have the highest risk
for HF.
56
In the ARIC (Atherosclerosis Risk in Communities)
study, incidence rate per 1000 person-years was lowest among
white women
52,53
and highest among black men,
57
with blacks
having a greater 5-year mortality rate than whites.
58
HF in
non-Hispanic black males and females has a prevalence of
4.5% and 3.8%, respectively, versus 2.7% and 1.8% in non-
Hispanic white males and females, respectively.
51
4.1. Mortality
Although survival has improved, the absolute mortality rates
for HF remain approximately 50% within 5 years of diagno-
sis.
53,59
In the ARIC study, the 30-day, 1-year, and 5-year case
fatality rates after hospitalization for HF were 10.4%, 22%,
and 42.3%, respectively.
58
In another population cohort study
with 5-year mortality data, survival for stage A, B, C, and
D HF was 97%, 96%, 75%, and 20%, respectively.
47
Thirty-
day post admission mortality rates decreased from 12.6% to
10.8% from 1993 to 2005; however, this was due to lower
in-hospital death rates. Postdischarge mortality actually
increased from 4.3% to 6.4% during the same time frame.
60

These observed temporal trends in HF survival are primar-
ily restricted to patients with reduced EF and are not seen in
those with preserved EF.
40
See Online Data Supplement 3 for additional data on
mortality.
4.2. Hospitalizations
HF is the primary diagnosis in >1 million hospitalizations annu-
ally.
51
Patients hospitalized for HF are at high risk for all-cause
rehospitalization, with a 1-month readmission rate of 25%.
61
In
2013, physician office visits for HF cost $1.8 billion. The total
cost of HF care in the United States exceeds $30 billion annu-
ally, with over half of these costs spent on hospitalizations.
51
4.3. Asymptomatic LV Dysfunction
The prevalence of asymptomatic LV systolic or diastolic dys-
function ranges from 6% to 21% and increases with age.
62–64

In the Left Ventricular Dysfunction Prevention study, partici-
pants with untreated asymptomatic LV dysfunction had a 10%
risk for developing HF symptoms and an 8% risk of death or
HF hospitalization annually.
65
In a community-based popula-
tion, asymptomatic mild LV diastolic dysfunction was seen in
21% and moderate or severe diastolic dysfunction in 7%, and
both were associated with an increased risk of symptomatic
HF and mortality.
64
Table 4. Comparison of ACCF/AHA Stages of HF and NYHA Functional Classifications
ACCF/AHA Stages of HF
38
NYHA Functional Classification
46
A At high risk for HF but without structural heart
disease or symptoms of HF
None
B Structural heart disease but without signs or
symptoms of HF
I No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
C Structural heart disease with prior or current
symptoms of HF
I No limitation of physical activity. Ordinary physical activity does not cause symptoms of HF.
II Slight limitation of physical activity. Comfortable at rest, but ordinary physical activity results
in symptoms of HF.
III Marked limitation of physical activity. Comfortable at rest, but less than ordinary activity
causes symptoms of HF.
IV Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.
IV Unable to carry on any physical activity without symptoms of HF, or symptoms of HF at rest.
D Refractory HF requiring specialized interventions
ACCF indicates American College of Cardiology Foundation; AHA, American Heart Association; HF, heart failure; and NYHA, New York Heart Association.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e249
4.4. Health-Related Quality of Life and
Functional Status
HF significantly decreases health-related quality of life
(HRQOL), especially in the areas of physical functioning and
vitality.
66,67
Lack of improvement in HRQOL after discharge
from the hospital is a powerful predictor of rehospitalization
and mortality.
68,69
Women with HF have consistently been
found to have poorer HRQOL than men.
67,70
Ethnic differences
also have been found, with Mexican Hispanics reporting better
HRQOL than other ethnic groups in the United States.
71
Other
determinants of poor HRQOL include depression, younger
age, higher body mass index (BMI), greater symptom burden,
lower systolic blood pressure, sleep apnea, low perceived con-
trol, and uncertainty about prognosis.
70,72–76
Memory problems
may also contribute to poor HRQOL.
76
Pharmacological therapy is not a consistent determinant of
HRQOL; therapies such as angiotensin-converting enzyme
(ACE) inhibitors and angiotensin-receptor blockers (ARBs)
improve HRQOL only modestly or delay the progressive
worsening of HRQOL in HF.
77
At present, the only therapies
shown to improve HRQOL are cardiac resynchronization
therapy (CRT)
78
and certain disease management and edu-
cational approaches.
79–82
Self-care and exercise may improve
HRQOL, but the results of studies evaluating these interven-
tions are mixed.
83–86
Throughout this guideline we refer to
meaningful survival as a state in which HRQOL is satisfac-
tory to the patient.
See Online Data Supplement 4 for additional data on
HRQOL and functional capacity.
4.5. Economic Burden of HF
In 1 in 9 deaths in the United States, HF is mentioned on the
death certificate. The number of deaths with any mention of
HF was as high in 2006 as it was in 1995.
51
Approximately 7%
of all cardiovascular deaths are due to HF.
As previously noted, in 2013, HF costs in the United States
exceeded $30 billion.
51
This total includes the cost of health-
care services, medications, and lost productivity. The mean
cost of HF-related hospitalizations was $23 077 per patient
and was higher when HF was a secondary rather than the pri-
mary diagnosis. Among patients with HF in 1 large population
study, hospitalizations were common after HF diagnosis, with
83% of patients hospitalized at least once and 43% hospital-
ized at least 4 times. More than half of the hospitalizations
were related to noncardiovascular causes.
87–89
4.6. Important Risk Factors for HF (Hypertension,
Diabetes Mellitus, Metabolic Syndrome, and
Atherosclerotic Disease)
Many conditions or comorbidities are associated with an
increased propensity for structural heart disease. The expedi-
ent identification and treatment of these comorbid conditions
may forestall the onset of HF.
14,27,90
A list of the important doc-
uments that codify treatment for these concomitant conditions
appears in Table 2.
Hypertension
Hypertension may be the single most important modifiable
risk factor for HF in the United States. Hypertensive men
and women have a substantially greater risk for developing
HF than normotensive men and women.
91
Elevated levels of
diastolic and especially systolic blood pressure are major risk
factors for the development of HF.
91,92
The incidence of HF is
greater with higher levels of blood pressure, older age, and
longer duration of hypertension. Long-term treatment of both
systolic and diastolic hypertension reduces the risk of HF by
approximately 50%.
93–96
With nearly a quarter of the American
population afflicted by hypertension and the lifetime risk of
developing hypertension at >75% in the United States,
97
strat-
egies to control hypertension are a vital part of any public
health effort to prevent HF.
Diabetes Mellitus
Obesity and insulin resistance are important risk factors for
the development of HF.
98,99
The presence of clinical diabetes
mellitus markedly increases the likelihood of developing HF
in patients without structural heart disease
100
and adversely
affects the outcomes of patients with established HF.
101,102
Metabolic Syndrome
The metabolic syndrome includes any 3 of the following:
abdominal adiposity, hypertriglyceridemia, low high-den-
sity lipoprotein, hypertension, and fasting hyperglycemia.
The prevalence of metabolic syndrome in the United States
exceeds 20% of persons ≥20 years of age and 40% of those
>40 years of age.
103
The appropriate treatment of hyperten-
sion, diabetes mellitus, and dyslipidemia
104
can significantly
reduce the development of HF.
Atherosclerotic Disease
Patients with known atherosclerotic disease (eg, of the cor-
onary, cerebral, or peripheral blood vessels) are likely to
develop HF, and clinicians should seek to control vascular risk
factors in such patients according to guidelines.
13
5. Cardiac Structural Abnormalities
and Other Causes of HF
5.1. Dilated Cardiomyopathies
5.1.1. Definition and Classification of Dilated
Cardiomyopathies
Dilated cardiomyopathy (DCM) refers to a large group of
heterogeneous myocardial disorders that are characterized by
ventricular dilation and depressed myocardial contractility in
the absence of abnormal loading conditions such as hyperten-
sion or valvular disease. In clinical practice and multicenter
HF trials, the etiology of HF has often been categorized into
ischemic or nonischemic cardiomyopathy, with the term DCM
used interchangeably with nonischemic cardiomyopathy. This
approach fails to recognize that “nonischemic cardiomyopa-
thy” may include cardiomyopathies due to volume or pres-
sure overload, such as hypertension or valvular heart disease,
which are not conventionally accepted as DCM.
105
With the
identification of genetic defects in several forms of cardiomy-
opathies, a new classification scheme based on genomics was
proposed in 2006.
23
We recognize that classification of car-
diomyopathies is challenging, mixing anatomic designations
(ie, hypertrophic and dilated) with functional designations (ie,
restrictive), and is unlikely to satisfy all users. The aim of the
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e250 Circulation October 15, 2013
present guideline is to target appropriate diagnostic and treat-
ment strategies for preventing the development and progres-
sion of HF in patients with cardiomyopathies; we do not wish
to redefine new classification strategies for cardiomyopathies.
5.1.2. Epidemiology and Natural History of DCM
The age-adjusted prevalence of DCM in the United States aver-
ages 36 cases per 100 000 population, and DCM accounts for
10 000 deaths annually.
106
In most multicenter RCTs and reg-
istries in HF, approximately 30% to 40% of enrolled patients
have DCM.
107–109
Compared with whites, African Americans
have almost a 3-fold increased risk for developing DCM, irre-
spective of comorbidities or socioeconomic factors.
108–110
Sex-
related differences in the incidence and prognosis of DCM
are conflicting and may be confounded by differing etiolo-
gies.
108,109,111
The prognosis in patients with symptomatic HF
and DCM is relatively poor, with 25% mortality at 1 year and
50% mortality at 5 years.
112
Approximately 25% of patients
with DCM with recent onset of HF symptoms will improve
within a short time even in the absence of optimal GDMT,
113

but patients with symptoms lasting >3 months who present
with severe clinical decompensation generally have less chance
of recovery.
113
Patients with idiopathic DCM have a lower
total mortality rate than patients with other types of DCM.
114

However, GDMT is beneficial in all forms of DCM.
78,109,115–117
5.2. Familial Cardiomyopathies
Increasingly, it is recognized that many (20% to 35%) patients
with an idiopathic DCM have a familial cardiomyopathy
(defined as 2 closely related family members who meet the
criteria for idiopathic DCM).
118,119
Consideration of familial
cardiomyopathies includes the increasingly important dis-
covery of noncompaction cardiomyopathies. Advances in
technology permitting high-throughput sequencing and geno-
typing at reduced costs have brought genetic screening to the
clinical arena. For further information on this topic, the reader
is referred to published guidelines, position statements, and
expert consensus statements
118,120–123
(Table 5).
5.3. Endocrine and Metabolic Causes of
Cardiomyopathy
5.3.1. Obesity
Obesity cardiomyopathy is defined as cardiomyopathy
due entirely or predominantly to obesity (Section 7.3.1.5).
Although the precise mechanisms causing obesity-related
HF are not known, excessive adipose accumulation results
in an increase in circulating blood volume. A subsequent,
persistent increase in cardiac output, cardiac work, and
systemic blood pressure
124
along with lipotoxicity-induced
cardiac myocyte injury and myocardial lipid accumulation
have been implicated as potential mechanisms.
125,126
A study
with participants from the Framingham Heart Study reported
that after adjustment for established risk factors, obesity was
associated with significant future risk of development of
HF.
99
There are no large-scale studies of the safety or effi-
cacy of weight loss with diet, exercise, or bariatric surgery in
obese patients with HF.
5.3.2. Diabetic Cardiomyopathy
Diabetes mellitus is now well recognized as a risk factor for
the development of HF independent of age, hypertension, obe-
sity, hypercholesterolemia, or CAD. The association between
mortality and hemoglobin A1c (HbA1c) in patients with
diabetes mellitus and HF appears U-shaped, with the lowest
risk of death in those patients with modest glucose control
(7.1% high or low HbA1c levels.
127
The optimal treatment strategy in
patients with diabetes mellitus and HF is controversial; some
studies have suggested potential harm with several glucose-
lowering medications.
127,128
The safety and efficacy of diabetes
mellitus therapies in HF, including metformin, sulfonylureas,
insulin, and glucagon-like peptide analogues, await further
data from prospective clinical trials.
129–131
Treatment with
thiazolidinediones (eg, rosiglitazone) is associated with fluid
retention in patients with HF
129,132
and should be avoided in
patients with NYHA class II through IV HF.
5.3.3. Thyroid Disease
Hyperthyroidism has been implicated in causing DCM but
most commonly occurs with persistent sinus tachycardia or AF
and may be related to tachycardia.
133
Abnormalities in cardiac
systolic and diastolic performance have been reported in hypo-
thyroidism. However, the classic findings of myxedema do
not usually indicate cardiomyopathy. The low cardiac output
results from bradycardia, decreased ventricular filling, reduced
cardiac contractility, and diminished myocardial work.
133,134
5.3.4. Acromegaly and Growth Hormone Deficiency
Impaired cardiovascular function has been associated with
reduced life expectancy in patients with growth hormone defi-
ciency and excess. Experimental and clinical studies implicate
growth hormone and insulin-like growth factor I in cardiac
development.
135
Cardiomyopathy associated with acromegaly
is characterized by myocardial hypertrophy with interstitial
fibrosis, lympho-mononuclear infiltration, myocyte necrosis,
and biventricular concentric hypertrophy.
135
Table 5. Screening of Family Members and Genetic Testing in Patients With Idiopathic or Familial DCM
Condition Screening of Family Members Genetic Testing
Familial DCM •     First-degree relatives not known to be affected should undergo periodic, 
serial echocardiographic screening with assessment of LV function and size.
•    Frequency of screening is uncertain, but every 3–5 y is reasonable.
118
•    Genetic testing may be considered in conjunction with genetic 
counseling.
118,121–123
Idiopathic DCM •    Patients should inform first-degree relatives of their diagnosis.
•    Relatives should update their clinicians and discuss whether they should 
undergo screening by echocardiography.
•    The utility of genetic testing in this setting remains uncertain.
•    Yield of genetic testing may be higher in patients with 
significant cardiac conduction disease and/or a family
history of premature sudden cardiac death.
118,121–123
DCM indicates dilated cardiomyopathy; and LV, left ventricular.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e251
5.4. Toxic Cardiomyopathy
5.4.1. Alcoholic Cardiomyopathy
Chronic alcoholism is one of the most important causes of
DCM.
136
The clinical diagnosis is suspected when biven-
tricular dysfunction and dilatation are persistently observed
in a heavy drinker in the absence of other known causes for
myocardial disease. Alcoholic cardiomyopathy most com-
monly occurs in men 30 to 55 years of age who have been
heavy consumers of alcohol for >10 years.
137
Women repre-
sent approximately 14% of the alcoholic cardiomyopathy
cases but may be more vulnerable with less lifetime alcohol
consumption.
136,138
The risk of asymptomatic alcoholic cardio-
myopathy is increased in those consuming >90 g of alcohol
per day (approximately 7 to 8 standard drinks per day) for >5
years.
137
Interestingly, in the general population, mild to mod-
erate alcohol consumption has been reported to be protective
against development of HF.
139,140
These paradoxical findings
suggest that duration of exposure and individual genetic sus-
ceptibility play an important role in pathogenesis. Recovery of
LV function after cessation of drinking has been reported.
141

Even if LV dysfunction persists, the symptoms and signs of
HF improve after abstinence.
141
5.4.2. Cocaine Cardiomyopathy
Long-term abuse of cocaine may result in DCM even with-
out CAD, vasculitis, or MI. Depressed LV function has been
reported in 4% to 18% of asymptomatic cocaine abusers.
142–144

The safety and efficacy of beta blockers for chronic HF due to
cocaine use are unknown.
145
5.4.3. Cardiotoxicity Related to Cancer Therapies
Several cytotoxic antineoplastic drugs, especially the anthra-
cyclines, are cardiotoxic and can lead to long-term cardiac
morbidity. Iron-chelating agents that prevent generation of
oxygen free radicals, such as dexrazoxane, are cardioprotec-
tive,
146,147
and reduce the occurrence and severity of anthracy-
cline-induced cardiotoxicity and development of HF.
Other antineoplastic chemotherapies with cardiac toxicity
are the monoclonal antibody trastuzumab (Herceptin), high-
dose cyclophosphamide, taxoids, mitomycin-C, 5-fluoroura-
cil, and the interferons.
148
In contrast to anthracycline-induced
cardiac toxicity, trastuzumab-related cardiac dysfunction
does not appear to increase with cumulative dose, nor is it
associated with ultrastructural changes in the myocardium.
However, concomitant anthracycline therapy significantly
increases the risk for cardiotoxicity during trastuzumab treat-
ment. The cardiac dysfunction associated with trastuzumab
is most often reversible on discontinuation of treatment and
initiation of standard medical therapy for HF.
149
The true inci-
dence and reversibility of chemotherapy-related cardiotoxic-
ity are not well documented, and meaningful interventions to
prevent injury have not yet been elucidated.
5.4.4. Other Myocardial Toxins and Nutritional Causes of
Cardiomyopathy
In addition to the classic toxins described above, a number of
other toxic agents may lead to LV dysfunction and HF, includ-
ing ephedra, cobalt, anabolic steroids, chloroquine, clozap-
ine, amphetamine, methylphenidate, and catecholamines.
150

Ephedra, which has been used for athletic performance
enhancement and weight loss, was ultimately banned by the
US Food and Drug Administration for its high rate of adverse
cardiovascular outcomes, including LV systolic dysfunction,
development of HF, and sudden cardiac death (SCD).
151
Primary and secondary nutritional deficiencies may lead
to cardiomyopathy. Chronic alcoholism, anorexia nervosa,
AIDS, and pregnancy can account for other rare causes of
thiamine deficiency–related cardiomyopathy in the western
world.
152
Deficiency in L-carnitine, a necessary cofactor for
fatty acid oxidation, may be associated with a syndrome of
progressive skeletal myopathy and cardiomyopathy.
153
5.5. Tachycardia-Induced Cardiomyopathy
Tachycardia-induced cardiomyopathy is a reversible cause of
HF characterized by LV myocardial dysfunction caused by
increased ventricular rate. The degree of dysfunction correlates
with the duration and rate of the tachyarrhythmia. Virtually any
supraventricular tachycardia with a rapid ventricular response
may induce cardiomyopathy. Ventricular arrhythmias, includ-
ing frequent premature ventricular complexes, may also induce
cardiomyopathy. Maintenance of sinus rhythm or control of
ventricular rate is critical to treating patients with tachycardia-
induced cardiomyopathy.
154
Reversibility of the cardiomyopa-
thy with treatment of the arrhythmia is the rule, although this
may not be complete in all cases. The underlying mechanisms
for this are not well understood.
Ventricular pacing at high rates may cause cardiomyopathy.
Additionally, right ventricular pacing alone may exacerbate
HF symptoms, increase hospitalization for HF, and increase
mortality.
155,156
Use of CRT in patients with a conduction delay
due to pacing may result in improved LV function and func-
tional capacity.
5.6. Myocarditis and Cardiomyopathies Due to
Inflammation
5.6.1. Myocarditis
Inflammation of the heart may cause HF in about 10% of cases
of initially unexplained cardiomyopathy.
105,157
A variety of infec-
tious organisms, as well as toxins and medications, most often
postviral in origin, may cause myocarditis. In addition, myocar-
ditis is also seen as part of other systemic diseases such as sys-
temic lupus erythematosus and other myocardial muscle diseases
such as HIV cardiomyopathy and possibly peripartum cardiomy-
opathy. Presentation may be acute, with a distinct onset, severe
hemodynamic compromise, and severe LV dysfunction as seen
in acute fulminant myocarditis, or it may be subacute, with an
indistinct onset and better-tolerated LV dysfunction.
158
Prognosis
varies, with spontaneous complete resolution (paradoxically
most often seen with acute fulminant myocarditis)
158
to the devel-
opment of DCM despite immunosuppressive therapy.
159
The role
of immunosuppressive therapy is controversial.
159
Targeting such
therapy to specific individuals based on the presence or absence
of viral genome in myocardial biopsy samples may improve
response to immunosuppressive therapy.
160
Giant cell myocarditis is a rare form of myocardial inflam-
mation characterized by fulminant HF, often associated with
refractory ventricular arrhythmias and a poor prognosis.
161,162

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e252 Circulation October 15, 2013
Histologic findings include diffuse myocardial necrosis with
numerous multinucleated giant cells without granuloma for-
mation. Consideration for advanced HF therapies, including
immunosuppression, mechanical circulatory support (MCS),
and transplantation, is warranted.
5.6.2. Acquired Immunodeficiency Syndrome
The extent of immunodeficiency influences the incidence of
HIV-associated DCM.
163–165
In long-term echocardiographic
follow-up,
166
8% of initially asymptomatic HIV-positive
patients were diagnosed with DCM during the 5-year follow-
up. Whether early treatment with ACE inhibitors and/or beta
blockers will prevent or delay disease progression in these
patients is unknown at this time.
5.6.3. Chagas Disease
Although Chagas disease is a relatively uncommon cause of
DCM in North America, it remains an important cause of death
in Central and South America.
167
Symptomatic chronic Chagas
disease develops in an estimated 10% to 30% of infected per-
sons, years or even decades after the Trypanosoma cruzi infec-
tion. Cardiac changes may include biventricular enlargement,
thinning or thickening of ventricular walls, apical aneurysms,
and mural thrombi. The conduction system is often affected,
typically resulting in right bundle-branch block, left anterior
fascicular block, or complete atrioventricular block.
5.7. Inflammation-Induced Cardiomyopathy:
Noninfectious Causes
5.7.1. Hypersensitivity Myocarditis
Hypersensitivity to a variety of agents may result in aller-
gic reactions that involve the myocardium, characterized by
peripheral eosinophilia and a perivascular infiltration of the
myocardium by eosinophils, lymphocytes, and histiocytes. A
variety of drugs, most commonly the sulfonamides, penicil-
lins, methyldopa, and other agents such as amphotericin B,
streptomycin, phenytoin, isoniazid, tetanus toxoid, hydro-
chlorothiazide, dobutamine, and chlorthalidone, have been
reported to cause allergic hypersensitivity myocarditis.
168

Most patients are not clinically ill but may die suddenly, pre-
sumably secondary to an arrhythmia.
5.7.2. Rheumatological/Connective Tissue Disorders
Along with a number of cardiac abnormalities (eg, pericar-
ditis, pericardial effusion, conduction system abnormali-
ties, including complete atrioventricular heart block), DCM
can be a rare manifestation of systemic lupus erythematosus
and usually correlates with disease activity.
169
Studies sug-
gest that echocardiographic evidence of abnormal LV filling
may reflect the presence of myocardial fibrosis and could be
a marker of subclinical myocardial involvement in systemic
lupus erythematosus patients.
170
Scleroderma is a rare cause of DCM. One echocardio-
graphic study showed that despite normal LV dimensions or
fractional shortening, subclinical systolic impairment was
present in the majority of patients with scleroderma.
171
Cardiac
involvement in rheumatoid arthritis generally is in the form
of myocarditis and/or pericarditis, and development of DCM
is rare.
172
Myocardial involvement in rheumatoid arthritis is
thought to be secondary to microvasculitis and subsequent
microcirculatory disturbances. Myocardial disease in rheuma-
toid arthritis can occur in the absence of clinical symptoms or
abnormalities of the electrocardiogram (ECG).
173
5.8. Peripartum Cardiomyopathy
Peripartum cardiomyopathy is a disease of unknown cause
in which LV dysfunction occurs during the last trimester of
pregnancy or the early puerperium. It is reported in 1:1300 to
1:4000 live births.
174
Risk factors for peripartum cardiomy-
opathy include advanced maternal age, multiparity, African
descent, and long-term tocolysis. Although its etiology remains
unknown, most theories have focused on hemodynamic and
immunologic causes.
174
The prognosis of peripartum cardio-
myopathy is related to the recovery of ventricular function.
Significant improvement in myocardial function is seen in 30%
to 50% of patients in the first 6 months after presentation.
174

However, for those patients who do not recover to normal or
near-normal function, the prognosis is similar to other forms
of DCM.
175
Cardiomegaly that persists for >4 to 6 months after
diagnosis indicates a poor prognosis, with a 50% mortality rate
at 6 years. Subsequent pregnancy in women with a history of
peripartum cardiomyopathy may be associated with a further
decrease in LV function and can result in clinical deterioration,
including death. However, if ventricular function has normal-
ized in women with a history of peripartum cardiomyopathy,
the risk may be less.
174
There is an increased risk of venous
thromboembolism, and anticoagulation is recommended, espe-
cially if ventricular dysfunction is persistent.
5.9. Cardiomyopathy Caused By Iron Overload
Iron overload cardiomyopathy manifests itself as systolic or
diastolic dysfunction secondary to increased deposition of
iron in the heart and occurs with common genetic disorders
such as primary hemochromatosis or with lifetime transfusion
requirements as seen in beta-thalassemia major.
176
Hereditary
hemochromatosis, an autosomal recessive disorder, is the
most common hereditary disease of Northern Europeans, with
a prevalence of approximately 5 per 1000. The actuarial sur-
vival rates of persons who are homozygous for the mutation
of the hemochromatosis gene C282Y have been reported to be
95%, 93%, and 66%, at 5, 10, and 20 years, respectively.
177

Similarly, in patients with thalassemia major, cardiac failure
is one of the most frequent causes of death. Chelation therapy,
including newer forms of oral chelators, such as deferoxamine,
and phlebotomy, have dramatically improved the outcome of
hemochromatosis, and the roles of gene therapy, hepcidin, and
calcium channel blockers are being actively investigated.
178
5.10. Amyloidosis
Cardiac amyloidosis involves the deposition of insoluble
proteins as fibrils in the heart, resulting in HF. Primary or
AL amyloidosis (monoclonal kappa or lambda light chains),
secondary amyloidosis (protein A), familial TTR amyloidosis
(mutant transthyretin), dialysis-associated amyloidosis (beta-
2-microglobulin), or senile TTR amyloidosis (wild-type
transthyretin) can affect the heart, but cardiac involvement
is primarily encountered in AL and TTR amyloidosis.
179
The
disease can be rapidly progressive, and in patients with ven-
tricular septum thickness >15 mm, LVEF <40%, and symp-
toms of HF, median survival may be <6 months.
180
Cardiac
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e253
biomarkers (eg, B-type natriuretic peptide [BNP], cardiac
troponin) have been reported to predict response and progres-
sion of disease and survival.
181
Three percent to 4% of African
Americans carry an amyloidogenic allele of the human serum
protein transthyretin (TTR V122I), which appears to increase
risk for cardiac amyloid deposition after 65 years of age.
182
5.11. Cardiac Sarcoidosis
Cardiac sarcoidosis is an underdiagnosed disease that may
affect as many as 25% of patients with systemic sarcoidosis.
Although most commonly recognized in patients with other
manifestations of sarcoidosis, cardiac involvement may occur
in isolation and go undetected. Cardiac sarcoidosis may pres-
ent as asymptomatic LV dysfunction, HF, atrioventricular
block, atrial or ventricular arrhythmia, and SCD.
183
Although
untested in clinical trials, early use of high-dose steroid ther-
apy may halt or reverse cardiac damage.
184
Cardiac magnetic
resonance and cardiac positron emission tomographic scan-
ning can identify cardiac involvement with patchy areas of
myocardial inflammation and fibrosis. In the setting of ven-
tricular tachyarrhythmia, patients may require placement of
an implantable cardioverter-defibrillator (ICD) for primary
prevention of SCD.
185
5.12. Stress (Takotsubo) Cardiomyopathy
Stress cardiomyopathy is characterized by acute reversible
LV dysfunction in the absence of significant CAD, triggered
by acute emotional or physical stress.
23
This phenomenon is
identified by a distinctive pattern of “apical ballooning,” first
described in Japan as takotsubo, and often affects postmeno-
pausal women.
186
A majority of patients have a clinical presen-
tation similar to that of acute coronary syndrome (ACS) and
may have transiently elevated cardiac enzymes.
6. Initial and Serial Evaluation
of the HF Patient
6.1. Clinical Evaluation
6.1.1. History and Physical Examination:
Recommendations
Class I
1. A thorough history and physical examination should
be obtained/performed in patients presenting with
HF to identify cardiac and noncardiac disorders or
behaviors that might cause or accelerate the develop-
ment or progression of HF. (Level of Evidence: C)
2. In patients with idiopathic DCM, a 3-generational
family history should be obtained to aid in establishing
the diagnosis of familial DCM. (Level of Evidence: C)
3. Volume status and vital signs should be assessed at
each patient encounter. This includes serial assess-
ment of weight, as well as estimates of jugular venous
pressure and the presence of peripheral edema or
orthopnea.
187–190
(Level of Evidence: B)
Despite advances in imaging technology and increas-
ing availability of diagnostic laboratory testing, a careful
history and physical examination remain the cornerstones
in the assessment of patients with HF. The components of
a focused history and physical examination for the patient
with HF are listed in Table 6. The history provides clues
to the etiology of the cardiomyopathy, including the diag-
nosis of familial cardiomyopathy (defined as ≥2 relatives
with idiopathic DCM). Familial syndromes are now rec-
ognized to occur in 20% to 35% of patients with appar-
ent idiopathic DCM
118
; thus, a 3-generation family history
should be obtained. The history also provides information
about the severity of the disease and the patient’s prognosis
and identifies opportunities for therapeutic interventions.
The physical examination provides information about the
severity of illness and allows assessment of volume status
and adequacy of perfusion. In advanced HFrEF, orthopnea
and jugular venous pressure are useful findings to detect
elevated LV filling pressures.
187,189,190
See Online Data Supplements 5, 6, and 7 for additional
data on stress testing and clinical evaluation.
6.1.2. Risk Scoring: Recommendation
Class IIa
1. Validated multivariable risk scores can be useful to
estimate subsequent risk of mortality in ambula-
tory or hospitalized patients with HF.
199–207
(Level of
Evidence: B)
In the course of standard evaluation, clinicians should rou-
tinely assess the patient’s potential for adverse outcome,
because accurate risk stratification may help guide thera-
peutic decision making, including a more rapid transition to
advanced HF therapies. A number of methods objectively
assess risk, including biomarker testing (Section 6.3), as well
as a variety of multivariable clinical risk scores (Table 7);
these risk scores are for use in ambulatory
199,203,205,206,208
and
hospitalized patients.
200,202,204,205,209
Risk models specifically for
patients with HFpEF have also been described.
201
One well-validated risk score, the Seattle Heart Failure
Model, is available in an interactive application on the
Internet
210
and provides robust information about risk of mor-
tality in ambulatory patients with HF. For patients hospital-
ized with acutely decompensated HF, the model developed
by ADHERE (Acute Decompensated Heart Failure National
Registry) incorporates 3 routinely measured variables on
hospital admission (ie, systolic blood pressure, blood urea
nitrogen, and serum creatinine) and stratifies subjects into
categories with a 10-fold range of crude in-hospital mortal-
ity (from 2.1% to 21.9%).
200
Notably, clinical risk scores have
not performed as well in estimating risk of hospital readmis-
sion.
211
For this purpose, biomarkers such as natriuretic pep-
tides hold considerable promise
212,213
(Section 6.3).
See Online Data Supplement 8 for additional data on clini-
cal evaluation risk scoring.
6.2. Diagnostic Tests: Recommendations
Class I
1. Initial laboratory evaluation of patients present-
ing with HF should include complete blood count,
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e254 Circulation October 15, 2013
urinalysis, serum electrolytes (including calcium and
magnesium), blood urea nitrogen, serum creatinine,
glucose, fasting lipid profile, liver function tests, and
thyroid-stimulating hormone. (Level of Evidence: C)
2. Serial monitoring, when indicated, should include
serum electrolytes and renal function. (Level of
Evidence: C)
3. A 12-lead ECG should be performed initially on all
patients presenting with HF. (Level of Evidence: C)
Class IIa
1. Screening for hemochromatosis or HIV is reasonable
in selected patients who present with HF.
216
(Level of
Evidence: C)
2. Diagnostic tests for rheumatologic diseases, amy-
loidosis, or pheochromocytoma are reasonable in
patients presenting with HF in whom there is a clini-
cal suspicion of these diseases. (Level of Evidence: C)
Table 6. History and Physical Examination in HF
Comments
History
Potential clues suggesting etiology of HF A careful family history may identify an underlying familial cardiomyopathy in patients with
idiopathic DCM.
118
Other etiologies outlined in Section 5 should be considered as well.
Duration of illness A patient with recent-onset systolic HF may recover over time.
113
Severity and triggers of dyspnea and fatigue, presence of chest pain,
exercise capacity, physical activity, sexual activity
To determine NYHA class; identify potential symptoms of coronary ischemia.
Anorexia and early satiety, weight loss Gastrointestinal symptoms are common in patients with HF. Cardiac cachexia is
associated with adverse prognosis.
191
Weight gain Rapid weight gain suggests volume overload.
Palpitations, (pre)syncope, ICD shocks Palpitations may be indications of paroxysmal AF or ventricular tachycardia. ICD shocks
are associated with adverse prognosis.
192
Symptoms suggesting transient ischemic attack or thromboembolism Affects consideration of the need for anticoagulation.
Development of peripheral edema or ascites Suggests volume overload.
Disordered breathing at night, sleep problems Treatment for sleep apnea may improve cardiac function and decrease pulmonary
hypertension.
193
Recent or frequent prior hospitalizations for HF Associated with adverse prognosis.
194
History of discontinuation of medications for HF Determine whether lack of GDMT in patients with HFrEF reflects intolerance, an adverse
event, or perceived contraindication to use. Withdrawal of these medications has been
associated with adverse prognosis.
195,196
Medications that may exacerbate HF Removal of such medications may represent a therapeutic opportunity.
Diet Awareness and restriction of sodium and fluid intake should be assessed.
Adherence to medical regimen Access to medications; family support; access to follow-up; cultural sensitivity
Physical Examination
BMI and evidence of weight loss Obesity may be a contributing cause of HF; cachexia may correspond with poor prognosis.
Blood pressure (supine and upright) Assess for hypertension or hypotension. Width of pulse pressure may reflect adequacy of
cardiac output. Response of blood pressure to Valsalva maneuver may reflect LV filling
pressures.
197
Pulse Manual palpation will reveal strength and regularity of pulse rate.
Examination for orthostatic changes in blood pressure and heart rate Consistent with volume depletion or excess vasodilation from medications.
Jugular venous pressure at rest and following abdominal
compression (http://wn.com/jugular_venous_distension_example)
Most useful finding on physical examination to identify congestion.
187–190,198
Presence of extra heart sounds and murmurs S
3
is associated with adverse prognosis in HFrEF.
188
Murmurs may be suggestive of
valvular heart disease.
Size and location of point of maximal impulse Enlarged and displaced point of maximal impulse suggests ventricular enlargement.
Presence of right ventricular heave Suggests significant right ventricular dysfunction and/or pulmonary hypertension.
Pulmonary status: respiratory rate, rales, pleural effusion In advanced chronic HF, rales are often absent despite major pulmonary congestion.
Hepatomegaly and/or ascites Usually markers of volume overload.
Peripheral edema Many patients, particularly those who are young, may be not edematous despite
intravascular volume overload. In obese patients and elderly patients, edema may
reflect peripheral rather than cardiac causes.
Temperature of lower extremities Cool lower extremities may reflect inadequate cardiac output.
AF indicates atrial fibrillation; BMI, body mass index; DCM, dilated cardiomyopathy; GDMT, guideline-directed medical therapy; HF, heart failure; HFrEF, heart
failure with reduced ejection fraction; ICD, implantable cardioverter-defibrillator; LV, left ventricular; and NYHA, New York Heart Association.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e255
6.3. Biomarkers: Recommendations
A. Ambulatory/Outpatient
Class I
1. In ambulatory patients with dyspnea, measure-
ment of BNP or N-terminal pro-B-type natriuretic
peptide (NT-proBNP) is useful to support clinical
decision making regarding the diagnosis of HF,
especially in the setting of clinical uncertainty.
217–223

(Level of Evidence: A)
2. Measurement of BNP or NT-proBNP is useful for
establishing prognosis or disease severity in chronic
HF.
222,224–229
(Level of Evidence: A)
Class IIa
1. BNP- or NT-proBNP–guided HF therapy can be
useful to achieve optimal dosing of GDMT in select
clinically euvolemic patients followed in a well-
structured HF disease management program.
230–237

(Level of Evidence: B)
Class IIb
1. The usefulness of serial measurement of BNP or
NT-proBNP to reduce hospitalization or mortality in
patients with HF is not well established.
230–237
(Level
of Evidence: B)
2. Measurement of other clinically available tests
such as biomarkers of myocardial injury or fibro-
sis may be considered for additive risk stratifica-
tion in patients with chronic HF.
238–244
(Level of
Evidence: B)
B. Hospitalized/Acute
Class I
1. Measurement of BNP or NT-proBNP is useful to sup-
port clinical judgment for the diagnosis of acutely
decompensated HF, especially in the setting of uncer-
tainty for the diagnosis.
212,245–250
(Level of Evidence: A)
2. Measurement of BNP or NT-proBNP and/or cardiac
troponin is useful for establishing prognosis or dis-
ease severity in acutely decompensated HF.
248,251–258

(Level of Evidence: A)
Class IIb
1. The usefulness of BNP- or NT-proBNP–guided ther-
apy for acutely decompensated HF is not well estab-
lished.
259,260
(Level of Evidence: C)
2. Measurement of other clinically available tests such
as biomarkers of myocardial injury or fibrosis may be
considered for additive risk stratification in patients
with acutely decompensated HF.
248,253,256,257,261–267
(Level
of Evidence: A)
In addition to routine clinical laboratory tests, other bio-
markers are gaining greater attention for their utility in HF
management. These biomarkers may reflect various patho-
physiological aspects of HF, including myocardial wall
stress, hemodynamic abnormalities, inflammation, myocyte
injury, neurohormonal upregulation, and myocardial remod-
eling, as well as extracellular matrix turnover. Thus, these
biomarkers are potentially powerful adjuncts to current stan-
dards for the diagnosis, prognosis, and treatment of acute
and chronic HF.
Table 7. Selected Multivariable Risk Scores to Predict Outcome in HF
Risk Score Reference/Link
Chronic HF
All patients with chronic HF
Seattle Heart Failure Model 203/http://SeattleHeartFailureModel.org
Heart Failure Survival Score 199/http://handheld.softpedia.com/get/Health/Calculator/HFSS-Calc-37354.shtml
CHARM Risk Score 206
CORONA Risk Score 207
Specific to chronic HFpEF
I-PRESERVE Score 201
Acutely decompensated HF
ADHERE Classification and Regression Tree (CART) Model 200
American Heart Association Get With The Guidelines Score 205/http://www.heart.org/HEARTORG/HealthcareProfessional/GetWithTheGuidelinesHFStroke/
GetWithTheGuidelinesHeartFailureHomePage/Get-With-The-Guidelines-Heart-Failure-Home-%20
Page_UCM_306087_SubHomePage.jsp
EFFECT Risk Score 202/http://www.ccort.ca/Research/CHFRiskModel.aspx
ESCAPE Risk Model and Discharge Score 214
OPTIMIZE HF Risk-Prediction Nomogram 215
ADHERE indicates Acute Decompensated Heart Failure National Registry; CHARM, Candesartan in Heart failure-Assessment of Reduction in Mortality and morbidity;
CORONA, Controlled Rosuvastatin Multinational Trial in Heart Failure; EFFECT, Enhanced Feedback for Effective Cardiac Treatment; ESCAPE, Evaluation Study of
Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; I-PRESERVE,
Irbesartan in Heart Failure with Preserved Ejection Fraction Study; and OPTIMIZE, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with
Heart Failure.
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e256 Circulation October 15, 2013
6.3.1. Natriuretic Peptides: BNP or NT-proBNP
BNP or its amino-terminal cleavage equivalent (NT-proBNP)
is derived from a common 108-amino acid precursor peptide
(proBNP
108
) that is generated by cardiomyocytes in the con-
text of numerous triggers, most notably myocardial stretch.
Following several steps of processing, BNP and NT-proBNP
are released from the cardiomyocyte, along with variable
amounts of proBNP
108
, the latter of which is detected by all
assays that measure either “BNP” or “NT-proBNP.”
Assays for BNP and NT-proBNP have been increasingly
used to establish the presence and severity of HF. In general,
BNP and NT-proBNP values are reasonably correlated, and
either can be used in patient care settings as long as their
respective absolute values and cut points are not used inter-
changeably. BNP and NT-proBNP are useful to support clin-
ical judgment for the diagnosis or exclusion of HF, in the
setting of chronic ambulatory HF
217–223
or acute decompen-
sated HF
245–250
; the value of natriuretic peptide testing is par-
ticularly significant when the etiology of dyspnea is unclear.
Although lower values of BNP or NT-proBNP exclude
the presence of HF and higher values have reasonably high
positive predictive value to diagnose HF, clinicians should be
aware that elevated plasma levels for both natriuretic peptides
have been associated with a wide variety of cardiac and non-
cardiac causes (Table 8).
268–271
BNP and NT-proBNP levels improve with treatment of
chronic HF,
225,272–274
with lowering of levels over time in gen-
eral, correlating with improved clinical outcomes.
248,251,254,260

Thus, BNP or NT-proBNP “guided” therapy has been studied
against standard care without natriuretic peptide measure-
ment to determine whether guided therapy renders superior
achievement of GDMT in patients with HF. However, RCTs
have yielded inconsistent results.
The positive and negative natriuretic peptide–guided
therapy trials differ primarily in their study populations,
with successful trials enrolling younger patients and only
those with HFrEF. In addition, a lower natriuretic peptide
goal and/or a substantial reduction in natriuretic peptides
during treatment are consistently present in the positive
“guided” therapy trials.
275
Although most trials examining
the strategy of biomarker “guided” HF management were
small and underpowered, 2 comprehensive meta-analyses
concluded that BNP-guided therapy reduces all-cause mor-
tality in patients with chronic HF compared with usual clin-
ical care,
231,232
especially in patients <75 years of age. This
survival benefit may be attributed to increased achieve-
ment of GDMT. In some cases, BNP or NT-proBNP levels
may not be easily modifiable. If the BNP or NT-proBNP
value does not fall after aggressive HF care, risk for death
or hospitalization for HF is significant. On the other hand,
some patients with advanced HF have normal BNP or
NT-proBNP levels or have falsely low BNP levels because
of obesity and HFpEF. All of these patients should still
receive appropriate GDMT.
6.3.2. Biomarkers of Myocardial Injury: Cardiac Troponin
T or I
Abnormal concentrations of circulating cardiac troponin are
found in patients with HF, often without obvious myocardial
ischemia and frequently in those without underlying CAD.
This suggests ongoing myocyte injury or necrosis in these
patients.
238–241,276
In chronic HF, elaboration of cardiac tropo-
nins is associated with impaired hemodynamics,
238
progres-
sive LV dysfunction,
239
and increased mortality rates.
238–241,276

Similarly, in patients with acute decompensated HF, elevated
cardiac troponin levels are associated with worse clinical out-
comes and mortality
253,257,263
; decrease in troponin levels over
time with treatment is associated with a better prognosis than
persistent elevation in patients with chronic
239
or acute HF.
277

Given the tight association with ACS and troponin elevation
as well as the link between MI and the development of acute
HF,
278
the measurement of troponin I or T should be rou-
tine in patients presenting with acutely decompensated HF
syndromes.
6.3.3. Other Emerging Biomarkers
Besides natriuretic peptides or troponins, multiple other bio-
markers, including those reflecting inflammation, oxidative
stress, neurohormonal disarray, and myocardial and matrix
remodeling, have been widely examined for their prognostic
value in HF. Biomarkers of myocardial fibrosis, soluble ST2 and
galectin-3 are not only predictive of hospitalization and death in
patients with HF but also additive to natriuretic peptide levels in
their prognostic value. Markers of renal injury may also offer
additional prognostic value because renal function or injury may
be involved in the pathogenesis, progression, decompensation,
or complications in chronic or acute decompensated HF.
242–
244,264,265,279
Strategies that combine multiple biomarkers may
ultimately prove beneficial in guiding HF therapy in the future.
See Table 9 for a summary of recommendations from this
section.
6.4. Noninvasive Cardiac Imaging:
Recommendations
See Table 10 for a summary of recommendations from this
section.
Table 8. Selected Causes of Elevated Natriuretic Peptide
Concentrations
Cardiac
•    Heart failure, including RV syndromes
•    Acute coronary syndrome
•    Heart muscle disease, including LVH
•    Valvular heart disease
•    Pericardial disease
•    Atrial fibrillation
•    Myocarditis
•    Cardiac surgery
•    Cardioversion
Noncardiac
•    Advancing age
•    Anemia
•    Renal failure
•    Pulmonary: obstructive sleep apnea, severe pneumonia, pulmonary 
hypertension
•    Critical illness
•    Bacterial sepsis
•    Severe burns
•    Toxic-metabolic insults, including cancer chemotherapy and envenomation
LVH indicates left ventricular hypertrophy; and RV, right ventricular.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e257
Class I
1. Patients with suspected or new-onset HF, or those
presenting with acute decompensated HF, should
undergo a chest x-ray to assess heart size and pul-
monary congestion and to detect alternative car-
diac, pulmonary, and other diseases that may cause
or contribute to the patient’s symptoms. (Level of
Evidence: C)
2. A 2-dimensional echocardiogram with Doppler should
be performed during initial evaluation of patients pre-
senting with HF to assess ventricular function, size,
wall thickness, wall motion, and valve function. (Level
of Evidence: C)
3. Repeat measurement of EF and measurement of the
severity of structural remodeling are useful to pro-
vide information in patients with HF who have had a
significant change in clinical status; who have experi-
enced or recovered from a clinical event; or who have
received treatment, including GDMT, that might
have had a significant effect on cardiac function; or
who may be candidates for device therapy. (Level of
Evidence: C)
Class IIa
1. Noninvasive imaging to detect myocardial ischemia
and viability is reasonable in patients presenting with
de novo HF, who have known CAD and no angina,
unless the patient is not eligible for revascularization
of any kind. (Level of Evidence: C)
2. Viability assessment is reasonable in select situations
when planning revascularization in HF patients with
CAD.
281–285
(Level of Evidence: B)
3. Radionuclide ventriculography or magnetic resonance
imaging can be useful to assess LVEF and volume when
echocardiography is inadequate. (Level of Evidence: C)
4. Magnetic resonance imaging is reasonable when
assessing myocardial infiltrative processes or scar
burden.
286–288
(Level of Evidence: B)
Class III: No Benefit
1. Routine repeat measurement of LV function assess-
ment in the absence of clinical status change or treat-
ment interventions should not be performed.
289,290

(Level of Evidence: B)
Table 9. Recommendations for Biomarkers in HF
Biomarker, Application Setting COR LOE References
Natriuretic peptides
Diagnosis or exclusion of HF Ambulatory, Acute I A 212, 217–223, 245–250
Prognosis of HF Ambulatory, Acute I A 222, 224–229, 248, 251–258
Achieve GDMT Ambulatory IIa B 230–237
Guidance for acutely
decom pensated HF therapy
Acute IIb C 259, 260
Biomarkers of myocardial injury
Additive risk stratification Acute, Ambulatory I A 238–241, 248, 253, 256–267
Biomarkers of myocardial fibrosis
Additive risk stratification Ambulatory IIb B 242–244
Acute IIb A 248, 253, 256, 258–260, 262, 264–267
COR indicates Class of Recommendation; GDMT, guideline-directed medical therapy; HF, heart failure; and LOE, Level of Evidence.
Table 10. Recommendations for Noninvasive Cardiac Imaging
Recommendations COR LOE
Patients with suspected, acute, or new-onset HF should undergo a chest x-ray I C
A 2-dimensional echocardiogram with Doppler should be performed for initial evaluation of HF I C
Repeat measurement of EF is useful in patients with HF who have had a significant change in
clinical status or received treatment that might affect cardiac function or for consideration
of device therapy
I C
Noninvasive imaging to detect myocardial ischemia and viability is reasonable in HF and CAD IIa C
Viability assessment is reasonable before revascularization in HF patients with CAD IIa B
281–285
Radionuclide ventriculography or MRI can be useful to assess LVEF and volume IIa C
MRI is reasonable when assessing myocardial infiltration or scar IIa B
286–288
Routine repeat measurement of LV function assessment should not be performed III: No Benefit B
289,290
CAD indicates coronary artery disease; COR, Class of Recommendation; EF, ejection fraction; HF, heart failure; LOE, Level of Evidence;
LV, left ventricular; LVEF, left ventricular ejection fraction; and MRI, magnetic resonance imaging.
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e258 Circulation October 15, 2013
The chest x-ray is important for the evaluation of patients pre-
senting with signs and symptoms of HF because it assesses
cardiomegaly and pulmonary congestion and may reveal alter-
native causes, cardiopulmonary or otherwise, of the patient’s
symptoms. Apart from congestion, however, other findings on
chest x-ray are associated with HF only in the context of clini-
cal presentation. Cardiomegaly may be absent in HF. A chest
x-ray may also show other cardiac chamber enlargement,
increased pulmonary venous pressure, interstitial or alveolar
edema, valvular or pericardial calcification, or coexisting tho-
racic diseases. Considering its low sensitivity and specificity,
the chest x-ray should not be the sole determinant of the spe-
cific cause of HF. Moreover, a supine chest x-ray has limited
value in acute decompensated HF.
Although a complete history and physical examination are
important first steps, the most useful diagnostic test in the
evaluation of patients with or at risk for HF (eg, postacute MI)
is a comprehensive 2-dimensional echocardiogram; coupled
with Doppler flow studies, the transthoracic echocardiogram
can identify abnormalities of myocardium, heart valves, and
pericardium. Echocardiography can reveal subclinical HF and
predict risk of subsequent events.
291–295
Use of echocardio-
grams in patients with suspected HF improves disease identi-
fication and provision of appropriate medical care.
296
Echocardiographic evaluation should address whether LVEF
is reduced, LV structure is abnormal, and other structural
abnormalities are present that could account for the clinical
presentation. This information should be quantified, including
numerical estimates of EF measurement, ventricular dimen-
sions, wall thickness, calculations of ventricular volumes, and
evaluation of chamber geometry and regional wall motion.
Documentation of LVEF is an HF quality-of-care performance
measure.
297
Right ventricular size and function as well as atrial
size and dimensions should also be measured. All valves should
be evaluated for anatomic and flow abnormalities. Secondary
changes, particularly the severity of mitral and tricuspid valve
insufficiency, should be determined. Noninvasive hemody-
namic data constitute important additional information. Mitral
valve inflow pattern, pulmonary venous inflow pattern, and
mitral annular velocity provide data about LV filling and left
atrial pressure. The tricuspid valve regurgitant gradient, cou-
pled with measurement of inferior vena cava diameter and
its response during respiration, provides estimates of systolic
pulmonary artery pressure and central venous pressure. Many
of these abnormalities are prognostically important and can be
present without manifest HF.
Serial echocardiographic evaluations are useful because
evidence of cardiac reverse remodeling can provide important
information in patients who have had a change in clinical sta-
tus or have experienced or recovered from an event or treat-
ment that affects cardiac function. However, the routine repeat
assessment of ventricular function in the absence of chang-
ing clinical status or a change in treatment intervention is not
indicated.
The preference for echocardiography as an imaging
modality is due to its widespread availability and lack of
ionizing radiation; however, other imaging modalities
may be of use. Magnetic resonance imaging assesses LV
volume and EF measurements at least as accurately as
echocardiography. However, additional information about
myocardial perfusion, viability, and fibrosis from mag-
netic resonance imaging can help identify HF etiology and
assess prognosis.
298
Magnetic resonance imaging provides
high anatomical resolution of all aspects of the heart and
surrounding structure, leading to its recommended use in
known or suspected congenital heart diseases.
5
Cardiac
computed tomography can also provide accurate assess-
ment of cardiac structure and function, including the
coronary arteries.
299
An advantage of cardiac computed
tomography over echocardiography may be its ability to
characterize the myocardium, but studies have yet to dem-
onstrate the importance of this factor. Reports of cardiac
computed tomography in patients with suspected HF are
limited. Furthermore, both cardiac computed tomography
and magnetic resonance imaging lose accuracy with high
heart rates. Radionuclide ventriculography may also be
used for evaluation of cardiac function when other tests are
unavailable or inadequate. However, as a planar technique,
radionuclide ventriculography cannot directly assess val-
vular structure, function, or ventricular wall thickness; it
may be more useful for assessing LV volumes in patients
with significant baseline wall motion abnormalities or dis-
torted geometry. Ventriculography is highly reproducible.
300

Single photon emission computed tomography or positron
emission tomography scans are not primarily used to deter-
mine LV systolic global and regional function unless these
parameters are quantified from the resultant images dur-
ing myocardial perfusion and/or viability assessment.
301,302

Candidates for coronary revascularization who present with
a high suspicion for obstructive CAD should undergo coro-
nary angiography. Stress nuclear imaging or echocardiog-
raphy may be an acceptable option for assessing ischemia
in patients presenting with HF who have known CAD and
no angina unless they are ineligible for revascularization.
303

Although the results of the STICH (Surgical Treatment for
Ischemic Heart Failure) trial have cast doubt on the role of
myocardial viability assessment to determine the mode of
therapy,
304
the data are nevertheless predictive of a positive
outcome. When these data are taken into consideration with
multiple previous studies demonstrating the usefulness of
this approach,
281–285
it becomes reasonable to recommend
viability assessment when treating patients with HFrEF
who have known CAD.
14
See Online Data Supplement 9 for additional data on
imaging−echocardiography.
6.5. Invasive Evaluation: Recommendations
See Table 11 for a summary of recommendations from this
section.
Class I
1. Invasive hemodynamic monitoring with a pulmo-
nary artery catheter should be performed to guide
therapy in patients who have respiratory distress
or clinical evidence of impaired perfusion in whom
the adequacy or excess of intracardiac filling pres-
sures cannot be determined from clinical assessment.
(Level of Evidence: C)
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e259
Class IIa
1. Invasive hemodynamic monitoring can be useful for
carefully selected patients with acute HF who have
persistent symptoms despite empiric adjustment of
standard therapies and
a. whose fluid status, perfusion, or systemic or pul-
monary vascular resistance is uncertain;
b. whose systolic pressure remains low, or is associ-
ated with symptoms, despite initial therapy;
c. whose renal function is worsening with therapy;
d. who require parenteral vasoactive agents; or
e. who may need consideration for MCS or trans-
plantation. (Level of Evidence: C)
2. When ischemia may be contributing to HF, coronary
arteriography is reasonable for patients eligible for
revascularization. (Level of Evidence: C)
3. Endomyocardial biopsy can be useful in patients pre-
senting with HF when a specific diagnosis is suspected
that would influence therapy. (Level of Evidence: C)
Class III: No Benefit
1. Routine use of invasive hemodynamic monitoring is
not recommended in normotensive patients with acute
decompensated HF and congestion with symptom-
atic response to diuretics and vasodilators.
305
(Level of
Evidence: B)
Class III: Harm
1. Endomyocardial biopsy should not be performed in
the routine evaluation of patients with HF. (Level of
Evidence: C)
6.5.1. Right-Heart Catheterization
There has been no established role for routine or periodic
invasive hemodynamic measurements in the management of
HF. Most drugs used for the treatment of HF are prescribed
on the basis of their ability to improve symptoms or survival
rather than their effect on hemodynamic variables. The initial
and target doses of these drugs are generally selected on the
basis of controlled trial experience rather than changes pro-
duced in cardiac output or pulmonary capillary wedge pres-
sure. Hemodynamic monitoring is indicated in patients with
clinically indeterminate volume status and those refractory to
initial therapy, particularly if intracardiac filling pressures and
cardiac output are unclear. Patients with clinically significant
hypotension (systolic blood pressure typically <90 mm Hg
or symptomatic low systolic blood pressure) and/or worsen-
ing renal function during initial therapy might also benefit
from invasive hemodynamic measurements.
305,306
Patients
being considered for cardiac transplantation or placement of
an MCS device are also candidates for complete right-heart
catheterization, including an assessment of pulmonary vascu-
lar resistance, a necessary part of the initial transplantation
evaluation. Invasive hemodynamic monitoring should be per-
formed in patients with 1) presumed cardiogenic shock requir-
ing escalating pressor therapy and consideration of MCS; 2)
severe clinical decompensation in which therapy is limited by
uncertain contributions of elevated filling pressures, hypoper-
fusion, and vascular tone; 3) apparent dependence on intrave-
nous inotropic infusions after initial clinical improvement; or
4) persistent severe symptoms despite adjustment of recom-
mended therapies. On the other hand, routine use of invasive
hemodynamic monitoring is not recommended in normoten-
sive patients with acute decompensated HF who have a symp-
tomatic response to diuretics and vasodilators. This reinforces
the concept that right-heart catheterization is best reserved for
those situations where a specific clinical or therapeutic ques-
tion needs to be addressed.
6.5.2. Left-Heart Catheterization
Left-heart catheterization or coronary angiography is indi-
cated for patients with HF and angina and may be useful
for those patients without angina but with LV dysfunction.
Invasive coronary angiography should be used in accordance
with the ACCF/AHA coronary artery bypass graft (CABG)
and percutaneous coronary intervention guidelines
10,12
and
should only be performed in patients who are potentially eli-
gible for revascularization.
307–309
In patients with known CAD
and angina or with significant ischemia diagnosed by ECG or
noninvasive testing and impaired ventricular function, coro-
nary angiography is indicated. Among those without a prior
diagnosis, CAD should be considered as a potential etiology
of impaired LV function and should be excluded wherever
possible. Coronary angiography may be considered in these
circumstances to detect and localize large-vessel coronary
obstructions. In patients in whom CAD has been excluded as
Table 11. Recommendations for Invasive Evaluation
Recommendations COR LOE
Monitoring with a pulmonary artery catheter should be performed in patients with respiratory
distress or impaired systemic perfusion when clinical assessment is inadequate
I C
Invasive hemodynamic monitoring can be useful for carefully selected patients with acute
HF with persistent symptoms and/or when hemodynamics are uncertain
IIa C
When ischemia may be contributing to HF, coronary arteriography is reasonable IIa C
Endomyocardial biopsy can be useful in patients with HF when a specific diagnosis is
suspected that would influence therapy
IIa C
Routine use of invasive hemodynamic monitoring is not recommended in normotensive
patients with acute HF
III: No Benefit B
305
Endomyocardial biopsy should not be performed in the routine evaluation of HF III: Harm C
COR indicates Class of Recommendation; HF, heart failure; and LOE, Level of Evidence.
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e260 Circulation October 15, 2013
the cause of LV dysfunction, coronary angiography is gener-
ally not indicated unless a change in clinical status suggests
interim development of ischemic disease.
6.5.3. Endomyocardial Biopsy
Endomyocardial biopsy can be useful when seeking a spe-
cific diagnosis that would influence therapy, and biopsy
should thus be considered in patients with rapidly progressive
clinical HF or worsening ventricular dysfunction that persists
despite appropriate medical therapy. Endomyocardial biopsy
should also be considered in patients suspected of having
acute cardiac rejection status after heart transplantation or
having myocardial infiltrative processes. A specific example
is to determine chemotherapy for primary cardiac amyloido-
sis. Additional other indications for endomyocardial biopsy
include in patients with rapidly progressive and unexplained
cardiomyopathy, those in whom active myocarditis, espe-
cially giant cell myocarditis, is being considered.
310
Routine
endomyocardial biopsy is not recommended in all cases of
HF, given limited diagnostic yield and the risk of procedure-
related complications.
See Online Data Supplement 10 for additional data on
biopsy.
7. Treatment of Stages A to D
7.1. Stage A: Recommendations
Class I
1. Hypertension and lipid disorders should be con-
trolled in accordance with contemporary guidelines
to lower the risk of HF.
27,94,311–314
(Level of Evidence: A)
2. Other conditions that may lead to or contribute to
HF, such as obesity, diabetes mellitus, tobacco use,
and known cardiotoxic agents, should be controlled or
avoided. (Level of Evidence: C)
7.1.1. Recognition and Treatment of Elevated Blood
Pressure
The lifetime risk for development of hypertension is consid-
erable and represents a major public health issue.
97
Elevated
blood pressure is a major risk factor for the development of both
HFpEF and HFrEF,
91,92
a risk that extends across all age ranges.
Long-term treatment of both systolic and diastolic hypertension
has been shown to reduce the risk of incident HF by approxi-
mately 50%.
94,311–314
Treatment of hypertension is particularly
beneficial in older patients.
311
One trial of a diuretic-based pro-
gram demonstrated a number needed to treat of 52 to prevent
1 HF event in 2 years.
311
In another study, elderly patients with
a history or ECG evidence of prior MI had a >80% risk reduc-
tion for incident HF with aggressive blood pressure control.
94

Given the robust outcomes with blood pressure reduction, clini-
cians should lower both systolic and diastolic blood pressure in
accordance with published guidelines.
27
Choice of antihypertensive therapy should also follow
guidelines,
27
with specific options tailored to concomitant
medical problems, such as diabetes mellitus or CAD. Diuretic-
based antihypertensive therapy has repeatedly been shown to
prevent HF in a wide range of patients; ACE inhibitors, ARBs,
and beta blockers are also effective. Data are less clear for
calcium antagonists and alpha blockers in reducing the risk
for incident HF.
7.1.2. Treatment of Dyslipidemia and Vascular Risk
Patients with known atherosclerotic disease are likely to develop
HF. Clinicians should seek to control vascular risk factors in
such patients according to guidelines.
28
Aggressive treatment
of hyperlipidemia with statins reduces the likelihood of HF in
at-risk patients.
315,316
Long-term treatment with ACE inhibitors
in similar patients may also decrease the risk of HF.
314,317
7.1.3. Obesity and Diabetes Mellitus
Obesity and overweight have been repeatedly linked to an
increased risk for HF.
99,318,319
Presumably, the link between
obesity and risk for HF is explained by the clustering of risk
factors for heart disease in those with elevated BMI (ie, the
metabolic syndrome). Similarly, insulin resistance, with or
without diabetes mellitus, is also an important risk factor for
the development of HF.
92,320–323
Diabetes mellitus is an espe-
cially important risk factor for women and may, in fact, triple
the risk for developing HF.
91,324
Dysglycemia appears to be
directly linked to risk, with HbA1c concentrations power-
fully predicting incident HF. Those with HbA1c >10.5% had a
nearly 4-fold increase in the risk for HF compared with those
with a value of <6.5%.
322
Current consensus advocates that
clinicians should make every effort to control hyperglycemia,
although such control has not yet been shown to reduce the
subsequent risk of HF. Additionally, standard therapies for dia-
betes mellitus, such as use of ACE inhibitors or ARBs, can pre-
vent the development of other risk factors for HF, such as renal
dysfunction,
325,326
and may themselves directly lower the likeli-
hood of HF.
327–329
Although risk models for the development of
incident HF in patients with diabetes mellitus have been devel-
oped,
323
their prospective use to reduce risk has not been vali-
dated. Despite the lack of supportive, prospective, randomized
data, consensus exists that risk factor recognition and modifi-
cation are vital for the prevention of HF among at-risk patients
(eg, obese patients or patients with diabetes mellitus).
7.1.4. Recognition and Control of Other Conditions That
May Lead to HF
A substantial genetic risk exists in some patients for the devel-
opment of HF. As noted in Section 6.1, obtaining a 3-genera-
tion family history of HF is recommended. Adequate therapy of
AF is advisable, given a clear association between uncontrolled
heart rate and development of HF. Many therapeutic agents can
exert important cardiotoxic effects, with consequent risk for
HF, and clinicians should be aware of such risk. For example,
cardiotoxic chemotherapy regimens (particularly anthracycline
based) and trastuzumab may increase the risk for HF in cer-
tain patients
330–332
; it may be reasonable to evaluate those who
are receiving (or who have received) such agents for LV dys-
function. The use of advanced echocardiographic techniques
or biomarkers to identify increased HF risk in those receiving
chemotherapy may be useful but remain unvalidated as yet.
333
Tobacco use is strongly associated with risk for incident
HF,
92,320,334
and patients should be strongly advised about the
hazards of smoking, with attendant efforts at quitting. Cocaine
and amphetamines are anecdotally but strongly associated with
HF, and their avoidance is mandatory. Although it is recog-
nized that alcohol consumption is associated with subsequent
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e261
development of HF,
92,139,140
there is some uncertainty about the
amount of alcohol ingested and the likelihood of developing
HF, and there may be sex differences as well. Nevertheless,
the heavy use of alcohol has repeatedly been associated with
heightened risk for development of HF. Therefore, patients
should be counseled about their alcohol intake.
Although several epidemiological studies have revealed
an independent link between risk for incident HF and bio-
markers such as natriuretic peptides,
335,336
highly sensitive
troponin,
337
and measures of renal function such as creati-
nine, phosphorus, urinary albumin, or albumin-creatinine
ratio,
320,323,334,336,338–340
it remains unclear whether the risk
for HF reflected by any of these biomarkers is modifiable.
Although routine screening with BNP before echocardiog-
raphy may be a cost-effective strategy to identify high-risk
patients,
341
routine measurement of biomarkers in stage A
patients is not yet justified.
See Online Data Supplement 11 for additional data on
stage A HF.
7.2. Stage B: Recommendations
See Table 12 for a summary of recommendations from this
section.
Class I
1. In all patients with a recent or remote history of MI
or ACS and reduced EF, ACE inhibitors should be
used to prevent symptomatic HF and reduce mor-
tality.
342–344
In patients intolerant of ACE inhibitors,
ARBs are appropriate unless contraindicated.
314,345

(Level of Evidence: A)
2. In all patients with a recent or remote history of MI
or ACS and reduced EF, evidence-based beta block-
ers should be used to reduce mortality.
346–348
(Level of
Evidence: B)
3. In all patients with a recent or remote history of MI
or ACS, statins should be used to prevent symptom-
atic HF and cardiovascular events.
104,349–354
(Level of
Evidence: A)
4. In patients with structural cardiac abnormalities,
including LV hypertrophy, in the absence of a history
of MI or ACS, blood pressure should be controlled
in accordance with clinical practice guidelines for
hypertension to prevent symptomatic HF.
27,94,311–313

(Level of Evidence: A)
5. ACE inhibitors should be used in all patients with a
reduced EF to prevent symptomatic HF, even if they
do not have a history of MI.
65,344
(Level of Evidence: A)
6. Beta blockers should be used in all patients with a
reduced EF to prevent symptomatic HF, even if they
do not have a history of MI. (Level of Evidence: C)
Class IIa
1. To prevent sudden death, placement of an ICD is rea-
sonable in patients with asymptomatic ischemic car-
diomyopathy who are at least 40 days post-MI, have
an LVEF of 30% or less, are on appropriate medical
therapy, and have reasonable expectation of survival
with a good functional status for more than 1 year.
355

(Level of Evidence: B)
Class III: Harm
1. Nondihydropyridine calcium channel blockers with
negative inotropic effects may be harmful in asymp-
tomatic patients with low LVEF and no symptoms of
HF after MI. (Level of Evidence: C)
Patients with reduced LVEF may not have HF symptoms and
are most often identified during an evaluation for another disor-
der (eg, abnormal heart sounds, abnormal ECG, abnormal chest
x-ray, hypertension or hypotension, an arrhythmia, acute MI, or
pulmonary or systemic thromboembolic event). However, the
cost-effectiveness of routine periodic population screening for
asymptomatic reduced LVEF is not recommended at this time.
Echocardiographic evaluation should be performed in selected
patients who are at high risk of reduced LVEF (eg, those with
a strong family history of cardiomyopathy, long-standing
Table 12. Recommendations for Treatment of Stage B HF
Recommendations COR LOE References
In patients with a history of MI and reduced EF, ACE inhibitors or ARBs
should be used to prevent HF
I A 314, 342–345
In patients with MI and reduced EF, evidence-based beta blockers
should be used to prevent HF
I B 346–348
In patients with MI, statins should be used to prevent HF I A 104, 349–354
Blood pressure should be controlled to prevent symptomatic HF I A 27, 94,
311–313
ACE inhibitors should be used in all patients with a reduced EF to prevent HF I A 65, 344
Beta blockers should be used in all patients with a reduced EF to prevent HF I C N/A
An ICD is reasonable in patients with asymptomatic ischemic cardiomyopathy
who are at least 40 d post-MI, have an LVEF ≤30%, and on GDMT
IIa B 355
Nondihydropyridine calcium channel blockers may be harmful in patients with low LVEF III: Harm C N/A
ACE indicates angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; COR, Class of Recommendation; EF, ejection fraction; GDMT, guideline-
directed medical therapy; HF, heart failure; ICD, implantable cardioverter-defibrillator; LOE, Level of Evidence; LVEF, left ventricular ejection fraction; MI, myocardial
infarction; and N/A, not available.
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e262 Circulation October 15, 2013
hypertension, previous MI, or those receiving cardiotoxic ther-
apies). In addition, it should be acknowledged that many adults
may have asymptomatic valvular abnormalities or congenital
heart lesions that if unrecognized could lead to the develop-
ment of clinical HF. Although these asymptomatic patients are
in stage B as well, the management of valvular and congenital
heart disease is beyond the scope of this guideline.
7.2.1. Management Strategies for Stage B
In general, all recommendations for patients with stage A HF also
apply to those with stage B HF, particularly with respect to con-
trol of blood pressure in the patient with LV hypertrophy
27,94,311,312

and the optimization of lipids with statins.
349,356
CAD is a major
risk factor for the development of HF and a key target for preven-
tion of HF. The 5-year risk of developing HF after acute MI is 7%
and 12% for men and women, respectively; for men and women
between the ages of 40 and 69 and those >70 years of age, the risk
is 22% and 25%, respectively.
51
Current evidence supports the use
of ACE inhibitors and (to a lower level of evidence) beta-blocker
therapy to impede maladaptive LV remodeling in patients with
stage B HF and low LVEF to improve mortality and morbidity.
344

At 3-year follow-up, those patients treated with ACE inhibitors
demonstrated combined endpoints of reduced hospitalization or
death, a benefit that extended up to a 12-year follow-up.
65
ARBs
are reasonable alternatives to ACE inhibitors. In 1 study, losartan
reduced adverse outcomes in a population with hypertension,
357

and in another study of patients post-MI with low LVEF, valsar-
tan was equivalent to captopril.
345
Data with beta blockers are
less convincing in a population with known CAD, although in 1
trial
346
carvedilol therapy in patients with stage B and low LVEF
was associated with a 31% relative risk reduction in adverse long-
term outcomes. In patients with previously established structural
heart disease, the administration of agents known to have nega-
tive inotropic properties such as nondihydropyridine calcium
channel blockers and certain antiarrhythmics should be avoided.
Elevations in both systolic and diastolic blood pressure are
major risk factors for developing LV hypertrophy, another
form of stage B.
91,92
Although the magnitude of benefit varies
with the trial selection criteria, target blood pressure reduc-
tion, and HF criteria, effective hypertension treatment invari-
ably reduces HF events. Consequently, long-term treatment
of both systolic and diastolic hypertension reduces the risk
of moving from stage A or B to stage C HF.
93,94,311,329
Several
large controlled studies have uniformly demonstrated that
optimal blood pressure control decreases the risk of new HF
by approximately 50%.
96
It is imperative that strategies to con-
trol hypertension be part of any effort to prevent HF.
Clinicians should lower both systolic and diastolic blood pres-
sure in accordance with published guidelines.
27
Target levels of
blood pressure lowering depend on major cardiovascular risk
factors, (eg, CAD, diabetes mellitus, or renal disease).
358
Thus,
when an antihypertensive regimen is devised, optimal control of
blood pressure should remain the primary goal, with the choice
of drugs determined by the concomitant medical problems.
Diuretic-based antihypertensive therapy has been shown to
prevent HF in a wide range of target populations.
359,360
In refrac-
tory hypertensive patients, spironolactone (25 mg) should be
considered as an additional agent.
27
Eplerenone, in synergy with
enalapril, has also demonstrated reduction in LV mass.
361
ACE inhibitors and beta blockers are also effective in the pre-
vention of HF.
27
Nevertheless, neither ACE inhibitors nor beta
blockers as single therapies are superior to other antihyperten-
sive drug classes, including calcium channel blockers, in the
reduction of all cardiovascular outcomes. However, in patients
with type 2 diabetes mellitus, ACE inhibitors and ARBs signifi-
cantly reduced the incidence of HF in patients.
327–329
In contrast,
calcium channel blockers and alpha blockers were less effective
in preventing the HF syndrome, particularly in HFrEF.
359
The Framingham studies have shown a 60% increased risk of
death in patients with asymptomatic low LVEF compared with
those with normal LVEF; almost half of these patients remained
free of HF before their death.
62–65
MADIT-II (Multicenter
Automatic Defibrillator Implantation Trial II)
362
demonstrated
a 31% relative risk reduction in all-cause mortality in patients
with post-MI with LVEF ≤30% receiving a prophylactic ICD
compared with standard of care.
355
These findings provided
justification for broad adoption of ICDs for primary prevention
of SCD in the post-MI setting with reduced LVEF, even in the
absence of HF symptoms, that is, patients in stage B HF.
Several other ACCF/AHA guidelines addressing the appro-
priate management of patients with stage B—those with car-
diac structural abnormalities but no symptoms of HF—are
listed in Table 13.
See Online Data Supplement 12 for additional data on
stage B HF.
7.3. Stage C
See Online Data Supplement 13 for additional data on stage C HF.
7.3.1. Nonpharmacological Interventions
7.3.1.1. Education: Recommendation
Class I
1. Patients with HF should receive specific education to
facilitate HF self-care.
363–368
(Level of Evidence: B)
The self-care regimen for patients with HF is complex and
multifaceted.
363
Patients need to understand how to monitor
their symptoms and weight fluctuations, restrict their sodium
Table 13. Other ACCF/AHA Guidelines Addressing Patients
With Stage B HF
Consideration Reference
Patients with an acute MI who have not developed
HF symptoms treated according to GDMT
2013 UA/NSTEMI Guideline
16
2013 STEMI Guideline
15
Coronary revascularization for patients without
symptoms of HF in accordance with GDMT
2011 PCI Guideline
12
2011 CABG Guideline
10

2012 SIHD Guideline
14
Valve replacement or repair for patients with
hemodynamically significant valvular stenosis
or regurgitation and no symptoms of HF in
accordance with GDMT
2008 Focused Update
incorporated into the
2006 VHD Guideline
17
ACCF indicates American College of Cardiology Foundation; AHA, American
Heart Association; CABG, coronary artery bypass graft; GDMT, guideline-
directed medical therapy; HF, heart failure; MI, myocardial infarction;
PCI, percutaneous coronary intervention; SIHD, stable ischemic heart disease;
STEMI, ST-elevation myocardial infarction; UA/NSTEMI, unstable angina/non–
ST-elevation myocardial infarction; and VHD, valvular heart disease.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e263
intake, take their medications as prescribed, and stay physi-
cally active. Education regarding these recommendations is
necessary, albeit not always sufficient, to significantly improve
outcomes. After discharge, many patients with HF need dis-
ease management programs, which are reviewed in Section 11.
A systematic review of 35 educational intervention studies
for patients with HF demonstrated that education improved
knowledge, self-monitoring, medication adherence, time to
hospitalization, and days in the hospital.
363
Patients who receive
in-hospital education have higher knowledge scores at discharge
and 1 year later when compared with those who did not receive
in-hospital education.
364
Data have called into question the sur-
vival benefit of discharge education.
369,370
However, prior data
have suggested that discharge education may result in fewer
days of hospitalization, lower costs, and lower mortality rates
within a 6-month follow-up.
365
Patients educated in all 6 catego-
ries of the HF core measures from The Joint Commission were
significantly less likely to be readmitted for any cause, includ-
ing HF.
366
Even a single home-based educational intervention
for patients and families has been shown to decrease emergency
visits and unplanned hospitalizations in adults with HF.
367
See Online Data Supplement 14 for additional data on
patient nonadherence.
7.3.1.2. Social Support
Social support is thought to buffer stress and promote treatment
adherence and a healthy lifestyle.
371
Most studies examining the
relationship between social support and hospitalization in adults
with HF have found that a lack of social support is associated
with higher hospitalization rates
372,373
and mortality risk.
374,375
7.3.1.3. Sodium Restriction: Recommendation
Class IIa
1. Sodium restriction is reasonable for patients with
symptomatic HF to reduce congestive symptoms.
(Level of Evidence: C)
Dietary sodium restriction is commonly recommended to
patients with HF and is endorsed by many guidelines.
18,376,377
The
data on which this recommendation is drawn upon, however, are
modest, and variances in protocols, fluid intake, measurement
of sodium intake and compliance, and other clinical and thera-
peutic characteristics among these studies make it challenging
to compare data and draw definitive conclusions. Observational
data suggest an association between dietary sodium intake with
fluid retention and risk for hospitalization.
378,379
Other studies,
however, have signaled a worsening neurohormonal profile with
sodium restriction in HF.
380–390
Sodium homeostasis is altered in
patients with HF as opposed to healthy individuals, which may
partially explain these trends. In most of these studies, patients
were not receiving GDMT; no study to date has evaluated the
effects of sodium restriction on neurohormonal activation
and outcomes in optimally treated patients with HF. With the
exception of 1 observational study that evaluated patients with
HFpEF,
383
all other studies have focused on patients with HFrEF.
These data are mostly from white patients; when the differences
in cardiovascular and renal pathophysiology among races are
considered, the effects of sodium restriction in nonwhite patients
with HF cannot be ascertained from these studies. To make this
more complicated, the 3 RCTs that assessed outcomes with
sodium restriction have all shown that lower sodium intake is
associated with worse outcomes in patients with HFrEF.
384–386
These limitations make it difficult to give precise recommenda-
tions about daily sodium intake and whether it should vary with
respect to the type of HF (eg, HFrEF versus HFpEF), disease
severity (eg, NYHA class), HF-related comorbidities (eg, renal
dysfunction), or other characteristics (eg, age or race). Because
of the association between sodium intake and hypertension, LV
hypertrophy, and cardiovascular disease, the AHA recommenda-
tion for restriction of sodium to 1500 mg/d appears to be appropri-
ate for most patients with stage A and B HF.
387–392
However, for
patients with stage C and D HF, currently there are insufficient data
to endorse any specific level of sodium intake. Because sodium
intake is typically high (>4 g/d) in the general population, clini-
cians should consider some degree (eg, <3 g/d) of sodium restric-
tion in patients with stage C and D HF for symptom improvement.
7.3.1.4. Treatment of Sleep Disorders: Recommendation
Class IIa
1. Continuous positive airway pressure can be benefi-
cial to increase LVEF and improve functional status
in patients with HF and sleep apnea.
393–396
(Level of
Evidence: B)
Sleep disorders are common in patients with HF. A study of
adults with chronic HF treated with evidence-based therapies
found that 61% had either central or obstructive sleep apnea.
397

Despite having less sleep time and sleep efficiency compared
with those without HF, patients with HF, including those with
documented sleep disorders, rarely report excessive daytime
sleepiness.
398
Thus, a high degree of suspicion for sleep disorders
should be maintained for these patients. The decision to refer a
patient to a sleep study should be based on clinical judgment.
The primary treatment for obstructive sleep apnea is noc-
turnal continuous positive airway pressure. In a major trial,
continuous positive airway pressure for obstructive sleep
apnea was effective in decreasing the apnea–hypopnea index,
improving nocturnal oxygenation, increasing LVEF, lowering
norepinephrine levels, and increasing the distance walked in
6 minutes; these benefits were sustained for up to 2 years.
394

Smaller studies suggest that continuous positive airway pres-
sure can improve cardiac function, sympathetic activity, and
HRQOL in patients with HF and obstructive sleep apnea.
395,396
See Online Data Supplement 15 for additional data on the
treatment of sleep disorders.
7.3.1.5. Weight Loss
Obesity is defined as a BMI ≥30 kg/m
2
. Patients with HF who
have a BMI between 30 and 35 kg/m
2
have lower mortality and
hospitalization rates than those with a BMI in the normal range.
99

Weight loss may reflect cachexia caused by the higher total
energy expenditure associated with HF compared with that of
healthy sedentary subjects.
399
The diagnosis of cardiac cachexia
independently predicts a worse prognosis.
191
At the other end
of the continuum, morbidly obese patients may have worse
outcomes compared with patients within the normal weight
range and those who are obese. A U-shaped distribution curve
has been suggested in which mortality is greatest in cachectic
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e264 Circulation October 15, 2013
patients; lower in normal, overweight, and mildly obese patients;
and higher again in more severely obese patients.
400
Although there are anecdotal reports about symptomatic
improvement after weight reduction in obese patients with
HF,
401,402
large-scale clinical trials on the role of weight loss in
patients with HF with obesity have not been performed. Because
of reports of development of cardiomyopathy, sibutramine is
contraindicated in HF.
403
7.3.1.6. Activity, Exercise Prescription, and Cardiac
Rehabilitation: Recommendations
Class I
1. Exercise training (or regular physical activity) is rec-
ommended as safe and effective for patients with HF
who are able to participate to improve functional sta-
tus.
404–407
(Level of Evidence: A)
Class IIa
1. Cardiac rehabilitation can be useful in clinically sta-
ble patients with HF to improve functional capacity,
exercise duration, HRQOL, and mortality.
404,406–411

(Level of Evidence: B)
Exercise training in patients with HF is safe and has numer-
ous benefits. Meta-analyses show that cardiac rehabilitation
reduces mortality; improves functional capacity, exercise
duration, and HRQOL; and reduces hospitalizations.
409
Other
benefits include improved endothelial function, blunted cat-
echolamine spillover, increased peripheral oxygen extraction,
and reduced hospital admission.
405,407,410,411
Many RCTs of exercise training in HF have been con-
ducted, but the statistical power of most was low.
408
A major
trial of exercise and HF randomly assigned 2331 patients
(mean EF, 25%; ischemic etiology, 52%) to either exercise
training for 3 months or usual care.
406
In unadjusted analyses,
there was no significant difference at the end of the study in
either total mortality or hospitalizations. When adjusted for
coronary heart disease risk factors, there was an 11% reduc-
tion in all-cause mortality, cardiovascular disease mortality, or
hospitalizations (P<0.03) in the exercise training group.
406
A
meta-analysis demonstrated improved peak oxygen consump-
tion and decreased all-cause mortality with exercise.
409
See Online Data Supplement 16 for additional data on car-
diac exercise.
7.3.2. Pharmacological Treatment for Stage C HFrEF:
Recommendations
Class I
1. Measures listed as Class I recommendations for
patients in stages A and B are recommended where
appropriate for patients in stage C. (Levels of
Evidence: A, B, and C as appropriate)
2. GDMT as depicted in Figure 1 should be the mainstay
of pharmacological therapy for HFrEF.
108,343,345,346,412–426

(Level of Evidence: A)
HFrEF Stage C
NYHA Class I – IV
Treatment:
ForNYHA class II-IVpatients.
Provided estimatedcreatinine
>30mL/minand K+ <5.0 mEq/dL
Forpersistently symptomatic
African Americans,
NYHA classIII-IV
ClassI,LOE A
ACEI or ARB AND
Beta Blocker
ClassI,LOE C
LoopDiuretics
ClassI,LOE A
Hydral-Nitrates
Class I, LOEA
Aldosterone
Antagonist
AddAdd Add
For all volume overload,
NYHA class II-IV patients
Figure 1. Stage C HFrEF: evidence-based, guideline-directed medical therapy. ACEI indicates angiotensin-converting enzyme inhibitor;
ARB, angiotensin-receptor blocker; HFrEF, heart failure with reduced ejection fraction; Hydral-Nitrates, hydralazine and isosorbide dini-
trate; LOE, Level of Evidence; and NYHA, New York Heart Association.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e265
7.3.2.1. Diuretics: Recommendation
Class I
1. Diuretics are recommended in patients with HFrEF
who have evidence of fluid retention, unless contrain-
dicated, to improve symptoms. (Level of Evidence: C)
Diuretics inhibit the reabsorption of sodium or chloride at spe-
cific sites in the renal tubules. Bumetanide, furosemide, and
torsemide act at the loop of Henle (thus, the term loop diuretics),
whereas thiazides, metolazone, and potassium-sparing agents
(eg, spironolactone) act in the distal portion of the tubule.
427,428

Loop diuretics have emerged as the preferred diuretic agents for
use in most patients with HF. Thiazide diuretics may be consid-
ered in hypertensive patients with HF and mild fluid retention
because they confer more persistent antihypertensive effects.
Controlled trials have demonstrated the ability of diuretic
drugs to increase urinary sodium excretion and decrease phys-
ical signs of fluid retention in patients with HF.
429,430
In inter-
mediate-term studies, diuretics have been shown to improve
symptoms and exercise tolerance in patients with HF
431–433
;
however, diuretic effects on morbidity and mortality are not
known. Diuretics are the only drugs used for the treatment
of HF that can adequately control the fluid retention of HF.
Appropriate use of diuretics is a key element in the success
of other drugs used for the treatment of HF. The use of inap-
propriately low doses of diuretics will result in fluid retention.
Conversely, the use of inappropriately high doses of diuretics
will lead to volume contraction, which can increase the risk of
hypotension and renal insufficiency.
7.3.2.1.1. Diuretics: Selection of Patients. Diuretics should
be prescribed to all patients who have evidence of, and to
most patients with a prior history of, fluid retention. Diuret-
ics should generally be combined with an ACE inhibitor, beta
blocker, and aldosterone antagonist. Few patients with HF will
be able to maintain target weight without the use of diuretics.
7.3.2.1.2. Diuretics: Initiation and Maintenance. The most
commonly used loop diuretic for the treatment of HF is furose-
mide, but some patients respond more favorably to other agents
in this category (eg, bumetanide, torsemide) because of their
increased oral bioavailability.
434,435
Table 14 lists oral diuretics
recommended for use in the treatment of chronic HF. In outpa-
tients with HF, diuretic therapy is commonly initiated with low
doses, and the dose is increased until urine output increases
and weight decreases, generally by 0.5 to 1.0 kg daily. Further
increases in the dose or frequency (ie, twice-daily dosing) of
diuretic administration may be required to maintain an active
diuresis and sustain weight loss. The ultimate goal of diuretic
treatment is to eliminate clinical evidence of fluid retention.
Diuretics are generally combined with moderate dietary
sodium restriction. Once fluid retention has resolved, treatment
with the diuretic should be maintained in some patients to pre-
vent the recurrence of volume overload. Patients are commonly
prescribed a fixed dose of diuretic, but the dose of these drugs
frequently may need adjustment. In many cases, this adjust-
ment can be accomplished by having patients record their
weight each day and adjusting the diuretic dosage if weight
increases or decreases beyond a specified range. Patients may
become unresponsive to high doses of diuretic drugs if they
consume large amounts of dietary sodium, are taking agents
that can block the effects of diuretics (eg, nonsteroidal anti-
inflammatory drugs [NSAIDs], including cyclooxygenase-2
inhibitors)
436–438
or have a significant impairment of renal func-
tion or perfusion.
434
Diuretic resistance can generally be over-
come by the intravenous administration of diuretics (including
the use of continuous infusions)
439
or combination of different
diuretic classes (eg, metolazone with a loop diuretic).
440–443
7.3.2.1.3. Diuretics: Risks of Treatment. The principal adverse
effects of diuretics include electrolyte and fluid depletion, as well
as hypotension and azotemia. Diuretics can cause the depletion
of potassium and magnesium, which can predispose patients to
serious cardiac arrhythmias.
444
The risk of electrolyte depletion
is markedly enhanced when 2 diuretics are used in combination.
See Online Data Supplement 17 for additional data on diuretics.
7.3.2.2. ACE Inhibitors: Recommendation
Class I
1. ACE inhibitors are recommended in patients with
HFrEF and current or prior symptoms, unless
Table 14. Oral Diuretics Recommended for Use in the
Treatment of Chronic HF
Drug Initial Daily Dose(s)
Maximum
Total
Daily Dose
Duration
of Action
Loop diuretics
Bumetanide 0.5 to 1.0 mg once
or twice
10 mg 4 to 6 h
Furosemide 20 to 40 mg once or
twice
600 mg 6 to 8 h
Torsemide 10 to 20 mg once 200 mg 12 to 16 h
Thiazide diuretics
Chlorothiazide 250 to 500 mg once
or twice
1000 mg 6 to 12 h
Chlorthalidone 12.5 to 25.0 mg once 100 mg 24 to 72 h
Hydrochlorothiazide 25 mg once or twice 200 mg 6 to 12 h
Indapamide 2.5 mg once 5 mg 36 h
Metolazone 2.5 mg once 20 mg 12 to 24 h
Potassium-sparing diuretics*
Amiloride 5 mg once 20 mg 24 h
Spironolactone 12.5 to 25.0 mg once 50 mg† 1 to 3 h
Triamterene 50 to 75 mg twice 200 mg 7 to 9 h
Sequential nephron blockade
Metolazone‡ 2.5 to 10.0 mg once
plus loop diuretic
N/A N/A
Hydrochlorothiazide 25 to 100 mg once
or twice plus loop
diuretic
N/A N/A
Chlorothiazide (IV) 500 to 1000 mg once
plus loop diuretic
N/A N/A
*Eplerenone, although also a diuretic, is primarily used in chronic HF.
†Higher doses may occasionally be used with close monitoring.
‡See Section 8.4.
HF indicates heart failure; IV, intravenous; and N/A, not applicable.
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e266 Circulation October 15, 2013
contraindicated, to reduce morbidity and mortal-
ity.
343,412–414
(Level of Evidence: A)
7.3.2.2.1. ACE Inhibitors: Selection of Patients. ACE inhibi-
tors can reduce the risk of death and reduce hospitalization in
HFrEF. The benefits of ACE inhibition were seen in patients
with mild, moderate, or severe symptoms of HF and in patients
with or without CAD. ACE inhibitors should be prescribed
to all patients with HFrEF. Unless there is a contraindication,
ACE inhibitors are used together with a beta blocker. Patients
should not be given an ACE inhibitor if they have experienced
life-threatening adverse reactions (ie, angioedema) during pre-
vious medication exposure or if they are pregnant or plan to
become pregnant. Clinicians should prescribe an ACE inhibitor
with caution if the patient has very low systemic blood pres-
sures (systolic blood pressure <80 mm Hg), markedly increased
serum levels of creatinine (>3 mg/dL), bilateral renal artery ste-
nosis, or elevated levels of serum potassium (>5.0 mEq/L).
7.3.2.2.2. ACE Inhibitors: Initiation and Maintenance. The
available data suggest that there are no differences among
available ACE inhibitors in their effects on symptoms or sur-
vival.
414
Treatment with an ACE inhibitor should be initiated
at low doses (Table 15), followed by gradual dose increments
if lower doses have been well tolerated. Renal function and
serum potassium should be assessed within 1 to 2 weeks of
initiation of therapy and periodically thereafter, especially
in patients with preexisting hypotension, hyponatremia, dia-
betes mellitus, azotemia, or in those taking potassium sup-
plements. In controlled clinical trials that were designed to
evaluate survival, the dose of the ACE inhibitor was not deter-
mined by a patient’s therapeutic response but was increased
until the predetermined target dose was reached.
343,413,414
Cli-
nicians should attempt to use doses that have been shown to
reduce the risk of cardiovascular events in clinical trials. If
these target doses of an ACE inhibitor cannot be used or are
poorly tolerated, intermediate doses should be used with the
expectation that there are likely to be only small differences
in efficacy between low and high doses. Abrupt withdrawal of
treatment with an ACE inhibitor can lead to clinical deteriora-
tion and should be avoided.
Table 15. Drugs Commonly Used for Stage C HFrEF
Drug Initial Daily Dose(s) Maximum Dose(s)
Mean Doses Achieved in
Clinical Trials
ACE inhibitors
Captopril 6.25 mg 3 times 50 mg 3 times 122.7 mg/d
422
Enalapril 2.5 mg twice 10 to 20 mg twice 16.6 mg/d
413
Fosinopril 5 to 10 mg once 40 mg once N/A
Lisinopril 2.5 to 5 mg once 20 to 40 mg once 32.5 to 35.0 mg/d
445
Perindopril 2 mg once 8 to 16 mg once N/A
Quinapril 5 mg twice 20 mg twice N/A
Ramipril 1.25 to 2.5 mg once 10 mg once N/A
Trandolapril 1 mg once 4 mg once N/A
ARBs
Candesartan 4 to 8 mg once 32 mg once 24 mg/d
420
Losartan 25 to 50 mg once 50 to 150 mg once 129 mg/d
421
Valsartan 20 to 40 mg twice 160 mg twice 254 mg/d
108
Aldosterone antagonists
Spironolactone 12.5 to 25.0 mg once 25 mg once or twice 26 mg/d
425
Eplerenone 25 mg once 50 mg once 42.6 mg/d
446
Beta blockers
Bisoprolol 1.25 mg once 10 mg once 8.6 mg/d
117
Carvedilol 3.125 mg twice 50 mg twice 37 mg/d
447
Carvedilol CR 10 mg once 80 mg once N/A
Metoprolol succinate extended release
(metoprolol CR/XL)
12.5 to 25 mg once 200 mg once 159 mg/d
448
Hydralazine and isosorbide dinitrate
Fixed-dose combination
424
37.5 mg hydralazine/20 mg
isosorbide dinitrate
3 times daily
75 mg hydralazine/40 mg isosorbide
dinitrate 3 times daily
~175 mg hydralazine/90 mg
isosorbide dinitrate daily
Hydralazine and isosorbide dinitrate
449
Hydralazine: 25 to 50 mg, 3
or 4 times daily and
isosorbide dinitrate: 20 to 30 mg
3 or 4 times daily
Hydralazine: 300 mg daily in divided
doses and isosorbide dinitrate: 120 mg
daily in divided doses
N/A
ACE indicates angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; CR, controlled release; CR/XL, controlled release/extended release; HFrEF, heart
failure with reduced ejection fraction; and N/A, not applicable.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e267
7.3.2.2.3. ACE Inhibitors: Risks of Treatment. The majority of
the adverse reactions of ACE inhibitors can be attributed to the
2 principal pharmacological actions of these drugs: those related
to angiotensin suppression and those related to kinin potentia-
tion. Other types of adverse effects may also occur (eg, rash and
taste disturbances). Up to 20% of patients will experience an ACE
inhibitor–induced cough. With the use of ACE inhibitors, particu-
lar care should be given to the patient’s volume status, renal func-
tion, and concomitant medications (Sections 7.3.2.1 and 7.3.2.9).
However, most HF patients (85% to 90%) can tolerate these drugs.
See Online Data Supplement 18 for additional data on ACE
inhibitors.
7.3.2.3. ARBs: Recommendations
Class I
1. ARBs are recommended in patients with HFrEF with
current or prior symptoms who are ACE inhibitor
intolerant, unless contraindicated, to reduce morbid-
ity and mortality.
108,345,415,450
(Level of Evidence: A)
Class IIa
1. ARBs are reasonable to reduce morbidity and mor-
tality as alternatives to ACE inhibitors as first-line
therapy for patients with HFrEF, especially for
patients already taking ARBs for other indications,
unless contraindicated.
451–456
(Level of Evidence: A)
Class IIb
1. Addition of an ARB may be considered in persis-
tently symptomatic patients with HFrEF who are
already being treated with an ACE inhibitor and a
beta blocker in whom an aldosterone antagonist is
not indicated or tolerated.
420,457
(Level of Evidence: A)
Class III: Harm
1. Routine combined use of an ACE inhibitor, ARB,
and aldosterone antagonist is potentially harmful for
patients with HFrEF. (Level of Evidence: C)
ARBs were developed with the rationale that a) angiotensin II
production continues in the presence of ACE inhibition, driven
through alternative enzyme pathways and b) interference with
the renin-angiotensin system without inhibition of kininase
would produce all of the benefits of ACE inhibitors while min-
imizing the risk of adverse reactions to them. However, it is
now known that some of the benefits of ACE inhibitors may be
related to the accumulation of kinins rather than to the suppres-
sion of angiotensin II formation, whereas some of the adverse
effects of ACE inhibitors in HF are related to the suppression
of angiotensin II formation.
In several placebo-controlled studies, long-term therapy with
ARBs produced hemodynamic, neurohormonal, and clinical
effects consistent with those expected after interference with
the renin-angiotensin system. Reduced hospitalization and mor-
tality have been demonstrated. ACE inhibitors remain the first
choice for inhibition of the renin-angiotensin system in systolic
HF, but ARBs can now be considered a reasonable alternative.
7.3.2.3.1. ARBs: Selection of Patients. ARBs are used in
patients with HFrEF who are ACE inhibitor intolerant; an
ACE-inhibition intolerance primarily related to cough is the
most common indication. In addition, an ARB may be used
as an alternative to an ACE inhibitor in patients who are
already taking an ARB for another reason, such as hyperten-
sion, and who subsequently develop HF. Angioedema occurs
in <1% of patients who take an ACE inhibitor, but it occurs
more frequently in blacks. Because its occurrence may be
life-threatening, clinical suspicion of this reaction justifies the
subsequent avoidance of all ACE inhibitors for the lifetime
of the patient. ACE inhibitors should not be initiated in any
patient with a history of angioedema. Although ARBs may
be considered as alternative therapy for patients who have
developed angioedema while taking an ACE inhibitor, there
are some patients who have also developed angioedema with
ARBs, and caution is advised when substituting an ARB in
a patient who has had angioedema associated with use of an
ACE inhibitor.
458–461
7.3.2.3.2. ARBs: Initiation and Maintenance. When used,
ARBs should be initiated with the starting doses shown in
Table 15. Many of the considerations with initiation of an
ARB are similar to those with initiation of an ACE inhibitor,
as discussed previously. Blood pressure (including postural
blood pressure changes), renal function, and potassium should
be reassessed within 1 to 2 weeks after initiation and followed
closely after changes in dose. Patients with systolic blood
pressure <80 mm Hg, low serum sodium, diabetes mellitus,
and impaired renal function merit close surveillance during
therapy with inhibitors of the renin angiotensin-aldosterone
system. Titration is generally achieved by doubling doses.
For stable patients, it is reasonable to add therapy with beta-
blocking agents before full target doses of either ACE inhibi-
tors or ARBs are reached.
7.3.2.3.3. ARBs: Risks of Treatment. The risks of ARBs are
attributed to suppression of angiotensin stimulation. These
risks of hypotension, renal dysfunction, and hyperkalemia are
greater when combined with another inhibitor of this neurohor-
monal axis, such as ACE inhibitors or aldosterone antagonists.
See Online Data Supplement 19 for additional data on
ARBs.
7.3.2.4. Beta Blockers: Recommendation
Class I
1. Use of 1 of the 3 beta blockers proven to reduce
mortality (eg, bisoprolol, carvedilol, and sustained-
release metoprolol succinate) is recommended for all
patients with current or prior symptoms of HFrEF,
unless contraindicated, to reduce morbidity and
mortality.
346,416–419,448
(Level of Evidence: A)
Long-term treatment with beta blockers can lessen the symp-
toms of HF, improve the patient’s clinical status, and enhance
the patient’s overall sense of well-being.
462–469
In addition, like
ACE inhibitors, beta blockers can reduce the risk of death and
the combined risk of death or hospitalization.
117,447,448,470,471

These benefits of beta blockers were seen in patients with or
without CAD and in patients with or without diabetes mel-
litus, as well as in women and blacks. The favorable effects
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e268 Circulation October 15, 2013
of beta blockers were also observed in patients already taking
ACE inhibitors.
Three beta blockers have been shown to be effective in
reducing the risk of death in patients with chronic HFrEF:
bisoprolol and sustained-release metoprolol (succinate), which
selectively block beta-1–receptors; and carvedilol, which
blocks alpha-1–, beta-1–, and beta-2–receptors. Positive find-
ings with these 3 agents, however, should not be considered
a beta-blocker class effect. Bucindolol lacked uniform effec-
tiveness across different populations, and short-acting meto-
prolol tartrate was less effective in HF clinical trials. Beta-1
selective blocker nebivolol demonstrated a modest reduction
in the primary endpoint of all-cause mortality or cardiovas-
cular hospitalization but did not affect mortality alone in an
elderly population that included patients with HFpEF.
472
7.3.2.4.1. Beta Blockers: Selection of Patients. Beta blockers
should be prescribed to all patients with stable HFrEF unless
they have a contraindication to their use or are intolerant of
these drugs. Because of its favorable effects on survival and
disease progression, a clinical trial–proven beta blocker should
be initiated as soon as HFrEF is diagnosed. Even when symp-
toms are mild or improve with other therapies, beta-blocker
therapy is important and should not be delayed until symp-
toms return or disease progression is documented. Therefore,
even if patients have little disability and experience seemingly
minimal symptomatic benefit, they should still be treated with
a beta blocker to reduce the risks of disease progression, clini-
cal deterioration, and sudden death.
117,448,469–471
Patients need not take high doses of ACE inhibitors before
initiation of beta-blocker therapy. In patients taking a low dose
of an ACE inhibitor, the addition of a beta blocker produces a
greater improvement in symptoms and reduction in the risk of
death than does an increase in the dose of the ACE inhibitor,
even to the target doses used in clinical trials.
445,473
In patients
with a current or recent history of fluid retention, beta blockers
should not be prescribed without diuretics, because diuretics
are needed to maintain sodium and fluid balance and prevent
the exacerbation of fluid retention that can accompany the
initiation of beta-blocker therapy.
474,475
Beta blockers may be
considered in patients who have reactive airway disease or
asymptomatic bradycardia but should be used cautiously in
patients with persistent symptoms of either condition.
7.3.2.4.2. Beta Blockers: Initiation and Maintenance. Treat-
ment with a beta blocker should be initiated at very low doses
(Table 15), followed by gradual increments in dose if lower
doses have been well tolerated. Patients should be monitored
closely for changes in vital signs and symptoms during this
uptitration period. Planned increments in the dose of a beta
blocker should be delayed until any adverse effects observed
with lower doses have disappeared. When such a cautious
approach was used, most patients (approximately 85%)
enrolled in clinical trials who received beta blockers were
able to tolerate short- and long-term treatment with these
drugs and achieve the maximum planned trial dose.
117,447,448,470

Data show that beta blockers can be safely started before dis-
charge even in patients hospitalized for HF, provided they do
not require intravenous inotropic therapy for HF.
476
Clinicians
should make every effort to achieve the target doses of the beta
blockers shown to be effective in major clinical trials. Even
if symptoms do not improve, long-term treatment should be
maintained to reduce the risk of major clinical events. Abrupt
withdrawal of treatment with a beta blocker can lead to clini-
cal deterioration and should be avoided.
477
7.3.2.4.3. Beta Blockers: Risks of Treatment. Initiation of treat-
ment with a beta blocker may produce 4 types of adverse reac-
tions that require attention and management: fluid retention and
worsening HF; fatigue; bradycardia or heart block; and hypoten-
sion. The occurrence of fluid retention or worsening HF is not
generally a reason for the permanent withdrawal of treatment.
Such patients generally respond favorably to intensification of
conventional therapy, and once treated, they remain excellent
candidates for long-term treatment with a beta blocker. The
slowing of heart rate and cardiac conduction produced by beta
blockers is generally asymptomatic and thus requires no treat-
ment; however, if the bradycardia is accompanied by dizziness or
lightheadedness or if second- or third-degree heart block occurs,
clinicians should decrease the dose of the beta blocker. Clini-
cians may minimize the risk of hypotension by administering the
beta blocker and ACE inhibitor at different times during the day.
Hypotensive symptoms may also resolve after a decrease in the
dose of diuretics in patients who are volume depleted. If hypo-
tension is accompanied by other clinical evidence of hypoperfu-
sion, beta-blocker therapy should be decreased or discontinued
pending further patient evaluation. The symptom of fatigue is
multifactorial and is perhaps the hardest symptom to address
with confidence. Although fatigue may be related to beta block-
ers, other causes of fatigue should be considered, including sleep
apnea, overdiuresis, or depression.
See Online Data Supplement 20 for additional data on beta
blockers.
7.3.2.5. Aldosterone Receptor Antagonists:
Recommendations
Class I
1. Aldosterone receptor antagonists (or mineralocor-
ticoid receptor antagonists) are recommended in
patients with NYHA class II–IV HF and who have
LVEF of 35% or less, unless contraindicated, to
reduce morbidity and mortality. Patients with NYHA
class II HF should have a history of prior cardiovas-
cular hospitalization or elevated plasma natriuretic
peptide levels to be considered for aldosterone recep-
tor antagonists. Creatinine should be 2.5 mg/dL or less
in men or 2.0 mg/dL or less in women (or estimated
glomerular filtration rate >30 mL/min/1.73 m
2
), and
potassium should be less than 5.0 mEq/L. Careful
monitoring of potassium, renal function, and diuretic
dosing should be performed at initiation and closely
followed thereafter to minimize risk of hyper-
kalemia and renal insufficiency.
425,426,478
(Level of
Evidence: A)
2. Aldosterone receptor antagonists are recommended
to reduce morbidity and mortality following an acute
MI in patients who have LVEF of 40% or less who
develop symptoms of HF or who have a history of
diabetes mellitus, unless contraindicated.
446
(Level of
Evidence: B)
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e269
Class III: Harm
1. Inappropriate use of aldosterone receptor antago-
nists is potentially harmful because of life-threat-
ening hyperkalemia or renal insufficiency when
serum creatinine is greater than 2.5 mg/dL in men
or greater than 2.0 mg/dL in women (or estimated
glomerular filtration rate <30 mL/min/1.73 m
2
),
and/or potassium greater than 5.0 mEq/L.
479,480

(Level of Evidence: B)
The landmark RALES trial (Randomized Aldactone
Evaluation Study)
425
showed a 30% reduction in all-cause mor-
tality as well as a reduced risk of SCD and HF hospitalizations
with the use of spironolactone in patients with chronic HFrEF
and LVEF <35%. Eplerenone has been shown to reduce all-
cause deaths, cardiovascular deaths, or HF hospitalizations in
a wider range of patients with HFrEF.
426,446
7.3.2.5.1. Aldosterone Receptor Antagonists: Selection of
Patients. Clinicians should strongly consider the addition of the
aldosterone receptor antagonists spironolactone or eplerenone for
all patients with HFrEF who are already on ACE inhibitors (or
ARBs) and beta blockers. Although the entry criteria for the tri-
als of aldosterone receptor antagonists excluded patients with a
creatinine >2.5 mg/dL, the majority of patients had much lower
creatinine (95% of patients had creatinine ≤1.7 mg/dL).
425,426,446

In contrast, one third of patients in EMPHASIS-HF (Eplerenone
in Mild Patients Hospitalization and Survival Study in Heart
Failure) had an estimated glomerular filtration rate of <60 mL/
min/1.73 m
2
.
426
Note also that the entry criteria for the EMPHA-
SIS-HF trial were age of at least ≥55 years, NYHA class II
symptoms, and an EF of no more than 30% (or, if >30% to 35%,
a QRS duration of >130 ms on ECG). To minimize the risk of
life-threatening hyperkalemia in euvolemic patients with HFrEF,
patients should have initial serum creatinine <2.5 mg/dL (or an
estimated glomerular filtration rate >30 mL/min/1.73 m
2
) with-
out recent worsening and serum potassium <5.0 mEq/L without
a history of severe hyperkalemia. Careful patient selection and
risk assessment with availability of close monitoring is essential
in initiating the use of aldosterone receptor antagonists.
7.3.2.5.2. Aldosterone Receptor Antagonists: Initiation and
Maintenance. Spironolactone should be initiated at a dose of
12.5 to 25 mg daily, while eplerenone should be initiated at a
dose of 25 mg/d, increasing to 50 mg daily. For those with con-
cerns of hyperkalemia or marginal renal function (estimated
glomerular filtration rate 30 to 49 mL/min/1.73 m
2
), an initial
regimen of every-other-day dosing is advised (Table 16). After
initiation of aldosterone receptor antagonists, potassium sup-
plementation should be discontinued (or reduced and carefully
monitored in those with a history of hypokalemia; Table 17),
and patients should be counseled to avoid foods high in potas-
sium and NSAIDs. Potassium levels and renal function should
be rechecked within 2 to 3 days and again at 7 days after initia-
tion of an aldosterone receptor antagonist. Subsequent moni-
toring should be dictated by the general clinical stability of
renal function and fluid status but should occur at least monthly
for the first 3 months and every 3 months thereafter. The addi-
tion or an increase in dosage of ACE inhibitors or ARBs should
trigger a new cycle of monitoring.
There are limited data to support or refute that spironolac-
tone and eplerenone are interchangeable. The perceived differ-
ence between eplerenone and spironolactone is the selectivity
of aldosterone receptor antagonism and not the effectiveness
of blocking mineralocorticoid activity. In RALES, there was
Table 16. Drug Dosing for Aldosterone Receptor Antagonists
Eplerenone Spironolactone
eGFR (mL/min/1.73 m
2
) ≥50 30 to −49 ≥50 30 to 49
Initial dose (only if K
+
≤5 mEq/L) 25 mg once daily 25 mg once every other day 12.5 to 25.0 mg once daily 12.5 mg once daily or every other day
Maintenance dose (after 4 wk for K
+

≤5 mEq/L)*
50 mg once daily 25 mg once daily 25 mg once or twice daily 12.5 to 25.0 mg once daily
*After dose initiation for K
+
, increase ≤6.0 mEq/L or worsening renal function, hold until K
+
<5.0 mEq/L. Consider restarting reduced dose after confirming resolution
of hyperkalemia/renal insufficiency for at least 72 h.
eGFR indicates estimated glomerular filtration rate; and, K
+
, potassium.
Adapted from Butler et al.
481
Table 17. Strategies to Minimize the Risk of Hyperkalemia in Patients Treated With Aldosterone Antagonists
1. Impaired renal function is a risk factor for hyperkalemia during treatment with aldosterone antagonists. The risk of hyperkalemia increases progressively when
serum creatinine is >1.6 mg/dL.* In elderly patients or others with low muscle mass in whom serum creatinine does not accurately reflect glomerular filtration
rate, determination that glomerular filtration rate or creatinine clearance is >30 mL/min/1.73 m
2
is recommended.
2. Aldosterone antagonists would not ordinarily be initiated in patients with baseline serum potassium >5.0 mEq/L.
3. An initial dose of spironolactone of 12.5 mg or eplerenone 25 mg is typical, after which the dose may be increased to spironolactone 25 mg or eplerenone 50 mg if
appropriate.
4. The risk of hyperkalemia is increased with concomitant use of higher doses of ACE inhibitors (captopril ≥75 mg daily; enalapril or lisinopril ≥10 mg daily).
5. In most circumstances, potassium supplements are discontinued or reduced when initiating aldosterone antagonists.
6. Close monitoring of serum potassium is required; potassium levels and renal function are most typically checked in 3 d and at 1 wk after initiating therapy and at
least monthly for the first 3 mo.
*Although the entry criteria for the trials of aldosterone antagonists included creatinine <2.5 mg/dL, the majority of patients had much lower creatinine; in 1 trial,
425

95% of patients had creatinine ≤1.7 mg/dL.
ACE indicates angiotensin-converting enzyme.
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e270 Circulation October 15, 2013
increased incidence (10%) of gynecomastia or breast pain
with use of spironolactone (a nonselective antagonist). The
incidence of these adverse events was <1% in EPHESUS
(Eplerenone Post-Acute Myocardial Infarction Heart Failure
Efficacy and Survival Study) and EMPHASIS-HF without
any difference in adverse events between the eplerenone and
placebo.
426,446
7.3.2.5.3. Aldosterone Receptor Antagonists: Risks of Treat-
ment. The major risk associated with use of aldosterone recep-
tor antagonists is hyperkalemia due to inhibition of potassium
excretion, ranging from 2% to 5% in large clinical trials
425,426,446

to 24% to 36% in population-based registries.
479,480
Routine
triple combination of an ACE inhibitor, ARB, and aldosterone
receptor antagonist should be avoided.
The development of potassium levels >5.5 mEq/L
(approximately 12% in EMPHASIS-HF
426
) should gen-
erally trigger discontinuation or dose reduction of the
aldosterone receptor antagonist unless other causes are
identified. The development of worsening renal function
should lead to careful evaluation of the entire medical regi-
men and consideration for stopping the aldosterone recep-
tor antagonist. Patients should be instructed specifically to
stop the aldosterone receptor antagonist during an episode
of diarrhea or dehydration or while loop diuretic therapy
is interrupted.
7.3.2.6. Hydralazine and Isosorbide Dinitrate:
Recommendations
Class I
1. The combination of hydralazine and isosorbide
dinitrate is recommended to reduce morbidity and
mortality for patients self-described as African
Americans with NYHA class III–IV HFrEF receiv-
ing optimal therapy with ACE inhibitors and beta
blockers, unless contraindicated.
423,424
(Level of
Evidence: A)
Class IIa
1. A combination of hydralazine and isosorbide dini-
trate can be useful to reduce morbidity or mortal-
ity in patients with current or prior symptomatic
HFrEF who cannot be given an ACE inhibitor or
ARB because of drug intolerance, hypotension, or
renal insufficiency, unless contraindicated.
449
(Level
of Evidence: B)
In a large-scale trial that compared the vasodilator combina-
tion with placebo, the use of hydralazine and isosorbide dini-
trate reduced mortality but not hospitalizations in patients with
HF treated with digoxin and diuretics but not an ACE inhibitor
or beta blocker.
449
However, in 2 other trials that compared
the vasodilator combination with an ACE inhibitor, the ACE
inhibitor produced more favorable effects on survival.
412,482

A post hoc retrospective analysis of these vasodilator trials
demonstrated particular efficacy of isosorbide dinitrate and
hydralazine in the African American cohort.
423
In a subse-
quent trial, which was limited to patients self-described as
African American, the addition of a fixed-dose combination of
hydralazine and isosorbide dinitrate to standard therapy with
an ACE inhibitor or ARB, a beta blocker, and an aldosterone
antagonist offered significant benefit.
424
7.3.2.6.1. Hydralazine and Isosorbide Dinitrate: Selection of
Patients. The combination of hydralazine and isosorbide dini-
trate is recommended for African Americans with HFrEF who
remain symptomatic despite concomitant use of ACE inhibi-
tors, beta blockers, and aldosterone antagonists. Whether this
benefit is evident in non–African Americans with HFrEF
remains to be investigated. The combination of hydralazine
and isosorbide dinitrate should not be used for the treatment
of HFrEF in patients who have no prior use of standard neu-
rohumoral antagonist therapy and should not be substituted
for ACE inhibitor or ARB therapy in patients who are tolerat-
ing therapy without difficulty. Despite the lack of data with
the vasodilator combination in patients who are intolerant of
ACE inhibitors or ARBs, the combined use of hydralazine and
isosorbide dinitrate may be considered as a therapeutic option
in such patients.
7.3.2.6.2. Hydralazine and Isosorbide Dinitrate: Initiation
and Maintenance. If the fixed-dose combination is avail-
able, the initial dose should be 1 tablet containing 37.5 mg
of hydralazine hydrochloride and 20 mg of isosorbide dini-
trate 3 times daily. The dose can be increased to 2 tablets 3
times daily for a total daily dose of 225 mg of hydralazine
hydrochloride and 120 mg of isosorbide dinitrate. When the 2
drugs are used separately, both pills should be administered at
least 3 times daily. Initial low doses of the drugs given sepa-
rately may be progressively increased to a goal similar to that
achieved in the fixed-dose combination trial.
424
7.3.2.6.3. Hydralazine and Isosorbide Dinitrate: Risks of
Treatment. Adherence to this combination has generally
been poor because of the large number of tablets required,
frequency of administration, and the high incidence of
adverse reactions.
412,449
Frequent adverse effects include
headache, dizziness, and gastrointestinal complaints. Nev-
ertheless, the benefit of these drugs can be substantial and
warrant a slower titration of the drugs to enhance tolerance
of the therapy.
See Table 18 for a summary of the treatment benefit of
GDMT in HFrEF.
Table 18. Medical Therapy for Stage C HFrEF: Magnitude of
Benefit Demonstrated in RCTs
GDMT
RR Reduction in
Mortality
(%)
NNT for Mortality
Reduction
(Standardized
to 36 mo)
RR Reduction
in HF
Hospitalizations
(%)
ACE inhibitor or ARB 17 26 31
Beta blocker 34 9 41
Aldosterone antagonist 30 6 35
Hydralazine/nitrate 43 7 33
ACE indicates angiotensin-converting enzyme; ARB, angiotensin-receptor
blocker; GDMT, guideline-directed medical therapy; HF, heart failure; HFrEF,
heart failure with reduced ejection fraction; NNT, number needed to treat; RCTs,
randomized controlled trials; and RR, relative risk.
Adapted with permission from Fonarow et al.
483
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e271
7.3.2.7. Digoxin: Recommendation
Class IIa
1. Digoxin can be beneficial in patients with HFrEF,
unless contraindicated, to decrease hospitalizations
for HF.
484–491
(Level of Evidence: B)
Several placebo-controlled trials have shown that treatment with
digoxin for 1 to 3 months can improve symptoms, HRQOL, and
exercise tolerance in patients with mild to moderate HF.
485–491

These benefits have been seen regardless of the underlying
rhythm (normal sinus rhythm or AF), cause of HF (ischemic
or nonischemic cardiomyopathy), or concomitant therapy (with
or without ACE inhibitors). In a long-term trial that primarily
enrolled patients with NYHA class II or III HF, treatment with
digoxin for 2 to 5 years had no effect on mortality but modestly
reduced the combined risk of death and hospitalization.
484
7.3.2.7.1. Digoxin: Selection of Patients. Clinicians may con-
sider adding digoxin in patients with persistent symptoms of
HFrEF during GDMT. Digoxin may also be added to the ini-
tial regimen in patients with severe symptoms who have not
yet responded symptomatically during GDMT.
Alternatively, treatment with digoxin may be delayed until
the patient’s response to GDMT has been defined and may be
used only in patients who remain symptomatic despite ther-
apy with the neurohormonal antagonists. If a patient is taking
digoxin but not an ACE inhibitor or a beta blocker, treatment
with digoxin should not be withdrawn, but appropriate ther-
apy with the neurohormonal antagonists should be instituted.
Digoxin is prescribed occasionally in patients with HF and
AF, but beta blockers are usually more effective when added
to digoxin in controlling the ventricular response, particularly
during exercise.
492–495
Patients should not be given digoxin if they have signifi-
cant sinus or atrioventricular block unless the block has been
addressed with a permanent pacemaker. The drug should be
used cautiously in patients taking other drugs that can depress
sinus or atrioventricular nodal function or affect digoxin levels
(eg, amiodarone or a beta blocker), even though such patients
usually tolerate digoxin without difficulty.
7.3.2.7.2. Digoxin: Initiation and Maintenance. Therapy with
digoxin is commonly initiated and maintained at a dose of
0.125 to 0.25 mg daily. Low doses (0.125 mg daily or every
other day) should be used initially if the patient is >70 years
of age, has impaired renal function, or has a low lean body
mass.
496
Higher doses (eg, digoxin 0.375 to 0.50 mg daily) are
rarely used or needed in the management of patients with HF.
There is no reason to use loading doses of digoxin to initiate
therapy in patients with HF.
Doses of digoxin that achieve a plasma concentration of
drug in the range of 0.5 to 0.9 ng/mL are suggested, given
the limited evidence currently available. There has been no
prospective, randomized evaluation of the relative efficacy
or safety of different plasma concentrations of digoxin.
Retrospective analysis of 2 studies of digoxin withdrawal
found that prevention of worsening HF by digoxin at lower
concentrations in plasma (0.5 to 0.9 ng/mL) was as great as
that achieved at higher concentrations.
497,498
7.3.2.7.3. Digoxin: Risks of Treatment. When administered
with attention to dose and factors that alter its metabolism,
digoxin is well tolerated by most patients with HF.
499
The
principal adverse reactions occur primarily when digoxin
is administered in large doses, especially in the elderly,
but large doses are not necessary for clinical benefits.
500–502

The major adverse effects include cardiac arrhythmias (eg,
ectopic and re-entrant cardiac rhythms and heart block),
gastrointestinal symptoms (eg, anorexia, nausea, and
vomiting), and neurological complaints (eg, visual distur-
bances, disorientation, and confusion). Overt digoxin tox-
icity is commonly associated with serum digoxin levels
>2 ng/mL.
However, toxicity may also occur with lower digoxin
levels, especially if hypokalemia, hypomagnesemia, or
hypothyroidism coexists.
503,504
The concomitant use of
clarithromycin, dronedarone, erythromycin, amiodarone,
itraconazole, cyclosporine, propafenone, verapamil, or
quinidine can increase serum digoxin concentrations and
may increase the likelihood of digoxin toxicity.
505–507
The
dose of digoxin should be reduced if treatment with these
drugs is initiated. In addition, a low lean body mass and
impaired renal function can also elevate serum digoxin lev-
els, which may explain the increased risk of digoxin toxicity
in elderly patients.
7.3.2.8. Other Drug Treatment
7.3.2.8.1. Anticoagulation: Recommendations
Class I
1. Patients with chronic HF with permanent/persistent/
paroxysmal AF and an additional risk factor for
cardioembolic stroke (history of hypertension, dia-
betes mellitus, previous stroke or transient ischemic
attack, or ≥75 years of age) should receive chronic
anticoagulant therapy.*
508–514
(Level of Evidence: A)
2. The selection of an anticoagulant agent (warfarin,
dabigatran, apixaban, or rivaroxaban) for permanent/
persistent/paroxysmal AF should be individualized on
the basis of risk factors, cost, tolerability, patient pref-
erence, potential for drug interactions, and other clini-
cal characteristics, including time in the international
normalized ratio therapeutic range if the patient has
been taking warfarin. (Level of Evidence: C)
Class IIa
1. Chronic anticoagulation is reasonable for patients
with chronic HF who have permanent/persistent/
paroxysmal AF but are without an additional risk
factor for cardioembolic stroke.*
509–511,515–517
(Level of
Evidence: B)
Class III: No Benefit
1. Anticoagulation is not recommended in patients with
chronic HFrEF without AF, a prior thromboem-
bolic event, or a cardioembolic source.
518–520
(Level of
Evidence: B)
*In the absence of contraindications to anticoagulation.
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e272 Circulation October 15, 2013
Patients with chronic HFrEF are at an increased risk of thrombo-
embolic events due to stasis of blood in dilated hypokinetic car-
diac chambers and in peripheral blood vessels
521,522
and perhaps
due to increased activity of procoagulant factors.
523
However,
in large-scale studies, the risk of thromboembolism in clini-
cally stable patients has been low (1% to 3% per year), even in
those with a very depressed EF and echocardiographic evidence
of intracardiac thrombi.
524–528
These rates are sufficiently low to
limit the detectable benefit of anticoagulation in these patients.
In several retrospective analyses, the risk of thromboem-
bolic events was not lower in patients with HF taking warfarin
than in patients not treated with antithrombotic drugs.
524,526,527

The use of warfarin was associated with a reduction in major
cardiovascular events and death in patients with HF in some
studies but not in others.
518,529,530
An RCT that compared the
outcome of patients with HFrEF assigned to aspirin, warfa-
rin, or clopidogrel was completed,
519
but no therapy appeared
to be superior. Another trial compared aspirin with warfarin
in patients with reduced LVEF, sinus rhythm, and no cardio-
embolic source and demonstrated no difference in either the
primary outcome of death, stroke, or intracerebral hemor-
rhage.
520
There was also no difference in the combined out-
come of death, ischemic stroke, intracerebral hemorrhage,
MI, or HF hospitalization. There was a significant increase in
major bleeding with warfarin. Given that there is no overall
benefit of warfarin and an increased risk of bleeding, there is
no compelling evidence to use warfarin or aspirin in patients
with HFrEF in the absence of a specific indication.
The efficacy of long-term warfarin for the prevention
of stroke in patients with AF is well established. However,
the ACCF/AHA guidelines for AF
6
recommend use of the
CHADS
2
[Congestive heart failure, Hypertension, Age ≥75
years, Diabetes mellitus, previous Stroke/transient ischemic
attack (doubled risk weight)] score to assess patient risk for
adverse outcomes before initiating anticoagulation therapy.
More recently, a revised score, CHADS2-VASc, has been sug-
gested as more applicable to a wider range of patients,
531
but this
revised score has not yet been fully studied in patients with HF.
Regardless of whether patients receive rhythm or rate control,
anticoagulation is recommended for patients with HF and AF
for stroke prevention in the presence of at least 1 additional risk
factor. For patients with HF and AF in the absence of another
cardioembolic risk factor, anticoagulation is reasonable.
Trials of newer oral anticoagulants have compared efficacy
and safety with warfarin therapy rather than placebo. Several
new oral anticoagulants are now available, including the factor
Xa inhibitors apixaban and rivaroxaban and the direct throm-
bin inhibitor dabigatran.
508,512–514
These drugs have few food
and drug interactions compared with warfarin and no need for
routine coagulation monitoring or dose adjustment. The fixed
dosing together with fewer interactions may simplify patient
management, particularly with the polypharmacy commonly
seen in HF. These drugs have a potential for an improved
benefit–risk profile compared with warfarin, which may
increase their use in practice, especially in those at increased
bleeding risk. However, important adverse effects have been
noted with these new anticoagulants, including gastrointesti-
nal distress, which may limit compliance. At present, there is
no commercially available agent to reverse the effect of these
newer drugs. Trials comparing new anticoagulants with war-
farin have enrolled >10 000 patients with HF. As more detailed
evaluations of the comparative benefits and risks of these
newer agents in patients with HF are still pending, the writ-
ing committee considered their use in patients with HF and
nonvalvular AF as an alternative to warfarin to be reasonable.
The benefit afforded by low-dose aspirin in patients with sys-
tolic HF but no previous MI or known CAD (or specifically in
patients proven free of CAD) remains unknown. A Cochrane
review failed to find sufficient evidence to support its use.
532

Retrospective and observational studies again had conflicting
results and used very different criteria to identify patients as
nonischemic, with some demonstrating protection from aspirin
overall
532
or only in patients with more severe depression of sys-
tolic function,
518
whereas others found no benefit from aspirin.
530

The high incidence of diabetes mellitus and hypertension in most
HF studies, combined with a failure to use objective methods to
exclude CAD in enrolled patients, may leave this question unan-
swered. Currently, data are insufficient to recommend aspirin for
empiric primary prevention in HF patients known to be free of
atherosclerotic disease and without additional risk factors.
See Online Data Supplement 21 for additional data on
anticoagulants.
7.3.2.8.2. Statins: Recommendation
Class III: No Benefit
1. Statins are not beneficial as adjunctive therapy
when prescribed solely for the diagnosis of HF in the
absence of other indications for their use.
533–538
(Level
of Evidence: A)
Statin therapy has been broadly implicated in prevention
of adverse cardiovascular events, including new-onset HF.
Originally designed to lower cholesterol in patients with car-
diovascular disease, statins are increasingly recognized for
their favorable effects on inflammation, oxidative stress, and
vascular performance. Several observational and post hoc
analyses from large clinical trials have implied that statin
therapy may provide clinical benefit to patients with HF.
533–536

However, 2 large RCTs have demonstrated that rosuvastatin
has neutral effects on long-term outcomes in patients with
chronic HFrEF when added to standard GDMT.
537,538
At pres-
ent, statin therapy should not be prescribed primarily for the
treatment of HF to improve clinical outcomes.
See Online Data Supplement 22 for additional data on
statin therapy.
7.3.2.8.3. Omega-3 Fatty Acids: Recommendation
Class IIa
1. Omega-3 polyunsaturated fatty acid (PUFA) supple-
mentation is reasonable to use as adjunctive therapy
in patients with NYHA class II–IV symptoms and
HFrEF or HFpEF, unless contraindicated, to reduce
mortality and cardiovascular hospitalizations.
539,540

(Level of Evidence: B)
Supplementation with omega-3 PUFA has been evaluated as an
adjunctive therapy for cardiovascular disease and HF.
541
Trials
in primary and secondary prevention of coronary heart disease
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e273
showed that omega-3 PUFA supplementation results in a 10% to
20% risk reduction in fatal and nonfatal cardiovascular events.
The GISSI (Gruppo Italiano per lo Studio della Sopravvivenza
nell’Infarto miocardico) Prevenzione trial demonstrated a
21% reduction in death among post-MI patients taking 1 g of
omega-3 PUFA (850 mg to 882 mg of eicosapentaenoic acid
[EPA] and docosahexaenoic acid [DHA] as ethyl esters in the
ratio of 1:1.2).
542
Post hoc subgroup analysis revealed that this
reduction in mortality and SCD was concentrated in the approx-
imately 2000 patients with reduced LVEF.
539
The GISSI-HF
investigators randomized 6975 patients in NYHA class II–IV
chronic HF to 1 g daily of omega-3 PUFA (850 mg to 882 mg
EPA/DHA) or matching placebo. Death from any cause was
reduced from 29% with placebo to 27% in those treated with
omega-3 PUFA.
540
The outcome of death or admission to hos-
pital for a cardiovascular event was also significantly reduced.
In reported studies, this therapy has been safe and very well
tolerated.
540–543
Further investigations are needed to better define
optimal dosing and formulation of omega-3 PUFA supple-
ments. The use of omega-3 PUFA supplementation is reason-
able as adjunctive therapy in patients with chronic HF.
See Online Data Supplement 23 for additional data on
omega-3 fatty acids.
7.3.2.9. Drugs of Unproven Value or That May Worsen HF:
Recommendations
Class III: No Benefit
1. Nutritional supplements as treatment for HF are
not recommended in patients with current or prior
symptoms of HFrEF.
544,545
(Level of Evidence: B)
2. Hormonal therapies other than to correct deficien-
cies are not recommended for patients with current
or prior symptoms of HFrEF. (Level of Evidence: C)
Class III: Harm
1. Drugs known to adversely affect the clinical status of
patients with current or prior symptoms of HFrEF
are potentially harmful and should be avoided or
withdrawn whenever possible (eg, most antiarrhyth-
mic drugs, most calcium channel–blocking drugs
[except amlodipine], NSAIDs, or thiazolidinedio-
nes).
546–557
(Level of Evidence: B)
2. Long-term use of infused positive inotropic drugs is
potentially harmful for patients with HFrEF, except as
palliation for patients with end-stage disease who can-
not be stabilized with standard medical treatment (see
recommendations for stage D). (Level of Evidence: C)
7.3.2.9.1. Nutritional Supplements and Hormonal Therapies.
Patients with HF, particularly those treated with diuretics,
may become deficient in vitamins and micronutrients. Sev-
eral nutritional supplements (eg, coenzyme Q10, carnitine,
taurine, and antioxidants) and hormonal therapies (eg, growth
hormone or thyroid hormone) have been proposed for the
treatment of HF.
558–563
Testosterone has also been evaluated
for its beneficial effect in HF with modest albeit preliminary
effects.
564
Aside from replenishment of documented deficien-
cies, published data have failed to demonstrate benefit for
routine vitamin, nutritional, or hormonal supplementation.
565

In most data or other literature regarding nutraceuticals, there
are issues, including outcomes analyses, adverse effects, and
drug-nutraceutical interactions, that remain unresolved.
No clinical trials have demonstrated improved survival
rates with use of nutritional or hormonal therapy, with the
exception of omega-3 fatty acid supplementation as previ-
ously noted. Some studies have suggested a possible effect for
coenzyme Q10 in reduced hospitalization rates, dyspnea, and
edema in patients with HF, but these benefits have not been
seen uniformly.
566–569
Because of possible adverse effects and
drug interactions of nutritional supplements and their wide-
spread use, clinicians caring for patients with HF should rou-
tinely inquire about their use. Until more data are available,
nutritional supplements or hormonal therapies are not recom-
mended for the treatment of HF.
7.3.2.9.2. Antiarrhythmic Agents. With atrial and ventricular
arrhythmias contributing to the morbidity and mortality of HF,
various classes of antiarrhythmic agents have been repeatedly
studied in large RCTs. Instead of conferring survival benefit,
however, nearly all antiarrhythmic agents increase mortality in
the HF population.
548–550
Most antiarrhythmics have some nega-
tive inotropic effect and some, particularly the class I and class
III antiarrhythmic drugs, have proarrhythmic effects. Hence,
class I sodium channel antagonists and the class III potassium
channel blockers d-sotalol and dronedarone should be avoided
in patients with HF. Amiodarone and dofetilide are the only
antiarrhythmic agents to have neutral effects on mortality in
clinical trials of patients with HF and thus are the preferred
drugs for treating arrhythmias in this patient group.
570–573
See Online Data Supplement 24 for additional data on anti-
arrhythmic agents.
7.3.2.9.3. Calcium Channel Blockers: Recommendation
Class III: No Benefit
1. Calcium channel–blocking drugs are not recom-
mended as routine treatment for patients with
HFrEF.
551,574,575
(Level of Evidence: A)
By reducing peripheral vasoconstriction and LV afterload, cal-
cium channel blockers were thought to have a potential role
in the management of chronic HF. However, first-generation
dihydropyridine and nondihydropyridine calcium channel
blockers also have myocardial depressant activity. Several
clinical trials have demonstrated either no clinical benefit or
even worse outcomes in patients with HF treated with these
drugs.
546,547,551–553
Despite their greater selectivity for calcium
channels in vascular smooth muscle cells, second-generation
calcium channel blockers, dihydropyridine derivatives such
as amlodipine and felodipine, have failed to demonstrate
any functional or survival benefit in patients with HF.
575–579

Amlodipine, however, may be considered in the management
of hypertension or ischemic heart disease in patients with HF
because it is generally well tolerated and had neutral effects
on morbidity and mortality in large RCTs. In general, calcium
channel blockers should be avoided in patients with HFrEF.
See Online Data Supplement 25 for additional data on cal-
cium channel blockers.
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e274 Circulation October 15, 2013
7.3.2.9.4. Nonsteroidal Anti-Inflammatory Drugs. NSAIDs
inhibit the synthesis of renal prostaglandins, which mediate
vasodilation in the kidneys and directly inhibit sodium resorp-
tion in the thick ascending loop of Henle and collecting tubule.
Hence, NSAIDs can cause sodium and water retention and blunt
the effects of diuretics. Several observational cohort studies have
revealed increased morbidity and mortality in patients with HF
using either nonselective or selective NSAIDs.
554–556,580–582
See Online Data Supplement 26 for additional data on NSAIDs.
7.3.2.9.5. Thiazolidinediones. Thiazolidinediones increase
insulin sensitivity by activating nuclear peroxisome prolifer-
ator-activated receptor gamma. Expressed in virtually all tis-
sues, peroxisome proliferator-activated receptor gamma also
regulates sodium reabsorption in the collecting ducts of the
kidney. In clinical trials, thiazolidinediones have been asso-
ciated with increased incidence of HF events, even in those
without any prior history of clinical HF.
557,583–588
See Table 19 for a summary of recommendations from
this section and Table 20 for strategies for achieving optimal
GDMT; see Online Data Supplement 27 for additional data on
thiazolidinediones.
7.3.3. Pharmacological Treatment for Stage C HFpEF:
Recommendations
See Table 21 for a summary of recommendations from this
section.
Class I
1. Systolic and diastolic blood pressure should be con-
trolled in patients with HFpEF in accordance with
published clinical practice guidelines to prevent mor-
bidity.
27,91
(Level of Evidence: B)
2. Diuretics should be used for relief of symptoms due
to volume overload in patients with HFpEF. (Level of
Evidence: C)
Class IIa
1. Coronary revascularization is reasonable in patients
with CAD in whom symptoms (angina) or demon-
strable myocardial ischemia is judged to be having
an adverse effect on symptomatic HFpEF despite
GDMT. (Level of Evidence: C)
2. Management of AF according to published clinical
practice guidelines in patients with HFpEF is reason-
able to improve symptomatic HF (Section 9.1). (Level
of Evidence: C)
3. The use of beta-blocking agents, ACE inhibitors, and
ARBs in patients with hypertension is reasonable
to control blood pressure in patients with HFpEF.
(Level of Evidence: C)
Class IIb
1. The use of ARBs might be considered to decrease
hospitalizations for patients with HFpEF.
589
(Level of
Evidence: B)
Class III: No Benefit
1. Routine use of nutritional supplements is not recom-
mended for patients with HFpEF. (Level of Evidence: C)
Trials using comparable and efficacious agents for HFrEF
have generally been disappointing when used in patients with
HFpEF.
590
Thus, most of the recommended therapies for HFpEF
are directed at symptoms, especially comorbidities, and risk fac-
tors that may worsen cardiovascular disease.
Blood pressure control concordant with existing hyperten-
sion guidelines remains the most important recommendation
in patients with HFpEF. Evidence from an RCT has shown
that improved blood pressure control reduces hospitalization
for HF,
591
decreases cardiovascular events, and reduces HF
mortality in patients without prevalent HF.
311
In hypertensive
patients with HFpEF, aggressive treatment (often with several
drugs with complementary mechanisms of action) is recom-
mended. ACE inhibitors and/or ARBs are often considered
as first-line agents. Specific blood pressure targets in HFpEF
have not been firmly established; thus, the recommended tar-
gets are those used for general hypertensive populations.
CAD is common in patients with HFpEF
592
; however, there are
no studies to determine the impact of revascularization on symp-
toms or outcomes specifically in patients with HFpEF. In general,
contemporary revascularization guidelines
10,12
should be used in
the care of patients with HFpEF and concomitant CAD. Specific
to this population, it might be reasonable to consider revascular-
ization in patients for whom ischemia appears to contribute to HF
symptoms, although this determination can be difficult.
Theoretical mechanisms for the worsening of HF symptoms
by AF among patients with HFpEF include shortened diastolic
filling time with tachycardia and the loss of atrial contribution to
LV diastolic filling. Conversely, chronotropic incompetence is
also a concern. Slowing the heart rate is useful in tachycardia but
not in normal resting heart rate; a slow heart rate prolongs diasta-
sis and worsens chronotropic incompetence. Currently, there are
no specific trials of rate versus rhythm control in HFpEF.
7.3.4. Device Therapy for Stage C HFrEF:
Recommendations
See Table 22 for a summary of recommendations from this
section.
Class I
1. ICD therapy is recommended for primary prevention
of SCD to reduce total mortality in selected patients
with nonischemic DCM or ischemic heart disease at
least 40 days post-MI with LVEF of 35% or less and
NYHA class II or III symptoms on chronic GDMT,
who have reasonable expectation of meaningful sur-
vival for more than 1 year.†
355,593
(Level of Evidence: A)
2. CRT is indicated for patients who have LVEF of 35%
or less, sinus rhythm, left bundle-branch block (LBBB)
with a QRS duration of 150 ms or greater, and NYHA
class II, III, or ambulatory IV symptoms on GDMT.
(Level of Evidence: A for NYHA class III/IV
38,78,116,594
;
Level of Evidence: B for NYHA class II
595,596
)
†Counseling should be specific to each individual patient and should
include documentation of a discussion about the potential for sudden death
and nonsudden death from HF or noncardiac conditions. Information
should be provided about the efficacy, safety, and potential complications
of an ICD and the potential for defibrillation to be inactivated if desired
in the future, notably when a patient is approaching end of life. This will
facilitate shared decision making between patients, families, and the
medical care team about ICDs.
30
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e275
Table 19. Recommendations for Pharmacological Therapy for Management of Stage C HFrEF
Recommendations COR LOE References
Diuretics
Diuretics are recommended in patients with HFrEF with fluid retention I C N/A
ACE inhibitors
ACE inhibitors are recommended for all patients with HFrEF I A 343, 412–414
ARBs
ARBs are recommended in patients with HFrEF who are ACE inhibitor intolerant I A 108, 345, 415, 450
ARBs are reasonable as alternatives to ACE inhibitors as first-line therapy in HFrEF IIa A 451–456
Addition of an ARB may be considered in persistently symptomatic patients with HFrEF on
GDMT
IIb A 420, 457
Routine combined use of an ACE inhibitor, ARB, and aldosterone antagonist is potentially
harmful
III: Harm C N/A
Beta blockers
Use of 1 of the 3 beta blockers proven to reduce mortality is recommended for all stable
patients
I A 346, 416–419, 448
Aldosterone receptor antagonists
Aldosterone receptor antagonists are recommended in patients with NYHA class II–IV who
have LVEF ≤35%
I A 425, 426, 478
Aldosterone receptor antagonists are recommended in patients following an acute MI who
have LVEF ≤40% with symptoms of HF or DM
I B 446
Inappropriate use of aldosterone receptor antagonists may be harmful III: Harm B 479, 480
Hydralazine and isosorbide dinitrate
The combination of hydralazine and isosorbide dinitrate is recommended for African
Americans with NYHA class III–IV HFrEF on GDMT
I A 423, 424
A combination of hydralazine and isosorbide dinitrate can be useful in patients with HFrEF
who cannot be given ACE inhibitors or ARBs
IIa B 449
Digoxin
Digoxin can be beneficial in patients with HFrEF IIa B 484–491
Anticoagulation
Patients with chronic HF with permanent/persistent/paroxysmal AF and an additional risk
factor for cardioembolic stroke should receive chronic anticoagulant therapy*
I A 508–514
The selection of an anticoagulant agent should be individualized I C N/A
Chronic anticoagulation is reasonable for patients with chronic HF who have permanent/
persistent/paroxysmal AF but are without an additional risk factor for cardioembolic stroke*
IIa B 509–511, 515–517
Anticoagulation is not recommended in patients with chronic HFrEF without AF, a prior
thromboembolic event, or a cardioembolic source
III: No Benefit B 518–520
Statins
Statins are not beneficial as adjunctive therapy when prescribed solely for HF III: No Benefit A 533–538
Omega-3 fatty acids
Omega-3 PUFA supplementation is reasonable to use as adjunctive therapy in HFrEF or HFpEF
patients
IIa B 539, 540
Other drugs
Nutritional supplements as treatment for HF are not recommended in HFrEF III: No Benefit B 544, 545
Hormonal therapies other than to correct deficiencies are not recommended in HFrEF III: No Benefit C N/A
Drugs known to adversely affect the clinical status of patients with HFrEF are potentially
harmful and should be avoided or withdrawn
III: Harm B 546–557
Long-term use of an infusion of a positive inotropic drug is not recommended and may be
harmful except as palliation
III: Harm C N/A
Calcium channel blockers
Calcium channel–blocking drugs are not recommended as routine treatment in HFrEF III: No Benefit A 551, 574, 575
*In the absence of contraindications to anticoagulation.
ACE indicates angiotensin-converting enzyme; AF, atrial fibrillation; ARB, angiotensin-receptor blocker; COR, Class of Recommendation; DM, diabetes mellitus; GDMT,
guideline-directed medical therapy; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; LOE, Level
of Evidence; LVEF, left ventricular ejection fraction; MI, myocardial infarction; N/A, not available; NYHA, New York Heart Association; and PUFA, polyunsaturated fatty acids.
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e276 Circulation October 15, 2013
3. ICD therapy is recommended for primary prevention
of SCD to reduce total mortality in selected patients at
least 40 days post-MI with LVEF of 30% or less, and
NYHA class I symptoms while receiving GDMT, who
have reasonable expectation of meaningful survival
for more than 1 year.†
362,597,598
(Level of Evidence: B)
Class IIa
1. CRT can be useful for patients who have LVEF of
35% or less, sinus rhythm, a non-LBBB pattern
with a QRS duration of 150 ms or greater, and
NYHA class III/ambulatory class IV symptoms on
GDMT.
78,116,594,596
(Level of Evidence: A)
2. CRT can be useful for patients who have LVEF of 35%
or less, sinus rhythm, LBBB with a QRS duration of
120 to 149 ms, and NYHA class II, III, or ambula-
tory IV symptoms on GDMT.
78,116,594–596,599
(Level of
Evidence: B)
3. CRT can be useful in patients with AF and LVEF
of 35% or less on GDMT if a) the patient requires
ventricular pacing or otherwise meets CRT cri-
teria and b) atrioventricular nodal ablation or
pharmacological rate control will allow near
100% ventricular pacing with CRT.
600–605
(Level of
Evidence: B)
4. CRT can be useful for patients on GDMT who have
LVEF of 35% or less and are undergoing placement
of a new or replacement device implantation with
anticipated requirement for significant (>40%)
ventricular pacing.
155,602,606,607
(Level of Evidence: C)
Table 20. Strategies for Achieving Optimal GDMT
1. Uptitrate in small increments to the recommended target dose or the highest tolerated dose for those medications listed in Table 15 with an appreciation that
some patients cannot tolerate the full recommended doses of all medications, particularly patients with low baseline heart rate or blood pressure or with a
tendency to postural symptoms.
2. Certain patients (eg, the elderly, patients with chronic kidney disease) may require more frequent visits and laboratory monitoring during dose titration and more
gradual dose changes. However, such vulnerable patients may accrue considerable benefits from GDMT. Inability to tolerate optimal doses of GDMT may
change after disease-modifying interventions such as CRT.
3. Monitor vital signs closely before and during uptitration, including postural changes in blood pressure or heart rate, particularly in patients with orthostatic
symptoms, bradycardia, and/or “low” systolic blood pressure (eg, 80 to 100 mm Hg).
4. Alternate adjustments of different medication classes (especially ACE inhibitors/ARBs and beta blockers) listed in Table 15. Patients with elevated or normal blood
pressure and heart rate may tolerate faster incremental increases in dosages.
5. Monitor renal function and electrolytes for rising creatinine and hyperkalemia, recognizing that an initial rise in creatinine may be expected and does not
necessarily require discontinuation of therapy; discuss tolerable levels of creatinine above baseline with a nephrologist if necessary.
6. Patients may complain of symptoms of fatigue and weakness with dosage increases; in the absence of instability in vital signs, reassure them that these
symptoms are often transient and usually resolve within a few days of these changes in therapy.
7. Discourage sudden spontaneous discontinuation of GDMT medications by the patient and/or other clinicians without discussion with managing clinicians.
8. Carefully review doses of other medications for HF symptom control (eg, diuretics, nitrates) during uptitration.
9. Consider temporary adjustments in dosages of GDMT during acute episodes of noncardiac illnesses (eg, respiratory infections, risk of dehydration, etc).
10. Educate patients, family members, and other clinicians about the expected benefits of achieving GDMT, including an understanding of the potential benefits of
myocardial reverse remodeling, increased survival, and improved functional status and HRQOL.
ACE indicates angiotensin-converting enzyme; ARB, angiotensin-receptor blocker; CRT, cardiac resynchronization therapy; GDMT, guideline-directed medical
therapy; HF, heart failure; and HRQOL, health-related quality of life.
Table 21. Recommendations for Treatment of HFpEF
Recommendations COR LOE
Systolic and diastolic blood pressure should be controlled according to published clinical
practice guidelines
I B
27,91
Diuretics should be used for relief of symptoms due to volume overload.
I C
Coronary revascularization for patients with CAD in whom angina or demonstrable myocardial
ischemia is present despite GDMT
IIa C
Management of AF according to published clinical practice guidelines for HFpEF to improve
symptomatic HF
IIa C
Use of beta-blocking agents, ACE inhibitors, and ARBs for hypertension in HFpEF
IIa C
ARBs might be considered to decrease hospitalizations in HFpEF
IIb B
589
Nutritional supplementation is not recommended in HFpEF III: No Benefit C
ACE indicates angiotensin-converting enzyme; AF, atrial fibrillation; ARBs, angiotensin-receptor blockers; CAD, coronary artery disease;
COR, Class of Recommendation; GDMT, guideline-directed medical therapy; HF, heart failure; HFpEF, heart failure with preserved ejection
fraction; and LOE, Level of Evidence.
†Counseling should be specific to each individual patient and should
include documentation of a discussion about the potential for sudden death
and nonsudden death from HF or noncardiac conditions. Information
should be provided about the efficacy, safety, and potential complications
of an ICD and the potential for defibrillation to be inactivated if desired
in the future, notably when a patient is approaching end of life. This will
facilitate shared decision making between patients, families, and the
medical care team about ICDs.
30
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e277
Class IIb
1. The usefulness of implantation of an ICD is of
uncertain benefit to prolong meaningful survival in
patients with a high risk of nonsudden death as pre-
dicted by frequent hospitalizations, advanced frailty,
or comorbidities such as systemic malignancy or
severe renal dysfunction.†
608–611
(Level of Evidence: B)
2. CRT may be considered for patients who have LVEF
of 35% or less, sinus rhythm, a non-LBBB pattern
with QRS duration of 120 to 149 ms, and NYHA
class III/ambulatory class IV on GDMT.
596,612
(Level
of Evidence: B)
3. CRT may be considered for patients who have LVEF of
35% or less, sinus rhythm, a non-LBBB pattern with a
QRS duration of 150 ms or greater, and NYHA class II
symptoms on GDMT.
595,596
(Level of Evidence: B)
4. CRT may be considered for patients who have LVEF
of 30% or less, ischemic etiology of HF, sinus rhythm,
LBBB with a QRS duration of 150 ms or greater, and
NYHA class I symptoms on GDMT.
595,596
(Level of
Evidence: C)
Class III: No Benefit
1. CRT is not recommended for patients with NYHA
class I or II symptoms and non-LBBB pattern with
QRS duration less than 150 ms.
595,596,612
(Level of
Evidence: B)
2. CRT is not indicated for patients whose comorbidi-
ties and/or frailty limit survival with good functional
capacity to less than 1 year.
38
(Level of Evidence: C)
See Figure 2, indications for CRT therapy algorithm.
Table 22. Recommendations for Device Therapy for Management of Stage C HF
Recommendations COR LOE References
ICD therapy is recommended for primary prevention of SCD in selected patients with HFrEF
at least 40 d post-MI with LVEF ≤35% and NYHA class II or III symptoms on chronic GDMT,
who are expected to live >1 y*
I A 355, 593
CRT is indicated for patients who have LVEF ≤35%, sinus rhythm, LBBB with a QRS
≥150 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT
I A (NYHA class III/IV) 38, 78, 116, 594
B (NYHA class II) 595, 596
ICD therapy is recommended for primary prevention of SCD in selected patients with HFrEF
at least 40 d post-MI with LVEF ≤30% and NYHA class I symptoms while receiving GDMT,
who are expected to live >1 y*
I B 362, 597, 598
CRT can be useful for patients who have LVEF ≤35%, sinus rhythm, a non-LBBB pattern with
QRS ≥150 ms, and NYHA class III/ambulatory class IV symptoms on GDMT
IIa A 78, 116, 594, 596
CRT can be useful for patients who have LVEF ≤35%, sinus rhythm, LBBB with a QRS 120 to
149 ms, and NYHA class II, III, or ambulatory IV symptoms on GDMT
IIa B 78, 116, 594–596,
599
CRT can be useful in patients with AF and LVEF ≤35% on GDMT if a) the patient requires
ventricular pacing or otherwise meets CRT criteria and b) AV nodal ablation or rate control
allows near 100% ventricular pacing with CRT
IIa B 600–605
CRT can be useful for patients on GDMT who have LVEF ≤35% and are undergoing new or
replacement device implantation with anticipated ventricular pacing (>40%)
IIa C 155, 602, 606, 607
An ICD is of uncertain benefit to prolong meaningful survival in patients with a high risk of
nonsudden death such as frequent hospitalizations, frailty, or severe comorbidities*
IIb B 608–611
CRT may be considered for patients who have LVEF ≤35%, sinus rhythm, a non-LBBB pattern
with a QRS duration of 120 to 149 ms, and NYHA class III/ambulatory class IV on GDMT
IIb B 596, 612
CRT may be considered for patients who have LVEF ≤35%, sinus rhythm, a non-LBBB pattern
with QRS ≥150 ms, and NYHA class II symptoms on GDMT
IIb B 595, 596
CRT may be considered for patients who have LVEF ≤30%, ischemic etiology of HF, sinus
rhythm, LBBB with QRS ≥150 ms, and NYHA class I symptoms on GDMT
IIb C 595, 596
CRT is not recommended for patients with NYHA class I or II symptoms and non-LBBB
pattern with QRS <150 ms
III: No Benefit B 595, 596, 612
CRT is not indicated for patients whose comorbidities and/or frailty limit survival to <1 y III: No Benefit C 38
*Counseling should be specific to each individual patient and should include documentation of a discussion about the potential for sudden death and nonsudden death
from HF or noncardiac conditions. Information should be provided about the efficacy, safety, and potential complications of an ICD and the potential for defibrillation to
be inactivated if desired in the future, notably when a patient is approaching end of life. This will facilitate shared decision making between patients, families, and the
medical care team about ICDs.
30
AF indicates atrial fibrillation; AV, atrioventricular; COR, Class of Recommendation; CRT, cardiac resynchronization therapy; GDMT, guideline-directed medical
therapy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; ICD, implantable cardioverter-defibrillator; LBBB, left bundle-branch block; LOE, Level of
Evidence; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NYHA, New York Heart Association; and SCD, sudden cardiac death.
†Counseling should be specific to each individual patient and should
include documentation of a discussion about the potential for sudden death
and nonsudden death from HF or noncardiac conditions. Information
should be provided about the efficacy, safety, and potential complications
of an ICD and the potential for defibrillation to be inactivated if desired
in the future, notably when a patient is approaching end of life. This will
facilitate shared decision making between patients, families, and the
medical care team about ICDs.
30
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e278 Circulation October 15, 2013
7.3.4.1. Implantable Cardioverter-Defibrillator
Patients with reduced LVEF are at increased risk for ventricu-
lar tachyarrhythmias leading to SCD. Sudden death in HFrEF
has been substantially decreased by neurohormonal antagonists
that alter disease progression and also protect against arrhyth-
mias. Nonetheless, patients with systolic dysfunction remain
at increased risk for SCD due to ventricular tachyarrhythmias.
Patients who have had sustained ventricular tachycardia, ven-
tricular fibrillation, unexplained syncope, or cardiac arrest are at
highest risk for recurrence. Indications for ICD therapy as sec-
ondary prevention of SCD in these patients are also discussed in
the ACCF/AHA/HRS device-based therapy guideline.
4
The use of ICDs for primary prevention of SCD in patients
with HFrEF without prior history of arrhythmias or syncope
has been evaluated in multiple RCTs. ICD therapy for primary
prevention was demonstrated to reduce all-cause mortality. For
patients with LVEF ≤30% after remote MI, use of ICD therapy
led to a 31% decrease in mortality over 20 months, for an abso-
lute decrease of 5.6%.
362
For patients with mild to moderate
symptoms of HF with LVEF ≤35% due either to ischemic or
nonischemic etiology, there was a 23% decrease in mortality
over a 5-year period, for an absolute decrease of 7.2%.
593
For
both these trials, the survival benefit appeared after the first year.
Other smaller trials were consistent with this degree of benefit,
except for patients within the first 40 days after acute MI, in
whom SCD was decreased but there was an increase in other
events such that there was no net benefit for survival.
598,614
Both
SCD and total mortality are highest in patients with HFrEF
with class IV symptoms, in whom ICDs are not expected to
prolong meaningful survival and are not indicated except in
those for whom heart transplantation or MCS is anticipated.
The use of ICDs for primary prevention in patients with HFrEF
should be considered only in the setting of optimal GDMT and
with a minimum of 3 to 6 months of appropriate medical ther-
apy. A repeat assessment of ventricular function is appropriate
to assess any recovery of ventricular function on GDMT that
would be above the threshold where an ICD is indicated. This
therapy will often improve ventricular function to a range for
which the risk of sudden death is too low to warrant placement
of an ICD. In addition, the trials of ICDs for primary prevention
of SCD studied patients who were already on GDMT.
ICDs are highly effective in preventing death from ventric-
ular arrhythmias, but frequent shocks can decrease HRQOL
and lead to posttraumatic stress syndrome.
615
Therapy with
antiarrhythmic drugs and catheter ablation for ventricular
tachycardia can decrease the number of ICD shocks given
and can sometimes improve ventricular function in cases of
very frequent ventricular tachyarrhythmias. Refined device
programming can optimize pacing therapies to avert the need
for shocks, minimize inappropriate shocks, and avoid aggra-
vation of HF by frequent ventricular pacing. Although there
have been occasional recalls of device generators, these are
exceedingly rare in comparison to complications related to
intracardiac device leads, such as fracture and infection.
Patient with cardiomyopathy on GDMT for ≥3 mo or on GDMT and ≥40 d after MI, or
with implantation of pacing or defibrillation device for special indications
LVEF ≤35%
Evaluate general health status
Comorbidities and/or frailty
limit survival with good
functional capacity to <1 y
Continue GDMT without
implanted device
Acceptable noncardiac health
Evaluate NYHA clinical status
NYHA class I
• LVEF ≤30%
• QRS ≥150 ms
• LBBB pattern
• Ischemic
cardiomyopathy
• QRS ≤150 ms
• Non-LBBB pattern
NYHA class II
• LVEF ≤35%
• QRS 120-149 ms
• LBBB pattern
• Sinus rhythm
• QRS ≤150 ms
• Non-LBBB pattern
• LVEF ≤35%
• QRS ≥150 ms
• LBBB pattern
• Sinus rhythm
• LVEF ≤35%
• QRS ≥150 ms
• Non-LBBB pattern
• Sinus rhythm
Colors correspond to the class of recommendations in the ACCF/AHA Table 1.
Benefit for NYHA class I and II patients has only been shown in CRT-D trials, and while patients may not experience immediate symptomatic benefit, late remodeling may be avoided along
with long-term HF consequences. There are no trials that support CRT-pacing (without ICD) in NYHA class I and II patients. Thus, it is anticipated these patients would receive CRT-D
unless clinical reasons or personal wishes make CRT-pacing more appropriate. In patients who are NYHA class III and ambulatory class IV, CRT-D may be chosen but clinical reasons and
personal wishes may make CRT-pacing appropriate to improve symptoms and quality of life when an ICD is not expected to produce meaningful benefit in survival.
NYHA class III &
Ambulatory class IV
• LVEF ≤35%
• QRS 120-149 ms
• LBBB pattern
• Sinus rhythm
• LVEF ≤35%
• QRS 120-149 ms
• Non-LBBB pattern
• Sinus rhythm
• LVEF ≤35%
• QRS ≥150 ms
• LBBB pattern
• Sinus rhythm
• LVEF ≤35%
• QRS ≥150 ms
• Non-LBBB pattern
• Sinus rhythm
• Anticipated to require
frequent ventricular
pacing (>40%)
• Atrial fibrillation, if
ventricular pacing is
required and rate
control will result in
near 100%
ventricular pacing
with CRT
Special CRT
Indications
Figure 2. Indications for CRT therapy algorithm. CRT indicates cardiac resynchronization therapy; CRT-D, cardiac resynchronization
therapy-defibrillator; GDMT, guideline-directed medical therapy; HF, heart failure; ICD, implantable cardioverter-defibrillator; LBBB, left
bundle-branch block; LVEF, left ventricular ejection fraction; MI, myocardial infarction; and NYHA, New York Heart Association.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e279
ICDs are indicated only in patients with a reasonable expec-
tation of survival with good functional status beyond a year, but
the range of uncertainty remains wide. The complex decision
about the relative risks and benefits of ICDs for primary pre-
vention of SCD must be individualized for each patient. Unlike
other therapies that can prolong life with HF, the ICD does not
modify the disease except in conjunction with CRT. Patients
with multiple comorbidities have a higher rate of implant com-
plications and higher competing risks of death from noncardiac
causes.
616
Older patients, who are at a higher risk of nonsudden
death, are often underrepresented in the pivotal trials where the
average patient is <65 years of age.
617
The major trials for sec-
ondary prevention of SCD showed no benefit in patients >75
years of age,
618
and a meta-analysis of primary prevention of
SCD also suggested lesser effectiveness of ICDs.
619
Populations
of patients with multiple HF hospitalizations, particularly in the
setting of chronic kidney disease, have a median survival rate
of <2 years, during which the benefit of the ICD may not be
realized.
608
There is widespread recognition of the need for fur-
ther research to identify patients most and least likely to benefit
from ICDs for primary prevention of SCD in HF. Similar con-
siderations apply to the decision to replace the device generator.
Consideration of ICD implantation is highly appropriate for
shared decision making.
30
The risks and benefits carry differ-
ent relative values depending on patient goals and preferences.
Discussion should include the potential for SCD and nonsud-
den death from HF or noncardiac conditions. Information
should be provided in a format that patients can understand
about the estimated efficacy, safety, and potential complica-
tions of an ICD and the ease with which defibrillation can
be inactivated if no longer desired.
620
As the prevalence of
implantable devices increases, it is essential that clearly
defined processes be in place to support patients and families
when decisions about deactivation arise.
621
7.3.4.2. Cardiac Resynchronization Therapy
In approximately one third of patients, HF progression is
accompanied by substantial prolongation of the QRS inter-
val, which is associated with worse outcome.
622
Multisite
ventricular pacing (termed CRT or biventricular pacing) can
improve ventricular contractile function, diminish second-
ary mitral regurgitation, reverse ventricular remodeling, and
sustain improvement in LVEF. Increased blood pressure with
CRT can allow increased titration of neurohormonal antago-
nist medications that may further contribute to improvement.
Benefits were proven initially in trials of patients with NYHA
class III or ambulatory class IV HF symptoms and QRS dura-
tion of ≥120 to 130 ms. These results have included a decrease
of approximately 30% in rehospitalization and reductions in
all-cause mortality in the range of 24% to 36%. Improvement
in survival is evident as early as the first 3 months of therapy.
Functional improvements have been demonstrated on aver-
age as a 1 to 2 mL/kg/min increase in peak oxygen consump-
tion, 50- to 70-meter increase in 6-minute walk distance, and
a reduction of 10 points or more in the 0- to 105-point scale
of the Minnesota Living With Heart Failure Questionnaire,
all considered clinically significant. These results include
patients with a wide range of QRS duration and, in most cases,
sinus rhythm.
78,116,594,623
Although it is still not possible to predict with confidence
which patients will improve with CRT, further experiences
have provided some clarification. Benefit appears confined
largely to patients with a QRS duration of at least 150 ms and
LBBB pattern.
624–628
The weight of the evidence has been accu-
mulated from patients with sinus rhythm, with meta-analyses
indicating substantially less clinical benefit in patients with
permanent AF.
604,605
Because effective CRT requires a high rate
of ventricular pacing,
629
the benefit for patients with AF is most
evident in patients who have undergone atrioventricular nodal
ablation, which ensures obligate ventricular pacing.
601–603
In general, most data derive from patients with class III
symptoms. Patients labeled as having class IV symptoms
account for a small minority of patients enrolled. Furthermore,
these patients, characterized as “ambulatory” NYHA class IV,
are not refractory due to fluid retention, frequently hospital-
ized for HF, or dependent on continuous intravenous inotropic
therapy. CRT should not be considered as “rescue” therapy for
stage D HF. In addition, patients with significant noncardiac
limitations are unlikely to derive major benefit from CRT.
Since publication of the 2009 HF guideline,
38
new evidence
supports extension of CRT to patients with milder symptoms.
LV remodeling was consistently reversed or halted, with ben-
efit also in reduction of HF hospitalizations.
595,596,599
In this
population with low 1-year mortality, reduction of HF hos-
pitalization dominated the composite primary endpoints, but
a mortality benefit was subsequently observed in a 2-year
extended follow-up study
630
and in a meta-analysis of 5 trials
of CRT in mild HF that included 4213 patients with class II
symptoms.
631
Overall benefits in class II HF were noted only
in patients with QRS ≥150 ms and LBBB, with an adverse
impact with shorter QRS duration or non-LBBB.
The entry criterion for LVEF in CRT trials has ranged
from ≤30% to ≤40%. The trials with class III–IV symptoms
included patients with LVEF ≤35%.
78,116,594
The 2 individual
trials showing improvement in mortality with class II HF
included patients with LVEF ≤30%.
632,633
Trials demonstrat-
ing significant improvement in LV size and EF have included
patients with LVEF ≤35%
115
and LVEF ≤40%,
599
which also
showed reduction in the secondary endpoint of time to hos-
pitalization and a reduction in the composite of clinical HF
events comparable to that of all of the CRT trials.
624
The con-
gruence of evidence from the totality of CRT trials with regard
to remodeling and HF events supports a common threshold of
35% for benefit from CRT in patients with class II, III, and IV
HF symptoms. For patients with class II HF, all but 1 of the
trials tested CRT in combination with an ICD, whereas there
is evidence for benefit with both CRT-defibrillator and CRT
alone in patients with class III–IV symptoms.
78,116
Although the weight of evidence is substantial for patients
with class II symptoms, these CRT trials have included only
372 patients with class I symptoms, most with concomitant
ICD for the postinfarction indication.
595,599
Considering the
risk–benefit ratio for class I, more concern is raised by the
early adverse events, which in 1 trial occurred in 13% of
patients with CRT-ICD compared with 6.7% in patients with
ICD only.
596
On the basis of limited data from MADIT-CRT
(Multicenter Automatic Defibrillator Implantation Trial-
Cardiac Resynchronization Therapy), CRT-ICD may be
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e280 Circulation October 15, 2013
considered for patients with class I symptoms >40 days after
MI, LVEF ≤30%, sinus rhythm, LBBB, and QRS ≥150 ms.
595
These indications for CRT all include expectation for ongo-
ing GDMT and diuretic therapy as needed for fluid reten-
tion. In addition, regular monitoring is required after device
implantation because adjustment of HF therapies and repro-
gramming of device intervals may be required. The trials
establishing the benefit of these interventions were conducted
in centers offering expertise in both implantation and follow-
up. Recommendations for CRT are made with the expectation
that they will be performed in centers with expertise and out-
come comparable to that of the trials that provide the bases of
evidence. The benefit–risk ratio for this intervention would be
anticipated to be diminished for patients who do not have access
to these specialized care settings or who are nonadherent.
See Online Data Supplements 28 and 29 for additional data
on device therapy and CRT.
7.4. Stage D
7.4.1. Definition of Advanced HF
A subset of patients with chronic HF will continue to progress
and develop persistently severe symptoms despite maximum
GDMT. Various terminologies have been used to describe this
group of patients who are classified with ACCF/AHA stage
D HF, including “advanced HF,” “end-stage HF,” and “refrac-
tory HF.” In the 2009 ACCF/AHA HF guideline, stage D was
defined as “patients with truly refractory HF who might be
eligible for specialized, advanced treatment strategies, such
as MCS, procedures to facilitate fluid removal, continuous
inotropic infusions, or cardiac transplantation or other inno-
vative or experimental surgical procedures, or for end-of-life
care, such as hospice.”
38
The European Society of Cardiology
has developed a definition of advanced HF with objective cri-
teria that can be useful
32
(Table 23). There are clinical clues
that may assist clinicians in identifying patients who are pro-
gressing toward advanced HF (Table 24). The Interagency
Registry for Mechanically Assisted Circulatory Support
(INTERMACS) has developed 7 profiles that further stratify
patients with advanced HF (Table 25).
635
7.4.2. Important Considerations in Determining If the
Patient Is Refractory
Patients considered to have stage D HF should be thoroughly
evaluated to ascertain that the diagnosis is correct and that there
are no remediable etiologies or alternative explanations for
advanced symptoms. For example, it is important to determine
that HF and not a concomitant pulmonary disorder is the basis
of dyspnea. Similarly, in those with presumed cardiac cachexia,
other causes of weight loss should be ruled out. Likewise, other
reversible factors such as thyroid disorders should be treated.
Severely symptomatic patients presenting with a new diagno-
sis of HF can often improve substantially if they are initially
stabilized. Patients should also be evaluated for nonadherence
to medications,
636–639
sodium restriction,
640
and/or daily weight
monitoring.
641
Finally, a careful review of prior medical man-
agement should be conducted to verify that all evidence-based
therapies likely to improve clinical status have been considered.
See Online Data Supplements 30 and 31 for additional data
on therapies—important considerations and sildenafil.
7.4.3. Water Restriction: Recommendation
Class IIa
1. Fluid restriction (1.5 to 2 L/d) is reasonable in stage
D, especially in patients with hyponatremia, to
reduce congestive symptoms. (Level of Evidence: C)
Recommendations for fluid restriction in HF are largely driven
by clinical experience. Sodium and fluid balance recommenda-
tions are best implemented in the context of weight and symp-
tom monitoring programs. Routine strict fluid restriction in all
Table 23. ESC Definition of Advanced HF
1. Severe symptoms of HF with dyspnea and/or fatigue at rest or with minimal
exertion (NYHA class III or IV)
2. Episodes of fluid retention (pulmonary and/or systemic congestion, peripheral
edema) and/or reduced cardiac output at rest (peripheral hypoperfusion)
3. Objective evidence of severe cardiac dysfunction shown by at least 1 of the
following:
a. LVEF <30%
b. Pseudonormal or restrictive mitral inflow pattern
c. Mean PCWP >16 mm Hg and/or RAP >12 mm Hg by PA catheterization
d. High BNP or NT-proBNP plasma levels in the absence of noncardiac causes
4. Severe impairment of functional capacity shown by 1 of the following:
a. Inability to exercise
b. 6-Minute walk distance ≤300 m
c. Peak V
·
O
2
<12 to 14 mL/kg/min
5. History of ≥1 HF hospitalization in past 6 mo
6. Presence of all the previous features despite “attempts to optimize”
therapy, including diuretics and GDMT, unless these are poorly tolerated
or contraindicated, and CRT when indicated
BNP indicates B-type natriuretic peptide; CRT, cardiac resynchronization
therapy; ESC, European Society of Cardiology; GDMT, guideline-directed
medical therapy; HF, heart failure; LVEF, left ventricular ejection fraction;
NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart
Association; PA, pulmonary artery; PWCP, pulmonary capillary wedge pressure;
and RAP, right atrial pressure.
Adapted from Metra et al.
32
Table 24. Clinical Events and Findings Useful for Identifying
Patients With Advanced HF
Repeated (≥2) hospitalizations or ED visits for HF in the past year
Progressive deterioration in renal function (eg, rise in BUN and creatinine)
Weight loss without other cause (eg, cardiac cachexia)
Intolerance to ACE inhibitors due to hypotension and/or worsening renal function
Intolerance to beta blockers due to worsening HF or hypotension
Frequent systolic blood pressure <90 mm Hg
Persistent dyspnea with dressing or bathing requiring rest
Inability to walk 1 block on the level ground due to dyspnea or fatigue
Recent need to escalate diuretics to maintain volume status, often reaching
daily furosemide equivalent dose >160 mg/d and/or use of supplemental
metolazone therapy
Progressive decline in serum sodium, usually to <133 mEq/L
Frequent ICD shocks
ACE indicates angiotensin-converting enzyme; BUN, blood urea nitrogen;
ED, emergency department; HF, heart failure; and ICD, implantable
cardioverter-defibrillator.
Adapted from Russell et al.
642
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e281
patients with HF regardless of symptoms or other considerations
does not appear to result in significant benefit.
644
Limiting fluid
intake to around 2 L/d is usually adequate for most hospitalized
patients who are not diuretic resistant or significantly hypona-
tremic. In 1 study, patients on a similar sodium and diuretic regi-
men showed higher readmission rates with higher fluid intake,
suggesting that fluid intake affects HF outcomes.
385
Strict fluid
restriction may best be used in patients who are either refractory
to diuretics or have hyponatremia. Fluid restriction, especially
in conjunction with sodium restriction, enhances volume man-
agement with diuretics. Fluid restriction is important to man-
age hyponatremia, which is relatively common with advanced
HF and portends a poor prognosis.
645,646
Fluid restriction may
improve serum sodium concentration; however, it is difficult to
achieve and maintain. In hot or low-humidity climates, exces-
sive fluid restriction predisposes patients with advanced HF to
the risk of heat stroke. Hyponatremia in HF is primarily due to
an inability to excrete free water. Norepinephrine and angioten-
sin II activation result in decreased sodium delivery to the distal
tubule, whereas arginine vasopressin increases water absorption
from the distal tubule. In addition, angiotensin II also promotes
thirst. Thus, sodium and fluid restriction in advanced patients
with HF is important.
7.4.4. Inotropic Support: Recommendations
Class I
1. Until definitive therapy (eg, coronary revasculariza-
tion, MCS, heart transplantation) or resolution of the
acute precipitating problem, patients with cardiogenic
shock should receive temporary intravenous inotropic
support to maintain systemic perfusion and preserve
end-organ performance. (Level of Evidence: C)
Class IIa
1. Continuous intravenous inotropic support is reason-
able as “bridge therapy” in patients with stage D HF
refractory to GDMT and device therapy who are eli-
gible for and awaiting MCS or cardiac transplanta-
tion.
647,648
(Level of Evidence: B)
Class IIb
1. Short-term, continuous intravenous inotropic support
may be reasonable in those hospitalized patients pre-
senting with documented severe systolic dysfunction
who present with low blood pressure and significantly
depressed cardiac output to maintain systemic per-
fusion and preserve end-organ performance.
592,649,650

(Level of Evidence: B)
2. Long-term, continuous intravenous inotropic support
may be considered as palliative therapy for symptom
control in select patients with stage D HF despite opti-
mal GDMT and device therapy who are not eligible
for either MCS or cardiac transplantation.
651–653
(Level
of Evidence: B)
Class III: Harm
1. Long-term use of either continuous or intermittent,
intravenous parenteral positive inotropic agents,
in the absence of specific indications or for reasons
Table 25. INTERMACS Profiles
Profile* Profile Description Features
1 Critical cardiogenic shock
(“Crash and burn”)
Life-threatening hypotension and rapidly escalating inotropic/pressor support, with critical organ hypoperfusion often
confirmed by worsening acidosis and lactate levels.
2 Progressive decline
(“Sliding fast” on inotropes)
“Dependent” on inotropic support but nonetheless shows signs of continuing deterioration in nutrition, renal function,
fluid retention, or other major status indicator. Can also apply to a patient with refractory volume overload, perhaps
with evidence of impaired perfusion, in whom inotropic infusions cannot be maintained due to tachyarrhythmias,
clinical ischemia, or other intolerance.
3 Stable but inotrope dependent Clinically stable on mild-moderate doses of intravenous inotropes (or has a temporary circulatory support device) after
repeated documentation of failure to wean without symptomatic hypotension, worsening symptoms, or progressive
organ dysfunction (usually renal).
4 Resting symptoms on oral therapy
at home
Patient who is at home on oral therapy but frequently has symptoms of congestion at rest or with activities of daily living
(dressing or bathing). He or she may have orthopnea, shortness of breath during dressing or bathing, gastrointestinal
symptoms (abdominal discomfort, nausea, poor appetite), disabling ascites, or severe lower-extremity edema.
5 Exertion intolerant (“housebound”) Patient who is comfortable at rest but unable to engage in any activity, living predominantly within the house or housebound.
6 Exertion limited
(“walking wounded”)
Patient who is comfortable at rest without evidence of fluid overload but who is able to do some mild activity. Activities of
daily living are comfortable and minor activities outside the home such as visiting friends or going to a restaurant can
be performed, but fatigue results within a few minutes or with any meaningful physical exertion.
7 Advanced NYHA class III Patient who is clinically stable with a reasonable level of comfortable activity, despite a history of previous decompensation
that is not recent. This patient is usually able to walk more than a block. Any decompensation requiring intravenous
diuretics or hospitalization within the previous month should make this person a Patient Profile 6 or lower.
*Modifier options: Profiles 3–6 can be modified with the designation frequent flyer for patients with recurrent decompensations leading to frequent (generally at
least 2 in last 3 mo or 3 in last 6 mo) emergency department visits or hospitalizations for intravenous diuretics, ultrafiltration, or brief inotropic therapy. Profile 3 can be
modified in this fashion if the patient is usually at home. If a Profile 7 patient meets the definition of frequent flyer, the patient should be moved to Profile 6 or worse.
Other modifier options include arrhythmia, which should be used in the presence of recurrent ventricular tachyarrhythmias contributing to the overall clinical course
(eg, frequent implantable cardioverter-defibrillator shocks or requirement of external defibrillation, usually more than twice weekly); or temporary circulatory support
for hospitalized patients profiles 1–3.
635
INTERMACS indicates Interagency Registry for Mechanically Assisted Circulatory Support; and NYHA, New York Heart Association.
Adapted from Stevenson et al.
643
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e282 Circulation October 15, 2013
other than palliative care, is potentially harmful in
the patient with HF.
416,654–659
(Level of Evidence: B)
2. Use of parenteral inotropic agents in hospitalized
patients without documented severe systolic dysfunc-
tion, low blood pressure, or impaired perfusion and evi-
dence of significantly depressed cardiac output, with or
without congestion, is potentially harmful.
592,649,650
(Level
of Evidence: B)
Despite improving hemodynamic compromise, positive inotro-
pic agents have not demonstrated improved outcomes in patients
with HF in either the hospital or outpatient setting.
416,654–658

Regardless of their mechanism of action (eg, inhibition of
phosphodiesterase, stimulation of adrenergic or dopaminergic
receptors, calcium sensitization), chronic oral inotrope treat-
ment increased mortality, mostly related to arrhythmic events.
Parenteral inotropes, however, remain as an option to help the
subset of patients with HF who are refractory to other therapies
and are suffering consequences from end-organ hypoperfusion.
Inotropes should be considered only in such patients with sys-
tolic dysfunction who have low cardiac index and evidence of
systemic hypoperfusion and/or congestion (Table 26). To mini-
mize adverse effects, lower doses are preferred. Similarly, the
ongoing need for inotropic support and the possibility of dis-
continuation should be regularly assessed.
See Online Data Supplements 32 and 33 for additional data
on inotropes.
7.4.5. Mechanical Circulatory Support: Recommendations
Class IIa
1. MCS is beneficial in carefully selected‡ patients with
stage D HFrEF in whom definitive management (eg,
cardiac transplantation) or cardiac recovery is antic-
ipated or planned.
660–667
(Level of Evidence: B)
2. Nondurable MCS, including the use of percutaneous
and extracorporeal ventricular assist devices (VADs),
is reasonable as a “bridge to recovery” or “bridge
to decision” for carefully selected‡ patients with
HFrEF with acute, profound hemodynamic compro-
mise.
668–671
(Level of Evidence: B)
3. Durable MCS is reasonable to prolong survival for
carefully selected‡ patients with stage D HFrEF.
672–675

(Level of Evidence: B)
MCS has emerged as a viable therapeutic option for patients
with advanced stage D HFrEF refractory to optimal GDMT
and cardiac device intervention. Since its initial use 50 years
ago for postcardiotomy shock,
676
the implantable VAD contin-
ues to evolve.
Designed to assist the native heart, VADs are differenti-
ated by the implant location (intracorporeal versus extra-
corporeal), approach (percutaneous versus surgical), flow
characteristic (pulsatile versus continuous), pump mecha-
nism (volume displacement, axial, centrifugal), and the
ventricle(s) supported (left, right, biventricular). VADs are
effective in both the short-term (hours to days) management
of acute decompensated, hemodynamically unstable HFrEF
that is refractory to inotropic support, and the long-term
(months to years) management of stage D chronic HFrEF.
Nondurable or temporary, MCS provides an opportunity for
decisions about the appropriateness of transition to defini-
tive management such as cardiac surgery or durable, that
is, permanent, MCS or, in the case of improvement and
recovery, suitability for device removal. Nondurable MCS
thereby may be helpful as either a bridge to decision or a
bridge to recovery.
More common scenarios for MCS, however, are long-
term strategies, including 1) bridge to transplantation, 2)
bridge to candidacy, and 3) destination therapy. Bridge to
transplant and destination therapy have the strongest evi-
dence base with respect to survival, functional capacity, and
HRQOL benefits.
Data from INTERMACS provides valuable information
on risk factors and outcomes for patients undergoing MCS.
Table 26. Intravenous Inotropic Agents Used in Management of HF
Inotropic Agent
Dose (mcg/kg)
Drug Kinetics
and Metabolism
Effects
Adverse Effects
Special
ConsiderationsBolus Infusion (/min) CO HR SVR PVR
Adrenergic agonists
Dopamine N/A 5 to 10 t
½
: 2 to 20 min
R,H,P
↑ ↑ � � T, HA, N, tissue
necrosis
Caution: MAO-I
N/A 10 to 15 ↑ ↑ ↑ �
Dobutamine N/A 2.5 to 5 t
½
: 2 to 3 min
H
↑ ↑ ↓ � ↑/↓BP, HA, T, N, F,
hypersensitivity
Caution: MAO-I;
CI: sulfite allergy
N/A 5 to 20 ↑ ↑ � �
PDE inhibitor
Milrinone N/R 0.125 to 0.75 t
½
: 2.5 h H ↑ ↑ ↓ ↓ T, ↓BP Renal dosing,
monitor LFTs
BP indicates blood pressure; CI, contraindication; CO, cardiac output; F, fever; H, hepatic; HA, headache; HF, heart failure; HR, heart rate; LFT, liver function test;
MAO-I, monoamine oxidase inhibitor; N, nausea; N/A, not applicable; N/R, not recommended; P, plasma; PDE, phosphodiesterase; PVR, pulmonary vascular resistance;
R, renal; SVR, systemic vascular resistance; T, tachyarrhythmias; and t
½
, elimination half-life.
‡Although optimal patient selection for MCS remains an active
area of investigation, general indications for referral for MCS therapy
include patients with LVEF <25% and NYHA class III–IV functional
status despite GDMT, including, when indicated, CRT, with either high
predicted 1- to 2-year mortality (eg, as suggested by markedly reduced
peak oxygen consumption and clinical prognostic scores) or dependence
on continuous parenteral inotropic support. Patient selection requires a
multidisciplinary team of experienced advanced HF and transplantation
cardiologists, cardiothoracic surgeons, nurses, and ideally, social workers
and palliative care clinicians.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e283
The greatest risk factors for death among patients undergoing
bridge to transplant include acuity and severity of clinical con-
dition and evidence of right ventricular failure.
677
MCS may
also be used as a bridge to candidacy. Retrospective studies
have shown reduction in pulmonary pressures with MCS ther-
apy in patients with HF considered to have “fixed” pulmonary
hypertension.
661–663
Thus, patients who may be transplant-inel-
igible due to irreversible severe pulmonary hypertension may
become eligible with MCS support over time. Other bridge-
to-candidacy indications may include obesity and tobacco use
in patients who are otherwise candidates for cardiac transplan-
tation. There is ongoing interest in understanding how MCS
facilitates LV reverse remodeling. Current scientific and trans-
lational research in the area aims to identify clinical, cellular,
molecular, and genomic markers of cardiac recovery in the
patient with VAD.
678,679
See Online Data Supplements 34 and 35 for additional data
on MCS and left VADs.
7.4.6. Cardiac Transplantation: Recommendation
Class I
1. Evaluation for cardiac transplantation is indicated
for carefully selected patients with stage D HF despite
GDMT, device, and surgical management.
680
(Level of
Evidence: C)
Cardiac transplantation is considered the gold standard for
the treatment of refractory end-stage HF. Since the first suc-
cessful cardiac transplantation in 1967, advances in immu-
nosuppressive therapy have vastly improved the long-term
survival of transplant recipients with a 1-, 3-, and 5-year post-
transplant survival rate of 87.8%, 78.5%, and 71.7% in adults,
respectively.
681
Similarly, cardiac transplantation has been
shown to improve functional status and HRQOL.
682–688
The
greatest survival benefit is seen in those patients who are at
highest risk of death from advanced HF.
689
Cardiopulmonary
exercise testing helps refine candidate selection.
690–696
Data
suggest acceptable posttransplant outcomes in patients with
reversible pulmonary hypertension,
697
hypertrophic car-
diomyopathy,
698
peripartum cardiomyopathy,
699
restrictive
cardiomyopathy,
700,701
and muscular dystrophy.
702
Selected
patients with stage D HF and poor prognosis should be
referred to a cardiac transplantation center for evaluation and
transplant consideration. Determination of HF prognosis is
addressed in Sections 6.1.2 and 7.4.2. The listing criteria and
evaluation and management of patients undergoing cardiac
transplantation are described in detail by the International
Society for Heart and Lung Transplantation.
680
See Table 27 for a summary of recommendations from this
section, Figure 3 for the stages of HF development; and Online
Data Supplement 36 for additional data on transplantation.
Table 27. Recommendations for Inotropic Support, MCS, and Cardiac Transplantation
Recommendations COR LOE References
Inotropic support
Cardiogenic shock pending definitive therapy or resolution I C N/A
BTT or MCS in stage D refractory to GDMT IIa B 647, 648
Short-term support for threatened end-organ dysfunction in hospitalized patients with
stage D and severe HFrEF
IIb B 592, 649, 650
Long-term support with continuous infusion palliative therapy in select stage D HF IIb B 651–653
Routine intravenous use, either continuous or intermittent, is potentially harmful in stage D HF III: Harm B 416, 654–659
Short-term intravenous use in hospitalized patients without evidence of shock or
threatened end-organ performance is potentially harmful
III: Harm B 592, 649, 650
MCS
MCS is beneficial in carefully selected* patients with stage D HF in whom definitive
management (eg, cardiac transplantation) is anticipated or planned
IIa B 660–667
Nondurable MCS is reasonable as a “bridge to recovery” or “bridge to decision” for
carefully selected* patients with HF and acute profound disease
IIa B 668–671
Durable MCS is reasonable to prolong survival for carefully selected* patients with
stage D HFrEF
IIa B 672–675
Cardiac transplantation
Evaluation for cardiac transplantation is indicated for carefully selected patients with
stage D HF despite GDMT, device, and surgical management
I C 680
*Although optimal patient selection for MCS remains an active area of investigation, general indications for referral for MCS therapy include patients
with LVEF <25% and NYHA class III–IV functional status despite GDMT, including, when indicated, CRT, with either high predicted 1- to 2-year mortality
(eg, as suggested by markedly reduced peak oxygen consumption and clinical prognostic scores) or dependence on continuous parenteral inotropic
support. Patient selection requires a multidisciplinary team of experienced advanced HF and transplantation cardiologists, cardiothoracic surgeons,
nurses and ideally, social workers and palliative care clinicians.
BTT indicates bridge to transplant; COR, Class of Recommendation; CRT, cardiac resynchronization therapy; GDMT, guideline-directed medical
therapy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; LOE, Level of Evidence; LVEF, left ventricular ejection fraction; MCS,
mechanical circulatory support; N/A, not applicable; and NYHA, New York Heart Association.
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e284 Circulation October 15, 2013
8. The Hospitalized Patient
8.1. Classification of Acute Decompensated HF
Hospitalization for HF is a growing and major public health
issue.
703
Presently, HF is the leading cause of hospitalization
among patients >65 years of age
51
; the largest percentage of
expenditures related to HF are directly attributable to hospi-
tal costs. Moreover, in addition to costs, hospitalization for
acutely decompensated HF represents a sentinel prognostic
event in the course of many patients with HF, with a high
risk for recurrent hospitalization (eg, 50% at 6 months) and
a 1-year mortality rate of approximately 30%.
211,704
The AHA
has published a scientific statement about this condition.
705
There is no widely accepted nomenclature for HF syndromes
requiring hospitalization. Patients are described as having
“acute HF,” “acute HF syndromes,” or “acute(ly) decompen-
sated HF”; while the third has gained greatest acceptance, it
too has limitations, for it does not make the important distinc-
tion between those with a de novo presentation of HF from
those with worsening of previously chronic stable HF.
Data from HF registries have clarified the profile of patients
with HF requiring hospitalization.
107,704,706,707
Characteristically,
such patients are elderly or near elderly, equally male or female,
and typically have a history of hypertension, as well as other
medical comorbidities, including chronic kidney disease, hypo-
natremia, hematologic abnormalities, and chronic obstructive
pulmonary disease.
107,706,708–713
A relatively equal percentage of
patients with acutely decompensated HF have impaired versus
preserved LV systolic function
707,714,715
; clinically, patients with
preserved systolic function are older, more likely to be female,
to have significant hypertension, and to have less CAD. The
overall morbidity and mortality for both groups is high.
Hospitalized patients with HF can be classified into impor-
tant subgroups. These include patients with acute coronary
ischemia, accelerated hypertension and acutely decompen-
sated HF, shock, and acutely worsening right HF. Patients
who develop HF decompensation after surgical procedures
also bear mention. Each of these various categories of HF has
specific etiologic factors leading to decompensation, presenta-
tion, management, and outcomes.
Noninvasive modalities can be used to classify the patient
with hospitalized HF. The history and physical examination
allows estimation of a patient’s hemodynamic status, that
is, the degree of congestion (“dry” versus “wet”), as well as
STAGE A
At high risk for HF but
without structural heart
disease or symptoms of HF
STAGE B
Structural heart disease
but without signs or
symptoms of HF
THERAPY
Goals
Control symptoms
Improve HRQOL
Prevent hospitalization
Prevent mortality
Strategies
Identification of
comorbidities
Treatment
Diuresis to relieve
symptoms of congestion
Follow guideline driven
indications for
comorbidities, e.g., HTN,
AF, CAD, DM
STAGE C
Structural heart disease
with prior or current
symptoms of HF
THERAPY
Goals
Control symptoms
Patient education
Prevent hospitalization
Prevent mortality
Drugs for routine use
Diuretics for fluid retention
ACEI or ARB
Beta blockers
Aldosterone antagonists
Drugs for use in selected patients
Hydralazine/isosorbide dinitrate
ACEI and ARB
Digitalis
In selected patients
CRT
ICD
Revascularization or valvular
surgery as appropriate
STAGE D
Refractory HF
THERAPY
Goals
Prevent HF symptoms
Prevent further cardiac
remodeling
Drugs
ACEI or ARB as
appropriate
Beta blockers as
appropriate
In selected patients

ICD
Revascularization or
valvular surgery as
appropriate
e.g., Patients with:
Known structural heart disease and
HF signs and symptoms
HFpEF HFrEF
THERAPY
Goals
Heart healthy lifestyle
Prevent vascular,
coronary disease
Prevent LV structural
abnormalities
Drugs
ACEI or ARB in
appropriate patients for
vascular disease or DM
Statins as appropriate
THERAPY
Goals
Control symptoms
Improve HRQOL
Reduce hospital
readmissions
Establish patient’s end-
of-life goals
Options
Advanced care
measures
Heart transplant
Chronic inotropes
Temporary or permanent
MCS
Experimental surgery or
drugs
Palliative care and
hospice
ICD deactivation
Refractory
symptoms of HF
at rest, despite
GDMT
At Risk for Heart FailureHeart Failure
e.g., Patients with:
Marked HF symptoms at
rest
Recurrent hospitalizations
despite GDMT
e.g., Patients with:
Previous MI
LV remodeling including
LVH and low EF
Asymptomatic valvular
disease
e.g., Patients with:
HTN
Atherosclerotic disease
DM
Obesity
Metabolic syndrome
or
Patients
Using cardiotoxins
With family history of
cardiomyopathy
Development of
symptoms of HF
Structural heart
disease
Figure 3. Stages in the development of HF and recommended therapy by stage. ACEI indicates angiotensin-converting enzyme inhibitor;
AF, atrial fibrillation; ARB, angiotensin-receptor blocker; CAD, coronary artery disease; CRT, cardiac resynchronization therapy;
DM, diabetes mellitus; EF, ejection fraction; GDMT, guideline-directed medical therapy; HF, heart failure; HFpEF, heart failure with
preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HRQOL, health-related quality of life; HTN, hypertension;
ICD, implantable cardioverter-defibrillator; LV, left ventricular; LVH, left ventricular hypertrophy; MCS, mechanical circulatory support;
and MI, myocardial infarction. Adapted from Hunt et al.
38
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e285
the adequacy of their peripheral perfusion (“warm” versus
“cold”)
716
(Figure 4). Chest x-ray is variably sensitive for the
presence of interstitial or alveolar edema, even in the presence
of elevated filling pressures. Thus, a normal chest x-ray does
not exclude acutely decompensated HF.
717
The utility of natri-
uretic peptides in patients with acutely decompensated HF
has been described in detail in Section 6.3.1. Both BNP and
NT-proBNP are useful for the identification or exclusion of
acutely decompensated HF in dyspneic patients,
247,249,250,718,719

particularly in the context of uncertain diagnosis.
720–722
Other
options for diagnostic evaluation of patients with suspected
acutely decompensated HF, such as acoustic cardiography,
723

bioimpedance vector monitoring,
724
or noninvasive cardiac
output monitoring
725
are not yet validated.
8.2. Precipitating Causes of Decompensated HF:
Recommendations
Class I
1. ACS precipitating acute HF decompensation
should be promptly identified by ECG and serum
biomarkers, including cardiac troponin testing,
and treated optimally as appropriate to the over-
all condition and prognosis of the patient. (Level of
Evidence: C)
2. Common precipitating factors for acute HF should
be considered during initial evaluation, as recogni-
tion of these conditions is critical to guide appropri-
ate therapy. (Level of Evidence: C)
ACS is an important cause of worsening or new-onset HF.
726

Although acute ST-segment elevation myocardial infarction
can be readily apparent on an ECG, other ACS cases may
be more challenging to diagnose. Complicating the clinical
scenario is that many patients with acute HF, with or with-
out CAD, have serum troponin levels that are elevated.
727
However, many other patients may have low levels of
detectable troponins not meeting criteria for an acute ischemic
event.
278,728
Registry data have suggested that the use of coro-
nary angiography is low for patients hospitalized with decom-
pensated HF, and opportunities to diagnose important CAD
may be missed.
729
For the patient with newly discovered HF,
clinicians should always consider the possibility that CAD is
an underlying cause of HF.
726
Besides ACS, several other precipitating causes of acute HF
decompensation must be carefully assessed to inform appro-
priate treatment, optimize outcomes, and prevent future acute
events in patients with HF.
730
See list below.
Common Factors That Precipitate Acute
Decompensated HF
s Nonadherence with medication regimen, sodium and/or
fluid restriction
s Acute myocardial ischemia
s Uncorrected high blood pressure
s AF and other arrhythmias
s Recent addition of negative inotropic drugs (eg, verapamil,
nifedipine, diltiazem, beta blockers)
s Pulmonary embolus
s Initiation of drugs that increase salt retention (eg, steroids,
thiazolidinediones, NSAIDs)
s Excessive alcohol or illicit drug use
s Endocrine abnormalities (eg, diabetes mellitus, hyperthy-
roidism, hypothyroidism)
s Concurrent infections (eg, pneumonia, viral illnesses)
s Additional acute cardiovascular disorders (eg, valve disease
endocarditis, myopericarditis, aortic dissection)
Hypertension is an important contributor to acute HF, par-
ticularly among blacks, women, and those with HFpEF.
731
In
the ADHERE registry, almost 50% of patients admitted with
HF had blood pressure >140/90 mm Hg.
107
Abrupt discon-
tinuation of antihypertensive therapy may precipitate wors-
ening HF. The prevalence of AF in patients with acute HF is
>30%.
731
Infection increases metabolic demands in general.
Pulmonary infections, which are common in patients with
HF, may add hypoxia to the increased metabolic demands
and are associated with worse outcomes.
730
The sepsis syn-
drome is associated with reversible myocardial depression
that is likely mediated by cytokine release.
732
Patients with
HF are hypercoagulable, and the possibility of pulmonary
embolus as an etiology of acute decompensation should be
considered. Deterioration of renal function can be both a con-
sequence and contributor to decompensated HF. Restoration
of normal thyroid function in those with hypothyroidism or
hyperthyroidism may reverse abnormal cardiovascular func-
tion.
733
In patients treated with amiodarone, thyroid distur-
bances should be suspected.
Excessive sodium and fluid intake may precipitate acute
HF.
379,384
Medication nonadherence for financial or other rea-
sons is a major cause of hospital admission.
734
Several drugs
may precipitate acute HF (eg, calcium channel blockers, anti-
arrhythmic agents, glucocorticoids, NSAIDs and cyclooxy-
genase-2 inhibitors, thiazolidinediones, and over-the-counter
agents like pseudoephedrine). Finally, excessive alcohol intake
and use of illicit drugs, such as cocaine and methamphet-
amine, also need to be investigated as potential causes of HF
decompensation.
See Online Data Supplement 37 for additional data on
comorbidities in the hospitalized patient.
Congestion at rest?
(e.g. orthopnea, elevated jugular venous pressure, pulmonary rales, S3 gallop, edema)
L
o
w

p
e
r
f
u
s
i
o
n

a
t

r
e
s
t
?
(
e
.
g
.

n
a
r
r
o
w

p
u
l
s
e

p
r
e
s
s
u
r
e
,

c
o
o
l

e
x
t
r
e
m
i
t
i
e
s
,

h
y
p
o
t
e
n
s
i
o
n
)
No
No
Yes
Yes
Warm and Dry Warm and Wet
Cold and Dry Cold and Wet
Figure 4. Classification of patients presenting with acutely decom-
pensated heart failure. Adapted with permission from Nohria et al.
716
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e286 Circulation October 15, 2013
8.3. Maintenance of GDMT During Hospitalization:
Recommendations
Class I
1. In patients with HFrEF experiencing a symptomatic
exacerbation of HF requiring hospitalization dur-
ing chronic maintenance treatment with GDMT, it
is recommended that GDMT be continued in the
absence of hemodynamic instability or contraindica-
tions.
195,735,736
(Level of Evidence: B)
2. Initiation of beta-blocker therapy is recommended
after optimization of volume status and successful
discontinuation of intravenous diuretics, vasodilators,
and inotropic agents. Beta-blocker therapy should be
initiated at a low dose and only in stable patients.
Caution should be used when initiating beta blockers
in patients who have required inotropes during their
hospital course.
195,735,736
(Level of Evidence: B)
The patient’s maintenance HF medications should be carefully
reviewed on admission, and it should be decided whether adjust-
ments should be made as a result of the hospitalization. In the
majority of patients with HFrEF who are admitted to the hos-
pital, oral HF therapy should be continued, or even uptitrated,
during hospitalization. It has been demonstrated that continu-
ation of ACE inhibitors or ARBs and beta blockers for most
patients is well tolerated and results in better outcomes.
195,735,736

Withholding of, or reduction in, beta-blocker therapy should
be considered only in patients hospitalized after recent initia-
tion or increase in beta-blocker therapy or with marked volume
overload or marginal/low cardiac output. Patients admitted with
significant worsening of renal function should be considered
for a reduction in, or temporary discontinuation of ACE inhibi-
tors, ARBs, and/or aldosterone antagonists until renal function
improves. Although it is important to ensure that evidence-
based medications are instituted before hospital discharge, it is
equally critical to reassess medications on admission and adjust
their administration in light of the worsening HF.
8.4. Diuretics in Hospitalized Patients:
Recommendations
Class I
1. Patients with HF admitted with evidence of signifi-
cant fluid overload should be promptly treated with
intravenous loop diuretics to reduce morbidity.
737,738

(Level of Evidence: B)
2. If patients are already receiving loop diuretic therapy,
the initial intravenous dose should equal or exceed their
chronic oral daily dose and should be given as either
intermittent boluses or continuous infusion. Urine out-
put and signs and symptoms of congestion should be seri-
ally assessed, and the diuretic dose should be adjusted
accordingly to relieve symptoms, reduce volume excess,
and avoid hypotension.
739
(Level of Evidence: B)
3. The effect of HF treatment should be monitored with
careful measurement of fluid intake and output, vital
signs, body weight that is determined at the same time
each day, and clinical signs and symptoms of systemic
perfusion and congestion. Daily serum electrolytes,
urea nitrogen, and creatinine concentrations should
be measured during the use of intravenous diuretics or
active titration of HF medications. (Level of Evidence: C)
Class IIa
1. When diuresis is inadequate to relieve symptoms, it
is reasonable to intensify the diuretic regimen using
either:
a. higher doses of intravenous loop diuretics
38,739

(Level of Evidence: B); or
b. addition of a second (eg, thiazide) diuretic.
740–743

(Level of Evidence: B).
Class IIb
1. Low-dose dopamine infusion may be considered in
addition to loop diuretic therapy to improve diuresis
and better preserve renal function and renal blood
flow.
744,745
(Level of Evidence: B)
Patients with significant fluid overload should be initially
treated with loop diuretics given intravenously during hospi-
talization. Therapy should begin in the emergency department
without delay, as early therapy has been associated with better
outcomes.
37,738
Patients should be carefully monitored, includ-
ing serial evaluation of volume status and systemic perfusion.
Monitoring of daily weight, supine and standing vital signs,
and fluid input and output is necessary for daily management.
Assessment of daily electrolytes and renal function should
be performed while intravenous diuretics are administered or
HF medications are actively titrated. Intravenous loop diuret-
ics have the potential to reduce glomerular filtration rate, fur-
ther worsen neurohumoral activation, and produce electrolyte
disturbances. Thus, although the use of diuretics may relieve
symptoms, their impact on mortality has not been well studied.
Diuretics should be administered at doses sufficient to achieve
optimal volume status and relieve congestion without induc-
ing an excessively rapid reduction in intravascular volume,
which could result in hypotension, renal dysfunction, or both.
Because loop diuretics have a relatively short half-life, sodium
reabsorption in the tubules will occur once the tubular concen-
tration of the diuretics declines. Therefore, limiting sodium
intake and dosing the diuretic continuously or multiple times
per day will enhance diuretic effectiveness.
434,737,746–748
Some patients may present with moderate to severe renal
dysfunction such that the diuretic response may be blunted,
necessitating higher initial diuretic doses. In many cases, reduc-
tion of fluid overload may improve congestion and improve
renal function, particularly if significant venous congestion is
reduced.
749
Clinical experience suggests it is difficult to deter-
mine whether congestion has been adequately treated in many
patients, and registry data have confirmed that patients are fre-
quently discharged after a net weight loss of only a few pounds.
Although patients may rapidly improve symptomatically, they
may remain congested or hemodynamically compromised.
Routine use of serial natriuretic peptide measurement or Swan-
Ganz catheter has not been conclusively shown to improve out-
comes among these patients. Nevertheless, careful evaluation
of all physical findings, laboratory parameters, weight change,
and net fluid change should be considered before discharge.
When a patient does not respond to initial intravenous diuret-
ics, several options may be considered. Efforts should be made to
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e287
make certain that congestion persists and that another hemody-
namic profile or alternate disease process is not evident. If there
is doubt about the fluid status, consideration should be given for
assessment of filling pressures and cardiac output using right-
heart catheterization. If volume overload is confirmed, the dose of
the loop diuretic should be increased to ensure that adequate drug
levels reach the kidney. Adding a second diuretic, typically a thia-
zide, can improve diuretic responsiveness.
435,442,443
Theoretically,
continuous diuretic infusion may enhance diuresis because con-
tinuous diuretic delivery to the nephron avoids rebound sodium
and fluid reabsorption.
440,441,750,751
However, the DOSE (Diuretic
Optimization Strategies Evaluation) trial did not find any signifi-
cant difference between continuous infusion versus intermittent
bolus strategies for symptoms, diuresis, or outcomes.
739
It is rea-
sonable to try an alternate approach of using either bolus or con-
tinuous infusion therapy different from the initial strategy among
patients who are resistant to diuresis. Finally, some data suggest
that low-dose dopamine infusion in addition to loop diuretics
may improve diuresis and better preserve renal function, although
ongoing trials will provide further data on this effect.
744
See Online Data Supplement 17 for additional data on
diuretics.
8.5. Renal Replacement Therapy—Ultrafiltration:
Recommendations
Class IIb
1. Ultrafiltration may be considered for patients with
obvious volume overload to alleviate congestive
symptoms and fluid weight.
752
(Level of Evidence: B)
2. Ultrafiltration may be considered for patients with
refractory congestion not responding to medical
therapy. (Level of Evidence: C)
If all diuretic strategies are unsuccessful, ultrafiltration may be
considered. Ultrafiltration moves water and small- to medium-
weight solutes across a semipermeable membrane to reduce
volume overload. Because the electrolyte concentration is
similar to plasma, relatively more sodium can be removed
than by diuretics.
753–755
Initial studies supporting use of ultra-
filtration in HF were small but provided safety and efficacy
data in acute HF.
755–757
Use of ultrafiltration in HF has been
shown to reduce neurohormone levels and increase diuretic
responsiveness. In a larger trial of 200 unselected patients
with acute HF, ultrafiltration did reduce weight compared with
bolus or continuous diuretics at 48 hours, had similar effects
on the dyspnea score compared with diuretics, and improved
readmission rate at 90 days.
752
A randomized acute HF trial
in patients with cardiorenal syndrome and persistent con-
gestion has failed to demonstrate a significant advantage of
ultrafiltration over bolus diuretic therapy.
758,759
Cost, the need
for veno-venous access, provider experience, and nursing sup-
port remain concerns about the routine use of ultrafiltration.
Consultation with a nephrologist is appropriate before initiat-
ing ultrafiltration, especially in circumstances where the non-
nephrology provider does not have sufficient experience with
ultrafiltration.
See Online Data Supplements 17 and 38 for additional data
on diuretics versus ultrafiltration in acute decompensated HF
and worsening renal function and mortality.
8.6. Parenteral Therapy in Hospitalized HF:
Recommendation
Class IIb
1. If symptomatic hypotension is absent, intravenous
nitroglycerin, nitroprusside, or nesiritide may be
considered an adjuvant to diuretic therapy for relief
of dyspnea in patients admitted with acutely decom-
pensated HF.
760–763
(Level of Evidence: A)
The different vasodilators include 1) intravenous nitroglyc-
erin, 2) sodium nitroprusside, and 3) nesiritide.
Intravenous nitroglycerin acts primarily through venodi-
lation, lowers preload, and may help to rapidly reduce pul-
monary congestion.
764,765
Patients with HF and hypertension,
coronary ischemia, or significant mitral regurgitation are often
cited as ideal candidates for the use of intravenous nitroglyc-
erin. However, tachyphylaxis to nitroglycerin may develop
within 24 hours, and up to 20% of those with HF may develop
resistance to even high doses.
766–768
Sodium nitroprusside is a balanced preload-reducing veno-
dilator and afterload-reducing arteriodilator that also dilates
the pulmonary vasculature.
769
Data demonstrating efficacy
are limited, and invasive hemodynamic blood pressure moni-
toring (such as an arterial line) is typically required; in such
cases, blood pressure and volume status should be monitored
frequently. Nitroprusside has the potential for producing
marked hypotension and is usually used in the intensive care
setting as well; longer infusions of the drug have been rarely
associated with thiocyanate toxicity, particularly in the setting
of renal insufficiency. Nitroprusside is potentially of value
in severely congested patients with hypertension or severe
mitral valve regurgitation complicating LV dysfunction.
Nesiritide (human BNP) reduces LV filling pressure but has
variable effects on cardiac output, urinary output, and sodium
excretion. An initial study demonstrated that the severity
of dyspnea is reduced more rapidly compared with diuret-
ics alone.
760
A large randomized trial in patients with acute
decompensated HF demonstrated nesiritide had no impact on
mortality, rehospitalization, or renal function, a small but sta-
tistically significant impact on dyspnea, and an increased risk
of hypotension.
762
Because nesiritide has a longer effective
half-life than nitroglycerin or nitroprusside, adverse effects
such as hypotension may persist longer. Overall, presently
there are no data that suggest that intravenous vasodilators
improve outcomes in the patient hospitalized with HF; as such,
use of intravenous vasodilators is limited to the relief of dys-
pnea in the hospitalized HF patient with intact blood pressure.
Administration of intravenous vasodilators in patients with
HFpEF should be done with caution because these patients
are typically more volume sensitive.
The use of inotropic support as indicated for hospitalized
HF with shock or impending shock and/or end-organ perfu-
sion limitations is addressed in Section 7.4.4. See Table 26 for
drug therapies and Online Data Supplements 32 and 33 for
additional information on inotropic support.
See Online Data Supplement 39 for additional data on
nesiritide.
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e288 Circulation October 15, 2013
8.7. Venous Thromboembolism Prophylaxis in
Hospitalized Patients: Recommendation
Class I
1. A patient admitted to the hospital with decompensated
HF should receive venous thromboembolism prophy-
laxis with an anticoagulant medication if the risk–
benefit ratio is favorable.
21,770
(Level of Evidence: B)
HF has long been recognized as affording additional risk for
venous thromboembolic disease, associated with a number of
pathophysiologic changes, including reduced cardiac output,
increased systemic venous pressure, and chemical changes
promoting blood clotting. When patients are hospitalized for
decompensated HF or when patients with chronic stable HF
are hospitalized for other reasons, they are at increased risk for
venous thromboembolic disease, although accurate numerical
estimates are lacking in the literature.
Most early data on the effectiveness of different anticoagulant
regimens to reduce the incidence of venous thromboembolic dis-
ease in hospitalized patients were either observational, retrospec-
tive reports
776,777
or prospective studies using a variety of drugs and
differing definitions of therapeutic effect and endpoints,
774,778–780

making summary conclusions difficult. Early studies involved
patients with far longer hospital lengths of stay than occur pres-
ently and were performed well before present standard-of-care
treatments and diagnostic tests were available.
774,778–780
Newer
trials using presently available antithrombotic drugs often were
not limited to patients with HF but included those with other
acute illnesses, severe respiratory diseases, or simply a broad
spectrum of hospitalized medical patients.
771–774,781
In most stud-
ies, patients were categorized as having HF by admitting diag-
nosis, clinical signs, or functional class, whereas only 1 study
782

provided LVEF data on enrolled study patients. All included tri-
als tried to exclude patients perceived to have an elevated risk of
bleeding complications or with an elevated risk of toxicity from
the specific agent tested (eg, enoxaparin in patients with com-
promised renal function). Patients with HF typically made up
a minority of the study cohort, and significance of results were
not always reported by the authors, making ACCF/AHA class I
recommendations difficult to support using this guideline meth-
odology. In some trials, concurrent aspirin was allowed but not
controlled for as a confounding variable.
772,783
For patients admitted specifically for decompensated HF and
with adequate renal function (serum creatinine <2.0 mg/dL),
randomized trials suggest that enoxaparin 40 mg subcutaneously
once daily
770,773,774,783
or unfractionated heparin 5000 units subcu-
taneously every 8 hours
771
will reduce radiographically demon-
strable venous thrombosis. Effects on mortality or clinically
significant pulmonary embolism rates are unclear. Lower doses
of enoxaparin do not appear superior to placebo,
770,773
whereas
continuing weight-based enoxaparin therapy up to 3 months after
hospital discharge does not appear to provide additional benefit.
782
A single prospective study failed to demonstrate certoparin
to be noninferior to unfractionated heparin,
783
whereas retro-
spective analysis of a prospective trial of dalteparin was under-
powered to determine benefit in its HF cohort.
776
Fondaparinux
failed to show significant difference from placebo in an RCT
that included a subgroup of 160 patients with HF.
781
No adequate trials have evaluated anticoagulant benefit in
patients with chronic but stable HF admitted to the hospital
for other reasons. However, the MEDENOX (Medical Patients
with Enoxaparin) trial suggested that the benefit of enoxaparin
may extend to this population.
770,773,774
A systematic review
784
failed to demonstrate prophylactic
efficacy of graded compression stockings in general medical
patients, but significant cutaneous complications were associ-
ated with their use. No studies were performed exclusively on
patients with HF. Two RCTs in patients with stroke found no
efficacy of these devices.
785,786
See Online Data Supplement 20 for additional data on
anticoagulation.
8.8. Arginine Vasopressin Antagonists:
Recommendation
Class IIb
1. In patients hospitalized with volume overload,
including HF, who have persistent severe hypona-
tremia and are at risk for or having active cognitive
symptoms despite water restriction and maximiza-
tion of GDMT, vasopressin antagonists may be con-
sidered in the short term to improve serum sodium
concentration in hypervolemic, hyponatremic states
with either a V
2
receptor selective or a nonselective
vasopressin antagonist.
787,788
(Level of Evidence: B)
Even mild hyponatremia may be associated with neurocogni-
tive problems, including falls and attention deficits.
789
Treatment
of hypervolemic hyponatremia with a V
2
-selective vasopressin
antagonist (tolvaptan) was associated with a significant improve-
ment in the mental component of the Medical Outcomes Study
Short Form General Health Survey.
788
Hyponatremia may be
treated with water restriction and maximization of GDMT that
modulate angiotensin II, leading to improved renal perfusion
and decreased thirst. Alternative causes of hyponatremia (eg,
syndrome of inappropriate antidiuretic hormone, hypothyroid-
ism, and hypoaldosteronism) should be assessed. Vasopressin
antagonists improve serum sodium in hypervolemic, hypo-
natremic states
787,788
; however, longer-term therapy with a V
2
-
selective vasopressin antagonist did not improve mortality in
patients with HF.
790,791
Currently, 2 vasopressin antagonists are
available for clinical use: conivaptan and tolvaptan. It may be
reasonable to use a nonselective vasopressin antagonist to treat
hyponatremia in patients with HF with cognitive symptoms due
to hyponatremia. However, the long-term safety and benefit of
this approach remains unknown. A summary of the recommen-
dations for the hospitalized patient appears in Table 28.
8.9. Inpatient and Transitions of Care:
Recommendations
See Table 29 for a summary of recommendations from this
section.
Class I
1. The use of performance improvement systems and/or
evidence-based systems of care is recommended in the
hospital and early postdischarge outpatient setting to
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e289
identify appropriate HF patients for GDMT, provide
clinicians with useful reminders to advance GDMT,
and assess the clinical response.
82,365,706,792–796
(Level of
Evidence: B)
2. Throughout the hospitalization as appropriate,
before hospital discharge, at the first postdischarge
visit, and in subsequent follow-up visits, the following
should be addressed.
204,795,797–799
(Level of Evidence: B):
a. initiation of GDMT if not previously established
and not contraindicated;
b. precipitant causes of HF, barriers to optimal care
transitions, and limitations in postdischarge support;
Table 28. Recommendations for Therapies in the Hospitalized HF Patient
Recommendations COR LOE References
HF patients hospitalized with fluid overload should be treated with intravenous
diuretics
I B 737, 738
HF patients receiving loop diuretic therapy should receive an initial parenteral
dose greater than or equal to their chronic oral daily dose; then dose should
be serially adjusted
I B 739
HFrEF patients requiring HF hospitalization on GDMT should continue GDMT
except in cases of hemodynamic instability or where contraindicated
I B 195, 735, 736
Initiation of beta-blocker therapy at a low dose is recommended after
optimization of volume status and discontinuation of intravenous agents
I B 195, 735, 736
Thrombosis/thromboembolism prophylaxis is recommended for patients
hospitalized with HF
I B 21, 770–774
Serum electrolytes, urea nitrogen, and creatinine should be measured during
titration of HF medications, including diuretics
I C N/A
When diuresis is inadequate, it is reasonable to
a. give higher doses of intravenous loop diuretics; or
b. add a second diuretic (eg, thiazide)
IIa
B 38, 739
B 740–743
Low-dose dopamine infusion may be considered with loop diuretics to improve
diuresis
IIb B 744, 745
Ultrafiltration may be considered for patients with obvious volume overload IIb B 752
Ultrafiltration may be considered for patients with refractory congestion IIb C N/A
Intravenous nitroglycerin, nitroprusside, or nesiritide may be considered an
adjuvant to diuretic therapy for stable patients with HF
IIb A 760–763
In patients hospitalized with volume overload and severe hyponatremia,
vasopressin antagonists may be considered
IIb B 787, 788
COR indicates Class of Recommendation; GDMT, guideline-directed medical therapy; HF, heart failure; HFrEF, heart failure with reduced
ejection fraction; LOE, Level of Evidence; and N/A, not available.
Table 29. Recommendations for Hospital Discharge
Recommendations or Indications COR LOE References
Performance improvement systems in the hospital and early postdischarge
outpatient setting to identify HF for GDMT
I B 82, 365,
706,
792–796
Before hospital discharge, at the first postdischarge visit, and in subsequent
follow-up visits, the following should be addressed:
a. initiation of GDMT if not done or contraindicated;
b. causes of HF, barriers to care, and limitations in support;
c. assessment of volume status and blood pressure with adjustment of HF
therapy;
d. optimization of chronic oral HF therapy;
e. renal function and electrolytes;
f . management of comorbid conditions;
g. HF education, self-care, emergency plans, and adherence; and
h. palliative or hospice care
I B 204, 795,
797–799
Multidisciplinary HF disease-management programs for patients at high risk for
hospital readmission are recommended
I B 82,
800–802
A follow-up visit within 7 to 14 d and/or a telephone follow-up within 3 d of
hospital discharge are reasonable
IIa B 101, 803
Use of clinical risk-prediction tools and/or biomarkers to identify higher-risk patients
are reasonable
IIa B 215
COR indicates Class of Recommendation; GDMT, guideline-directed medical therapy; HF, heart failure; and LOE, Level of Evidence.
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e290 Circulation October 15, 2013
c. assessment of volume status and supine/upright
hypotension with adjustment of HF therapy as
appropriate;
d. titration and optimization of chronic oral HF therapy;
e. assessment of renal function and electrolytes where
appropriate;
f. assessment and management of comorbid
conditions;
g. reinforcement of HF education, self-care, emer-
gency plans, and need for adherence; and
h. consideration for palliative care or hospice care in
selected patients.
3. Multidisciplinary HF disease-management programs
are recommended for patients at high risk for hospi-
tal readmission, to facilitate the implementation of
GDMT, to address different barriers to behavioral
change, and to reduce the risk of subsequent rehospi-
talization for HF.
82,800–802
(Level of Evidence: B)
Class IIa
1. Scheduling an early follow-up visit (within 7 to 14 days)
and early telephone follow-up (within 3 days) of hospi-
tal discharge are reasonable.
101,803
(Level of Evidence: B)
2. Use of clinical risk-prediction tools and/or biomark-
ers to identify patients at higher risk for postdischarge
clinical events are reasonable.
215
(Level of Evidence: B)
Decisions about pharmacological therapies delivered dur-
ing hospitalization likely can impact postdischarge outcome.
Continuation or initiation of HF GDMT prior to hospital dis-
charge is associated with substantially improved clinical out-
comes for patients with HFrEF. However, caution should be used
when initiating beta blockers in patients who have required ino-
tropes during their hospital course or when initiating ACE inhibi-
tors, ARBs, or aldosterone antagonists in those patients who have
experienced marked azotemia or are at risk for hyperkalemia.
The patient should be transitioned to oral diuretic therapy to ver-
ify its effectiveness. Similarly, optimal volume status should be
achieved. Blood pressure should be adequately controlled, and,
in patients with AF, ventricular response should also be well con-
trolled. The hospitalization is a “teachable moment” to reinforce
patient and family education and develop a plan of care, which
should be communicated to the appropriate healthcare team.
Safety for patients hospitalized with HF is crucial. System
changes necessary to achieve safer care include the adoption
by all US hospitals of a standardized set of 30 “Safe Practices”
endorsed by the National Quality Forum
804
and National Patient
Safety Goals espoused by The Joint Commission.
805
Improved
communication between clinicians and nurses, medication
reconciliation, carefully planned transitions between care set-
tings, and consistent documentation are examples of patient
safety standards that should be ensured for patients with HF
discharged from the hospital.
The prognosis of patients hospitalized with HF, and espe-
cially those with serial readmissions, is suboptimal. Hence,
appropriate levels of symptomatic relief, support, and pal-
liative care for patients with chronic HF should be addressed
as an ongoing key component of the plan of care, especially
when patients are hospitalized with acute decompensation.
806

The appropriateness of discussion about advanced therapy or
end-of-life preferences is reviewed in Section 11.
For patients with HF, the transition from inpatient to outpatient
care can be an especially vulnerable period because of the pro-
gressive nature of the disease state, complex medical regimens,
the large number of comorbid conditions, and the multiple clini-
cians who may be involved. Patient education and written dis-
charge instructions or educational material given to the patient,
family members, and/or caregiver during the hospital stay or at
discharge to home are essential components of transition care.
These should address all of the following: activity level, diet,
discharge medications, follow-up appointment, weight monitor-
ing, and what to do if symptoms worsen.
297
Thorough discharge
planning that includes special emphasis on ensuring adherence
to an evidence-based medication regimen
795
is associated with
improved patient outcomes.
792,797,807
More intensive delivery of
discharge instructions, coupled tightly with subsequent well-
coordinated follow-up care for patients hospitalized with HF, has
produced positive results in several studies.
82,793,800
The addition
of a 1-hour, nurse educator–delivered teaching session at the time
of hospital discharge, using standardized instructions, resulted
in improved clinical outcomes, increased self-care and treat-
ment adherence, and reduced cost of care. Patients receiving the
education intervention also had a lower risk of rehospitalization
or death and lower costs of care.
365
There are ongoing efforts to
further develop evidence-based interventions in this population.
Transitional care extends beyond patient education. Care
information, especially changes in orders and new diagnostic
information, must be transmitted in a timely and clearly under-
standable form to all of the patient’s clinicians who will be
delivering follow-up care. Other important components of tran-
sitional care include preparation of the patient and caregiver for
what to expect at the next site of care, reconciliation of medi-
cations, follow-up plans for outstanding tests, and discussions
about monitoring signs and symptoms of worsening conditions.
Early outpatient follow-up, a central element of transitional care,
varies significantly across US hospitals. Early postdischarge fol-
low-up may help minimize gaps in understanding of changes
to the care plan or knowledge of test results and has been asso-
ciated with a lower risk of subsequent rehospitalization.
803
A
follow-up visit within 7 to 14 days and/or a telephone follow-up
within 3 days of hospital discharge are reasonable goals of care.
See Online Data Supplement 40 for additional data on oral
medications for the hospitalized patient.
9. Important Comorbidities in HF
9.1. Atrial Fibrillation§
Patients with HF are more likely than the general population to
develop AF.
808
There is a direct relationship between the NYHA
class and prevalence of AF in patients with HF progressing
from 4% in those who are NYHA class I to 40% in those who
are NYHA class IV.
809
AF is also a strong independent risk fac-
tor for subsequent development of HF.
376,808
In addition to those
§The “ACC/AHA/ESC 2006 Guidelines for the Management of
Patients With Atrial Fibrillation” and the 2 subsequent focused updates
from 2011
6–8
are considered policy at the time of publication of the present
HF Guideline; however, a fully revised AF guideline, which will include
updated recommendations on AF, is in development, with publication
expected in 2013 or 2014.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e291
with HFrEF, patients with HFpEF are also at greater risk for
AF than the general age-matched population.
811
HF and AF can
interact to promote their perpetuation and worsening through
mechanisms such as rate-dependent worsening of cardiac func-
tion, fibrosis, and activation of neurohumoral vasoconstrictors.
AF can worsen symptoms in patients with HF, and, conversely,
worsened HF can promote a rapid ventricular response in AF.
Similar to other patient populations, for those with AF and
HF, the main goals of therapy are prevention of thromboembo-
lism and symptom control. Most patients with AF and HF would
be expected to be candidates for systemic anticoagulation unless
otherwise contraindicated. General principles of management
include correction of underlying causes of AF and HF as well as
optimization of HF management (Table 30). As in other patient
populations, the issue of rate control versus rhythm control has
been investigated. For patients who develop HF as a result of AF,
a rhythm control strategy should be pursued. It is important to
recognize that AF with a rapid ventricular response is one of the
few potentially reversible causes of HF. Because of this, a patient
who presents with newly detected HF in the presence of AF with
a rapid ventricular response should be presumed to have a rate-
related cardiomyopathy until proved otherwise. In this situation,
2 strategies can be considered. One is rate control of the patient’s
AF and see if HF and EF improve. The other is to try to restore
and maintain sinus rhythm. In this situation, it is common prac-
tice to initiate amiodarone and then arrange for cardioversion
1 month later. Amiodarone has the advantage of being both an
effective rate-control medication and the most effective antiar-
rhythmic medication with a lower risk of proarrhythmic effect.
In patients with HF who develop AF, a rhythm-control strat-
egy has not been shown to be superior to a rate-control strat-
egy.
812
If rhythm control is chosen, limited data suggest that AF
catheter ablation in HF patients may lead to improvement in LV
function and quality of life but is less likely to be effective than
in patients with intact cardiac function.
813,814
Because of their
favorable effect on morbidity and mortality in patients with
systolic HF, beta-adrenergic blockers are the preferred agents
for achieving rate control unless otherwise contraindicated.
Table 30. Clinical Evaluation in Patients With AF
Minimum evaluation
1. History and physical examination, to define •    Presence and nature of symptoms associated with AF
•    Clinical type of AF (paroxysmal, persistent, or permanent)
•    Onset of first symptomatic attack or date of discovery of AF
•    Frequency, duration, precipitating factors, and modes of termination of AF
•    Response to any pharmacological agents that have been administered
•    Presence of any underlying heart disease or other reversible conditions (eg, hyperthyroidism or alcohol 
consumption)
2. ECG, to identify •    Rhythm (verify AF)
•    LV hypertrophy
•    P-wave duration and morphology or fibrillatory waves
•    Preexcitation
•    Bundle-branch block
•    Prior MI
•    Other atrial arrhythmias
•    To measure and follow the R-R, QRS, and QT intervals in conjunction with antiarrhythmic drug therapy
3. Transthoracic echocardiogram, to identify •    Valvular heart disease
•    LA and RA size
•    LV and RV size and function
•    Peak RV pressure (pulmonary hypertension)
•    LV hypertrophy
•    LA thrombus (low sensitivity)
•    Pericardial disease
4. Blood tests of thyroid, renal, and hepatic function •    For a first episode of AF, when the ventricular rate is difficult to control
Additional testing (one or several tests may be necessary)
1. 6-Minute walk test •    If the adequacy of rate control is in question
2. Exercise testing •    If the adequacy of rate control is in question (permanent AF)
•    To reproduce exercise-induced AF
•    To exclude ischemia before treatment of selected patients with a type IC antiarrhythmic drug
3. Holter monitoring or event recording •    If diagnosis of the type of arrhythmia is in question
•    As a means of evaluating rate control
4. Transesophageal echocardiography •    To identify LA thrombus (in the LA appendage)
•    To guide cardioversion
5. Electrophysiological study •    To clarify the mechanism of wide-QRS-complex tachycardia
•    To identify a predisposing arrhythmia such as atrial flutter or paroxysmal supraventricular tachycardia
•    To seek sites for curative ablation or AV conduction block/modification
6. Chest x-ray to evaluate •    Lung parenchyma, when clinical findings suggest an abnormality
•    Pulmonary vasculature, when clinical findings suggest an abnormality
Type IC refers to the Vaughan Williams classification of antiarrhythmic drugs.
AF indicates atrial fibrillation; AV, atrioventricular; ECG, electrocardiogram; LA, left atrial; LV, left ventricular; MI, myocardial infarction; RA, right atrial; and RV, right
ventricular.
Reproduced from Fuster et al.
6
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e292 Circulation October 15, 2013
Figure 5. Pharmacological man-
agement of patients with newly
discovered AF. AF indicates atrial
fibrillation; and HF, heart failure.
Reproduced from Fuster et al.
6
Pharmacologic management of the patient with newly
discovered AF
Pharmacologicmanagement of thepatient withnewly
discoveredAF
Paroxysmal
Paroxysmal
Persistent
Persistent
No therapy needed unless
significant symptoms (e.g.,
hypotension, HF, angina pectoris)
No therapy needed unless
significant symptoms(e.g.,
hypotension, HF, angina pectoris)
Anticoagulation as needed
Anticoagulationasneeded
Accept permanent AF
Accept permanent AF
ate control and
anticoagulation as needed
Rate control and
anticoagulationasneeded
Anticoagulation
and rate control
as needed
Anticoagulation
and ratecontrol
as needed
Consider antiarrhythmic
drug therapy
Consider antiarrhythmic
drug therapy
Cardioversion
Cardioversion
Long-term antiarrhythmic
drug therapy as necessary
Long-term antiarrhythmic
drug therapyasnecessary
Figure 6. Pharmacological
management of patients with recur-
rent paroxysmal AF. AF indicates
atrial fibrillation. Reproduced from
Fuster et al.
6
Pharmacologic management of the patient with recurrent
paroxysmal AF
Pharmacologic management of thepatient with recurrent
paroxysmalAF
inimal or no symptoms
Minimalorno symptoms
Disabling symptoms in AF
Disabling symptoms in AF
Anticoagulation and rate control
as needed
Anticoagulation and rate control
as needed
No drug for prevention of AF
No drug forprevention of AF
Anticoagulation and rate
control as needed
Anticoagulation andrate
controlasneeded
ntiarrhythmic therapy
Antiarrhythmictherapy
AF ablation if
antiarrhytyy hmic therapy
treatment fails
AF ablation if
antiarrhythmic therapy
treatment fails
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e293
Digoxin may be an effective adjunct to a beta blocker. The non-
dihydropyridine calcium antagonists, such as diltiazem, should
be used with caution in those with depressed EF because of
their negative inotropic effect. For those with HFpEF, nondihy-
dropyridine calcium antagonists can be effective for achieving
rate control but may be more effective when used in combina-
tion with digoxin. For those for whom a rate-control strategy
is chosen, when rate control cannot be achieved either because
of drug inefficacy or intolerance, atrioventricular node abla-
tion and CRT device placement can be useful.
78,116,595,596
See
Figures 5 and 6 for AF treatment algorithms.
See Online Data Supplement 41 for additional data on AF.
9.2. Anemia
Anemia is a common finding in patients with chronic HF.
Although variably reported, in part due to the lack of con-
sensus on the definition of anemia, the prevalence of anemia
among patients with HF increases with HF severity. Anemia
is also more common in women and is seen in both patients
with HFrEF and HFpEF.
818–823
The World Health Organization
defines anemia as a hemoglobin level of <12 g/dL in women and
<13 g/dL in men. Registries have reported anemia to be present
in 25% to 40% of HF patients.
818–820
Anemia is associated with
an increased mortality risk in HF. In a large study of >150,000
patients, the mortality risk was approximately doubled in ane-
mic HF patients compared with those without anemia, and this
risk persisted after controlling for other confounders, including
renal dysfunction and HF severity.
818
Anemia is also associated
with reduced exercise capacity, impaired HRQOL, and a higher
risk for hospitalization.
225,819,824,825
These risks are inversely and
linearly associated with hemoglobin levels, although a U-shaped
risk with the highest hemoglobin levels has been reported.
822,826
Multiple etiological factors, many of which coexist within
individual patients, contribute to the development of anemia
in HF. Anemia in patients with HF is often normocytic and
accompanied by an abnormally low reticulocyte count.
825,827

Evaluation of anemia in HF requires careful consideration of
other causes, the most common being secondary causes of iron
deficiency anemia.
In persons without identifiable causes of anemia, erythropoi-
esis-stimulating agents have gained significant interest as poten-
tial adjunctive therapy in the patient with HF. In a retrospective
study of erythropoiesis-stimulating agents in 26 patients with
HF and anemia, the hemoglobin level, LVEF, and functional
class improved.
828
These patients required lower diuretic doses
and were hospitalized less often. Similar findings were also
observed in a randomized open-label study of 32 patients.
829
A
single-blind RCT showed that erythropoietin increased hemo-
globin, peak oxygen uptake, and exercise duration in patients
with severe HF and anemia.
830
Two further studies confirmed
these findings; however, none of these were double blind.
831,832
These positive data led to 2 larger studies. A 165-patient study
showed that darbepoetin alfa was associated with improvement
in several HRQOL measures with a trend toward improved
exercise capacity (6-minute walking distance +34±7 m versus
+11±10 m, P=0.074).
833
In STAMINA-HeFT (Study of Anemia
in Heart Failure Trial), 319 patients were randomly assigned
to darbepoetin alfa or placebo for 12 months.
834
Although dar-
bepoetin alfa did not improve exercise duration, it was well
tolerated, and a trend toward improvement in the composite
endpoint of all-cause mortality or first hospitalization for HF
was seen (hazard ratio: 0.68; 95% confidence interval: 0.43 to
1.08; P=0.10).
834
These favorable data led to the design and
initiation of the RED-HF (Phase III Reduction of Events With
Darbepoetin alfa in Heart Failure) trial.
835
Two trials in erythropoiesis-stimulating agents, however,
later raised concerns that patients treated with an erythropoi-
esis-stimulating agent may have an increased risk of cardio-
vascular events.
836,837
Because the populations in these trials
differed, the RED-HF trial was continued. Nevertheless, at
the completion of the trial, the investigators concluded that
treatment with darbepoetin alfa did not improve clinical out-
comes in patients with systolic HF and mild-to-moderate
anemia.
838
Finally, a trial using intravenous iron as a supple-
ment in patients with HFrEF with iron deficiency showed an
improvement in functional status.
840
There were no untoward
adverse effects of iron in this trial. In the absence of a defini-
tive evidence base, the writing committee has deferred a spe-
cific treatment recommendation regarding anemia.
9.3. Depression
Depression is common in patients with HF; those with
depressive symptoms have lower HRQOL, poorer self-care,
worse clinical outcomes, and more use of healthcare ser-
vices.
841–843
Although it might be assumed that depression
occurs only among hospitalized patients,
844
a multicenter
study demonstrated that even at least 3 months after a hos-
pitalization, 63% of patients with HF reported symptoms
of depression.
845
Potential pathophysiologic mechanisms
proposed to explain the high prevalence of depression in
HF include autonomic nervous system dysfunction, inflam-
mation, cardiac arrhythmias, and altered platelet function,
but the mechanism remains unclear.
846
Although remission
from depression may improve cardiovascular outcomes, the
most effective intervention strategy is not yet known.
842
9.4. Other Multiple Comorbidities
Although there are additional and important comorbidities
that afflict patients with HF as shown in Table 31, how best to
generate specific recommendations remains uncertain, given
the status of current evidence.
10. Surgical/Percutaneous/Transcatheter
Interventional Treatments of
HF: Recommendations
See Table 32 for a summary of recommendations from this
section.
Class I
1. Coronary artery revascularization via CABG or
percutaneous intervention is indicated for patients
(HFpEF and HFrEF) on GDMT with angina and suit-
able coronary anatomy, especially for a left main ste-
nosis (>50%) or left main equivalent disease.
10,12,14,848

(Level of Evidence: C)
Class IIa
1. CABG to improve survival is reasonable in patients
with mild to moderate LV systolic dysfunction (EF
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e294 Circulation October 15, 2013
35% to 50%) and significant (≥70% diameter ste-
nosis) multivessel CAD or proximal left anterior
descending coronary artery stenosis when viable
myocardium is present in the region of intended
revascularization.
848–850
(Level of Evidence: B)
2. CABG or medical therapy is reasonable to improve
morbidity and cardiovascular mortality for patients
with severe LV dysfunction (EF <35%), HF, and sig-
nificant CAD.
309,851
(Level of Evidence: B)
3. Surgical aortic valve replacement is reasonable for
patients with critical aortic stenosis and a predicted
surgical mortality of no greater than 10%.
852
(Level
of Evidence: B)
4. Transcatheter aortic valve replacement after careful
candidate consideration is reasonable for patients
with critical aortic stenosis who are deemed inoper-
able.
853
(Level of Evidence: B)
Class IIb
1. CABG may be considered with the intent of improv-
ing survival in patients with ischemic heart disease
with severe LV systolic dysfunction (EF <35%) and
operable coronary anatomy whether or not viable
myocardium is present.
307–309
(Level of Evidence: B)
2. Transcatheter mitral valve repair or mitral valve
surgery for functional mitral insufficiency is of
uncertain benefit and should only be considered after
careful candidate selection and with a background of
GDMT.
854–857
(Level of Evidence: B)
Table 32. Recommendations for Surgical/Percutaneous/Transcatheter Interventional Treatments of HF
Recommendations COR LOE References
CABG or percutaneous intervention is indicated for HF patients on GDMT with
angina and suitable coronary anatomy, especially significant left main
stenosis or left main equivalent
I C 10, 12, 14, 848
CABG to improve survival is reasonable in patients with mild to moderate
LV systolic dysfunction and significant multivessel CAD or proximal LAD
stenosis when viable myocardium is present
IIa B 848–850
CABG or medical therapy is reasonable to improve morbidity and mortality for
patients with severe LV dysfunction (EF <35%), HF, and significant CAD
IIa B 309, 851
Surgical aortic valve replacement is reasonable for patients with critical
aortic stenosis and a predicted surgical mortality of no greater than 10%
IIa B 852
Transcatheter aortic valve replacement is reasonable for patients with critical
aortic stenosis who are deemed inoperable
IIa B 853
CABG may be considered in patients with ischemic heart disease, severe
LV systolic dysfunction, and operable coronary anatomy whether or not
viable myocardium is present
IIb B 307–309
Transcatheter mitral valve repair or mitral valve surgery for functional mitral
insufficiency is of uncertain benefit
IIb B 854–857
Surgical reverse remodeling or LV aneurysmectomy may be considered in HFrEF
for specific indications, including intractable HF and ventricular arrhythmias
IIb B 858
CABG indicates coronary artery bypass graft; CAD, coronary artery disease; COR, Class of Recommendation; EF, ejection fraction; GDMT,
guideline-directed medical therapy; HF, heart failure; HFrEF, heart failure with reduced ejection fraction; LAD, left anterior descending; LOE,
Level of Evidence; and LV, left ventricular.
Table 31. Ten Most Common Co-Occurring Chronic Conditions Among Medicare Beneficiaries With HF (N=4 947 918), 2011
Beneficiaries Age ≥65 y (N=4 376 150)* Beneficiaries Age <65 y (N=571 768)†
N % N %
Hypertension 3 685 373 84.2 Hypertension 461 235 80.7
Ischemic heart disease 3 145 718 71.9 Ischemic heart disease 365 889 64.0
Hyperlipidemia 2 623 601 60.0 Diabetes 338 687 59.2
Anemia 2 200 674 50.3 Hyperlipidemia 325 498 56.9
Diabetes 2 027 875 46.3 Anemia 284 102 49.7
Arthritis 1 901 447 43.5 Chronic kidney disease 257 015 45.0
Chronic kidney disease 1 851 812 42.3 Depression 207 082 36.2
COPD 1 311 118 30.0 Arthritis 201 964 35.3
Atrial fibrillation 1 247 748 28.5 COPD 191 016 33.4
Alzheimer’s disease/dementia 1 207 704 27.6 Asthma 88 816 15.5
*Mean No. of conditions is 6.1; median is 6.
†Mean No. of conditions is 5.5; median is 5.
COPD indicates chronic obstructive pulmonary disease; and HF, heart failure.
Data source: Centers for Medicare and Medicaid Services administrative claims data, January 2011−December 2011, from the Chronic Condition Warehouse (CCW),
ccwdata.org.
847
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e295
3. Surgical reverse remodeling or LV aneurysmectomy
may be considered in carefully selected patients with
HFrEF for specific indications, including intractable HF
and ventricular arrhythmias.
858
(Level of Evidence: B)
Surgical therapies and percutaneous interventions that are
commonly integrated, or at least considered, in HF man-
agement include coronary revascularization (eg, CABG,
angioplasty, stenting); aortic valve replacement; mitral valve
replacement or repair; septal myectomy or alcohol septal
ablation for hypertrophic cardiomyopathy; surgical ablation
of ventricular arrhythmia; MCS; and cardiac transplanta-
tion.
675,680,859,860
Surgical placement of ICDs or LV pacing leads
is of historical importance but may be considered in situations
where transvenous access is not feasible.
The most common reason for intervention is CAD.
Myocardial viability indicates the likelihood of improved out-
comes with either surgical or medical therapy but does not
identify patients with greater survival benefit from revascular-
ization.
304
The dictum of CABG for left main CAD and reduced
LV function was considered absolute and subsequently extrap-
olated to all severities of LV dysfunction without a confirma-
tory evidence base.
848
Newer studies have addressed patients
with multivessel CAD, HF, and at least moderately severe to
severe LV systolic dysfunction.
861,862
Both surgical and medical
therapies have similar outcomes, and decisions about revas-
cularization should be made jointly by the HF team and car-
diothoracic surgeon. The most important considerations in the
decision to proceed with a surgical or interventional approach
include coronary anatomy that is amenable to revasculariza-
tion and appropriate concomitant GDMT. Valvular heart dis-
ease is not an infrequent cause of HF; however, when valvular
disease is managed correctly and pre-emptively, its adverse
consequences on ventricular mechanics can be ameliorated.
The advent of effective transcatheter approaches to both mitral
and aortic disease creates the need for greater considerations
of structural interventions for patients with LV systolic dys-
function and valvular heart disease. To date, the surgical or
transcatheter management of functional mitral insufficiency
has not been proven superior to medical therapy. A decision
to intervene in functional mitral regurgitation should be made
on a case-by-case basis, and consideration should be given to
participation in clinical trials and/or databases. The surgical or
transcatheter management of critical aortic stenosis is an effec-
tive strategy with reasonable outcomes noted even in patients
with advanced age (>80 years). Indications for other surgical
or percutaneous interventions in the setting of HF are driven
by other relevant guidelines or other sections of this guideline,
including myomectomy for hypertrophic cardiomyopathy, sur-
gical or electrophysiological procedures for AF, nondurable or
durable MCS, and heart transplantation.
Several procedures under evaluation hold promise but are
not yet appropriate for a guideline-driven indication (Table 33).
This includes revascularization as a means to support cel-
lular regenerative therapies. For patients willing to consider
regenerative technologies, the ideal strategy is referral to an
enrolling clinical trial at a center experienced in both high-
risk revascularization and cell-based science.
863–865
Surgical
reverse-ventricular remodeling (ventricular reconstruction)
does not appear to be of benefit but may be considered in
carefully selected patients with HFrEF for specified indica-
tions, including retractable HF and ventricular arrhythmias.
858
11. Coordinating Care for Patients
With Chronic HF
11.1. Coordinating Care for Patients With Chronic
HF: Recommendations
Class I
1. Effective systems of care coordination with special atten-
tion to care transitions should be deployed for every
patient with chronic HF that facilitate and ensure effec-
tive care that is designed to achieve GDMT and prevent
hospitalization.
80,82,793,870–884
(Level of Evidence: B)
2. Every patient with HF should have a clear, detailed,
and evidence-based plan of care that ensures the
achievement of GDMT goals, effective management
of comorbid conditions, timely follow-up with the
healthcare team, appropriate dietary and physical
activities, and compliance with secondary prevention
guidelines for cardiovascular disease. This plan of
care should be updated regularly and made readily
available to all members of each patient’s healthcare
team.
13
(Level of Evidence: C)
3. Palliative and supportive care is effective for patients
with symptomatic advanced HF to improve quality
of life.
30,885–888
(Level of Evidence: B)
Education, support, and involvement of patients with HF and
their families are critical and often complex, especially dur-
ing transitions of care. Failure to understand and follow a
detailed and often nuanced plan of care likely contributes to
the high rates of HF 30-day rehospitalization and mortality
seen across the United States.
61,889
One critical intervention to
ensure effective care coordination and transition is the provi-
sion of a comprehensive plan of care, with easily understood,
Table 33. Surgical/Percutaneous/Transcatheter Interventions
in Patients With HF
References
Appropriate Guideline-Directed Surgical/Percutaneous/
Transcatheter Interventions for HF
1. Surgical or percutaneous revascularization 10, 12, 14
2. Surgical or transcatheter aortic valve replacement 852, 853
3. Surgical myomectomy or alcohol ablation for hypertrophic
cardiomyopathy
11
4. Nondurable MCS for cardiogenic shock 668–671
5. Durable MCS for advanced HF 672–675
6. Heart transplantation 680
7. Surgical/electrophysiological ablation of ventricular tachycardia 866
Surgical/Percutaneous/Transcatheter Interventions Under
Evaluation in Patients With HF
1. Transcatheter intervention for functional mitral
insufficiency
854–857
2. Left atrial resection/left atrial appendage removal, surgical
or percutaneous, for AF
867
3. MCS for advanced HF as a bridge to recovery 868, 869
AF indicates atrial fibrillation; HF, heart failure; and MCS, mechanical
circulatory support.
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e296 Circulation October 15, 2013
culturally sensitive, and evidence-based educational materials,
to patients with HF and/or caregivers during both hospital and
office-based encounters. A comprehensive plan of care should
promote successful patient self-care.
870,884,890
Hence, the plan of
care for patients with HF should continuously address in detail
a number of complex issues, including adherence to GDMT,
timely follow-up with the healthcare professionals who man-
age the patient’s HF and associated comorbidities, appropriate
dietary and physical activities, including cardiac rehabilitation,
and adherence to an extensive list of secondary prevention rec-
ommendations based on established guidelines for cardiovas-
cular disease (Table 34). Clinicians must maintain vigilance
about psychosocial, behavioral, and socioeconomic issues that
patients with HF and their caregivers face, including access to
care, risk of depression, and healthcare disparities.
639,891–895
For
example, patients with HF who live in skilled nursing facilities
are at higher risk for adverse events, with a 1-year mortality rate
>50%.
896
Furthermore, community-dwelling patients with HF
are often unable to afford the large number of medications pre-
scribed, thereby leading to suboptimal medication adherence.
897
11.2. Systems of Care to Promote Care
Coordination for Patients With Chronic HF
Improved communication between clinicians and nurses, med-
ication reconciliation, carefully planned transitions between
care settings, and consistent documentation are examples of
patient safety standards that should be ensured for all patients
with HF. The National Quality Forum has also endorsed a set of
patient-centered “Preferred Practices for Care Coordination,”
898

which detail comprehensive specifications for successful care
coordination for patients and their families.
Systems of care designed to support patients with HF and
other cardiac diseases can produce a significant improvement in
outcomes. Furthermore, the Centers for Medicare and Medicaid
Services is now financially penalizing hospitals for avoidable
hospitalizations and readmissions, thereby emphasizing the
importance of such systems-based care coordination of patients
with HF.
899
However, the quality of evidence is mixed for specific
components of HF clinical management interventions, such as
home-based care,
871,872
disease management,
873,874,880
and remote
telemonitoring programs.
80,875,876,878
Unfortunately, numerous
and nonstandardized definitions of disease management,
873,879,880

including the specific elements that compose disease manage-
ment, impede efforts to improve the care of patients with HF.
Hence, more generic multidisciplinary strategies for improv-
ing the quality and cost-effectiveness of systems-based HF care
should be evaluated with equal weight to those interventions
focused on improving adherence to GDMT. For example, multi-
disciplinary approaches can reduce rates of hospitalization for HF.
Programs involving specialized follow-up by a multidisciplinary
team decrease all-cause hospitalizations and mortality; however,
this has not been shown for “disease management programs” that
focus only on self-care activities.
82,793,881,882,900
Furthermore, patient
characteristics may be important predictors of HF and other car-
diac disease–related survival and hospitalization. Overall, very
few specific interventions have been consistently identified and
successfully applied in clinical practice.
204,214,901–903
See Online Data Supplements 42 and 43 for additional data
on disease management and telemonitoring.
11.3. Palliative Care for Patients With HF
The core elements of comprehensive palliative care for HF
delivered by clinicians include expert symptom assessment and
management. Ongoing care should address symptom control,
psychosocial distress, HRQOL, preferences about end-of-life
care, caregiver support, and assurance of access to evidence-based
disease-modifying interventions. The HF team can help patients
and their families explore treatment options and prognosis. The
HF and palliative care teams are best suited to help patients and
families decide when end-of-life care (including hospice) is
appropriate.
30,885–888,904
Assessment for frailty and dementia is part
of this decision care process offered to the patient and family.
Data suggest that advance directives specifying limitations in
end-of-life care are associated with significantly lower levels of
Medicare spending, lower likelihood of in-hospital death, and
higher use of hospice care in regions characterized by higher lev-
els of end-of-life spending.
905
In newly diagnosed cancer patients,
palliative care interventions delivered early have had a positive
impact on survival and HRQOL. This approach may also be
relevant for HF.
906
Access to formally trained palliative care spe-
cialists may be limited in ambulatory settings. Therefore, cardi-
ologists, primary care physicians, physician assistants, advanced
practice nurses, and other members of the HF healthcare team
should be familiar with these local treatment options. Evaluation
for cardiac transplantation or MCS in experienced centers should
include formal palliative care consultation, which can improve
advanced care planning and enhance the overall quality of deci-
sion making and integrated care for these patients, regardless of
the advanced HF therapy selected.
907
12. Quality Metrics/Performance
Measures: Recommendations
Class I
1. Performance measures based on professionally devel-
oped clinical practice guidelines should be used with
the goal of improving quality of care for HF.
706,801,917

(Level of Evidence: B)
Class IIa
1. Participation in quality improvement programs and
patient registries based on nationally endorsed, clini-
cal practice guideline–based quality and performance
measures can be beneficial in improving the quality of
HF care.
706,801
(Level of Evidence: B)
Quality measurement and accountability have become inte-
gral parts of medical practice over the past 2 decades. HF has
been a specific target of quality measurement, improvement,
and reporting because of its substantial impact on population
morbidity and mortality. Commonly used performance mea-
sures for HF can be considered in 2 distinct categories: pro-
cess measures and outcomes measures.
Process performance measures focus on the aspects of care
that are delivered to a patient (eg, the prescription of a particu-
lar drug such as an ACE inhibitor in patients with LV systolic
dysfunction and without contraindications). Process measures
derive from the most definitive guideline recommendations
(ie, class I and class III recommendations). A small group
of process measures for hospitalized patients with HF have
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e297
Table 34. Plan of Care for Patients With Chronic HF
Plan of Care Relevant Guideline Section/Reference
Guideline-directed medical and device therapy
ACE inhibitor/ARB Sections 7.3.2.2 and 7.3.2.3
Beta blocker Section 7.3.2.4
Aldosterone receptor antagonist Section 7.3.2.5
Diuretic Sections 7.3.2.1 and 8.4
Hydralazine and isosorbide dinitrate Section 7.3.2.6
Digoxin Section 7.3.2.7
Discontinuation of drugs that may worsen HF Section 7.3.2.9
Biomarker-related therapeutic goals Section 6.3
HF-related devices (MCS, CRT, ICD) Sections 7.3.4 and 7.4.5
Management of comorbidities (examples)
Ischemic heart disease 2012 ACCF/AHA SIHD Guideline
14
Antithrombotic therapies Section 7.3.2.8.1
Arrhythmia/arrhythmia risk Sections 7.3.2.9.2 and 9.1
Hypertension Section 7.1.1, JNC-VII
27
Diabetes mellitus 2012 ADA Standards
90
Chronic renal failure Section 8.5
Chronic obstructive pulmonary disease 2011 ACCP/ATS/ERS Guideline
908
Secondary prevention interventions (eg, lipids, smoking cessation,
influenza and pneumococcal vaccines)
2011 AHA/ACCF Secondary Prevention and Risk Reduction Guidelines and
Centers for Disease Control Adult Vaccinations
13,909,910
Patient/family education
Diet and fluid restriction, weight monitoring Sections 7.3.1.1, 7.3.1.3, 7.3.1.5, and 7.4.3
Recognizing signs and symptoms of worsening HF Table 24
Risk assessment and prognosis Sections 3, 4.6, 6.1.2
QOL assessment 2012 AHA Scientific Statement on Advanced HF
30
Advance care planning (eg, palliative care and advance directives) Section 11.3
30,888
CPR training for family members AHA Family & Friends CPR
911
Social support Section 7.3.1.2
Physical activity/cardiac rehabilitation
Exercise regimen Sections 7.3.1.5 and 7.3.1.6
Activities of daily living Section 7.3.1.6
Functional status assessment and classification Section 3
Psychosocial factors
Sex-specific issues 2011 AHA Guidelines for the Prevention of Cardiovascular Disease in Women
912
Sexual activity 2012 AHA Scientific Statement on Sexual Activity
913
Depression screening US Preventive Services Task Force Guidelines
914
Clinician follow-up and care coordination
Cardiologists and other relevant specialists 2000 AHA Scientific Statement for Team Management of Patients With HF
900
Primary care physician NQF Preferred Practices for Care Coordination
898
Advanced practice nurse Section 11.1–11.3, Joint Commission 2013 National Patient Safety Goals
915
Other healthcare providers (eg, home care)
Medication reconciliation
Establishment of electronic personal health records
HHS Meaningful Use Criteria
Socioeconomic and cultural factors
Culturally sensitive issues NQF: A Comprehensive Framework and Preferred Practices for Measuring and
Reporting Cultural Competency
916
Education and health literacy Section 7.3.1.1
Social support Section 7.3.1.2
ACCF indicates American College of Cardiology Foundation; ACCP, American College of Chest Physicians; ACE, angiotensin-converting enzyme; ADA, American
Diabetes Association; AHA, American Heart Association; ARB, angiotensin-receptor blocker; ATS, American Thoracic Society; CPR, cardiopulmonary resuscitation; CRT,
cardiac resynchronization therapy; ERS, European Respiratory Society; HF, heart failure; HHS, Health and Human Services; ICD, implantable cardioverter-defibrillator;
JNC, Joint National Committee; MCS, mechanical circulatory support; NQF, National Quality Forum; QOL, quality of life; and SIHD, stable ischemic heart disease.
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e298 Circulation October 15, 2013
been reported to the public by the Centers for Medicare and
Medicaid Services as part of the Hospital Compare program.
918
Measures used to characterize the care of patients with
HF should be those developed in a multiorganizational
consensus process using an explicit methodology focusing
on measurability, validity, reliability, feasibility, and ideally,
correlation with patient outcomes,
919,920
and with transparent
disclosure and management of possible conflicts of interest.
In the case of HF, several national outcome measures are
currently in use (Table 35), and the ACCF/AHA/American
Medical Association–Physician Consortium for Performance
Improvement recently published revised performance mea-
sures document includes several process measures for both
inpatient and outpatient HF care (Table 36).
921
Of note, the
ACCF/AHA distinguish between processes of care that can be
considered “Performance Measures” (ie, suitable for use for
accountability purposes) and “Quality Metrics” (ie, suitable
for use for quality improvement but not accountability).
922
Measures are appealing for several reasons; by definition,
they reflect the strongest guideline recommendations. When
appropriately specified, they are relatively easy to calculate and
Table 35. Outcome Measures for HF
Measure Developer
Congestive HF mortality rate
(NQF endorsed)
Agency for Health Research and Quality
HF 30-day mortality rate
(NQF endorsed)
Centers for Medicare and Medicaid Services
Congestive HF admission rate
(NQF endorsed)
Agency for Health Research and Quality
HF 30-day risk-standardized
HF readmission rate
(NQF endorsed)
Centers for Medicare and Medicaid Services
HF indicates heart failure; and NQF, National Quality Forum.
Table 36. ACCF/AHA/AMA-PCPI 2011 HF Measurement Set
Measure Description* Care Setting Level of Measurement
1. LVEF assessment Percentage of patients aged ≥18 y with a diagnosis of HF for whom the quantitative
or qualitative results of a recent or prior (any time in the past) LVEF assessment is
documented within a 12-mo period
Outpatient Individual practitioner
2. LVEF assessment Percentage of patients aged ≥18 y with a principal discharge diagnosis of HF with
documentation in the hospital record of the results of an LVEF assessment
performed either before arrival or during hospitalization, OR documentation in the
hospital record that LVEF assessment is planned for after discharge
Inpatient •   Individual practitioner
•   Facility
3. Symptom and activity
assessment
Percentage of patient visits for those patients aged ≥18 y with a diagnosis of HF with
quantitative results of an evaluation of both current level of activity and clinical
symptoms documented
Outpatient Individual practitioner
4. Symptom management† Percentage of patient visits for those patients aged ≥18 y with a diagnosis of HF
and with quantitative results of an evaluation of both level of activity AND clinical
symptoms documented in which patient symptoms have improved or remained
consistent with treatment goals since last assessment OR patient symptoms
have demonstrated clinically important deterioration since last assessment with a
documented plan of care
Outpatient Individual practitioner
5. Patient self-care education†‡ Percentage of patients aged ≥18 y with a diagnosis of HF who were provided with self-
care education on ≥3 elements of education during ≥1 visits within a 12-mo period
Outpatient Individual practitioner
6. Beta-blocker therapy for
LVSD (outpatient and
inpatient setting)
Percentage of patients aged ≥18 y with a diagnosis of HF with a current or prior LVEF
<40% who were prescribed beta-blocker therapy with bisoprolol, carvedilol, or
sustained-release metoprolol succinate either within a 12-mo period when seen in
the outpatient setting or at hospital discharge
Inpatient and
outpatient
•   Individual practitioner
•   Facility
7. ACE inhibitor or ARB therapy
for LVSD (outpatient and
inpatient setting)
Percentage of patients aged ≥18 y with a diagnosis of HF with a current or prior LVEF
<40% who were prescribed ACE inhibitor or ARB therapy either within a 12-mo
period when seen in the outpatient setting or at hospital discharge
Inpatient and
outpatient
•   Individual practitioner
•   Facility
8. Counseling about ICD
implantation for patients
with LVSD on combination
medical therapy†‡
Percentage of patients aged ≥18 y with a diagnosis of HF with current LVEF ≤35%
despite ACE inhibitor/ARB and beta-blocker therapy for at least 3 mo who were
counseled about ICD implantation as a treatment option for the prophylaxis of
sudden death
Outpatient Individual practitioner
9. Postdischarge appointment
for HF patients
Percentage of patients, regardless of age, discharged from an inpatient facility to
ambulatory care or home health care with a principal discharge diagnosis of HF for
whom a follow-up appointment was scheduled and documented, including location,
date, and time for a follow-up office visit or home health visit (as specified)
Inpatient Facility
NB, Regarding test measure no. 8, implantation of ICD must be consistent with published guidelines. This measure is intended to promote counseling only.
*Refer to the complete measures for comprehensive information, including measure exception.
†Test measure designated for use in internal quality improvement programs only. These measures are not appropriate for any other purpose (eg, pay for performance,
physician ranking, or public reporting programs).
‡New measure.
ACCF indicates American College of Cardiology Foundation; ACE, angiotensin-converting enzyme; AHA, American Heart Association; AMA-PCPI, American Medical
Association−Physician Consortium for Performance Improvement; ARB, angiotensin-receptor blocker; HF, heart failure; ICD, implantable cardioverter-defibrillator; LVEF,
left ventricular ejection fraction; and LVSD, left ventricular systolic dysfunction.
Adapted from Bonow et al.
921
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e299
they provide a clear target for improvement. However, they do
not capture the broader range of care; they apply only to those
patients without contraindications to therapy. Evidence of the
relation between better performance with respect to process mea-
sures and patient outcomes is conflicting, and performance rates
for those measures that have been used as part of public report-
ing programs are generally high for all institutions, limiting the
ability of these measures to identify high- and low-performing
centers.
These limitations of process measures have generated
interest in the use of outcomes measures as a complementary
approach to characterize quality. With respect to HF, 30-day
mortality and 30-day readmission are reported by the Centers
for Medicare and Medicaid Services as part of the Hospital
Compare program (Table 35) and are incorporated in the
Centers for Medicare and Medicaid Services value-based pur-
chasing program.
918
Outcomes measures are appealing because
they apply universally to almost all patients, and they provide
a perspective on the performance of health systems.
923
On the
other hand, they are limited by the questionable adequacy of
risk adjustment and by the challenges of improvement. The
ACCF and AHA have published criteria that characterize the
necessary attributes of robust outcomes measures.
924
See Online Data Supplement 44 for additional data on
quality metrics and performance measures.
13. Evidence Gaps and Future
Research Directions
Despite the objective evidence compiled by the writing com-
mittee on the basis of hundreds of clinical trials, there are huge
gaps in our knowledge base about many fundamental aspects
of HF care. Some key examples include an effective manage-
ment strategy for patients with HFpEF beyond blood pressure
control; a convincing method to use biomarkers in the opti-
mization of medical therapy; the recognition and treatment
of cardiorenal syndrome; and the critical need for improving
patient adherence to therapeutic regimens. Even the widely
embraced dictum of sodium restriction in HF is not well sup-
ported by current evidence. Moreover, the majority of the
clinical trials that inform GDMT were designed around the
primary endpoint of mortality, so that there is less certainty
about the impact of therapies on the HRQOL of patients. It
is also of major concern that the majority of RCTs failed to
randomize a sufficient number of the elderly, women, and
underrepresented minorities, thus, limiting insight into these
important patient cohorts. A growing body of studies on
patient-centered outcomes research is likely to address some
of these deficiencies, but time will be required.
HF is a syndrome with a high prevalence of comorbidi-
ties and multiple chronic conditions, but most guidelines are
developed for patients with a single disease. Nevertheless,
the coexistence of additional diseases such as arthritis, renal
insufficiency, diabetes mellitus, or chronic lung disease with
the HF syndrome should logically require a modification of
treatment, outcome assessment, or follow-up care. About 25%
of Americans have multiple chronic conditions; this figure
rises to 75% in those >65 years of age, including the diseases
referred to above, as well as asthma, hypertension, cognitive
disorders, or depression.
847
Most RCTs in HF specifically
excluded patients with significant other comorbidities from
enrollment, thus limiting our ability to generalize our recom-
mendations to many real-world patients. Therefore, the clini-
cian must, as always, practice the art of using the best of the
guideline recommendations as they apply to a specific patient.
Future research will need to focus on novel pharmaco-
logical therapies, especially for hospitalized HF; regenerative
cell-based therapies to restore myocardium; and new device
platforms that will either improve existing technologies (eg,
CRT, ICD, left VAD) or introduce simpler, less morbid devices
that are capable of changing the natural history of HF. What is
critically needed is an evidence base that clearly identifies best
processes of care, especially in the transition from hospital to
home. Finally, preventing the burden of this disease through
more successful risk modification, sophisticated screening,
perhaps using specific omics technologies (ie, systems biol-
ogy) or effective treatment interventions that reduce the pro-
gression from stage A to stage B is an urgent need.
Presidents and Staff
American College of Cardiology Foundation
John Gordon Harold, MD, MACC, President
Shalom Jacobovitz, Chief Executive Officer
William J. Oetgen, MD, MBA, FACC, Senior Vice President,
Science and Quality
Charlene L. May, Senior Director, Science and Clinical Policy
American College of Cardiology Foundation/
American Heart Association
Lisa Bradfield, CAE, Director, Science and Clinical Policy
Debjani Mukherjee, MPH, Associate Director, Evidence-
Based Medicine
Ezaldeen Ramadhan III, Specialist, Science and Clinical
Policy
Sarah Jackson, MPH, Specialist, Science and Clinical Policy
American Heart Association
Donna K. Arnett, PhD, MD, FAHA, President
Nancy Brown, Chief Executive Officer
Rose Marie Robertson, MD, FAHA, Chief Science Officer
Gayle R. Whitman, PhD, RN, FAHA, FAAN, Senior Vice
President, Office of Science Operations
Judy Bezanson, DSN, RN, CNS-MS, FAHA, Science and
Medicine Advisor
Jody Hundley, Production Manager, Scientific Publications,
Office of Science Operations
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KEY WORDS: AHA Scientific Statements � cardio-renal physiology/
pathophysiology � congestive heart failure � CV surgery: transplantation,
ventricular assistance, cardiomyopathy � epidemiology � health policy and
outcome research � heart failure � other heart failure
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e320 Circulation October 15, 2013
Appendix 1. Author Relationships With Industry and Other Entities (Relevant)—2013 ACCF/AHA Guideline for the Management of
Heart Failure
Committee
Member Employment Consultant
Speaker’s
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational, or
Other Financial
Benefit
Expert
Witness
Voting
Recusals by
Section*
Clyde W.
Yancy, Chair
Northwestern
University—Chief,
Division of Cardiology
and Magerstadt
Professor of Medicine
None None None None None None None
Mariell Jessup,
Vice Chair
University of
Pennsylvania—
Professor of Medicine
None None None •   Amgen
•   Celladon
•   HeartWare
None None 7.4.4
7.4.5
7.4.6
10
Biykem
Bozkurt
Michael E. DeBakey VA
Medical Center—The
Mary and Gordon Cain
Chair and Professor of
Medicine
None None None None None None None
Javed Butler Emory Healthcare—
Director of Heart
Failure Research;
Emory University
School of Medicine—
Professor of Medicine
•   Amgen
•   CardioMEMS
•   Gambro
•   Takeda
None None None •   Amgen
•   Biotronic
•   Boston Scientific
•   CardioMEMS
•   Corthera†
•   FoldRx
•   iOcopsys
•   Johnson & 
Johnson
•   Medtronic
•   Thoratec
•   World Heart
None 6.4
7.1
7.2
7.3.2
7.3.3
7.3.4
7.4.4
7.4.5
7.4.6
8.6
8.7
10
Donald E.
Casey, Jr
Clinically Integrated
Physician Network,
NYU Langone Medical
Center—Vice
President and Medical
Director
None None None None None None None
Mark H.
Drazner
University of Texas
Southwestern Medical
Center—Professor,
Internal Medicine
None None None •   HeartWare
•    Scios/Johnson & 
Johnson†
•   Medtronic
•   Thoratec†
None 7.1
7.2
7.3.2
7.3.4
7.4.4
7.4.5
7.4.6
8.6
8.7
10
Gregg C.
Fonarow
Director Ahmanson—
UCLA Cardiomyopathy
Center; Co-Chief—
UCLA Division of
Cardiology
•    Gambro 
(formerly CHF
Solutions)
•   Medtronic
•   Novartis†
•   Takeda
None None •    Gambro (formerly 
CHF Solutions)
•   Novartis†
•    Medtronic None 7.1
7.2
(Class IIa)
7.3.2
7.3.4
8.3
8.4
8.7
10
Stephen A.
Geraci
Quillen College
of Medicine/East
Tennessee State
University—Chairman
of Internal Medicine
None None None None None None None
(continued)
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e321
Appendix 1. Continued
Committee
Member Employment Consultant
Speaker’s
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational, or
Other Financial
Benefit
Expert
Witness
Voting
Recusals by
Section*
Tamara
Horwich
Ahmanson—UCLA
Cardiomyopathy
Center—Assistant
Professor of Medicine,
Cardiology
None None None None None None None
James L.
Januzzi
Harvard Medical
School—Associate
Professor of Medicine;
Massachusetts General
Hospital—Director,
Cardiac Intensive Care
Unit
•   Critical 
Diagnostics†
•   Roche 
Diagnostics†
None None •    Critical 
Diagnostics†
•    Roche 
Diagnostics†
None None 6.2
6.3
Maryl R.
Johnson
University of
Wisconsin, Madison—
Professor of Medicine,
Director Heart Failure
and Transplantation
None None None None None None None
Edward K.
Kasper
Johns Hopkins
Hospital— E. Cowles
Andrus Professor in
Cardiology
Director, Clinical
Cardiology
None None None None None None None
Wayne C. Levy University of
Washington—
Professor of Medicine,
Division of Cardiology
•   Cardiac 
Dimensions†
•   CardioMEMS
•    GE/Scios/ 
Johnson &
Johnson
•   Amarin
•    Boehringer 
Ingelheim
•   GlaxoSmithKline
None •   Amgen†
•   HeartWare†
•   Amgen
•   Epocrates
•   GE Healthcare
•   HeartWare
•   Thoratec
None 6.4
6.5
7.1
7.2
7.3.1
7.3.2
7.3.4
7.4.5
8.3
8.6
8.7
10
Frederick A.
Masoudi
University of Colorado,
Denver—Associate
Professor of Medicine,
Division of Cardiology
None None None None None None None
Patrick E.
McBride
University of Wisconsin
School of Medicine
and Public Health—
Professor of Medicine
and Family Medicine,
Associate Dean for
Students, Associate
Director, Preventive
Cardiology
None None None None None None None
John J.V.
McMurray
University of Glasgow,
Scotland, BHF Glasgow
Cardiovascular
Research Center—
Professor of Medical
Cardiology
None None None •   GlaxoSmithKline†
•   Novartis
•   Roche (DSMB)
•   Novartis 
(PARADIGM–PI)
None 6.2
6.3
7.1
7.2
(Class I and
Class III)
7.3.2
8.3
8.7
(continued)
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e322 Circulation October 15, 2013
Appendix 1. Continued
Committee
Member Employment Consultant
Speaker’s
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational, or
Other Financial
Benefit
Expert
Witness
Voting
Recusals by
Section*
Judith E.
Mitchell
SUNY Downstate Medical
Center—Director, Heart
Failure Center; Associate
Professor of Medicine
None None None None None None None
Pamela N.
Peterson
University of Colorado,
Denver Health Medical
Center—Associate
Professor of Medicine,
Division of Cardiology
None None None None None None None
Barbara Riegel University of
Pennsylvania School of
Nursing—Professor
None None None None None None None
Flora Sam Boston University
School of Medicine,
Whitaker Cardiovascular
Institute—Associate
Professor of Medicine,
Division of Cardiology/
Cardiomyopathy Program
None None None None None None None
Lynne W.
Stevenson
Brigham and Women’s
Hospital Cardiovascular
Division—Director,
Cardiomyopathy and Heart
Failure Program
None None None •   Biosense Webster None None 7.3.4
W.H. Wilson
Tang
Cleveland Clinic
Foundation—Associate
Professor of Medicine,
Research Director for
Heart Failure/Transplant
•   Medtronic
•    St. Jude Medical
None None •   Abbott†
•   FoldRx
•   Johnson & 
Johnson
•   Medtronic†
•   St. Jude Medical†
None None 6.2
6.3
7.1
7.2
7.3.2
7.3.3
7.3.4
8.6
8.7
10
Emily J. Tsai Temple University School
of Medicine—Assistant
Professor of Medicine,
Cardiology
None None None None None None None
Bruce L.
Wilkoff
Cleveland Clinic—
Director, Cardiac Pacing
and Tachyarrhythmia
Devices; Director,
Clinical EP Research
None None None •   Biotronic
•   Boston Scientific
•   Medtronic
•   St. Jude Medical
None None 7.2
(Class IIa)
7.3.4
10
This table represents the relationships of committee members with industry and other entities that were determined to be relevant to this document. These
relationships were reviewed and updated in conjunction with all meetings and/or conference calls of the writing committee during the document development process.
The table does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the interest
represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$10 000 of the fair market value of the business entity; or if funds
received by the person from the business entity exceed 5% of the person’s gross income for the previous year. Relationships that exist with no financial benefit are
also included for the purpose of transparency. Relationships in this table are modest unless otherwise noted.
According to the ACCF/AHA, a person has a relevant relationship IF: a) The relationship or interest relates to the same or similar subject matter, intellectual property
or asset, topic, or issue addressed in the document; or b) The company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in
the document, or makes a competing drug or device addressed in the document; or c) The person or a member of the person’s household, has a reasonable potential
for financial, professional or other personal gain or loss as a result of the issues/content addressed in the document.
*Writing committee members are required to recuse themselves from voting on sections to which their specific relationships with industry and other entities may
apply. Section numbers pertain to those in the full-text guideline.
†Indicates significant relationship.
DSMB indicates Data Safety Monitoring Board; EP, electrophysiology; NYU, New York University; PARADIGM, a Multicenter, Randomized, Double-blind, Parallel
Group, Active-controlled Study to Evaluate the Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality in Patients With Chronic Heart Failure
and Reduced Ejection Fraction; PI, Principal Investigator; SUNY, State University of New York; UCLA, University of California, Los Angeles; and VA, Veterans Affairs.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e323
Appendix 2. Reviewer Relationships With Industry and Other Entities (Relevant)—2013 ACCF/AHA Guideline for the Management
of Heart Failure
Reviewer Representation Employment Consultant
Speaker’s
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational, or
Other Financial
Benefit
Expert
Witness
Nancy Albert Official
Reviewer—
ACCF/AHA
Task Force
on Practice
Guidelines
Kaufman Center for
Heart Failure—Senior
Director of Nursing
Research
•   BG Medicine
• Medtronic
• Merck†
None None None None None
Kathleen Grady Official
Reviewer—AHA
Bluhm Cardiovascular
Institute—
Administrative
Director, Center for
Heart Failure
None None None None None None
Paul Hauptman Official
Reviewer—AHA
St Louis University
School of Medicine—
Professor of Internal
Medicine, Division of
Cardiology
• BG Medicine
• BioControl Medical
• Otsuka*
None None None •   EvaHeart† None
Hector Ventura Official
Reviewer—
ACCF Board of
Governors
Ochsner Clinic
Foundation—
Director, Section of
Cardiomyopathy and
Heart Transplantation
• Otsuka • Actelion None None None None
Mary Norine
Walsh
Official
Reviewer—
ACCF Board of
Trustees
St. Vincent Heart
Center of Indiana—
Medical Director
• United Healthcare None None None None None
Jun Chiong Organizational
Reviewer—
ACCP
Loma Linda
University—Associate
Clinical Professor of
Medicine
None None None None • Otsuka (DSMB) None
David DeLurgio Organizational
Reviewer—HRS
The Emory Clinic—
Associate Professor,
Director of EP
Laboratory
None None None None None None
Folashade
Omole
Organizational
Reviewer—AAFP
Morehouse School of
Medicine—Associate
Professor of Clinical
Family Medicine
None None None None None None
Robert Rich, Jr Organizational
Reviewer—AAFP
Bladen Medical
Associates—Family
Practice
None None None None None None
David Taylor Organizational
Reviewer—
ISHLT
Cleveland Clinic,
Department of
Cardiology—
Professor of Medicine
None None None None •   Biotronix†
• Genentech†
• HeartWare†
• ISHLT
•   Novartis†
•   St. Jude’s 
Medical†
None
Kimberly
Birtcher
Content
Reviewer—
ACCF
Cardiovascular
Team Council
University of
Houston College of
Pharmacy—Clinical
Professor
None None None None None None
Kay Blum Content
Reviewer—
ACCF
Cardiovascular
Team Council
Medstar Southern
Maryland Hospital
Center—Nurse
Practitioner
None None None None None None
(continued)
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e324 Circulation October 15, 2013
Appendix 2. Continued
Reviewer Representation Employment Consultant
Speaker’s
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational, or
Other Financial
Benefit
Expert
Witness
Michael Chan Content
Reviewer—
ACCF
Cardiovascular
Team Council
Royal Alexandra
Hospital—Co-
Director, Heart
Function Program;
University of
Alberta—Associate
Clinical Professor of
Medicine
None None None None •   Medtronic None
Jane Chen Content
Reviewer—
ACCF EP
Committee
Washington University
School of Medicine—
Assistant Professor of
Medicine
• Medtronic
•   St. Jude Medical
None None None None None
Michael Clark Content
Reviewer—
ACCF
Cardiovascular
Team Council
North Texas
Cardiology and EP—
Associate Professor
None • Abbott
Pharma
None None None None
Marco Costa Content
Reviewer—
ACCF Imaging
Council
University Hospital for
Cleveland—Professor
of Medicine
•   Abbott Vascular
•   Boston Scientific
•   Cardiokinetix*
•   Medtronic
• St. Jude Medical
• Daiichi-
Sankyo
• Eli Lilly
• Sanofi
None None • Abbott Vascular*
•   Boston Scientific
• Cardiokinetix†
•   Medtronic*
• St. Jude Medical
None
Anita Deswal Content
Reviewer
Baylor College of
Medicine—Associate
Professor of Medicine
None None None • Amgen†
• Novartis†
None None
Steven Dunn Content
Reviewer—
ACCF Prevention
Committee
University of Virginia
Health System—
Clinical Pharmacy
Specialist
None None None None None None
Andrew Epstein Content
Reviewer
University of
Pennsylvania—
Professor of Medicine
•   Biotronic
•   Boehringer 
Ingelheim
•   Medtronic
•   Zoll
None None •   Biosense 
Webster*
•   Boston 
Scientific*
•   Cameron 
Health*
•   Boston Scientific*
•   St. Jude Medical*
None
Justin Ezekowitz Content
Reviewer—AHA
Mazankowski Alberta
Heart Institute—
Director, Heart
Function Clinic
•   Abbott Labs
•   AstraZeneca
•   Pfizer
None None • Amgen
• Bristol-Myers
Squibb
None None
Gerasimos
Filippatos
Content
Reviewer
University of
Athens—Department
of Cardiology
None None None None •   Corthera
• Vifor
None
Linda Gillam Content
Reviewer—
ACCF Imaging
Council
Morristown Medical
Center—Professor of
Cardiology
None None None None •   Edwards 
Lifesciences†
None
Paul
Heidenreich
Content
Reviewer
Stanford VA Palo Alto
Medical Center—
Assistant Professor of
Medicine
None None None • Medtronic† None None
Paul Hess Content
Reviewer—
ACCF EP
Committee
Duke University
School of
Medicine—Fellow
None None None None None None
(continued)
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e325
(continued)
Appendix 2. Continued
Reviewer Representation Employment Consultant
Speaker’s
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational, or
Other Financial
Benefit
Expert
Witness
Sharon Ann
Hunt
Content
Reviewer
Stanford
University Medical
Center—Professor,
Department of
Cardiovascular
Medicine
None None None None None None
Charles McKay Content
Reviewer—
ACCF Council on
Cardiovascular
Care for Older
Adults
Harbor-UCLA Medical
Center—Professor of
Medicine
None None None None None None
James
McClurken
Content
Reviewer—
ACCF Surgeons’
Scientific
Council
Temple University
School of
Medicine—Director
of Cardiothoracic
Perioperative Services
None None None None None None
Wayne Miller Content
Reviewer—
ACCF Heart
Failure and
Transplant
Council
Mayo Clinic—
Professor of Medicine
None None None None None None
Rick Nishimura Content
Reviewer
Mayo Clinic—
Professor of
Medicine
None None None None None None
Donna
Petruccelli
Content
Reviewer—
ACCF Heart
Failure and
Transplant
Council
Lehigh Valley
Health Network—
Heart Failure
Nurse Practitioner/
Clinical Nurse
Specialist,
Center for Advanced
Heart Failure
None None None None None None
Geetha
Raghuveer
Content
Reviewer—
ACCF Board of
Governors
Children’s Mercy
Hospital—Associate
Professor of
Pediatrics
None None None None None None
Pasala
Ravichandran
Content
Reviewer—
ACCF Surgeons’
Scientific
Council
Oregon Health &
Science University—
Associate Professor
None None None None None None
Michael Rich Content
Reviewer—
ACCF Council on
Cardiovascular
Care for Older
Adults
Washington University
School of Medicine—
Professor of Medicine
None None None None None None
Anitra Romfh Content
Reviewer—
ACCF Adult
Congenital
and Pediatric
Cardiology
Council
Children’s Hospital
Boston—Clinical
Fellow in Pediatrics
None None None None None None
at UNIV OF WISCONSIN MADISON on January 3, 2014http://circ.ahajournals.org/Downloaded from

e326 Circulation October 15, 2013
Appendix 2. Continued
Reviewer Representation Employment Consultant
Speaker’s
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational, or
Other Financial
Benefit
Expert
Witness
Andrea Russo Content
Reviewer—
ACCF Task
Force on
Appropriate Use
Criteria
Cooper University
Hospital—Professor
of Medicine
• Biotronik
•   Boston Scientific
• Cameron Health
•   Medtronic
•   St. Jude Medical
None None •   Cameron 
Health
• Medtronic
None None
Dipan Shah Content
Reviewer—ACCF
Imaging Council
Methodist
DeBakey Heart
Center—Director
None •   AstraZeneca*
• Lantheus
Medical
Imaging
None None • Astellas Pharma
• Siemens Medical
Solutions*
None
Randy Starling Content
Reviewer
Cleveland Clinic,
Department of
Cardiovascular
Medicine—Vice
Chairman
•   Novartis None None None • Biotronik
•   Medtronic
None
Karen Stout Content
Reviewer—
ACCF Adult
Congenital
and Pediatric
Cardiology
Council
University of
Washington—
Director, Adult
Congenital Heart
Disease Program
None None None None None None
John Teerlink Content
Reviewer
San Francisco VA
Medical Center—
Professor of Medicine
•   Amgen*
•   Anexon
•   CardioMEMS*
•   Cytokinetics
•   Novartis*
•   St. Jude Medical*
• Scios/Johnson &
Johnson
• Trevena
None None None •   Amgen*
• Merck
•   Novartis*
None
Robert Touchon Content
Reviewer—
ACCF Prevention
Committee
Marshall University,
Joan C. Edwards
School of Medicine—
Professor of Medicine
None None None None None None
Hiroyuki Tsutsui Content
Reviewer
Hokkaido
University—Professor
of Medicine
•   Daiichi-Sankyo*
• Novartis*
•   Pfizer
•   Takeda*
None None None None None
Robert Vincent Content
Reviewer—ACCF
Adult Congenital
and Pediatric
Cardiology
Council
Emory University
School of Medicine—
Professor of
Pediatrics
None None None None • AGA None
This table represents the relationships of reviewers with industry and other entities that were disclosed at the time of peer review and determined to be relevant to
this document. It does not necessarily reflect relationships with industry at the time of publication. A person is deemed to have a significant interest in a business if the
interest represents ownership of ≥5% of the voting stock or share of the business entity, or ownership of ≥$10 000 of the fair market value of the business entity; or
if funds received by the person from the business entity exceed 5% of the person’s gross income for the previous year. A relationship is considered to be modest if it
is less than significant under the preceding definition. Relationships that exist with no financial benefit are also included for the purpose of transparency. Relationships
in this table are modest unless otherwise noted. Names are listed in alphabetical order within each category of review.
According to the ACCF/AHA, a person has a relevant relationship IF: a) The relationship or interest relates to the same or similar subject matter, intellectual property
or asset, topic, or issue addressed in the document; or b) The company/entity (with whom the relationship exists) makes a drug, drug class, or device addressed in
the document, or makes a competing drug or device addressed in the document; or c) The person or a member of the person’s household has a reasonable potential
for financial, professional, or other personal gain or loss as a result of the issues/content addressed in the document.
*Significant relationship.
†No financial benefit.
AAFP indicates American Academy of Family Physicians; ACCF, American College of Cardiology Foundation; ACCP, American College of Chest Physicians; AHA,
American Heart Association; DSMB, data safety monitoring board; EP, electrophysiology; HRS, Heart Rhythm Society; ISHLT, International Society for Heart and Lung
Transplantation; and VA, Veterans Affairs.
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Yancy et al 2013 ACCF/AHA Heart Failure Guideline e327
Appendix 3. Abbreviations
ACE = angiotensin-converting enzyme
ACS = acute coronary syndrome
AF = atrial fibrillation
ARB = angiotensin-receptor blocker
BMI = body mass index
BNP = B-type natriuretic peptide
CABG = coronary artery bypass graft
CAD = coronary artery disease
CRT = cardiac resynchronization therapy
DCM = dilated cardiomyopathy
ECG = electrocardiogram
EF = ejection fraction
GDMT = guideline-directed medical therapy
HbA1c = hemoglobin A1c
HF = heart failure
HFpEF = heart failure with preserved ejection fraction
HFrEF = heart failure with reduced ejection fraction
HRQOL = health-related quality of life
ICD = implantable cardioverter-defibrillator
LBBB = left bundle-branch block
LV = left ventricular
LVEF = left ventricular ejection fraction
MCS = mechanical circulatory support
MI = myocardial infarction
NSAIDs = nonsteroidal anti-inflammatory drugs
NT-proBNP = N-terminal pro-B-type natriuretic peptide
NYHA = New York Heart Association
PUFA = polyunsaturated fatty acids
RCT = randomized controlled trial
SCD = sudden cardiac death
VAD = ventricular assist device
at UNIV OF WISCONSIN MADISON on January 3, 2014http://circ.ahajournals.org/Downloaded from

© American College of Cardiology Foundation and American Heart Association, Inc.        1 
 
2013 Heart Failure Guideline Data Supplements
(Section numbers correspond to the full-text guideline.)
Table of Contents
Data Supplement 1. HFpEF (Section 2.2)............................................................................................................................... 3 
Data Supplement 2. NYHA and AHA/ACC Class (Section 3) .............................................................................................. 4 
Data Supplement 3. Prognosis – Mortality (Section 4.1)........................................................................................................ 5 
Data Supplement 4. Health-Related Quality of Life and Functional Capacity (Section 4.4) ................................................. 7 
Data Supplement 5. Stress Testing (Initial and Serial Evaluation) of the HF Patient (Section 6.1.1) .................................. 11 
Data Supplement 6. Clinical Evaluation – History (Orthopnea) (Section 6.1.1) .................................................................. 13 
Data Supplement 7. Clinical Evaluation – Examination (Section 6.1.1) .............................................................................. 13 
Data Supplement 8. Clinical Evaluation – Risk Scoring (Section 6.1.2) .............................................................................. 16 
Data Supplement 9. Imaging Echocardiography (Section 6.4) ............................................................................................. 18 
Data Supplement 10. Biopsy (Section 6.5.3) ........................................................................................................................ 21 
Data Supplement 11. Stage A: Prevention of HF (Section 7.1) ............................................................................................ 22 
Data Supplement 12. Stage B: Preventing the Syndrome of Clinical HF With Low EF (Section 7.2) ................................ 28 
Data Supplement 13. Stage C: Factors Associated With Outcomes, All Patients (Section 7.3) ........................................... 30 
Data Supplement 14. Nonadherence (Section 7.3.1.1) ......................................................................................................... 38 
Data Supplement 15. Treatment of Sleep Disorders (Section 7.3.1.4) ................................................................................. 47 
Data Supplement 16. Cardiac Rehabilitation-Exercise (Section 7.3.1.6) ............................................................................. 49 
Data Supplement 17. Diuretics Versus Ultrafiltration in Acute Decompensated HF (Section 7.3.2.1) ............................... 60 
Data Supplement 18. ACE Inhibitors (Section 7.3.2.2) ........................................................................................................ 76 
Data Supplement 19. ARBs (Section 7.3.2.3) ....................................................................................................................... 82 
Data Supplement 20. Beta Blockers (Section 7.3.2.4) .......................................................................................................... 85 
Data Supplement 21. Anticoagulation (Section 7.3.2.8.1) .................................................................................................... 89 
Data Supplement 22. Statin Therapy (Section 7.3.2.8.2) ...................................................................................................... 94 
Data Supplement 23. Omega 3 Fatty Acids (Section 7.3.2.8.3) ......................................................................................... 101 
Data Supplement 24. Antiarrhythmic Agents to Avoid in HF (7.3.2.9.2) .......................................................................... 104 
Data Supplement 25. Calcium Channel Blockers to Avoid in HF (Section 7.3.2.9.3) ....................................................... 105 
Data Supplement 26. NSAIDs Use in HF (Section 7.3.2.9.4) ............................................................................................ 106 
Data Supplement 27. Thiazolidinediones in HF (Section 7.3.2.9.5) ................................................................................... 107 
Data Supplement 28. Device-Based Management (Section 7.3.4) ..................................................................................... 108 
Data Supplement 29. CRT (Section 7.3.4.2) ....................................................................................................................... 109 
Data Supplement 30. Therapies, Important Considerations (Section 7.4.2) ....................................................................... 114 
Data Supplement 31. Sildenafil (Section Section 7.4.2) ..................................................................................................... 120 

© American College of Cardiology Foundation and American Heart Association, Inc.        2 
 
Data Supplement 32. Inotropes (Section 7.4.4) .................................................................................................................. 123 
Data Supplement 33. Inotropic Agents in HF (Section 7.4.4) ............................................................................................ 135 
Data Supplement 34. Mechanical Circulatory Support (Section 7.4.5) .............................................................................. 136 
Data Supplement 35. LVADs (Section 7.4.5) ..................................................................................................................... 138 
Data Supplement 36. Transplantation (Section 7.4.6) ........................................................................................................ 149 
Data Supplement 37. Comorbidities in the Hospitalized Patient (Section 8.1) .................................................................. 159 
Data Supplement 38. Worsening Renal Function, Mortality and Readmission in Acute HF (Section 8.5) ....................... 161 
Data Supplement 39. Nesiritide (Section 8.7) ..................................................................................................................... 165 
Data Supplement 40. Hospitalized Patients – Oral Medications (Section 8.8) ................................................................... 177 
Data Supplement 41. Atrial Fibrillation (Section 9.1) ........................................................................................................ 186 
Data Supplement 42. HF Disease Management (Section 11.2) .......................................................................................... 187 
Data Supplement 43. Telemonitoring (Section 11.2) ......................................................................................................... 189 
Data Supplement 44. Quality Metrics and Performance Measures (Section 12) ................................................................ 191 
References ........................................................................................................................................................................... 192 


© American College of Cardiology Foundation and American Heart Association, Inc.        3 
 
Data Supplement 1. HFpEF (Section 2.2)
Study Name,
Author, Year
Aim of Study Study Type Study
Size
Patient Population Endpoints Statistical Analysis
(Results)
Study Limitations Findings/ Comments
Inclusion Criteria Exclusion Criteria
Masoudi JACC
2003;41:217-
223
12535812 (1)
To assess factors
associated with
preserved LVSF in
pts with HF
Cross
sectional
cohort study
19,710 Medicare beneficiary;
hospitalized with
principal discharge
diagnosis of HF; acute
care hospitalization;
hospitalized between
4/1998-3/1999
No documentation of
LVEF
Preserved LVSF Multivariable logistic
regression to assess
factors associated with
preserved LVSF
Limited to Medicare
population; limited to
hospitalized pts; missing
LVEF in a portion of the
population
Factors associated with
preserved LVSF, which
included gender, advanced
age, HTN, AF; and absence
of coronary disease
Owan NEJM
2006;355:251-
259
16855265 (2)
Define temporal
trends in prevalence
of HF with preserved
LVEF over 15 y
period
Retrospective
cohort study
4,596 Consecutive pts admitted
to Mayo Clinic hospitals;
Discharge code for HF;
1987-2001
No documentation of
LVEF
Proportion of pts with
preserved LVSF;
survival
Linear regression and
survival analysis
Limited to Olmsted County,
MN; limited to hospitalized
pts; missing LVEF in a
portion of the population
Overall, more than half the
population had preserved
LVSF; this proportion
increased overtime; survival
in pts with HFpEF was only
slightly better than for those
with HFrEF (HR:0.96)
Bhatia NEJM
2006;355:260-
269
16855266 (3)

Evaluate the
epidemiological
features and
outcomes of pts with
HFpEF vs. HFrEF
Retrospective
cohort study
2,802 Pts admitted to 103
Ontario hospitals;
4/1999-3/2001;
discharge diagnosis of
HF
No documentation of
LVEF
Death within 1 y;
readmission for HF
Multivariable survival
analysis
Limited to Ontario; limited
to hospitalized pts; missing
LVEF in a portion of the
population
31% had HFpEF; HFpEF
more often female, older, with
AF, and HTN; Unadjusted
mortality similar (22% for
HFpEF vs. 26% for HFrEF);
adjusted mortality also similar
(aHR:1.13); readmission rates
also similar between groups.
Lee Circulation
2009;119:3070-
3077
19506115 (4)

Assess the
contribution of risk
factors and disease
pathogenesis to
HFpEF
Retrospective
cohort study
534 Framingham
participants; incident HF
N/A Factors associated
with HFpEF; Mortality
Multivariable logistic
regression (risk
factors); multivariable
survival analysis
(mortality)
Limited to Framingham
cohort; relatively small
sample size
Factors associated with
HFpEF included female
gender; elevated SBP; AF;
and absence of CAD. Long-
term prognosis equally poor
(overall cohort median
survival of 2.1 y; 5-y mortality
74%).

© American College of Cardiology Foundation and American Heart Association, Inc.        4 
 
Kane JAMA
2011;306:856-
863
21862747 (5)
Measure changes in
diastolic function and
assess the
relationship between
diastolic
abnormalities and HF
risk
Retrospective
cohort study
2042 Random sample from
Olmsted County MN in
1997; age ≥45;
participating in baseline
and follow up
assessments
N/A Diastolic function
grade; incident HF
Multivariable survival
analysis
Limited to Olmsted County,
MN; limited to those
following up for 2
nd

examination
In 4 y between baseline and
follow-up, prevalence of
diastolic dysfunction
increased from 23.8% to
39.2%. Diastolic dysfunction
associated with incident HF
(HR:1.81)
AF indicates atrial fibrillation; CAD, coronary artery disease; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fraction; HTN, hypertension; LVEF, left ventricular ejection fraction; LVSF, left ventricular
systolic function; MN, Minnesota; N/A, not applicable; pts, patients, and SBP, systolic blood pressure.
 
Data Supplement 2. NYHA and AHA/ACC Class (Section 3)
Study Name,
Author, Year
Aim of Study Study Type
Study
Size
Patient Population Endpoints
Statistical Analysis
(Results)
Study Limitations
Findings/
Comments
Inclusion
Criteria
Exclusion
Criteria
Primary
Endpoint
Secondary
Endpoint

Madsen BK, 1994
8013501 (6)
Predict CHF mortality Longitudinal
registry
190 N/A Must be
ambulatory
Death N/A Kaplan-Meier
Mortality increased with
increased NYHA class and
with decreased EF
N/A Conducted primarily
outside U.S.
Holland R, 2010
20142027 (7)
Predict CHF mortality
using self-assessed
NYHA class
Longitudinal
registry
293 Adults with CHF
after CHF
admission
N/A Readmission
over 6 mo
MLHF
questionnaire and
death
Survival analysis
Readmission rate increased
with higher NYHA class
No clinician assessment
to compare to pt
assessment
Conducted primarily
outside U.S.
Anmar KA, 2007
17353436 (8)
Measure association of
HF stages with mortality
Cross-
sectional
cohort
2,029 Residents of
Olmsted Co, MN
N/A 5-y survival rates BNP Survival analysis
HF stages associated with
progressively worsening 5-y
survival rates
Retrospective
classification of stage
N/A
Goldman L, 1981
7296795 (9)

Reproducibility for
assessing CV functional
class
Longitudinal
registry
75 All those referred
for treadmill
testing
N/A Reproducibility
testing
N/A NYHA classification

N/A Reproducibility only
56%
BNP indicates B-type natriuretic peptide; CHF, congestive heart failure; CV, cardiovascular; EF, ejection fraction; HF, heart failure; MLHF, Minnesota Living with Heart Failure; N/A, not applicable; NYHA, New York Heart Association; and pt, patient.
 
 

© American College of Cardiology Foundation and American Heart Association, Inc.        5 
 
Data Supplement 3. Prognosis - Mortality (Section 4.1)
Study Name,
Author, Year
Aim of
Study
Study Type Study Size Patient Population Endpoints
Statistical
Analysis
(Results)
P Values
& 95% CI:
Study Limitations
Findings/
Comments

Inclusion Criteria Exclusion Criteria
Primary
Endpoint
Secondary
Endpoint
The Seattle HF
Model: Prediction
of Survival in HF
Levy, Wayne Circ
2006
16534009 (10)

Develop and
validate a risk
model for
1,2,and 3-y
mortality
Cohort Derivation: 1,125
Validation: 9,942
Derivation Cohort: EF
<30%, NYHA class III-IV
Validation Cohort: EF
<40%, NYHA class II-IV
Both derivation and
validation cohorts primarily
out-pts (both clinical trial
populations)
N/A Prediction of
1,2,3-y
mortality
N/A Predicted vs.
actual survival for
1, 2, and 3 y:
88.2% vs 87.8%,
79.2% vs 77.6%,
71.8% vs. 68.0%
ROC:
0.729; 95%
CI: 0.714-
0.744
Population not
representative of HF
population in general:
clinical trial
populations, restricted
to HF with LVSD.
Estimation of risk
score is complex and
requires
computer/calculator.
24 variables
included in risk
score
Predicting
Mortality Among
Pts Hospitalized
with HF
(EFFECT) Lee,
Douglas JAMA
2003
14625335 (11)
Develop and
validate a risk
model for 30-d
and 1-y
mortality
Cohort Derivation: 2,624
Validation: 1,407
No EF requirement;
Community-based pts
hospitalized with HF in
Canada (met modified
Framingham HF criteria)
Pts who developed HF after
admit, transferred from
different facility, over 105 y,
nonresidents
30-d and 1-y
mortality
N/A Derivation Cohort:
in-hospital
mortality: 8.9%,
30-d mortality:
10.7%; 1-y
mortality: 32.9%
Validation cohort:
in-hospital
mortality: 8.2%,
30-d mortality:
10.4%; 1-y
mortality:30.5%
ROC: 0.79
for 30-d
mortality;
ROC; 0.76
for 1-y
mortality
N/A Variables in
Model: age,
SBP, resp rate,
Na <136, Hbg
<10, BUN, CVD,
COPD,
dementia,
cirrhosis, cancer
Predictors of
Mortality After
Discharge in pts
Hospitalized w/
HF (OPTIMIZE-
HF) O'Connor,
Christopher
AHJ 2008
18926148 (12)
Develop
models
predictive of
60 and 90 d
mortality
Cohort
study/registry
4,402 No EF criteria (49% with
LVSD), pts hospitalized
with HF at institutions
participating in OPIMIZE-
HF performance-
improvement program
N/A Death at 60-
90 d
Hospitalization;
death or
rehospitalization
60-90 d mortality:
8.6%; death or
rehospitalization:
36.2%
c index:
0.735;
bias-
corrected c
index:
0.723
Validity - assessed by
bootstraping
Developed a
nomogram.
Variables
included in
score: Age,
weight, SBP,
sodium, Cr, liver
disease,
depression,
RAD

© American College of Cardiology Foundation and American Heart Association, Inc.        6 
 
Predictors of
Mortality and
Morbidity in Pts
with Chronic HF
Pocock, Stuart
EHJ 2006
16219658 (13)
Develop
prognostic
models for 2-y
mortality
Cohorts: used
pts in the
CHARM
program
7,599 No EF criteria; out-pts;
symptomatic HF
K >5.5; Cr >265 umol/L; MI or
stroke in prior 4 wk;
noncardiac disease limiting
survival
Mortality CV death or
hospitalization
N/A ROC:0.75,
bias
corrected:
0.74; ROC:
0.73 in low
EF and in
preserved
EF cohorts
Population studied
not representative of
HF in general (pts
enrolled in CHARM);
validity - assessed by
bootstrapping;
laboratory data not
available.
23 variables
included in
model
Risk Stratification
for Inhospital
Mortality in
Acutely
Decompensated
HF: Classification
and Regression
Tree Analysis
Fonarow, Gregg
JAMA 2005
15687312 (14)
Estimate
mortality risk in
pts
hospitalized
with HF
Cohort/registry Derivation:33,046
Validation: 32,229
Pts admitted with HF to
hospital participating in the
ADHERE registry; no EF
criteria;
None In-hospital
mortality
N/A Classification and
regression tree
analysis;
In-hospital
mortality: 4.1%;
95% CI:2.1%-
21.9%
N/A N/A Classifies pts
into 5 risk
categories.
Discriminating
nodes: BUN;
SBP; Cr
A validated risk
score of in-
hospital mortality
in pts with HF
from the AHA
GWTG Program
Peterson, Pamela
CircCQO 2010
20123668 (15)
Develop a risk
score for
inhospital
mortality
Cohort/registry Derivation:27,850;
Validation:11,933
Pts admitted with HF to
hospitals participating in
the GWTG-HF program
Transfers, missing LVEF data Inhospital
mortality
Inhospital mortality
2.86%; C index
0.75
N/A Validation cohort from
same population.
GWTG is a voluntary
registry
Variables
included in risk
score: SBP,
BUN, Sodium,
age, heart rate,
race, COPD
Predictors of
inhospital
mortality in pts
hospitalized for
HF. Insights from
OPTIMIZE-HF
Abraham, William
JACC 2008
18652942 (16)
Develop a
clinical
predictive
model of in-
hospital
mortality
Cohort/registry 40,201 Pts admitted to hospital
participating in OPTIMIZE-
HF (registry/performance
improvement program); no
EF criteria (LVSD in 49%
of those with measured
EF); included those
admitted with different
diagnosis than the
discharge diagnosis of HF
N/A Inhospital
mortality
Inhospital
mortality: 3.8%; C
index 0.77
N/A Validity - assessed by
bootstrapping
Risk prediction
nomogram: age,
HR, SBP,
sodium, Cr,
primary cause
for admit, LVSD
Predictors of fatal
and non-fatal
outcomes in the
CORONA:
Develop
prognostic
models in
elderly pts and
Cohort 3,342 Pts enrolled in the
CORONA study. Pts ≥60
y; NYHA class II-IV HF;
investigator reported
Recent CV event or
procedure/operation, acute or
chronic liver disease or ALT
>2x ULN; BUN >2.5 mg/dL;
Composite:
CV mortality,
nonfatal MI or
nonfatal
All-cause
mortality; CV
mortality; fatal or
nonfatal MI;
Total mortality: C
index of 0.719;
death due to HF:
C index of 0.80;
N/A Used a clinical trial
population; limited to
ischemic etiology
Elderly pts on
contemporary
HF therapy; NT-
proBNP added

© American College of Cardiology Foundation and American Heart Association, Inc.        7 
 
incremental value
of apolipoprotein
A-1, high-
sensitivity C-
reactive peptide
and NT proBNP
Wedel, Hans
EJHF 2009
19168876 (17)
evaluate the
relative
prognostic
significance of
new
biomarkers
ischemic etiology; EF
≤40% (or 35% if NYHA II)
chronic muscle disease or
unexplained CK >2.5x ULNl;
TSH >2x ULN; any condition
substantially reducing life
expectancy
stroke (time
to event)
death from any
cause or
hospitalization
for HF
all-cause mortality
or HF
hospitalization: C
index of 0.701 (all
models included
NT-proBNP)
predictive
information
Comparison of
Four Clinical
Prediction Rules
for Estimating
Risk in HF
Auble, Thomas E
Annals of
Emergency
Medicine 2007
17449141 (18)
Examine the
performance
of 4 clinical
prediction
rules
(ADHERE
decision tree,
ADHERE
regression
model,
EFFECT,
Brigham and
Women's
Hospital rule)
for inpatient
death, 30-d
death, and
inhospital
death or
serious
complications
Cohort 33,533 Pts with primary ICD-9
discharge diagnosis of HF
admitted at one of 2
Pennsylvania hospitals
from the ED
N/A Inhospital
mortality; in-
hospital
mortality or
serious
complication;
30-d mortality
N/A Inhospital
mortality: 4.5%;
Inhospital mortality
or serious medical
complication:
11.2%; 30-d
mortality: 7.9%
ADHERE rules
could not be used
in 4.1% because
BUN or SCr were
N/A.
N/A N/A Variability
among rules in
the number of
pts assigned to
risk groups and
the observed
mortality within
risk group.
EFFECT
identified pts at
the lowest risk,
ADHERE tree
identified largest
proportion of pts
in the lowest risk
group
ADHERE indicates Acute Decompensated Heart Failure National Registry; AHA, American Heart Association; BUN, blod urea nitrogen; CHARM, Candesartan in Heart Failure: Assessment of Reduction in Mortality and morbidity; COPD, chronic obstructive
pulmonary disease; CORONA, Controlled Rosuvastatin Multinational Trial in HF; CV, cardiovascular; CVD, cardiovascular disease; ED, emergency department; EF, ejection fraction; EFFECT, Enhanced Feedback for Effective Cardiac Treatment; GWTG, Get
With the Guidelines; HF, heart failure; Hgb, hemoglobin; HR, heart rate; ICD-9, international classification of diseases; LVSD, left ventricular systolic dysfunction; MI, myocardial infarction; Na, sodium, N/A, not applicable; NT-proBNP; n-terminal pro-B-type
natriuretic peptide; NYHA, New York Heart Association; OPIMIZE-HF, Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients with Heart Failure; pts, patients; RAD, reactive airway disease; ROC, receiver operating characteristic curve;
SBP, systolic blood pressure; SCr, serum creatinine; TSH, thyroid stimulating hormone; ULN, upper limit of normal.  
 
Data Supplement 4. Health-Related Quality of Life and Functional Capacity (Section 4.4)
Study Name,
Author, Year
Aim of Study Study Type
Study
Size
Patient Population Endpoints Statistical Analysis (Results) Study Limitations Findings/Comments

Inclusion Exclusion Primary Secondary


© American College of Cardiology Foundation and American Heart Association, Inc.        8 
 
Criteria Criteria Endpoint Endpoint
Improvement in
HRQoL after
hospitalization
predicts event-
free survival in
pts with advanced
HF. Moser et al
2009
19879462 (19)

To determine the
frequency,
durability, and
prognostic
significance of
improved
HRQoL after
hospitalization for
decompensated
HF.
Secondary
analysis of
data from the
ESCAPE trial







425 Hospitalized for
NYHA class IV, at
least 1 sign of fluid
overload
EF <30%
history of prior HF
hospitalization or
chronic high
maintenance
diuretic doses
survived to
discharge from
index admission
Significant
comorbid condition
that could shorten
life (e.g. cancer),
pulmonary artery
catheter,
mechanical
circulatory or
ventilatory support,
IV milrinone within
48 h, dobutamine/
dopamine within
24 h, listed for CTX
HRQoL
measured with
the MLHFQ
Event-free
survival
At baseline HRQoL was severely impaired
but improved on average at 1 mo (74.2 ±
17.4 vs 56.7 ± 22.7) and improved most at
6 mo. HRQOL worsened in 51 (16.3%) pts
and remained the same in 49 (15.7%).
OR: 3.3; p<.009
The only characteristic that distinguished
among these groups was whether or not
the pt was too ill to perform the 6-min
walk. There was a group by time
interaction; the degree of improvement
across time differed between pts who
survived without an event and those who
died or were rehospitalized by 6 mo. Pts
with events between 1 and 6 mo did not
experience as much improvement in
HRQoL. A decrease in MLHFQ of >5
points predicted better event-free survival.
(p<.0001 group time interaction)
Potential for survivor bias.
Self-reported HRQoL.
Relatively short follow-up
period of 6 mo.
In pts hospitalized with
severe HF
decompensation, HRQoL is
seriously impaired but
improves substantially
within 1 mo for most pts
and remains improved for 6
mo. Pts for whom HRQoL
does not improve by 1 mo
after hospital admission
merit specific attention both
to improve HRQoL and to
address high risk for poor
event-free survival
QoL and
depressive
symptoms in the
elderly: a
comparison
between pts with
HF and age and
gender matched
community
controls. Lesman-
Leegte et al,
2009.
19181289 (20)
To examine
whether there are
differences in
QoL and
depressive
symptoms
between HF pts
and an age and
gender matched
group of
community-
dwelling elderly
and determine
how chronic
comorbid
conditions qualify
the answer
Secondary
analysis of
COACH trial
data plus
enrollment of
a community
sample from
Netherlands
781 NYHA II-IV, ≥18 y,
structural heart
disease.

Community sample
randomly selected
from population
≥55 y and not
living at same
address. 45%
response rate.
Enrollment in a
study requiring
additional research
visits or invasive
intervention within
last 6 mo or next 3
mo, terminal
disease, active
psychiatric
diagnosis.
QoL measured
with Medical
Outcome Study
36-item General
Health Survey
and Cantril
Ladder of Life.
Depressive
symptoms with
CES-D.
Chronic
conditions
abstracted
from chart of
pts, self-
reported by
community
sample.
QoL significantly impaired in HF pts
compared to matched elderly. Largest
differences were in physical functioning
and vitality. Role limitations due to
physical functioning very low in HF pts.
QoL was lower in HF pts with COPD or
diabetes.
Depressive symptoms higher in HF pts
(39% vs 21%) all p<0.001.




Manner in which comorbid
conditions were assessed
differed between HF pts
and controls. List used was
not all inclusive.
HF has a large impact on
QoL and depressive
symptoms, especially in
women with HF.
Differences persist, even in
the absence of common
comorbidities. Results
demonstrate the need for
studies of representative
HF pts with direct
comparisons to age- and
gender-matched controls.

© American College of Cardiology Foundation and American Heart Association, Inc.        9 
 
Ethnic
Differences in
QoL in Persons
With HF.
Riegel et al 2008
18226772 (21)
To compare
HRQoL in non-
Hispanic white,
black, and
Hispanic adults
with HF
Longitudinal
comparative
study with
propensity
scoring
1,212 Established
diagnosis of
chronic HF
Recent MI, USA,
cognitive
impairment, severe
psychiatric
problems,
homeless, or
discharged to an
extended care or
skilled nursing
facility
HRQoL
measured with
the MLHFQ
N/A HRQoL improved over time (baseline to 3-
and 6-mo) in all groups but most
dramatically among Hispanics. Hispanics
improved more than whites (p<0.0001).
Hispanics improved more than blacks
(p=0.004).


Secondary analysis of
existing data. Hispanic
sample was primarily
Mexican so results cannot
be generalized to all
Hispanics. Samples
received different
treatments at various sites;
treatment was controlled in
the analysis. Other factors
that could explain these
differences were not
measured. Cultural bias in
the data obtained from the
MLHFQ is possible.
Cultural differences in the
interpretation of and
response to chronic illness
may explain why
HRQoL improves more
over time in Hispanic pts
with HF compared with
white and black
pts.
The impact of
chronic HF on
HRQoL data
acquired in the
baseline phase of
the CARE-HF
study. Calvert,
Melanie. 2005
15701474 (22)
To assess the
QoL of pts with
HF, due to LV
dysfunction,
taking optimal
medical therapy
using baseline
QoL assessments
from the CARE-
HF trial, and to
evaluate the
appropriateness
of using the EQ-
5D in pts with HF.
RCT 813 NYHA II-IV HF None specified QoL Euroquol
EQ-5D and
MLHFQ
N/A There is a relationship between the EQ-5D
score and gender, on average females
enrolled had a worse QoL than male
participants.
r=-0.08; 95% CI: -0.13 to -04; p=0.00004
Mean EQ-5D score for NYHA III pts was
higher than for NYHA IV pts (mean
difference 0.17)
p<0.0001; 95% CI: 0.08-0.25
Association between MLWHF and EQ-5D
scores (increasing MLWFH associated
with a decrease in EQ-5D)
r=-0.00795;
95% CI: (-0.00885 to -0.00706); p<0.0001
HF is shown to have an important impact
on all aspects of QoL but particularly on
pts mobility and usual activities and leads
to significant reductions in comparison
with a representative sample of the UK
population.
Pts assessed in the study
are not a random sample of
pts with severe HF.
CARE-HF is an int’l study
but used available
normative data from a
representative sample of
the UK population to
evaluate burden of disease.
A study comparing UK and
Spanish time trade-off
values for EQ-5D health
states demonstrated that
although the general
pattern of value assignation
was similar, there were
differences in values
assigned to a number of
health states
The impact of HF varies
amongst pts but the overall
burden of disease appears
to be comparable to other
chronic conditions such as
motor neurone or
Parkinson’s disease. The
EQ-5D appears to be an
acceptable valid measure
for use in pts with HF
although further evidence of
the responsiveness of this
measure in such pts is
required.

© American College of Cardiology Foundation and American Heart Association, Inc.        10 
 
Characterization
of HRQoL in HF
pts
with preserved vs
low EF in
CHARM, Lewis et
al, 2007
17188020 (23)

To characterize
HRQoL in a large
population of HF
pts with
preserved and
low LVEF and to
determine the
factors
associated with
worse HRQoL.
Secondary
analysis of
data from the
CHARM trial
2,709 “CHARM-
Alternative” pts:
LVEF ≤40% and
not receiving an
ACE-I; “CHARM-
Added” pts: LVEF
≤40% and taking
ACE-Is. Pts in
NYHA class II
required admission
to hospital with a
CV problem in
prior 6 mo (which
increased
proportion of
NYHA class III/IV
in CHARM-Added.
“CHARM-
Preserved” pts had
LVEF >40% with
or without ACEI
N/A QoL N/A 9 independent clinical determinants of
worse HRQoL: younger age, higher BMI,
lower SBP, female sex, worse NYHA
class, angina, PND, rest dyspnea, lack of
ACE-I. Characteristics did not differ by
group. LVEF was NS.

Population was healthy
enough to enroll so may
have fewer comorbidities.
Asymptomatic pts were
excluded. Only enrolled in
Canada and US. Groups
without ACE-I therapy may
have affected HRQoL. No
gold standard for
measuring HRQoL.
Independent factors
associated with worse
HRQoL in both populations
included female sex,
younger age, higher BMI,
lower SBP, greater
symptom burden, and
worse functional status.
The enigma of
QoL in pts with
HF. Dobre D,
2008
17400313 (24)

To review RCTs
that assessed the
impact of
pharmacologic
treatments on
QoL
Brief
communicatio
n
N/A Clinical trials N/A QoL Survival N/A N/A Life prolonging therapies,
such as ACE-Is and ARBs
improve modestly or only
delay the progressive
worsening of QoL in HF.
Beta blockers do not affect
QoL in any way. Therapies
that improve QoL (e.g.,
inotropic agents) do not
seem beneficial in relation
to survival.

© American College of Cardiology Foundation and American Heart Association, Inc.        11 
 
QoL in individuals
with HF. Harrison,
Margaret. 2002
12021683 (25)

To evaluate
whether the use
of usual providers
and a
reorganization of
discharge
planning and
transition care
with improved
intersector
linkages
between nurses,
could improve
QoL and health
services
utilization for
individuals
admitted
to hospital with
HF.
Prospective
randomized
trial
192 Admitted to
hospital with a
diagnosis of CHF
Residing in the
regional home
care radius.
Expected to be
discharged with
home nursing care
English or French
speaking
Admitted for more
than 24 h to the
nursing units
Cognitively
impaired (score >8
on Short Portable
Mental Status
Exam)
HRQoL
(MLWHF),
symptom
distress and
function at 6-
and 12-wk
postdischarge
The no. of all-
cause ED
visits, hospital
readmissions,
and QoL
measured with
a generic
measure,
Medical
Outcome Study
Short Form
The overall MLHFQ score was better
among the Transitional Care pts than the
usual care pts:
At 6 wk after hospital discharge (p=0.002)
At 12 wk after hospital discharge
(p<0.001)
The MLHFQ’s Physical Dimension
subscale score was better among the
Transitional Care pts than the usual care
pts:
At 6 wk after hospital discharge (p=0.01)
At 12 wk after hospital discharge
(p<0.001)
The MLHFQ’s Emotional Dimension
subscale score was better among the
Transitional Care pts than the usual care
pts at 6 wk after hospital discharge
(p=0.006)
46% of the Usual Care group visited the
ED compared with 29% in the Transitional
Care group (p=0.03)
At 12 wk postdischarge, 31% of the Usual
Care pts had been readmitted compared
with 23% of the Transitional Care pts
(p=0.26).
Conducted the trial in a
naturalistic manner in the
usual setting of care with
usual providers.
Possibility of contamination
with the hospital nurses
providing usual care.
Pts may have inadvertently
alerted the research
coordinators of their
assignment to usual care or
transitional care.
With multiple interventions
it's not easy to assess
neither the relative
contribution of each
component nor the
synergistic effect of the sum
of the parts.
Transitional Care has an
important role to play in
altering the course of pts
hospitalized with HF. Our
results suggest that with
modest adjustments to
usual discharge and
transition from hospital-to-
home, pts with CHF can
experience improved QoL,
and decreased use of ED,
for 3 mo after
hospitalization. This
approach will provide the
needed adjunct to current
management of HF.
ACEI; angiotensin-converting-enzyme inhibitor; ARB, angiotensin receptor blocker; BMI, body mass index; CARE-HF Cardiac Resynchronisation in Heart Failure; CES-D, Center for Epidemiological Studies-Depression scale; CHARM, Candesartan in Heart
failure: Assessment of Reduction in Mortality and morbidity; CHF, congestive heart failure; COACH, Comparative study on guideline adherence and patient compliance in heart failure patients; CTX, chest x-ray; CV, cardiovascular; ED, emergency
department; EF, ejection fraction; ESCAPE, Evaluation Study of Congestive Heart Failure and PulmonaryArtery Catheterization Effectiveness; HF, heart failure; HRQoL, health-related quality of life; MI, myocardial infarction; MLHFQ score, Minnesota Living
With Heart Failure; N/A, not applicable; NYHA, New York Heart Association; pts, patients; PND, Paroxysmal nocturnal dyspnea; QoL, quality of life; RCT, randomized control trial; and SBP, systolic blood pressure.

Data Supplement 5. Stress Testing (Initial and Serial Evaluation) of the HF Patient (Section 6.1.1)
Study Name,
Author, Year Aim of Study
Study
Type
Background
Therapy Study Size Etiology Patient Population Severity Endpoints Mortality
Trial
Duration
Statistical
Analysis
(Results)

Study
Limitations
Pre-trial
standard
treatment.
N (Total)
n
(Experimental)
n (Control)
Ischemic/
Non-
Ischemic
Inclusion
Criteria
Exclusio
n Criteria
Severity
of HF
Sympto
ms
Study
Entry
Sverity
Criteria
Primary
Endpoint
Secondary
Endpoint
Annualize
d Mortality
1st Year
Mortality

© American College of Cardiology Foundation and American Heart Association, Inc.        12 
 
Defining the
Optimal
Prognostic
Window for CPX
in Pts with HF.
Arena et al. Circ
Heart Fail 2010;
3: 405-411
20200329 (26)
Assess the
change in
prognostic
characteristic
s of CPX at
different time
intervals
Cohort 1 year 791


51%
ischemic
HF and LV
dysfunction
NYHA
2.4 +/-
0.67
N/A Major
cardiac
events -
mortality,
LV device
implantatio
n, urgent
heart
transplant
Cardiac
mortality
N/A 75
deaths
(of 791)
36 mo
FU
For 24 mo post
CPX (high vs.
low Ve/VCO2):
cardiac events
p<0.001 (95%
CI: 2.1 - 5.5);
cardiac
mortality
p<0.001 (95%
CI: 2.2 - 5.8)
HR:dichotomou
s3.4; 3.5
Observation
al
Value of peak
exercise oxygen
consumption for
optimal timing of
cardiac
transplantation
in ambulatory
pts with HF.
Mancini et al.
Circulation
1991;83;778-
786
1999029 (27)
To determine
if maximal
exercise
testing and
measurement
of PKVO2
identifies pts
in whom heart
transplant can
be safely
deferred
Observati
onal
prospectiv
e cohort
Focus on
hemodynami
c and NYHA
class
122
52
(PKVO2>14)
35
(PKVO2=<14)
46%
ischemic
Ambulatory
pts referred
for heart
transplant
Unable
to
perform
exercise
testing
due to
angina
70%
NYHA
III
N/A Survival N/A N/A 94%
survival
in those
with high
PKVO2
vs. 70%
for those
with low
PKVO2
2 y FU p<0.005 Wide
complex
tachycardia
in 1 pt
Peak Oxygen
Consumption as
a Predictor of
Death in Pts
With HF
Receiving Beta
Blockers. O'Neill
JO et al.
Circulation
2005;111;2313-
2318
15867168 (28)
To determine
whether
PKVO2 is a
reliable
indicator of
prognosis in
the beta
blocker era
Observati
onal
prospectiv
e cohort
Cutoff of 14
mL/kg1
2,105;
n=909 on beta
blocker;
n=1,196 no
beta blocker
52%
ischemic
Referral for
HF with
LVEF<35%
Age <20,
ESRD,
prior
OHT
N/A N/A Death Death or
transplantatio
n
N/A N/A N/A Pts on beta
blockers:
Death p<0.001,
(95% CI: 1.18–
1.36); death
and transplant
p<0.001,
(95% CI: 1.18–
1.32)
aHR: 1.26;
1.25 per 1-
mL/min/kg
N/A
CPX indicates cardiopulmonary exercise testing; EF, ejection fraction; ESRD, end-stage renal disease; FU, follow up; HF, heart failure; pts, patients; LVEF, left ventricular ejection fraction; N/A, not applicable; NYHA, New York Heart Association; OHT,
orthotopic heart transplantation; PKVO2; peak oxygen consumption; and RCT, randomized control trial.


© American College of Cardiology Foundation and American Heart Association, Inc.        13 
 
Data Supplement 6. Clinical Evaluation – History (Orthopnea) (Section 6.1.1)
Study Name, Author, Year Study Type Study Size Patient Population Utility in Detecting Elevated PCWP
Stevenson, LW; Perloff
JAMA 1989:261:884-888
2913385 (29)
Single center, prospective 50 Stage D Orthopnea within preceding wk
91% of 43 pts with PCWP ≥22
0/7 pts with PCWP <22
Chakko et al; Am J Medicine
1991:90:353-9
1825901 (30)
Single center, prospective 42 Stage D For PCWP >20
Sensitivity 66%, Specificity 47%, PPV 61%, NPV 37%
Drazner et al Circ HF
2008:1:170-177
19675681 (31)
Multicenter substudy of ESCAPE 194 (with PAC) Stage D Orthopnea (≥ 2 pillows)
OR 2.1 (95% CI: 1.0-4.4); PPV 66%, NPV 51%; +LR 1.15, (-) LR 1.8; all for PCWP>22
OR 3.6 (95% CI: 1.02 -12.8) for PCWP>30
ESCAPE indicates Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness; LR, likelihood ratio; NPV, negative predictive value; OR, odds ratio; PAC, pulmonary artery catheter; PCWP, Pulmonary Capillary
Wedge Pressure; PPV, positive predictive value; and pts, patients.

Data Supplement 7. Clinical Evaluation - Examination (Section 6.1.1)
Study Name,
Author, Year
Study Type Study Size Patient Population Utility in Detecting Elevated PCWP
Jugular venous pressure for assessing right atrial pressure
Stevenson, LW;
Perloff
JAMA
1989:261:884-888
2913385 (29)
Single center,
prospective
50 Stage D 21/28 (75%) of pts with RAP ≥10 had elevated JVP
Butman et al
JACC
1993:22:968-974
8409071 (32)
Single center,
prospective
52 Stage D RAP associated with JVD and HJR
–HJR,-JVD: RAP 4 (2)
+HJR, -JVD: RAP 8 (5)
+HJR, +JVD: RAP 13 (5)
Stein et al
AJC
1997;80:1615-1618
9416951 (33)
Single center 25 Class 3-4 RAP estimated from JVP vs. measured RA: r=0.92.
Clinical estimates underestimate elevated JVP. Interaction between utility of estimated RAP and measured RAP (more of an
underestimate as measured RAP increased). Bias 0.1 (RAP 0-8), 3.6 (RAP 9-14), 5 (RAP ≥15).
Drazner et al
Circ HF
2008:1:170-177
19675681 (31)
Multicenter
substudy of
ESCAPE
194 (with
PAC)
Stage D
Estimated RAP for RAP >12
AUC 0.74

© American College of Cardiology Foundation and American Heart Association, Inc.        14 
 
Jugular Venous Pressure for Detecting Elevated PCWP
Stevenson, LW;
Perloff
JAMA
1989:261:884-888
2913385 (29)
Single center,
prospective
50 Stage D Elevated JVP associated with PCWP ≥22
58% sensitivity
100% specificity (0/7 with PCWP ≤18 mm Hg)
However 8/18 pts with PCWP ≥35 mm Hg without elevated JVP
Chakko et al
Am J Medicine
1991;90:353-359
1825901 (30)
Single center,
prospective
52 Stage D “High JVP” for PCWP >20 mm Hg
Sensitivity 70%, Specificity 79%, PPV 85%, NPV 62%
Butman et al
JACC
1993:22:968-974
8409071 (32)
Single center,
prospective
52 Stage D JVD at rest or with HJR for PCWP>18 mm Hg: Sens 81%, Spec 80%, PPV 91%, NPV 63%
Badgett et al
JAMA
1997; 277:1712-
1719
9169900 (34)
Literature review
“Rational Clinical
Examination”
series

NA Stage D citing above
3 studies
Suggested algorithm:
If known low LVEF, and population with high prevalence of increased filling pressure, then elevated JVP is “very helpful” and
associated with >90% chance of elevated filling pressures

Drazner et al
Circ HF
2008:1:170-177
19675681 (31)
Multicenter
substudy of
ESCAPE
194 (with
PAC)
Stage D JVP≥12 mm Hg for PCWP>22
Sensitivity: 65%, Specificity: 64%, PPV 75%, NPV 52%, +LR 1.79, (-)LR 1.8
Prognostic Utility of JVP
Drazner et al
NEJM
2001;345:574-81
11529211 (35)

Retrospective
analysis of
SOLVD
Treatment Trial
2569 Stage C Multivariate analysis for elevated JVP
Mean f/u 32 months
Death RR 1.15 (95% CI: 0.95-1.38)
HF hospitalization 1.32 (95% CI: 1.08-1.62)
Death/HF hospitalization 1.30 (95% CI: 1.11-1.53)
Drazner et al
Am J Med
2003;114:431-437
12727575 (36)

Retrospective
analysis of
SOLVD
Prevention Trial
4102 Stage B Multivariate analysis for elevated JVD
Mean follow-up 34 mo
Development of HF RR 1.38 (95% CI: 1.1-1.7)
Death or Development of HF RR 1.34 (95% CI: 1-1,1.6)

© American College of Cardiology Foundation and American Heart Association, Inc.        15 
 
Drazner et al
Circ HF
2008:1:170-177
19675681 (31)

Multicenter
substudy of
ESCAPE
194 (with
PAC)
Stage D Multivariate analysis

Enrollment estimated RAP associated with survival outside hospital at 6 mo (Referent RAP<13)
RAP 13-16 HR 1.2 (95% CI: 0.96-1.5)
RAP >16 HR 1.6 (95% CI: 1.2-2.1)
Meyer et al
AJC
2009 103:839-844
19268742 (37)
Retrospective
analysis of DIG
trial
7788 Stage C Mean follow-up 34 mo

Univariate analysis
Elevated JVP associated with
Death: HR 1.7 (95% CI: 1.54-1.88)
All-cause hosp: HR 1.35 (95% CI: 1.25-1.47)
After adjusting for propensity score associations no longer significant; aHR: 0.95 (death), aHR:0.97 (hosp),
p>0.5
Utility of Valsalva Maneuver for Detecting Elevated PCWP
Schmidt et al
AJC 1993;71:462-5
8430644 (38)
Prospective
single center
38 Unknown
(%HF not stated)
Utility of square wave for LVEDP ≥15 mm Hg: sens 100%, spec 91%, PPV 82%, NPV 100%
Rocca et al
Chest
1999; 116:861-7
10531144 (39)
Single center,
prospective
study
45 Stage C Pulse amplitude ratio by Valsalva correlated with BNP (r=0.6, p<0.001)
Givertz et al
AJC
2001 1213-1215
11356404 (40)
Single center,
prospective
study of Vericor
system
30 men Class 3/4 Predicted PCWP by Valsalva vs measured PCWP: r=0.9, p<0.001.
Mean difference 0.07 ±2.9 mm Hg
Predicted PCWP had sensitivity: 91%, specificity: 100% for PCWP ≥18 mm Hg
Sharma et al
Arch Intern Med
2002:162:2084-
2088
12374516 (41)
Prospective
study of
commercial
device (VeriCor)
at 2 centers
57 pts (2
women)
Unknown
Majority pts with CAD
Pulse amplitude ratio correlated with LVEDP (r=0.86)
84% of measurements within 4 mm Hg of LVEDP
Felker et al
Am J Medicine
2006;119:117-132
16443410 (42)
Review paper N/A N/A Significant correlation between CV response to Valsalva and LV filling pressures
AUC indicates area under the concentration curve; BNP, B-Type Natriuretic Peptide; CAD, coronary artery disease; CV, cardiovascular; DIG, Digitalis Investigation Group; f/u, follow-up; ESCAPE, Evaluation Study of Congestive Heart
Failure and Pulmonary Artery Catheterization Effectiveness HJR, hepatojugular reflux; LVEF, left ventricular ejection fraction; LVEDP, Left Ventricular End-Diastolic Pressure; JVD, jugular venous distension; JVP, jugular venous pressure;
N/A, not applicable; NPV, negative predictive value; PCWP, Pulmonary Capillary Wedge Pressure; PPV, positive predictive value, Pts, patients; r, Pearson’s correlation coefficient; RAP, right arterial pressure; and SOLVD, Studies of left
ventricular dysfunction.


© American College of Cardiology Foundation and American Heart Association, Inc.        16 
 
Data Supplement 8. Clinical Evaluation – Risk Scoring (Section 6.1.2)
Study Name, Author,
Year
Study Type Study Size Patient population Variables Utility
Stage C
Levy et al
Circulation
2006;113:1424-1433
Seattle HF score
16534009 (10)
Derivation cohort (PRAISE
1); then tested in 5
additional trial databases
1125
(Derivation)
9942
(Validation)

Largely Stage C Available on website 2 year survival for scores 0, 1,2,3,4 was:
93%, 89%, 78% 58%, 30%, 11%
AUC 0.729 (0.71 to 0.74)
Pocock et al
Eur Heart J
2006;27:65-75
CHARM
16219658 (13)
Analysis of CHARM 7,599 Stage C HF 21 variables 2 year mortality
Lowest to highest deciles 2.5% to 44%
C statistic 0.75


Stage D
Aaronson et al
Circulation
1997;95:2660-7
HF Survival Score
9193435 (2)
Derivation and Validation
2 transplant centers


268
(Derivation)
199
(Validation)

Stage D Ischemic cardiomyopathy, resting
heart rate, LVEF, IVCD (QRS
duration 0.12 sec of any cause),
mean resting BP, peak O2, and
serum sodium PCWP (invasive)
3 strata
Event-free survival rates at 1 y for the low-, medium-, and high-risk

HFSS strata were 93±2%, 72±5%, and 43±7%
AUC 1 y 0.76-0.79
Lucas et al
Am Heart J
2000;140:840-7
“Congestion Score”
11099986 (43)
Retrospective, single center 146 Stage D Congestion score: orthopnea, JVD,
edema, weight gain, new increase
diuretics
Post discharge (4-6 wk) score vs. 2 y death
0: 54%
1-2: 67%
3-5: 41%
Nohria et al
JACC
2003:41:1797-1804
“Stevenson profiles”
12767667 (44)
Prospective, single center 452 pts Stage D Stevenson classification
Profiles A,B,C,L


Profile B associated with death+urgent transplant in multivariate
analysis (HR: 2.5, p=0.003).
Drazner et al
Circ HF
2008;1:170-7
“Stevenson profiles”
19675681 (31)
Substudy of ESCAPE 388 Stage D Stevenson classification Discharge profile “wet or cold” HR 1.5 (1.1, 2.1) for number of d
alive outside hosp at 6 mo in multivariate analysis
Levy et al
J Heart Lung Tx
Retrospective analysis of
REMATCH
129
REMATCH
Stage D Seattle HF Score The 1-y ROC was 0.71 (95% CI: 0.62-0.80).

© American College of Cardiology Foundation and American Heart Association, Inc.        17 
 
2009:28: 231-236.
Seattle HF Score
19285613 (45)
Gorodeski et al
Circ Heart Fail
2010;3:706-714
Seattle HF Score
20798278 (46)
Single center study of
ambulatory pts presented to
transplant committee
215 (between
2004-2007)
Stage D Seattle HF score ACM, VAD, Urgent HT
2 y f/u
C index 0.68 (1 yr), 0.65 (2 yr)
Calibration overestimated survival among UNOS 2 pts

Hospitalized Patients
Lee et al
JAMA
2003:290:2581-2587
14625335 (11)

Retrospective study of
multiple hospitals in Ontario
Canada
2624
(derivation
1999-2001)
1407
(validation
1997-1999)




Hospitalized pts Age, SBP, RR, Na<136, Hgb <10,
BUN, CVA, Dementia, COPD,
cirrhosis, Cancer
Predicted and observed mortality rates matched well

30 d mortality
AUC derivation 0.82
Validation 0.79

1 y mortality
AUC
Derivation 0.77
Validation 0.76
Fonarow et al
JAMA
2005:293:572-580
ADHERE
15687312 (14)
CART analysis of ADHERE
national registry 2001-2003
33,046
(derivation)
32,229
(Validation)

Hospitalized pts BUN ≥43, SBP<115, SCr ≥2.75 In-hospital mortality
AUC 67-69%
Morality ranges from 1.8(low risk) to ~25% (high risk)

Rohde et al
J Cardiac Failure
2006;12:587-593
“HF Revised Score”
17045176 (47)
Single center study 2000-
2004
779 Hospitalized pts Cancer, SBP ≤124, Cr >1,4m
BUN>37, Na <136, Age>70
In-hospital mortality
Bootstrap C=0.77 (0.689-0.85)
6 increasing groups: 0,5%, 7%, 10%, 29%, 83%
Abraham et al
JACC
2008;52:347-356
OPTIMIZE-HF
18652942 (16)
Analysis of OPTIMIZE-HF
registry
2003-2004

48,612 pts
Validated in
ADHERE

Hospitalized pts 19 variables In-hospital mortality
C statistic 0.77
Validation C statistic 0.746
Excellent reliability for mortality

© American College of Cardiology Foundation and American Heart Association, Inc.        18 
 
Peterson et al
Circ Cardiovasc Qual
Outcomes
2010:3:25-32
GWTG
20123668 (15)
Analysis of GWTG admitted
2005-2007
27,850
(Derivation)
11,933
(Validation)

Hospitalized pts Age, SBP, BUN, HR, Na, COPD,
nonblack race
In-hospital mortality
C index 0.75
Predicted probability mortality over deciles ranged from 0.4% - 9.7%
and corresponded with true mortality

Other
Gheorghiade et al
Eur J of Heart Failure
2010:12:423-433
ESC Congestion Score
20354029 (48)

Scientific Statement from
Acute HF Committee of HF
Association of ESC
N/A N/A Congestion score
Bedside assessment (Orthopnea,
JVD, HM, Edema)
Lab (BNP or NT proBNP)
Orthostatic BP
6 min walk test
Valsalva
Needs to be tested
ACM indicates all cause mortality; ADHERE, Acute Decompensated Heart Failure National Registry; AUC, area under the curve; BNP, B-type natriuretic peptide; BP, blood pressure; BUN, blood urea nitrogen; CART, Classification and
regression trees; CHARM, Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity; COPD, chronic obstructive pulmonary disease; CVA, Cerebrovascular Accident; ESC, European Society of Cardiology; ESCAPE,
Evaluation Study of Congestive Heart Failure and Pulmonary Artery Catheterization Effectiveness; GWTG, Get With the Guidelines; HF, heart failure; HFSS, heart failure survival score; Hgb, hemoglobin; HR, heart rate; HT, heart
transplantation; HM, hepatomegaly; IVCD, intraventricular conduction delay; JVD, jugular venous distension; LVEF, left ventricular ejection fraction; N/A, not applicable; Na, sodium; NT proBNP, n-terminal pro-B-type natriuretic peptide;
OPTIMIZE-HF, Organized Program to Initiate Lifesaving Treatment in Hospitalized Pts with HF; PCWP, Pulmonary Capillary Wedge Pressure; PRAISE, Prospective Randomized Amlodipine Survival Evaluation; pts, patients; REMATCH,
Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure; ROC, receiver operating characteristic curve; RR, respiratory rate; SBP, systolic blood pressure; SCr, serum creatinine; UNOS, United
Network of Organ Sharing; and VAD, ventricular assist device.


Data Supplement 9. Imaging Echocardiography (Section 6.4)
Study
Name,
Author,
Year
Aim of Study Study Type Study Size Patient Population Endpoints Statistical Analysis (Results) Study Limitations
Inclusion Criteria Exclusion Criteria
IS. Syed
2010
20159642
(49)
Evaluate LGE-CMR
in identifying CA;
investigate
associations
between LGE and
clinical, morphologic,
functional, and
biochemical
features.
Observational 120 (35 with
positive cardiac
histology, 49
without cardiac
histology but with
echo evidence of
CA, 36 without
histology or echo
evidence of CA)
Histologically proven
amyloidosis and, in the
case of AL amyloidosis,
confirmatory evidence of
monoclonal protein in the
serum or urine and/or a
monoclonal population of
plasma cells in the bone
marrow.
Prior MI, myocarditis,
prior peripheral blood
stem cell
transplantation, or
prior heart
transplantation
LGE-CMR presentation
in pts with amyloidosis;
associations between
LGE and clinical,
morphologic, functional,
and biochemical
features.
Of the 35 pts with histology, abnormal LGE was present in
97% of the 49 with echo evidence, abnormal LGE was
present in 86% of the 36 without histology or ECHO evidence
of CA, abnormal LGE was present in 47%.
In all pts, LGE presence and pattern was associated with
NYHA functional class, ECG voltage, LV mass index, RV wall
thickness, troponin-T, and BNP levels.
No control group,
cardiac histology was only
present in a subset of pts
contraindication to the use of
Gd

© American College of Cardiology Foundation and American Heart Association, Inc.        19 
 
V Rizzello
2009
19443475
(50)

Evaluate the
prognosis of viable
pts with and without
improvement of
LVEF after coronary
revascularisation.
Observational 90; group 1:
viable pts with
LVEF
improvement
(n = 27); group 2,
viable pts without
LVEF
improvement
(n = 15), group 3,
non-viable pts
(n = 48)
Pts were already
scheduled for coronary
revascularization
according to clinical
criteria of reduced LVEF
(40%), symptoms of HF
and/or angina,
presence/absence of
ischemia and presence of
critical coronary disease
at angiography.
Only pts who had
undergone coronary
revascularisation alone
were included in the study
Pts who had
undergone mitral
valvuloplasty or
aneurismectomy in
association with
revascularisation
were excluded.
Cardiac events were
evaluated during a 4-y
follow-up (cardiac death,
new MI, admission to
hospital for HF)

Cardiac event rate was low (4%) in group 1, intermediate
(21%) in group 2 and high (33%) in group 3.
After revascularization, the mean (SD) LVEF improved from
32 (9)% to 42 (10)% in group 1, but did not change
significantly in group 2 and in group 3, p,0.001 by ANOVA.
HF symptoms improved in both groups 1 (mean (SD) NYHA
class from 3.1 (0.9) to 1.7 (0.7)) and 2 (from 3.2 (0.7)-1.7
(0.9)), but not in group 3 (from 2.8 (1.0)-2.7 (0.5)), p=0.001
by ANOVA.
The difference in event rate was not statistically significant
between groups 1 and 2 -small number of pts- but it was
significant between the 3 groups using Kaplan–Meier p=0.01

N/A
Kevin C
Allman
2002
11923039
(51)
Examines late
survival with
revascularization vs
medical therapy after
myocardial viability
testing in pts with
severe CAD and LV
dysfunction
Meta-analysis of
observational
studies
3,088 (viability
demonstrated in
42%)
Pts with CAD and LV
dysfunction who were
tested for myocardial
viability with cardiac
imaging procedures from
24 viability studies
reporting pt survival using
thallium perfusion
imaging, F-18
fluorodeoxyglucose
metabolic imaging or
dobutamine ECHO.
Those not reporting
deaths or where
deaths could not be
apportioned to pts
with vs without
viability were
excluded
Annual mortality rates,
pts followed for 25±10
mo.

For pts with defined myocardial viability, annual mortality rate
was 16% in medically treated pts but only 3.2% in
revascularized pts (χ
2
=147, p<0.0001). This represents a
79.6% relative reduction in risk of death for revascularized
pts. For pts without viability, annual mortality was not
significantly different by treatment method: 7.7% with
revascularization vs 6.2% for medical therapy (p=NS).
The individual studies are
observational,
nonrandomized,
unblinded and subject to
publication and other biases.
In this metaanalysis, viability
could only be interpreted as
“present” or “absent” based
on individual studies’
definitions
Beanlands
RS. 2002
12446055
(52)
Whether the extent
of viability or scar is
important in the
amount of recovery
of LV function
and to develop a
model for predicting
recovery after
revascularization
that could be tested
in a randomized trial.
Prospective
multicenter
cohort
82; Complete
follow-up was
available on 70
pts.
Pts CAD and severe LV
dysfunction with EF 35%
by any quantitative
technique, who were
being scheduled for
revascularization
PTs with MI within the
preceding 6 wk,
severe valve disease
requiring valve
replacement,
requirement for
aneurysm resection,
and inability to obtain
informed consent.
Absolute change in EF
determined by
radionuclide angiograms
3 mo
postrevascularization

Amount of scar was a significant independent predictor of LV
function recovery after revascularization.
Across tertiles of scar scores (I, small: 0% to 16%; II,
moderate: 16% to 27.5%; III, large: 27.5% to 47%), the
changes in EFs were 9.0±1.9%, 3.7±1.6%, and 1.3±1.5%
(p=0.003: I vs. III), respectively.

Pt population in this study
included pts who were
predominantly men,
predominately between 53-
71 y of age (1 SD from the
mean), had multivessel
disease, and had bypassable
vessels.
Although improvement in LV
function has been noted at 3
mo of follow-up in many
previous studies, recent data
suggest that more recovery
may be observed with longer
follow-up time

© American College of Cardiology Foundation and American Heart Association, Inc.        20 
 
Paul R.
Pagley 1997
9264484
(53)
Hypothesized that
pts with poor
ventricular function
and predominantly
viable myocardium
have a better
outcome after
bypass surgery
compared with those
with less viability.
Retrospective
cohort
70 Pts with EFs <40%
without significant valvular
disease who were
referred for a first
coronary bypass surgery
and underwent
preoperative quantitative
planar 201Tl imaging for
viability determination.
Prior CABG,
coexisting valvular
disease and
underwent concurrent
aortic or MV
replacement, or those
with SPECT imaging
CV death or cardiac
transplantation; median
time to follow-up was
1177 d (range, 590 to
1826)

The viability index was significantly related to 3-y survival
free of cardiac event (cardiac death or heart transplant) after
bypass surgery (p=0.011) and was independent of age, EF,
and number of diseased coronary vessels. Survival free of
cardiac death or transplantation was significantly better in
group 1 pts on Kaplan-Meier analysis (p=0.018).

N/A
Senior R,
1999
10362184
(54)

To evaluate the
effect of
revascularization on
survival in pts with
CHF due to ischemic
LV systolic
dysfunction based
on the presence of
myocardial viability
Observational
prospective
87 CHF (NYHA class II-IV)
for at least 3 mo that was
treated medically;
LVEF ≤35%;
clinical evidence of CAD
Significant valvular
disease, unstable
angina, MI within
three months,
sustained ventricular
tachycardia or AF
Cardiac deaths were
defined as those
resulting from acute MI,
refractory CHF or
occurring suddenly and
not being attributed to
other known causes
after a mean follow-up of
40 ± 17 mo
Pts with at least 5 segments showing myocardial viability
underwent revascularization, mortality was reduced by an
average of 93% which was associated with improvement in
NYHA class as well as LVEF. Pts with
<5 segments showing myocardial viability who underwent
revascularization (and thus, showing mostly scar), and those
with at least 5 segments demonstrating myocardial viability
who were treated medically, had a much higher mortality.
(95% CI: 22%-99%)
Single-center study where
selection bias is unavoidable.
Selection bias may have
favored taking one group to
surgery over another.
Kwon DH
2009
19356530
(55)
To determine
whether the extent of
LV scar, measured
with DHE-CMR
predicts survival in
pts with ischemic
cardiomyopathy ICM
and severely
reduced LVEF.
Observational 349 Pts with documented ICM
(on the basis of 70%
stenosis in at least 1
epicardial coronary vessel
on angiography and/or
history of MI or coronary
revascularization), who
were referred for the
assessment of myocardial
viability with CMR
Pts with standard
CMR
contraindications
including severe
claustrophobia, AF,
and the presence of
pacemakers,
defibrillators, or
aneurysm clips
All-cause mortality was
ascertained by social
security death index
after a mean of follow-up
2.6 ± 1.2 y (median 2.4
y)

Mean scar percentage and transmurality score were higher in
pts with events vs those without
(39±22 vs 30±20, p=0.003, and 9.7±5 vs. 7.8±5, p=0.004).
*On Cox proportional hazard survival analysis, quantified
scar was greater than the median (30% of total myocardium),
and female gender predicted events
(RR: 1.75; 95% CI: 1.02-3.03 and RR:1.83; 95% CI: 1.06-
3.16, respectively, both p=0.03).
Selection bias of an
observational study
conducted at a large tertiary
referral center. Only the
pts with no contraindications
to CMR underwent the
examination.
Ordovas
KG. 2011
22012903
(56)
N/A Review paper N/A N/A N/A N/A
An international multicenter study (54) reported a sensitivity
of 99% for detection of acute infarction and 94% for detection
of chronic infarction.
Delayed enhancement occurs in both acute and chronic
(scar) infarctions and in an array of other myocardial
processes that cause myocardial necrosis, infiltration, or
fibrosis. These include myocarditis, hypertrophic
cardiomyopathy, amyloidosis, sarcoidosis, and other
myocardial conditions.
In several of these diseases, the presence and extent of
delayed enhancement has prognostic implications.
N/A
AF, atrial fibrillation; AL, Amyloid Light-chain; ANOVA, analysis of variance; CA, cardiac amyloidosis; CABG, coronary artery bypass graft; CAD, coronary artery disease; CHF, congestive heart failure; CMR, cardiovascular magnetic resonance; CV, cardiovascular; DHE-CMR, delayed
hyperenhancement cardiac magnetic resonance; ECHO, echocardiography; EF, ejection fraction; Gd, gadolinium; ICM, ischemic cardiomyopathy; LGE-CMR, late gadolinium enhancement cardiac magnetic resonance; LV, left ventricular; LVEF, left ventricular ejection fraction; MI,
myocardial infarction; N/A, not applicable; NS, not significant; NYHA, New York Heart Association; pts, patients; RV, right ventricular; SD, standard deviation; and SPECT, single-photon emission computed tomography.

© American College of Cardiology Foundation and American Heart Association, Inc.        21 
 

Data Supplement 10. Biopsy (Section 6.5.3)
Study Name, Author, Year Aim of Study Study Type Study Size Patient Population Results
Cooper LT, Baughman KL, Feldman AM et al. The role of
endomyocardial biopsy in the management of CV disease:
Circulation 2007 November 6;116(19):2216-33.
17959655 (57)
Role of
endomyocadial
biopsy for
management of CV
disease
A scientific statement
from the AHA, ACC, &
ESC
N/A N/A N/A
Kasper EK, Agema WR, Hutchins GM, Deckers JW, Hare
JM, Baughman KL. The causes of dilated cardiomyopathy: a
clinicopathologic review of 673 consecutive pts. J Am Coll
Cardiol 1994 March 1;23(3):586-90.
8113538 (58)
To document causes
of DCM in a large
group of adult HF pts
Retrospective Cohort 673 DCM pts with symptoms
within 6 mo, evaluated at
Johns Hopkins Hospital
1982-1991
Most common causes of DCM: idiopathic (47%), myocarditis (12%)
and CAD (11%), other causes (31%)
Fowles RE, Mason JW. Endomyocardial biopsy. Ann Intern
Med 1982 December;97(6):885-94.
6756241 (59)
Complication risk
with RV biopsies
Review N/A N/A Complication rate of 1% in 4000 biopsies (performed in
transplantation and CMP pts)
4 tamponade (0.14%), 3 pneumothorax, 3 AF, 1 ventricular
arrhythmia, and 3 focal neurological complications
Deckers JW, Hare JM, Baughman KL. Complications of
transvenous right ventricular endomyocardial biopsy in adult
pts with cardiomyopathy: a seven-year survey of 546
consecutive diagnostic procedures in a tertiary referral
center. J Am Coll Cardiol 1992 January;19(1):43-7.
1729344 (60)


To determine the
incidence, nature and
subsequent
management of
complications
occurring during RV
endomyocardial
biopsy in pts with
cardiomyopathy
Prospective Cohort 546 546 consecutive biopsies
for DCM pts at single
center,
33 total complications (6%):
15 (2.7%) during catheter insertion: 12 arterial punctures (2%), 2
vasovagal reactions (0.4%) and 1 prolonged bleeding (0.2%),
18 (3.3%) during biopsy: 6 arrhythmias (1.1%), 5 conduction
abnormalities (1%), 4 possible perforations (0.7%) and 3 definite
perforations (0.5%).
2 (0.4%) of the 3 pts with a perforation died
Ardehali H, Qasim A, Cappola T et al. Endomyocardial
biopsy plays a role in diagnosing pts with unexplained
cardiomyopathy. Am Heart J 2004 May;147(5):919-23.
15131552 (61)
To evaluate the utility
of RV biopsy in
confirming or
excluding a clinically
suspected diagnosis
Retrospetive chart
review
845 Pts with initially
unexplained
cardiomyopathy (1982-
1997) at The Johns
Hopkins Hospital.
Clinical assessment of the etiology inaccurate in 31%
EMBx helps establish the final diagnosis in most
Holzmann M, Nicko A, Ku¨hl U, et al. Complication rate of
right ventricular endomyocardial biopsy via the femoral
approach. A retrospective and prospective study analyzing
3048 diagnostic procedures over an 11-year period.
Circulation 2008;118:1722–8.
To determine
complication rate of
RV biopsy
Cohort 2415 1919 pts underwent 2505
endomyocardial biopsy
retrospectively (1995-
2003), and 496 pts
underwent 543
Major complications cardiac tamponade requiring pericardiocentesis
or complete AV block requiring permanent pacing rare: 0.12% in the
retrospective study and 0% in the prospective study.
Minor complications such as pericardial effusion, conduction
abnormalities, or arrhythmias in 0.20% in the retrospective study

© American College of Cardiology Foundation and American Heart Association, Inc.        22 
 
18838566 (62) endomyocardial biopsy
prospectively (2004-
2005) to evaluate
unexplained LV
dysfunction
and 5.5% in the prospective study
Elliott P, Arbustini E. The role of endomyocardial biopsy in
the management of CV disease: a commentary on joint
AHA/ACC/ESC guidelines. Heart 2009 May;95(9):759-760.
19221107 (63)

N/A Commentary N/A N/A Emphasizes genetic causes of CMP
ACC indicates American College of Cardiology; AHA, American Heart Association; AF, atrial fibrillation; AV, atrioventricular; CAD, coronary artery disease; CMP, cardiomyopathy; DCM, dilated cardiomyopathy; EMBx, endomyocardial biopsy; ESC, European
Society of Cardiology; LV, left ventricular; N/A, not applicable; pts, patients; and RV, right ventricular.
 
Data Supplement 11. Stage A: Prevention of HF (Section 7.1)
Study Name,
Author, Year
Aim of Study Study Type Study Size Patient Population Endpoints Trial
Duration
(Years)
Statistical Analysis (Results) Study Limitations
N (Total)
n (Experimental)
n (Control) Inclusion Criteria Exclusion Criteria
Lloyd-Jones et al, The
lifetime risk for
developing HF;
Circulation, 2002;
106:3068-3072
12473553 (64)
Examine lifetime risk of
developing CHF among
those without incident
or prevalent disease
Prospective
cohort
8229


Free of CHF at
baseline
N/A N/A N/A Lifetime risk is 1 in 5 for men and
women; significant association
between MI and HTN in lifetime
risk of CHF.
Subjects mostly white and results not
generalizable to other races.
Vasan et al, Residual
lifetime risk for
developing HTN in
middle-aged women
and men; JAMA,
2002:287:1003-1010.
11866648 (65)

Quantify risk of HTN
development
Prospective
cohort
1298

Ages 55-65 y and
free of HTN at
baseline.
N/A N/A N/A Residual lifetime risk for
developing HTN was 90%. Risk
did not differ by sex or age,
lifetime risk for women vs men
aged 55 y, HR: 0.91 (95% CI,
0.80-1.04); for those aged 65 y,
HR:0.88 (95% CI, 0.76-1.04)

Measured HTN in middle age, when a
large portion of people develop HTN at
younger ages so actual risk may be
different for younger people. Did not take
into account other risks for HTN like
obesity, family history of high BP, dietary
sodium and potassium intake, and
alcohol consumption
Levy et al, The
progression from HTN
to CHF; JAMA,
1996;275:1557-62
8622246 (66)
Analysis of expected
rates of HF associated
with diagnosis of HTN
Prospective
cohort
5,143


Free of CHF at
baseline.
N/A Developmen
t of HF
20 Those with HTN at a higher risk
for CHF:
Men, HR: 2.04; 95% CI: 1.50-
2.78;
Women, HR: 3.21; 95% CI: 2.20-
4.67
Subjects mostly white and results not
generalizable to other races. Possible
misclassification bias as some subjects
diagnosed w/HTN before use of
echocardiography.

© American College of Cardiology Foundation and American Heart Association, Inc.        23 
 
PAR for CHF in those with HTN:
39% for men and 59% in women.
Wilhelmsen et al, HF in
the general population
of men: morbidity, risk
factors, and prognosis;
J Intern Med
2001;249:253-261
11285045 (67)
Identification of risk
associated with HTN
Population-
based
intervention
trial
7,495


N/A N/A Developmen
t of HF
27 CAD and HTN were the most
common concomitant diseases in
HF pts (79.1%).
N/A
Kostis, et al, Prevention
of HF by
antihypertensive drug
treatment in older
persons with isolated
systolic HTN; JAMA
1997;278:212-216.
9218667 (68)
To assess the effect of
antihypertensive care
on the incidence of HF
in older pts with systolic
HTN
RCT 4,736; 2,365; 2,371 Age ≥60y, Isolated
systolic HTN: SBP
160-219 mm Hg with
DBP <90 mm Hg.
Recent MI, CABG,
DM, alcohol abuse,
demential stroke, AF,
AV block, multiform
premature ventricular
contractions,
bradycardia <50
beats/min; diuretic
therapy.
Fatal and
non-fatal HF
4.5 49% reduction
RR: 0.51; 95% CI: 0.37-0.71;
p<.001
Noteworthy that pts with prior MI had an
80% risk reduction.
Staessen, Wang and
Thijs; CV prevention
and BP reduction: a
quantitative overview
updated until 1 March
2003; J Hypertens
2003;21:1055-1076
12777939 (69)

Assessment of various
drugs and their
reduction of HF
Meta analysis 120,574


N/A N/A CV events N/A CCB, resulted in better stroke
protection than older drugs:
including (-8%, p=0.07) or
excluding verapamil (-10%,
p=0.02), as well as ARB (-24%,
p=0.0002). The opposite trend
was observed for ACEI (+10%,
Pp=0.03). The risk of HFwas
higher (p< 0.0001) on CCB
(+33%) and alpha blockers
(+102%) than on conventional
therapy involving diuretics
N/A
Sciaretta, et al;
Antihypertensive
treatment and
development of HF in
hypertension: a
Bayesian network meta-
analysis of studies in
pts with HTN and high
CV risk.
Arch Intern Med. 2011
Mar 14;171(5):384-94.
21059964 (70)

Compare various drugs
and risk for HF
Meta analysis 223,313


Studies had to be
RCTs from 1997-
2009; pts with HTN
or a population
characterized as
having a “high” CV
risk profile and a
predominance of pts
with HTN (>65%); the
sample size ≥200
pts; and information
on the absolute
incidence of HF and
N/A HF N/A Diuretics vs. placebo: OR: 0.59;
95% CrI: 0.47-0.73;
ACE-I vs. placebo: OR: 0.71; 95%
CrI: 0.59-0.85;
ARB: OR: 0.71; 95% CrI: 0.59-
0.85.
Beta blockers and CCB less
effective
N/A

© American College of Cardiology Foundation and American Heart Association, Inc.        24 
 
other major CV
events
Lind et al, Glycaemic
control and incidence of
HF in 20985 pts with
type 1 diabetes: an
observational study.
Lancet 2011; Jun 24.
21705065 (71)
Assessment of glycemic
control and risk for HF
Meta analysis 20,985
or higher
A1C <6.5%
Type 1 DM N/A HF N/A A1C ≥10.5% vs A1C <6.5%:
aHR: 3.98; 95% CI: 2.23-7.14;
p<.001;
Used hospital admissions and did not
include asymptomatic HF pts, so true
incidence of HF underestimated.
Pfister, et al, A clinical
risk score for HF in pts
with type 2 diabetes
and macrovascular
disease: an analysis of
the PROactive study.
Int J Cardiol. 2011;May
31.
21636144 (72)
Identification of risk
associated with DM
RCT 4,951


Type 2 DM N/A HF 3 Medium risk: HR: 3.5; 95% CI:
2.0-6.2; p<0.0001
High risk: HR: 10.5; 95% CI: 6.3-
17.6; p<0.0001


HF was pre-defined by investigator, but
rather reported as SAE in the trial. Trial
population may not be generalizable to
clinical population.
Kenchaiah et al,
Obesity and the risk of
HF. NEJM,
2002;347:305-313.
12151467 (73)
Assessment of HF risk
associated with obesity
Prospective
cohort
5,881


≥30 y; BMI
≥18.5;free of HF at
baseline
N/A HF 14 Women, HR: 2.12; 95% CI: 1.51-
2.97
Men, HR: 1.90; 95% CI: 1.30-2.79


Possible misclassification of HF and
subjects mostly white and results not
generalizable to other races.
Kenchaiah, Sesso,
Gaziano, Body mass
index and vigorous
physical activity and the
risk of HF among men.
Circulation,
2009;119:44-52.
19103991 (74)
Assessment of risk
associated with obesity
and effect of exercise
Prospective
cohort,
secondary
analysis of
RCT
21,094


Free of known heart
disease at baseline.
N/A Incidence of
HF
20.5 Every 1 kg/m2 increase in BMI is
associated with 11% (95% CI: 9-
13) increase in risk of HF.
Compared to lean active men:
Lean inactive: HR:1.19; 95% CI:
0.94-1.51, Overweight active:
HR:1.49; 95% CI: 1.30-1.71),
Overweight inactive: HR: 1.78;
95% CI: 1.43- 2.23),
Obese active: HR: 2.68; 95% CI:
2.08-3.45, Obese inactive: HR:
3.93; 95% CI: 2.60-5.96
Low incidence of HF as cohort comprised
of physicians who are healthier than the
general population. BMI measures and
physical activity were self-reported.
These measures were only taken at
baseline and tend to change over time.
This cohort consisted only of men and
results not generalizable to women.

© American College of Cardiology Foundation and American Heart Association, Inc.        25 
 
Verdecchia et al,
Effects of telmisartan,
ramipril and their
combination on LVH in
individuals at high
vascular risk in
ONTARGET and
TRANSCEND.
Circulation
2009;120:1380-1389.
19770395 (75)
Evaluate effects of
ACE, ARB, or both on
development of LVH in
pts with atherosclerotic
disease.
RCT 23,165 for
ONTARGET,
5,343 in
TRANSCEND


Hx of CAD, PAD,
cerebrovascular
disease.
N/A LVH 5 Telmisartan vs placebo:
OR: 0.79; 95% CI: 0.68-0.91;
p=0.0017.
Telmisartan vs. ramipril:
OR: 0.92; 95% CI; 0.83-1.01;
p=0.07
Telmisartan + ramipril vs. ramipril:
OR: 0.93; 95% CI: 0.84-1.02;
p=0.12)
Telmisartan vs telmisartan +
ramipril:
OR: 1.01; 95% CI: 0.91-1.12
Diagnosis of LVH was based on ECG,
which is less sensitive than
echocardiography and was binary
(yes/no) instead of quantitative.
Braunwald et al; ACE
inhibition in stable
coronary artery disease.
NEJM 2004;351:2058-
2068.
15531767 (76)
Evaluate the effect of
trandolapril on vascular
events
RCT 8,290;
4,158 (trandolpril);
4,132 (placebo)
Stable CAD N/A Major CV
events
4.8 HR: 0.95; 95% CI: 0.88-1.06;
p=0.43
Results not significant possibly because
the pts enrolled were at lower risk for CV
events compared to other trials of ACEI.
Mills et al, Primary
prevention of
cardiovascualr mortality
and events with statin
treatments. J Am Coll
Cardiol; 2008;52:1769-
1781
19022156 (77)
Evaluation of primary
prevention of CV events
with statins
Meta analysis 53,371


N/A N/A Major CV
events
N/A RR: 0.84; 95% CI: 0.77-0.95;
p=0.004
N/A
Taylor et al, Statins for
the primary prevention
of CV disease.
Cocrane Database Syst
Rev, 2011; CD004816
21249663 (78)

Assess benefit and risk
of statins for prevention
of CVD
Meta analysis 34,272


RCTs of statins with
minimum duration of
1 y and f/u of 6 mo, in
adults with no
restrictions on their
total LDL or HDL
cholesterol levels,
and where ≤10% had
a hx of CVD, were
included.
N/A All-cause
mortality and
fatal/nonfatal
CVD
N/A All-cause mortality:
RR: 0.84; 95% CI: 0.73-0.96)
Fatal/non-fatal CVD:
RR: 0.70, 95% CI: 0.61-0.79
N/A
Abramson et al;
Moderate alcohol
consumption and risk fo
HF among older
persons. JAMA,
2001;285:1971-1977.
11308433 (79)
Assessment of risk
associated with alcohol
use in older adults.
Prospective
cohort
2,235


Age ≥65 y; lived in
New Haven, Conn,
and free of HF at
baseline
Heavy alcohol
consumption (>70
oz.)
New HF N/A No alcohol: aRR: 1.00 (referent),
1-20 oz: aRR: 0.79; 95% CI: 0.60-
1.02),
21-70 oz: aRR: 0.53; 95% CI:
0.32-0.88.
(p for trend=0.02)
Observational study, could not account
for all possible confounders, alcohol
consumption was self-reported.

© American College of Cardiology Foundation and American Heart Association, Inc.        26 
 
Walsh et al; Alcohol
consumption and risk
for CHF in the
Framingham Heart
Study. Ann Intern Med,
2002; 136:181-191.
11827493 (80)
Assessment of risk
associated with alcohol
use
Community
based cohort
7,223


N/A N/A New CHF N/A Compared to men who consumed
<1 drink/wk, men who consumed
8-14 drinks/wk: HR for CHF: 0.41;
95% CI: 0.21-0.81.
In women: those who consumed
3-7 drinks/wk HR: 0.49; 95% CI:
0.25-0.96, compared with those
who consumed <1 drink/wk.
Self-reported alcohol consumption.
Choueiri et al, CHF risk
in pts with breast
cancer treaated with
bevacizumab. J Clin
Oncol, 2011; 29:632-
638.
21205755 (81)
Risk of CHF pts with
breast cancer receiving
bevacizumab
Meta analysis 3,784


RCTs published
between January
1966-March 2010 in
English.
N/A New CHF N/A RR: 4.74; 95% CI; 1.84-12.19;
p=0.001)
Data on other risk factors for CHF were
not collected or unavailable.
Du et al; Cardiac risk
associated with the
receipt of anthracycline
and trastuzumab in a
alarge nationwide
cohort of older women
with breast cancer,
1998-2005. Med Oncol,
2010;Oct 22.
20967512 (82)
New HF Registry 47,806


Women with breast
cancer ≥65 y
N/A New HF N/A HR: 1.19 anthracycline alone, HR:
1.97 trastuzumab alone, HR: 2.37
combo
N/A
Sawaya et al; Early
detection and prediction
of cardiotoxicity in
chemotherapy treated
pts. Am J Cardiol,
2011; 107:1375-80.
21371685 (83)
To assess whether
early ECHO
measurements of
myocardial deformation
and biomarkers (hsTnI
and NT-proBNP)
could predict the
development of
chemotherapy-induced
cardiotoxicity in pts
treated with
anthracyclines and
trastuzumab.
Prospective
cohort
43


>18 y of age
diagnosed with HER-
2-overexpressing
breast cancer and
either scheduled to
receive treatment
including
anthracyclines and
trastuzumab or
scheduled to receive
trastuzumab after
previous
anthracycline
treatment.
Pts with LVEFs
≤50%
Cardiotoxicit
y
N/A Elevated hsTnI at 3 mo (p =0.02)
and a decrease in longitudinal
strain
between baseline and 3 mo (p
=0.02) remained independent
predictors of later cardiotoxicity.
Neither the change in NT-proBNP
between baseline and 3 mo nor
an NT-proBNP level higher than
normal limits at 3 mo predicted
cardiotoxicity


Small sample size

© American College of Cardiology Foundation and American Heart Association, Inc.        27 
 
McKie et al; The
prognostic value of NT-
proBNP for death and
CV events in healthy
normal and stage A/B
HF subjects. J Am Coll
Cardiol, 2010;55:2140-
2147.
20447539 (84)
NT-proBNP as a
predictor of death, CV
events
Cohort 1,991


Age ≥45 y, lives in
Olmsted County,
Minnesota
Symptomatic
HF (stages C and D
HF)
Death, HF,
CVA, MI
8.9 years HR:1.26 per log increase in fully
adjusted model in stage A/B pts
(95% CI: 1.05–1.51; p=0.015).
NT-proBNP was not predictive of
death or CV events in the healthy
normal subgroup.
Underpowered to detect association of
NT-proBNP with adverse outcomes in the
healthy normal subgroup.
Velagaleti et al;
Multimarker approach
for the prediction of HF
incidence in the
community. Circulation,
2010;122:1700-1706.
20937976 (85)
Evaluation of markers
for HF development in
the community
Cohort 2,754


Free of HF N/A HF N/A BNP: aHR: 1.52; 95% CI: 1.24–
1.87; p<0.0001
UACR: aHR: 1.35; 95% CI: 1.11–
1.66; p=0.004
Subjects mostly white and results not
generalizable to other races.
Blecker et al; High
normal albuminuria and
risk of HF in the
community. Am J
Kidney Dis, 2011;
58:47-55.
21549463 (86)
Evaluation of
albuminuria as risk for
new HF
Cohort 10,975


Free of HF N/A HF 8.3 aHR: 1.54 (95% CI,:1.12-2.11)
UACR normal to intermediate-
normal; aHR: 1.91 (95% CI: 1.38-
2.66) high-normal; aHR: 2.49
(95% CI: 1.77-3.50) micro; aHR:
3.47 (95% CI: 2.10-5.72) macro
(p<0.001)
N/A
deFilippi et al;
Association of serial
measures of cardiac
troponin T using a
sensitive assay with
incident HF and CV
mortality in older adults.
JAMA, 2010; 304:2494-
2502.
21078811 (87)
Assessment as to
whether baseline cTnT
or changes predict HF
Cohort 4,221


N/A N/A HF 11.8 Complex
>99th percentile at baseline: 6.4;
change from neg to pos: 1.61
increase.
Samples were available in ~3/4 of the
cohort at baseline, and differential
absence of cTnT measures may have
introduced bias into the estimates of
associations with HF and CV death.
Heidenreich, et al, Cost-
effectiveness of
screening with BNP to
identify pts with reduced
LVEF. J Am Coll
Cardiol, 2004;43:1019-
1026.
15028361 (88)
Cost effectiveness of
BNP screening
Cost benefit
analysis
N/A Asymptomatic pts. N/A N/A N/A BNP testing followed by
echocardiography is a cost-
effective screening
strategy for men and possibly
women at age 60 y - for every
125 men screened,1 y of life
would be gained at a cost of
$23,500.
Did not evaluate other
blood tests such as pro-BNP as
prevalence and outcome data were not
available.
ACEI indicates angiotensin-converting-enzyme inhibitor; AF, atrial fibrillation; AV, atrioventricular; BMI, body mass index; BP, blood pressure; CABG, coronary artery bypass graft; CAD, coronary artery disease; CCB, calcium channel blocker; CHF, congestive
heart failure; cTnT, cardiac troponin T; CV, cardiovascular; CVA, cerebrovascular accident; CVD, cardiovascular disease; DM, diabetes mellitus; DBP, diastolic blood pressure; ECG, electrocardiography; HDL, high density lipoprotein; HF, heart failure; hsTnI,

© American College of Cardiology Foundation and American Heart Association, Inc.        28 
 
high-sensitivity troponin I; HTN, hypertension; LDL, low density lipoprotein; Hx, history; LVH, left ventricular hypertrophy; MI, myocardial infarction; N/A, not applicable; N-terminal pro–B-type natriuretic peptide; ONTARGET, Ongoing Telmisartan Along and in
Combination with Ramipril Global Endpoint Trial; PAD, peripheral arterial disease; PAR, population attributable risk; pro-BNP, pro–B-type natriuretic peptide; pts, patients; RCT, randomized clinical trial; SAE, serious adverse event; SBP, systolic blood
pressure; TRANSCEND, Telmisartan Randomized Assessment Study in ACE Intolerant Subjects with CV Disease; and UACR, urinary albumin-to-creatinine ratio.

Data Supplement 12. Stage B: Preventing the Syndrome of Clinical HF With Low EF (Section 7.2)
Study Name,
Author, Year Aim of Study
Study
Type
Study
Size Patient Population Endpoints
Statistical
Analysis
(Results)
P Values &
95% CI:
OR: HR:
RR:
Study
Limitations
Findings/
Comments
Inclusion
Criteria
Exclusion
Criteria
Primary
Endpoint
Secondary
Endpoint
ACE Inhibitors
Effect of
Captopril on
Mortality and
Morbidity in Pts
with LVD after MI
Pfeffer, Marc A;
NEJM 1992
(SAVE)
1386652 (89)
Investigate
whether captopril
could reduce
morbidity and
mortality in pts
with LVSD after
an MI
RCT 2,331 Within 3-60 d of
MI; EF <40%; no
overt HF or
ischemic
symptoms; age
21-80 y;
Cr > 2.5 mg/dL;
relative
contraindication to
ACEI; need for
ACEI to treat
symptomatic HF or
HTN; other
conditions limiting
survival; "unstable
course" after MI
All-cause
mortality; CV
mortality;
mortality &
derease in EF of
9 units;
development of
overt HF (despite
diuretics and
digoxin therapy);
hospitalization for
HF; fatal or
nonfatal MI; mean
f/u 42 months
N/A N/A Risk Reduction:
All-cause mortality 19% (95%
CI: 3-32% p=0.019);
death from CV cause 21% (95%
CI: 5-35%; p<0.001);
development of severe HF 37%
(95% CI: 20-50%; p<0.001);
HF hospitalization 22% (95% CI:
4-37%; p= 0.019); recurrent MI
25% (95% CI: 5-40%; p=0.015)

Low rate of beta
blocker use;
Recruitment 1987-
1990: significant
changes in
revascularization
strategies
Reduction in
severe HF and
HF
hospitalization
among pts with
MI and LVSD
without
symptoms of HF
Effect of Enalapril
on Mortality and
the Development
of HF in
Asymptomatic
Pts with Reduced
LVEF. The
SOLVD
Investigators.
NEJM 1992
(SOLVD
Prevention)
1463530 (90)
Study the effect
of an ACEI,
enalapril, on
outcomes in pts
with LVSD not
receiving drug
therapy for HF
RCT 4228 EF<35%; not
receiving
diuretics, digoxin
or vasodilators for
HF (asymptomatic
LVSD)
N/A All-cause
mortality; mean
f/u 37.4 months
Development of
HF & mortality; HF
hospitalization &
mortality
N/A Risk Reduction:
All-cause mortality 8% (95% CI:
95% CI -8 - 21%; p=0.3); CV
mortality 12% (95% CI: -3 -
26%; p=0.12);
mortality & development of HF
29% (95% CI: 21-36%;
p<0.001);
mortality & HF hospitalization
20% (95% CI: 9-30%; p<0.001)

Low rate of beta-
blocker use
Reduction in
combined
endpoints of
development of
HF & mortality
and HF
hospitalization
and mortality
among pts with
asymptomatic
LVSD

© American College of Cardiology Foundation and American Heart Association, Inc.        29 
 
Effect of enalapril
on 12-y survival
and life
expectancy in pts
with LVSD: a
follow-up study.
Jong, P
Lancet 2003
12788569 (91)
12-y follow-up of
SOLVD to
establish if the
mortality
reduction with
enalapril among
pts with HF was
sustained and
wheather
susequent
reduction in
mortality would
emerge among
those with
asymptomatic
ventricular
dysfunction
Cohort 5,165 SOLVED
prevention and
treatment trial
populations alive
at completion of
RCTs
N/A All-cause
mortality
N/A In combined trials
(Prevention and
Treatment),
enalapril
extended median
survival 9.4 mo
(95% CI 2.8-16.5;
p=0.004)
In the Prevention Trial mortality
50.9% in enalapril group vs.
56.4% in placebo group;
p=0.001.
In overall cohort, HR for
mortality 0.9 (0.84-0.95);
p=0.0003 for enalapril vs.
placebo
N/A Mortality benefit
of enalapril
among pts with
asymptomatic
LVSD
Statins
Intensive Statin
Therapy and the
Risk of
Hospitalization
for HF After an
ACS in the
PROVE IT-TIMI
22 Study
Scirica, Benjamin
M JACC
2006
16750703 (92)
Determine
whether
intensive satin
therapy reduces
hospitalization
for HF in high
risk pts (intensive
statin therapy
simvastatin 80
vs. moderate
statin therapy
pravastatin
40mg)
RCT 4,162 ACS (AMI or high-
risk UA) within 10
d; total cholesterol
<240 mg/dL;
stable condition;
Life-expectancy <2
y; PCI within the
prior 6 mo (other
than for qualifying
event); CABG
within 2 mo;
planned CABG
Hospitalization for
HF (time to first
HF hospitalization
that occurred 30 d
or longer after
randomization)
MI Meta-analysis of
4 large RCTs of
statin therapy
(TNT, A to Z,
IDEAL, PROVE-
IT) N=27,546
Reduction in HF
hospitalization:
OR: 0.73; 95%
CI: 0.63-0.84;
p<0.001 [x2 for
heterogeneity =
2.25, p=0.523)
Atorvastatin 80mg associated
with reduction in HF
hospitalization: 1.6% vs. 3.1%;
HR 0.55; 95% CI: 0.35-0.85;
p=0.008
when adjusted for history or
prior HF HR 0.55; 95% CI: 0.35-
0.36; p=0.008

Sub-study of
PROVE IT-TIMI 22.
Did not exclude
those with prior HF
(low rates)
In pts with ACS,
intensive statin
therapy reduced
new onset HF
Also perfomred
meta-analysis of
4 large statin
trials (2 ACS, 1
hx of MI, 1
clinically evident
CHD)
demonstrating
benefit of
intensive stating
therapy in
preventing HF
hospitalizaiton
Early Intensive vs
a Delayed
Conservative
Simvastatin
Strategy in Pts
with ACS. Phase
Z of the A to Z
Trial.
To compare
early initiation of
an intensive
statin regimen
with delayed
initiation of a less
intensive
regimen in pts
RCT 4,479 STEMI or
NSTEMI; total
cholesterol ≤250
mg/dL; age 21-80;
at least 1 high-risk
characteristic
(>70, DM, hx of
CAD, PVD or
Receiving statin
therapy, planned
CABG, PCI
planned within 2
wks of enrollment,
ALT level >20%
ULN, Cr
>2.0mg/dL,
Composite: CV
death, non-fatal
MI, readmission
for ACS, stroke
Individual
components of
primary endpoint
and
reascularization
due to
documented
ischemia, all-cause
N/A New onset HF reduced with
intensive therapy: 5% vs 3.7%;
HR 0.72; 95% CI: 0.53-0.98;
p=0.04
Primary endpoint did not
achieve significance: 16.7% vs
14.4%; HR 0.89; 95% CI: 0.76-
1.04; p=0.14
Development of HF
was a secondary
endpoint Did
not achieve primary
endpoint
In pts with ACS,
intensive statin
therapy reduced
new onset HF

© American College of Cardiology Foundation and American Heart Association, Inc.        30 
 
de Lemos, James
A. JAMA
2004
15337732 (93)
with ACS stroke, elevated
CKMB or
trooponin levels,
recurrent angina
with ST changes,
ECG evidence of
ischemia on pre-
discharge stress
test, multivessel
disease)
concomitant
therapy with
agents known to
enhance myopathy
risk; prior hx of
non-exercise
related elevations
in CK or
nontraumatic
rhabdomyolysis
mortality, new-
onset HF
(requiring
medications or
hospitalization),
CV hosptialization

ACEI indicates angiotensin-converting-enzyme inhibitor; ACS acute coronary syndrome; ALT, alanine aminotransferase; AMI, acute myocardial infarction; CABG, coronary artery bypass surgery; CAD, coronary artery disease; CHD, chronic heart disease;
CKMB, creatine kinase-MB; Cr, creatinine; CV, cardiovascular; DM, diabetes mellitus; ESG, electrocardiogram; EF, ejection fraction; f/u, follow-up; HF, heart failure; HTN, hypertension; hx, history; LVSD, left ventricular systolic dysfunction; LVD, left
ventricular dysfunction; MI, myocardial infarction; NSTEMI, non-ST elevation mysocardial infarction; PCI, Percutaneous coronary intervention; PROVE IT-TIMI 22, Pravastatin or Atorvastatin Evaluation and Infection Therapy -- Thrombolysis in Myocardial
Infarction 22; Pts, patients; PVD, Peripheral artery disease; RCT, randomized control trial; SAVE, The Survival and Ventricular Enlargement trial; SOVLD, Studies of Left Ventricular Dysfunction; STEMI, ST elevation myocardial infarction; UA, unstable angina;
and ULN, upper limit of normal.

Data Supplement 13. Stage C: Factors Associated With Outcomes, All Patients (Section 7.3)
Study Name,
Author, Year Aim of Study Study Type
Study
Size Patient Population Endpoints Statistical Analysis (Results) Study Limitations Findings/Comments
Inclusion
Criteria
Exclusion
Criteria
Primary
Endpoint
Secondary
Endpoint
Education

© American College of Cardiology Foundation and American Heart Association, Inc.        31 
 
Long-term
prospective RCT
using repetitive
education at 6-mo
intervals and
monitoring for the
adherence in HF
outpt (The
REMADHE Trial).
Bocchi, Edimar
Alcides. 2008
12196335 (94)
To determine
whether a
disease
management
program with
repeated
multidisciplinary
education and
telephone
monitoring
benefits HF
outpt already
under the care
of a with HF
experience
cardiologist.
RCT 350 Diagnosed with
HF
N/A Combined death
or unplanned first
hospitalization
and QoL
changes
Hospitalization,
death and
adherence.
In the intervention group:
QoL improved and
Lower: deaths (p<0.003) or unplanned
hospitalizations (p=0.008; 95% CI:
0.43- 0.88) , hospitalizations(p<0.001) ,
total hospital d during follow-up
(p<0.001), and ED visits (p<0.001)

No difference in estimated total
mortality (p=ns; 95% CI: 0.55-1.13) or
death during hospitalization (p=ns;
95%CI: 0.53-1.41)
Absence of blinding.
Perception of better QoL in
the intervention group due
healthcare provider support
as needed. Confouding by
social conditions.
Despite modest adherence
program reduced unplanned
hospitalization, total hospital
d, the need for emergency
care and improved QoL.
Effect of discharge
instructions on
readmission of
hospitalized pts with
HF: do all of the
joint commission on
accreditation of
healthcare
organizations HF
core measures
reflect better care?
VanSuch, M. 2006
17142589 (95)
To determine
whether
documentation
of compliance
with any or all of
the 6 required
discharge
instructions is
correlated with
readmissions to
hospital or
mortality.
Retrospective
study
782 Age >18 y,
principal
diagnosis of HF,
hypertensive
heart disease
with HF, or
hypertensive
heart and renal
disease with HF,
discharged to
home, home
care or home
care with IV
treatment
Pts discharged
to skilled
nursing facilities
or other acute-
care hospitals.
Time to:
death and
readmission for
HF or
readmission for
any cause
N/A 68% of pts received all instructions, and
6% received no instructions.

Pts with all instructions (compared to
those who missed at least one type of
instruction) were significantly less likely
to be readmitted for any cause or HF
(p= 0.003)

Documentation of discharge
instructions was correlated with
reduced readmission rates.

No association between documentation
of discharge and instructions and
mortality.
Discharge instructions given
but not documented.
Discharge instructions could
be a surrogate indicator for
another intervention such as
higher quality nursing care.
Pt factor could have
influenced confounding
results.
Generalizability limited.
No active follow-up.
Not all quality of care
outcomes were assessed.
Documentation of discharge
information
and pt education appears to
be associated with reductions
in both mortality and
readmissions.

© American College of Cardiology Foundation and American Heart Association, Inc.        32 
 
Discharge
education improves
clinical outcomes in
pts with chronic HF.
Koelling, T. 2005
15642765 (96)
To assess
whether a pt
discharge
education
program (the
study
intervention)
improves clinical
outcomes in
chronic HF pts.
RCT 223 Admitted to
hospital with a
diagnosis of HF
and documented
left ventricular
systolic
dysfunction (EF
<40%)
Evaluation for
cardiac surgery,
Noncardiac
illness likely to
increase 6-mo
mortality or
hospitalization
risk, Inpatient
cardiac
transplantation
evaluation
Total number of d
hospitalized or
dead in the 180-d
follow-up period.
Clinical events,
symptoms, and
self-care practices.
The intervention group versus controls
had fewer d hospitalized or dead in the
180-d follow-up period (p= 0.009),
lower risk of rehospitalization or death
(RR: 0.65; 95% CI: 0.45-0.93, p=
0.018), as well as lower costs of care,
including cost of the intervention (lower
by $2823 per pt, p= 0.035).
May not be generalizable-
only 223 (38%) participated.
pts being evaluated for
transplantation not studied.
Pts followed by the UMHFP
not enrolled. Nurse
coordinator unblined. Lack of
reliability of self-reported
self-care measures.
A 1-h teaching session at the
time of hospital discharge
resulted in improved clinical
outcomes, increased self-
care and adherence, and
reduced cost of care in pts
with systolic HF.
Effects of an
interactive CD-
program on 6 mo
readmission rate in
pts with HF- a RCT.
Linne, A. 2006
16796760 (97)
To evaluate the
impact of added
CD-ROM
education on
readmission rate
or death during
6 mo.
RCT 230 Diagnosis of HF
(either LVEF <
40% by ECHO or
at least 2 of
these criteria:
pulmonary rates,
peripheral
edema, a 3rd
heart sound and
signs of HF on
chest x-ray).
Somatic
disease,
physical
handicap with
difficulty
communicating
or handling
technical
equipment,
inability to speak
Swedish,
incompliance
due to
alcohol/drug
abuse or major
psychiatric
illness,
Participation in
another trial
Difference in rate
of all cause
readmission and
death within 6 mo
after discharge.
N/A Intervention group achieved better
knowledge and a marginally better
outcome (p=NS).

Only 37% completed
questionnaire, pts had to
come twice to the CD-based
education, first as inpts, then
2 wk after discharge.
Returning to the hospital may
have discouraged
participation,
especially in sicker pts.
Additional education of HF
pts with an interactive
program had no effect on
readmission rate or death
within 6 mo after discharge.

© American College of Cardiology Foundation and American Heart Association, Inc.        33 
 
Computer-based
education for pts
with chronic HF. A
randomized,
controlled,
multicenter trial of
the effects on
knowledge,
compliance and
QoL. Stromberg, A.
2006
16469469 (98)
To evaluate the
effects of a
single-session,
interactive
computer-based
educational
program on
knowledge,
compliance and
QoL in HF pts.
To assess
gender
differences.
RCT 154 Diagnosis of HF None specified Knowledge of
HF, treatment
compliance, self-
care and QoL.
N/A Computer-based group (intervention),
knowledge increased: After 1 mo: p=
0.07,
After 6 mo: p= 0.03

Women: significantly lower QoL and did
not improve after 6 mo as men did (p=
0.0001).

No differences between groups in
compliance, self-care or QoL.
Data on knowledge collected
through questionnaire,
small sample size.
Computer-based education
increased knowledge about
HF compared to traditional
teaching alone.
Long-term result
after a telephone
intervention in
chronic HF.
Ferrante, D. 2010
20650358 (99)
To assess rate
of death and
hospitalization
for HF 1 and 3 y
after a
randomized trial
of telephone
intervention with
education to
improve
compliance in
stable HF pts
with HF.
Follow-up after
a RCT
1,518 Outpt with
stable, chronic
HF
None specified Death and
hospitalization for
HF, 1 and 3 y
after intervention
ended.
Long term benefits Rate of death or hospitalization for HF
lower in the intervention group:
1 y: RR: 0.81; p= 0.013 95% CI: 0.69-
0.96
3 y : RR: 0.72; p= 0.0004 95% CI:
0.60-0.87

Benefit caused by a reduction in
admission for HF after 3 y
Functional capacity better in
intervention group
Pts who showed improvement in 1 or
more of 3 key compliance indicators
(diet, weight control, and medication)
had lower risks of events (p< 0.0001).
Classification bias of events
due to open trial design.
Benefit observed during the
intervention period persisted
and was sustained 1 and 3 y
after the intervention ended.
This maybe due to the
intervention impact on pt
behavior and habits.
HF self-
management
education: a
systematic review of
the evidence.
Boren, S. 2009
21631856 (100)
To identify
educational
content and
techniques that
lead to
successful self-
management
and improve
outcomes.
Systematic
review of RCTs
7,413 pts
from 35
trials
RCTs evaluating
a self-
management
education
program with
patient-specific
outcome
measures.
Not randomized,
No control
group,
Not in English,
Failure to
identify the
content of the
program,
Providing similar
educational
content in all
study arms,
Satisfaction,
learning, self-
care behavior,
medication,
clinical
improvement,
social
functioning,
hospital
admissions and
readmissions,
mortality, and
N/A Programs incorporated 20 educational
topics in 4 categories- knowledge and
self-management, social interaction
and support, fluid management, and
diet and activity. 113 unique outcomes
were measured and 53% showed
significant improvement in at least one
study.
Education on: sodium restriction
associated with decreased mortality
(p=0.07), appropriate follow-up
associated with decreased cost
Unable to combine all the
results. Difficult to compare
interventions due to poor
descriptions, and lack of
transparency. All
interventions not
reproducible.
Review supports the benefits
of educational interventions
in chronic HF and suggests
that some topics are related
to certain outcomes.

© American College of Cardiology Foundation and American Heart Association, Inc.        34 
 
Did not identify
educational
techniques
used,
Measured only
knowledge as
an outcome.
cost. (p=0.10), management and recognition
of worsening function associated with
lower social functioning (p= 0.10).
Discussion of fluids associated with
increased hospitalization (p=0.01)
and increased cost (p=0.10).
Effect of sequential
education and
monitoring program
on QoL components
in HF. Cruz, Fatima
das Dores. 2010
20670963 (101)

To determine if
a DMP applied
over the long-
term could
produce
different effects
on each of the
QoL
components.
Retrospective
analysis
(Extension of
REMADHE
trial, a RCT)
412 Under
ambulatory care
in a tertiary
referral center
and followed by
a cardiologist
with experience
in HF.
Age >18
Irreversible HF
based on the
modified
Framingham
criteria for at
least 6-mo
Unable to attend
educational
sessions or who
could not be
monitored due
to lack of
transportation,
or social or
communication
barriers,
MI or unstable
angina within
past 6 mo,
cardiac surgery
or angioplasty
within past 6
mo,
hospitalized or
recently
discharged,
any severe
systemic
disease that
could impair
expected
survival,
procedures that
could influence
follow-up,
pregnancy or
child-bearing
potential
Change in QoL
components
during follow-up
Influence of the
QoL score at
baseline on pt
survival.
Improved in the DMP intervention
group:
Global QoL scores: p<0.01
Physical component: p<0.01
Emotional component: p<0.01

QoL can be confounding.
Loss of data due to morality
during follow-up may have
influenced QoL scores.
Retrospective analysis of
quality of life components.
Improvement of QoL is a
fundamental target for the
success of treatment of pts
with HF. Specific components
of the QoL assessment can
behave differently over time
and should stimulate the
identification and
development of new
strategies and interventions.
Targeting male pts and the
emotional components of the
QoL assessment in DMPs
may be important in order to
achieve a greater early
improvement in QoL.
Social Support

© American College of Cardiology Foundation and American Heart Association, Inc.        35 
 
Long-term effect of
social relationships
on mortality in pts
with CHF. Murberg,
Terje. 2004
15666956 (102)

To evaluate the
effects of social
relationships on
morality risk in
pts with stable,
symptomatic
HF.
Follow-up
study
119 Diagnosed with
HF
Unable to
complete
the
questionnaires
due to mental
debilitation,
previous heart
transplantation
Perceived social
support and
isolation.
N/A Social isolation a significant predictor
of mortality (controlling for neuroticism,
HF severity, functional status, gender,
age): RR= 1.36; 95% CI: 1.04-1.78;
p<0.03
Small sample size Perceived social
isolation an independent
predictor of mortality in HF
pts during a 6-y follow-up
period. Experience of social
isolation seems to be more
critical than lack of social
support.
The importance and
impact of social
support on
outcomes in pts with
HF: An overview of
the literature. Luttik,
M.L. 2005
15870586 (103)
To review the
literature on
what is
scientifically
known about the
impact of social
support on
outcomes in
pts with HF.
Review 17
studies
Studies that
investigated the
relationship
between social
support and
different
outcomes in HF.
None specified Social support
and different
outcomes in HF
(readmission,
mortality, QoL
and depression).
N/A 4 studies found clear relationships
between social support and
rehospitalizations and mortality; the
relationship between QoL and
depression was less clear.

None noted Social support is a strong
predictor of hospital
readmissions and mortality in
HF pts. Emotional support in
particular is important. Some
studies show that support is
also related to the prevalence
of depression and with
remission of major
depression in HF. Less
evidence to support a
relationship between social
support and QoL.
Social deprivation
increases cardiac
hospitalisations
in chronic HF
independent of
disease
severity and diuretic
non-adherence.
Struthers, A. 2000
10618326 (104)
To examine
whether social
deprivation has
an independent
effect on
emergency
cardiac
hospitalization in
pts with chronic
HF.
Cohort study 478 Admitted with an
MI between
January 1989-
December 1992
and
subsequently
admitted for
chronic HF
between January
1989- December
1992, ≥3 diuretic
prescriptions had
to have been
dispensed
between January
1993- January
1994.
None specified Emergency
hospital
admissions (all
causes and for
cardiac causes
only)
N/A Social deprivation significantly
associated with an increase in the
number of cardiac hospitalizations
(p=0.007).

Effect mainly caused by increasing the
proportion of pts hospitalized in each
deprivation category. 26% in
deprivation category 1–2 vs. 40% in
deprivation category 5–6 (p= 0.03).

Effect of deprivation: independent of
disease severity (as judged by the
dose of prescribed diuretic), death
rate, and duration of each hospital
stay. Non-adherence with diuretic
treatment could not account for these
findings either.
Assessed adherence by
whether pt had enough
tablets in the
house to cover the
appropriate time period-
measuring pt’s maximum
possible level of adherence.
Poor adherence was
associated with being male
versus female but not with
age, social deprivation, or
diuretic dose. It is possible
that diuretics caused more
troublesome
urinary symptoms in men
because of prostatism,
leading to poorer adherence.
Social deprivation increases
the chance of
rehospitalization
independent of disease
severity. Possible
explanations are that doctors
who look after socially
deprived pts have a lower
threshold for cardiac
hospitalization or that social
deprivation alters the way a
HF pt accesses medical care
during decompensation.
Understanding how social
deprivation influences both
doctor and pt behavior in the
prehospital phase is crucial to
reduce the amplifying effect
that social deprivation has

© American College of Cardiology Foundation and American Heart Association, Inc.        36 
 
cardiac hospitalizations.
Social support and
self-care in HF.
Gallager, R. 2011
21372734 (105)
To determine
the types of
social support
provided to HF
pts and the
impact
of differing
levels of social
support on HF
pts’ self-care
Cross-
sectional,
descriptive
(COACH sub-
study )
333 Admitted to
hospital for HF at
least once
before the initial
hospitalization of
the original study
Age >18 y
NYHA II-IV;
evidence of
underlying
structural heart
disease
Undergone
cardiac surgery
or PCI in the
previous 6 mo,
or if these
procedures or
heart
transplantation
was planned,
Unable to
participate in the
COACH
intervention or
to complete the
data collection
forms
Self-care and
social support
N/A High level of support, compared to low
or moderate levels reported
significantly better self-care (p= .002)

High level of social support, compared
medium or low levels, significantly
more likely to: consult with a health
professional for weight gain (p= 0.011),
limit fluid intake (p= 0.02), take their
medication (p= 0.017), get a flu
shot(p= 0.001), and exercise on a
regular basis (p< 0.001).
Secondary analysis. Social
support not prespecified in
COACH trial.
The measure and categories
of social support have not
been used previously either
separately or as a composite
measure.
It is likely that other important
factors influence HF self-care
behavior as the multivariate
model was not adequate.
The presence of social
support by a partner is not
sufficient to influence HF pts’
self-care. Social support
provided by partners needs
to be of a quality and content
that matches HF pts’
perception of need to
influence self-care.
Comorbidities
A qualitative meta-
analysis of HF self-
care practices
among individuals
with multiple
comorbid
conditions. Dickson,
V. 2011
21549299 (106)
To explore how
comorbidity
influences HF
self-care
Qualitative
meta-analysis
99 pts
from 3
trials
Mixed method
studies.
Included pts with
HF with at least
1 comorbid
condition
None specified Perceptions about
HF and HF selfcare
N/A Narrative accounts revealed the most
challenging self-care skills: adherence
to diet, symptom monitoring, and
differentiating symptoms of multiple
conditions.

Emerging themes included: 1)
attitudes drive self-care prioritization
and 2) fragmented self-care instruction
leads to poor self-care integration and
self-care skill deficits.
Generalizability limited due to
homogeneous sample.
Interpretation of findings
relied on interview data
available from the primary
studies.
Findings may be baised
because samples were
recruited from HF specialty
settings, possibly better
managed clinically than
community samples.
Individuals with multiple
chronic conditions are
vulnerable to poor self-care
because of difficulties
prioritizing and integrating
multiple protocols. Adherence
to a low-salt diet, symptom
monitoring, and differentiating
symptoms of HF from other
chronic conditions are
particularly challenging.
Difficulty integrating self-care
of different diseases and
fragmented instructions
regarding those conditions
may contribute to poor
outcomes.

© American College of Cardiology Foundation and American Heart Association, Inc.        37 
 
Psychiatric
comorbidity and
greater
hospitalization risk,
longer length of stay
and higher
hospitalization costs
in older adults with
HF. Sayers, Steven.
2007
17714458 (107)
To explore
associations
between
psychiatric
comorbidity and
rehospitalization
risk, length of
hospitalization,
and costs in
adults with HF.
Cohort study 21429 Medicare
beneficiaries
hospitalized
during 1999.
HF was not a
primary cause of
any admission
during 1999,
Comorbid
dementia or
organic brain
syndrome
diagnosis
Psychiatric
comorbidity and
rehospitalization risk,
length of
hospitalization, and
costs.
N/A Overall, 15.8% of pts hospitalized for
HF had a coded psychiatric
comorbidity.

Most commonly coded comorbid
psychiatric disorder was depression
(8.5% of the sample) (p< 0.001).

Most forms of psychiatric comorbidity
were associated with greater inpatient
utilization, including risk of additional
hospitalizations, d of stay, and
hospitalization charges (p< 0.001).

Additional hospitalization costs
associated with psychiatric comorbidity
ranged up to $7,763, and additional
length of stay ranged up to 1.4 d (p<
0.001).
Claims usage based
administrative data.
Information unavailable
regarding the severity of HF
in the sample.
The possibility that outcomes
may be worse for pts with
coded comorbid psychiatric
diagnoses
as opposed to the presence
of the conditions themselves
cannot be excluded. Cross-
sectional design.
Psychiatric comorbidity
appears in a significant
minority of pts hospitalized
for HF and may affect their
clinical and economic
outcomes. The associations
between psychiatric
comorbidity and use of
inpatient care are likely to be
underestimated because
psychiatric illness is known to
be under detected in older
adults and in hospitalized
medical pts.
The relevance of
comorbidities for HF
treatment in primary
care: A European
survey. Sturm, H.
2006
16084761 (108)
To determine
the impact of pt
characteristics
and
comorbidities on
chronic HF
management,
and to identify
areas of
prescribing that
could be
improved.
Descriptive
study
11,062 Diagnosis of
chronic HF
and/or a history
of MI during a 2-
mo period in
1999
None specified Influence of pt
characteristics on
drug regimens
Combined drug regimens given to 48%
of HF pts (2.2 drugs on average). Pt
characteristics accounted for 35%,
42% and 10% of the variance in 1-, 2-
and 3-drug regimens, respectively.

MI, AF, DM, HTN, and lung disease
influenced prescribing most (OR=1.3;
95% CI: 1.2-1.4)

AF made all combinations containing
beta blockers more likely.

For single drug regimes, MI increased
the likelihood of non-recommended
beta blocker monotherapy while for
combination therapy, recommended
regimes were most likely.

For both HTN and DM, ACEI were the
most likely single drug, while the most
likely second drugs were beta blockers
in HTN and digoxin in DM.
Drug regimens defined to
make comparisons within
levels of similar treatment
intensity possible.
Adherence rates depend on
the indicators used.
Pt characteristics have a
clear impact on prescribing in
European primary care. Up to
56% of drug regimens were
rational, taking pt
characteristics into account.
Situations of insufficient
prescribing, such as pts post
MI, need to be addressed
specifically.

© American College of Cardiology Foundation and American Heart Association, Inc.        38 
 
Frequent non-
cardiac
comorbidities in pts
with chronic HF.
Dahlstrom, Ulf.
2005
15718170 (109)
To discuss in
more detail the
impact of co-
existing
HTN, DM,
COPD in pts
with HF.
Review 37
studies
None specified None specified N/A N/A About 50% of pts with untreated HTN
will develop HF. Pressure overload
leads to the development of LV
hypertrophy and diastolic dysfunction.

DM occurs in about 20–30% of pts
with HF.

COPD occurs in approximately 20–
30% of HF pts.

Anemia occurs in 20–30% of HF pts
and is associated with functional
impairment and increased mortality
and morbidity. Combined treatment
with erythropoietin and intravenous
iron has shown beneficial effects on
clinical symptoms and morbidity.
No limitations addressed. This review of the literature
clearly demonstrates that
noncardiac comorbidities are
common in pts with HF and
that it is important to
recognize these conditions
and
take them into consideration
when selecting treatment for
these pts. Appropriate
treatment of the HF as well
as the concomitant diseases
will improve the prognosis of
these pts.
ACEI indicates angiotensin-converting-enzyme inhibitor; AF, atrial fibrillation; CHF, congestive heart failure; COACH, Community Outreach and Cardiovascular Health; DM, diabetes mellitus; DMP, disease management program; ECHO, echocardiogram; ED,
emergency department; EF, ejection fraction; HF, heart failure; HTN, hypertension; IV, intravenous; LVEF, left ventricular ejection fraction; MI, myocardial infarction; N/A, not applicable; NS, not significant; NYHA, New York Heart Association; PCI; percutaneous
coronary intervention; pts, patients; QoL, quality of life; RCT, randomized control trial; REHMADE, Repetitive Education at Six-Month Intervals and Monitoring for Adherence in Heart Failure; UMHFP, University of Michigan Heart Failure Program
 
Data Supplement 14. Nonadherence (Section 7.3.1.1)
Study Name,
Author, Year Aim of Study Study Type
Study
Size Patient Population Endpoints Statistical Analysis (Results) Study Limitations
Findings/
Comments
Inclusion
Criteria
Exclusion
Criteria
Primary
Endpoint
Secondary
Endpoint
Noncompliance

© American College of Cardiology Foundation and American Heart Association, Inc.        39 
 
Use of telehealth by
older adults to
manage HF. Dansky,
K. 2008
20078015 (110)
To investigate the
influence of telehealth
on self-management of
HF in older adults.
RCT 284 Admitted to a
home health
agency,
Primary or
secondary
diagnosis of HF
None specified Self-management
of HF.
N/A Confidence is a predictor of self-
management behaviors.

Pts using a video-based telehealth
system showed the greatest gain
in confidence levels with time (p=
0.035).
Small sample size.
The home health agencies may
have limited the external
validity of the study.
Examination of the effects of
the telehealth interventions on
specific behaviors was not
possible.
Confidence is a
positive predictor of
self-management,
which should
encourage the
development of
interventions that
focus on building self-
care confidence in HF
pts. These results
contradict the
stereotype that older
adults are unable or
unwilling to use
technology.
Characteristics and
inhospital outcomes
for nonadherent pts
with HF: findings
from GWTG-HF.
Ambardekar, A. 2009
19781426 (111)
To determine the
characteristics,
treatments, quality of
care, and inhospital
outcomes of pts
nonadherent to dietary
and medication advice
as precipitating factors
for HF hospitalization.
Cohort study 54,322 Ages >18, pts
reported in the
GWTG-HF
database from
January 1, 2005-
December 30,
2007
Pts with new
diagnoses of HF
2 groups: Those
in whom
nonadherence
contributed to HF
admission and
those without
nonadherence.
Hospital outcomes
and quality of care
among
nonadherent pts
vs. those who were
adherent.
Multivariate analysis of
characteristics of nonadherence:
Younger age (per y decrease)
p<0.0001; 95% CI: 1.019-1.026;
Male gender (vs. female)
p<0.0001; 95% CI: (1.196-1.358);
Nonwhite race (vs. white)
p<0.0001; 95% CI: 1.358-1.632
No health insurance (vs.
insurance)
p<0.0001; 95% CI: 1.236-1.633
Multivariate analysis of outcomes
with vs. without nonadherence:
Mortality 1.55% v. 3.49%;
p<0.0001 95% CI: 0.51-0.86
Mean length of stay 4.99 d vs. 5.63
p= 0.0017; 95% CI: 0.92-0.97
Rates of nonadherence may be
underestimated due to self
reporting and biased based on
pt characteristics. GWTG-HF is
a voluntary program so could
over-represent high-performing
hospitals. Data collected by
chart reviews, only in-hospital
measures were tracked so long
term follow-up unknown.
Nonadherence is a
common precipitant
for HF admission.
Medication
nonadherence
greater in younger
pts, ethnic minorities
and uninsured
whereas dietary
nonadherence was
observed in older,
overweight and
diabetic pts.
Nonadherent pts
present with evidence
of lower EF and
greater volume
overload yet have an
inhospital course
characterized by a
shorter LOS and
lower mortality. Care
of nonadherent pts
conformed with Joint
Commission core
measures but at
lower rates with other

© American College of Cardiology Foundation and American Heart Association, Inc.        40 
 
guideline-based
therapies.
Utilization of and
adherence to drug
therapy among
Medicaid
beneficiaries with
CHF. Bagchi, A.
2007
17919558 (112)
To determine the
number of Medicaid
beneficiaries with HF,
identify the rate of HF
drug use, estimate
adherence rates,
examine factors
associated with HF
drug use and treatment
adherence, and explore
policy implications.
N/A 45,572 Living in
Arkansas,
California, Indiana
or New Jersey,
enrolled in fee-for
service Medicaid
with pharmacy
benefit coverage
during 1998 and
1999 or until
death
HF (hospitalized
and diagnosed
during 1998 or
diagnosed on ≥ 2
ambulatory visits
during 1998)
Stays in nursing
home facilities at
any time during
1999
Adherence based
on:
MPR (no. of d a pt
is supplied with
>1 HF drug in
relation to the no.
of dbetween the
pt's first and last
prescription
dates),
MP (no.of d of
continuous use of
HF medications
per mo)
N/A Odds of having a HF prescription
claim were higher with people:
Age 65-74 vs. <65:
p<0.01; 95% CI: 1.193- 1.344
Age 75-84 vs. <65:
p<0.01; 95% CI: 1.458- 1.676
Age >85 vs. <65:
p<0.01; 95% CI: 1.162, 1.353

Dual Eligible :
p<0.01; 95% CI: 1.466-1.580
Disabled:
p<0.01; 95% CI: 1.388-1.537
Had CAD :
p<0.01; 95% CI: 3.309-3.676
Had DM:
p<0.01 95% CI: 2.085- 2.284
Hospitalized for HF in 1998:
p<0.01; 95% CI: 1.579-1.701

Odds of having a HF prescription
claim were lower among -
Blacks vs. whites:
p<0.01; 95% CI: 0.735-0.795
Other /unknown ethnic group vs.
whites:
p<0.01 95% CI: 0.840,-0.919
Men vs. women:
p<0.01 95% CI: 0.722-0.775

Adherence better among age >85
y than <64 y, men than women,
racial and ethnic minorities, dual
Measures of use and
adherence are proxies based
on prescriptions filled versus
observations; findings may
overestimate adherence to HF
medications.
Diagnoses recorded in claims
may be incomplete, resulting in
the omission of some pts from
the study.
Limited number of states may
lead to biased results if
Medicaid beneficiaries in study
states are different than other
states.
15.2% of diagnosed
beneficiaries were not
using any HF
medications. Adults
<65 y, men, ethnic
minorities with
hospital admissions
for conditions other
than HF, and
beneficiaries with
high CDPS scores
had lower adherence.

© American College of Cardiology Foundation and American Heart Association, Inc.        41 
 
eligible and disabled, those with
CAD or DM, those with HF related
hospitalization (p<0.01).

Adherence lower among those with
larger proportions of claims for
generic HF drugs, higher CDPS
risk scores and those with non-HF-
related Hospitalizations (p<0.01).
Drug copayment and
adherence in chronic
HF: effect on cost
and outcomes. Cole,
A. 2006
16863491 (113)
To measure the
associations among
prescription copayment,
drug adherence and
subsequent health
outcomes in pts with HF
Retrospective
Cohort Study
5,259
receiving
ACE
inhibitor

5,144
receiving
Beta
Blockers

2,373
receiving
both
In Ingenix
Research Data
Mart, diagnosed
with HF, and
enrolled in
commercial
and/or Medicare
supplemental
plans in 2002;
≥2 physician
visits or
hospitalizations
related to HF in
2002;
$100-10,000 in
costs associated
with HF
diagnoses in
2002;
continuously
enrolled in health
plan for all of
2002 and at least
1 d in 2003.
ACEI and/or beta
blockers
dispensed at least
twice.
Receiving 1
dispensing of
ACEI,
receiving 1
dispensing of beta
blockers, had
switched ACEI,
had switched beta
blockers, MPR
<20% or >120%,
had conflicting
data in their
dispensing
records
Total cost of
health care and
hospitalization for
HF MPR:
proportion of d a
pt was exposed to
a drug while
receiving a
regimen
N/A For pts taking ACEI, a $10
increase in copayment was
associated with a 2.6% decrease
in MPR (95% CI: 2.0 - 3.1%)

This change in adherence was
associated with:
a predicted 0.8% decrease in
medical costs (95 %CI: -4.2 -
2.5%)
a predicted 6.1% increase in the
risk of hospitalization for chronic
HF (95% CI: 0.5 - 12%).

For pts taking beta blockers, a $10
increase in copayment was
associated with a 1.8% decrease
in MPR (95% CI: 1.4 - 2.2%)

This change in adherence was
associated with:
a predicted 2.8% decrease in
medical costs (95% CI: -5.9 -
0.1%).
a predicted 8.7% increase in the
risk of hospitalization for chronic
HF (95% CI: 3.8 - 13.8%)
Using prescription dispensing
data to assess drug adherence
eliminates pts to whom a drug
is dispensed only once so may
have contributed to high
adherence observed.
Dispensing data does not
capture actual usage.
ACEI more expensive than
beta blockers resulting in
higher copayment.
Total medical costs might have
been insensitive to specific
changes in adherence to HF
therapies.
Among pts with HF,
higher drug
copayments were
associated with
poorer adherence,
although the
magnitude of change
was small and did not
affect total health
care costs. It was
sufficient to increase
risk of hospitalization
for HF though.

© American College of Cardiology Foundation and American Heart Association, Inc.        42 
 
The impact of
perceived adverse
effects on medication
changes in HF pts.
De Smedt, R. 2010
20142025 (114)
To evaluate the impact
of perceived adverse
HF drug effects
Retrospective
Cohort Study
754 Hospitalized for
symptomatic HF
NYHA class II-IV
Age >18
Evidence of
structural
underlying heart
disease
Invasive
procedures in the
mo before or
planned within 3
mo after baseline
Already enrolled in
other studies
Follow-up
treatment at
another HF clinic
Impact of
perceived adverse
effects on
likelihood and
type of changes of
potential causal
cardiovascular
medication &
initiation of
medication to
alleviate the
adverse effect.
Risk of a related medication
change significantly increased after
dry cough, nausea, dizziness, or
diarrhea. Dry cough showing the
highest increase in risk (83%; 95%
CI: 1.35-2.49)

Pts with gout had a 4-fold higher
likelihood of having alleviating
medication started or intensified
(95% CI: 2.23-8.05)
With dry cough, a 10-fold increase
in the likelihood of having ACE
inhibitor switched to an ARB (95%
CI: 3.2-35.55)
Pts with gout had a 3-fold higher
likelihood of having diuretics
temporarily discontinued and
reinitiated at a lower dosage (95%
CI: 1.09-10.04)
Cannot be certain that the
reported problems resulted
from medication. Focused on
specific medication changes
and did not take all possible
adequate actions into account.
Recall bias possible- pts may
not have reported all perceived
problems in the questionnaires.
A considerable
number of HF pts
perceived possible
AEs. The likelihood of
medication being
changed after pts
perceived AEs was
low. A high number of
pts perceive
medication AE.
Associations
between outpt HF
process-of-care
measures and
mortality. Fonarow,
G. 2011
21464053 (115)
To examine the
relationships
between adherence to
several current and
emerging
outpt HF process
measures and clinical
outcomes.
Longitudinal/
Registry
15,177 Clinical diagnosis
of HF or post-MI,
LVEF <35%, ≥2
office visits with a
cardiologist in the
last 2 y
Noncardiovascular
medical condition
associated with an
estimated survival
of <1 y, received
cardiac
transplantation
Process-of-care
HF measures:
ACE inhibitor or
ARB use, beta
blocker use,
aldosterone
antagonist use,
anticoagulant
therapy for AF or
flutter, CRT with
defibrillator or
pacemaker, ICD,
and HF education
for eligible pts.
Each 10% improvement in
composite care was associated
with a 13% lower odds of 24-mo
mortality (p <0.0001; 95% CI: 0.84-
0.90)

All process measures, except
aldosterone antagonist use, were
each independently associated
with improved 24-mo survival (p
<0.01 for all except aldosterone
antagonist use).






Errors and omissions in the
medical chart review process
could have occurred.
NYHA functional status was not
quantified in many of the
records, and was instead
based on qualitative
description. This study
analyzed medications
prescribed rather than actual pt
adherence. Follow-up on vital
status was not achieved for all
pts. Race/ethnicity,
socioeconomic status or pt
adherence may be confounding
variables. Findings may not
apply to practices that differ
from the IMPROVE HF outpt
cardiology practices in this
These data
demonstrate that
adherence to HF
process measures for
ACEI/ARB, beta
blocker,
anticoagulation for
AF, and HF education
is significantly
associated with
survival in outpts with
HF. These HF
measures may be
useful for assessing
and improving HF
care.

© American College of Cardiology Foundation and American Heart Association, Inc.        43 
 
study.
A nurse-based
management
program in HF pts
affects females and
persons with
cognitive dysfunction
most. Karlsson, M.
2005
16009290 (116)
To assess the effect of
a nurse-based
management program
aimed at increasing HF
pts' knowledge about
disease and self-care
and to relate the results
to gender and cognitive
function.
Substudy of
the OPTIMAL
project- a
RCT
208 Age >60
Systolic
dysfunction
EF <45%
NYHA II-IV
None specified Pt knowledge of
HF and self-care.
N/A At baseline men knew more about
HF compared to women (p<0.01).

Females in the intervention group
increased their knowledge of self-
care between baseline and 6 mo
compared to the female control
group (p <0.05).

Pts with cognitive dysfunction
(MMSE <24) presented lower
scores on knowledge as compared
to those with a MMSE of >24 at
baseline. These differences
disappeared after the intervention
(p<0.01).
Some pts were included one d
after hospitalization and
some the d before discharge;
condition improvement may
explain low number of pts
scoring low on the MMSE; The
drop-out rate was high in the
MMSE sub-study.

Nurse-based outpt
clinic with specially
trained nurses
effective in increasing
pt knowledge about
self-care. Females
and those with
cognitive impairment
gain from such
programs.

© American College of Cardiology Foundation and American Heart Association, Inc.        44 
 
Pharmacist
intervention to
improve medication
adherence in HF.
Murray, M. 2007
10030506
(117)
To determine whether a
pharmacist intervention
improves medication
adherence and health
outcomes compared
with usual care for low-
income pts with HF.
RCT 314 Age >50 y,
confirmed
diagnosis of HF,
regularly used at
least 1 CV
medication for
HF, not using or
not planning to
use a medication
container
adherence aid,
access to a
working
telephone, and
adequate hearing
Dementia Medication
adherence
(tracked by using
electronic
monitors) and
clinical
exacerbations that
required visits to
the ED or
hospitalization.
Health-related
QoL, satisfaction
with pharmacy
services, and total
direct health care
costs.
Medication adherence greater in
the intervention group 78.8% vs.
67.9% usual care group (95% CI:
5.0-16.7).

At 3 mo, adherence decreased
70.6% in intervention and 66.7 in
usual care (95% CI: -5.9-6.5).

Medications were taken on
schedule 47.2% in the usual care
and 53.1% in the intervention
group (95%CI: 0.4-11.5).

At the end of intervention, taking of
medication on schedule decreased
48.9% for usual care and 48.6% in
intervention (95% CI: -5.9-6.5)

ED visits and hospital admissions
were 19.4% less in the intervention
group (95% CI: 0.73-0.93).

Annual direct health care costs
were lower in the intervention
group (95% CI: $-7603-$1338)
Pts were not permitted to use
medication container
adherence aids.
Intervention involved 1
pharmacist and a single study
site that served a large,
indigent, inner-city population
of pts.
Because the intervention had
several components, results
could not be attributed to a
single component.
A pharmacist
intervention for outpts
with HF can improve
adherence to
cardiovascular
medications and
decrease health care
use and costs, but
the benefit probably
requires
constant intervention
because the effect
dissipates when the
intervention ceases.
Short and long-term
results of a program
for the prevention of
readmissions and
mortality in pts with
HF: are effects
maintained after
stopping the
program? Ojeda, S.
2005
16051519
(118)
To evaluate whether
improvement obtained
during an intervention
program were
maintained after the
program was stopped.
RCT 153 Discharged with a
primary diagnosis
of HF from the
hospital
cardiology ward.
Terminal disease,
expected survival
<6 mo, possibility
of specific etiology
treatment, wait list
for heart
transplant
Decrease in
readmissions due
to HF and in all-
cause mortality
event-free
survival, defined
on the basis of
time to death or
HF readmission.
Changes in
pharmacological
treatment and
changes in quality
of life MLHFQ
During the 16 +8 mo treatment
period, intervention group had:
Lower rate of HF readmissions
(p <0.01), and Less all-cause
mortality Improvement in QoL
(p=0.03)

1 y after the intervention, there
were no differences between the
groups (p=0.03).
Results cannot be extrapolated
to all HF pts since the study
included pts discharged from a
cardiology service, who are
usually younger and with fewer
co-morbidities.
This intervention can
reduce HF morbidity
and mortality and
improve quality of life
but favorable effects
decrease after
program ends. Long-
term programs are
required to maintain
beneficial effects.

© American College of Cardiology Foundation and American Heart Association, Inc.        45 
 
Excessive daytime
sleepiness is
associated with poor
medication
adherence in adults
with HF. Riegel, et al
2011
21440873 (119)
To determine if
medication adherence
differs in adults with HF
and EDS compared to
those without EDS and
to test cognition as the
mechanism of the
effect.
Prospective
cohort
comparison
study
280 Chronic stage C
HF confirmed,
able to complete
the protocol
(vision, hearing,
English literacy),
no more than mild
cognitive
impairment
Living in a long
term care setting,
working nights or
rotating shifts,
renal failure
requiring dialysis,
imminently
terminal illness,
plans to move out
of the area, history
of serious drug or
alcohol abuse in
prior y, major
depression
Self-reported
medication
adherence
Cognition
measured with a
battery of
neuropsychological
tests
62% were nonadherent with
medication regimen.
Medication nonadherence was
significantly more common in those
with EDS
Subjects with EDS and cognitive
decline were >2 times more likely
to be nonadherent (aOR 2.36,
95%CI: 1.12-4.99; p=.033).
Secondary models using the
Epworth Sleepiness score:
The odds of nonadherence
increased by 11% for each unit
increase in ED (aOR 1.11, 95%CI:
1.04-1.19; p=.025).
Subjects with EDS and mild
cognitive decline were 1.6 times
more likely to be nonadherent over
6 mo follow-up (aOR 1.61; 95%CI:
1-03-2.50; p=.001).

The group with EDS but without
cognitive decline was twice as
likely to be nonadherent (p=.014).
9% increase in the odds of
nonadherence for each unit
increase in EDS (p=.001).
Lack of cognitive vigilance
associated with nonadherence.
(p=.024)
Medication adherence was
self-reported.
HF pts who are
sleepy have difficulty
paying attention and
thus forget to take
their medications.

© American College of Cardiology Foundation and American Heart Association, Inc.        46 
 
Compliance with non-
pharmacological
recommendations
and outcome in HF
pts, van der Wal et
al, 2010
20436049 (120)
To investigate the
association between
compliance with non-
pharmacological
recommendations (diet,
fluid restriction,
weighing, exercise) and
outcome in pts with HF.
Secondary
analysis of
data from the
COACH trial
830 Recently
hospitalized for
symptomatic HF,
confirmed by the
cardiologist, with
evidence for
underlying heart
disease.
Invasive
intervention within
the last 6 mo or
planned for the
next 3 mo,
inclusion in
another study with
additional visits to
provider, or
evaluation of CTX.
Composite of
death or HF
readmission and
the number of
unfavorable d.
mortality and
readmission for HF
Pts non-compliant with ≥1
recommendations had a higher risk
of mortality or HF readmission
(p=0.01).
Non-compliance with exercise was
associated with an increased risk
for mortality or HF readmission
(p<0.01).
Non-compliance with daily
weighing was associated with an
increased risk of mortality (p=0.02).
Non-compliance (overall) and non-
compliance with exercise were
associated with a higher risk for HF
readmission (p<0.05).
Pts who were overall non-
compliant or with weighing and
exercise had more unfavourable d
than compliant pts (p= 0.01).
Almost half had a first
diagnosis of HF during the
index hospitalization and then
compliance was evaluated 1
mo after discharge, which
could have influenced rates.
'Unfavorable d' difficult to
evaluate. Self-report instrument
used to measure compliance.
Socially desirable responses
possible.
HF pts who follow
prescribed
nonpharmacologic
therapy have better
outcomes than those
who do not. Exercise
and monitoring of
daily weights are
particularly important.
Nonpharmacologic
Measures and Drug
Compliance in Pts
with HF: Data from
the EuroHF Survey,
Lainscak et al, 2007
17378994 (121)

To describe the recall of
and adherence to
nonpharmacologic
advice of pts enrolled in
the European HF
Survey
Descriptive
survey of pts
from 115
hospitals
from 24
European
countries
2,331 Clinical diagnosis
of HF
Self-reported
adherence to
nonpharmacologic
advice
After hospitalization for HF, pts
recalled receiving 4.1 ± 2.7 items
of advice with some regional
differences. Recall of dietary
advice was higher (63%) than for
influenza vaccination (36%) and
avoidance of NSAIDS (17%).
Among those who recalled the
advice, many did not follow it
completely (cholesterol and fat
intake 61%; dietary salt 63%;
influenza vaccination 75%;
avoidance of NSAIDS 80%). A few
indicated they ignored the advice
completely. Pts who recalled >4
items versus <4 items were
younger and more often received
ACE-I (71% vs 62%), beta
blockers (51% vs 38%), and
spironolactone (25% vs 21%).
Younger pts who were more
mobile and had greater social
support were more likely to
attend interview. Possible
response bias.
Younger age and
prescription of
appropriate
pharmacologic
treatment are
associated with
higher rates of recall
and implementation.
ACEI indicates angiotensin-converting-enzyme inhibitor; AE, adverse event; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CAD, coronary artery disease; CDPS, Chronic illness and disability payment system; CHF, congestive heart failure; COACH,
Community Outreach and Cardiovascular Health; CTX, chest x-ray; CRT, Cardiac resynchronization therapy; CV, cardiovascular; DM, diabetes mellitus; ED, emergency department; EDS, excessive daytime sleepiness; EF, ejection fraction; GWTG-HF; Get
with the Guidelines-Heart Failure; HF, heart failure; ICD, implantable cardioverter-defibrillator; IMPROVE-HF, The Registry to Improve the Use of Evidence-Based Heart Failure Therapies in the Outpatient Setting; LOS, length of stay; LVEF, left ventricular

© American College of Cardiology Foundation and American Heart Association, Inc.        47 
 
ejection fraction; MI, myocardial infarction; MLHFQ, Minnesota Living with Heart Failure questionnaire; MMSE, Mini Mental State Examination; MP, Medication Persistence; MPR, medication possession ratio, N/A, not applicable; NSAID, nonsteroidal
antiinflammatory drugs; NYHA, New York Heart Association; OPTIMAL, optimising congestive heart failure outpatient clinic project; pts, patients; QoL, quality of life; and RCT, randomized clinical trial.

Data Supplement 15. Treatment of Sleep Disorders (Section 7.3.1.4)
Study Name,
Author, Year
Aim of study Study
Type
Study
Size
Patient Population Endpoints Statistical Analysis
(Results)
Study Limitations Findings/
Comments
Inclusion Criteria Exclusion
Criteria
Primary Endpoint Secondary
Endpoint

Continuous positive
airway pressure for
central sleep apnea
and HF (CANPAP).
Bradley, T.D. et al
2005
16282177 (122)
To test the
hypothesis that
long-term
treatment of CSA
with CPAP in HF
pts receiving
optimal medical
therapy reduces
the combined
rates of death and
heart transplant.
11 center
RCT
258 18-79 y, NYHA II-IV, HF
due to ischemia, HTN, or
idiopathic DCM, stable
condition, optimal
medical therapy for 1+
mo, LVEF <40%, CSA
with ≥15 apnea-
hypopnea index (AHI)
and >50% of AHI had to
be central.
Pregnancy, MI,
USA, cardiac
surgery within
prior 3 mo, OSA
Death and heart
transplantation
Hospitalizations,
EF, exercise
capacity, QoL,
neurohormones
No difference between control
(n=130) and CPAP (n=128)
groups in number of
hospitalizations, QoL, ANP
levels. No difference in overall
event rates (p=0.54).
Underpowered
because trial stopped
early for low
enrollment
CPAP did not extend
life, decrease
transplant rate in CSA
but may be indicated
for OSA.
Suppresion CSA by
CPAP and transplant-
free survival in HF.
Arzt, M. 2007
17562959 (123)
To investigate
whether
suppression of
CSA below
threshold by
CPAP would
improve LVEF and
heart transplant–
free survival.
Post-hoc
analysis of a
randomized
trial.
210 Age 18 to 79 y,
NYHA II-IV
HF due to ischemic,
hypertensive, or
idiopathic DCM,
stabilized with optimal
medical therapy for at
least 1 month
LVEF <40%,
Central sleep apnea
Pregnancy,
MI, Unstable
angina, cardiac
surgery within 3
mo of enrollment,
OSA
Combined rate of all-
cause mortality or heart
transplantation
Apnea-hypopnea
index (AHI) mean
nocturnal SaO2,
and LVEF
Despite similar CPAP pressure
and hours of use in the 2 groups,
CPAP-CSA– suppressed
subjects, compared to controls,
experienced:
A greater increase in LVEF at 3
mo (p=0.001)

Significantly better transplant-
free survival (HR: 0.37; 95% CI:
0.142-0.967; p=0.043)









Stratification of
CPAP-treated pts
based on
polysomnogram
performed 3 mo after
randomization.
Because suppressed
and unsuppressed
status could not be
ascertained until
completion of PSG,
events that occurred
during the first 3 mo
could not be
included; more
deaths occurred in
the pts randomized to
CPAP than control (5
vs. 3).
The CPAP-CSA–
These results suggest
that in HF pts, CPAP
may improve both
LVEF and heart
transplant–free
survival if CSA is
suppressed soon after
it begins.

© American College of Cardiology Foundation and American Heart Association, Inc.        48 
 


suppressed group
was younger, had a
lower AHI, and had a
slightly lower
proportion of central
events than the
CPAP CSA–
unsuppressed group
Effect of continuous
positive airway
pressure on sleep
structure in heart
failure pts with central
sleep apnea.
Ruttanaumpawan, P.
2009
19189783 (124)
To determine
whether
attenuation of CSA
by CPAP in pts
with HF reduces
the frequency of
arousals from
sleep or improves
sleep structure.
RCT 205 Age 18 to 79 y;
NYHA II -IV
HF due to ischemic,
hypertensive,
oridiopathic DCM,
stabilized on optimal
medical therapy ≥ 1 mo,
LVEF <40% by
radionuclide
angiography, CSA
defined as an AHI ≥ 15,
with >50% of apneas
and hypopneas central
in nature
Pregnancy,
MI,
UA or cardiac
surgery within 3
mo of enrollment,
obstructive sleep
apnea
Apnea-hypopnea index
and frequency of
arousals.
N/A In controls, there no change in
AHI or frequency of arousals.

In CPAP group, AHI decreased
significantly but neither the
frequency of arousals nor sleep
structure changed significantly
(p<0.001).



Did not classify
arousals as being
respiratory or non-
respiratory related,
and did not examine
their timing.
Attenuation of CSA by
CPAP does not reduce
arousal frequency in
HF pts. Arousals not
mainly a consequence
of CSA and may not
have been a defense
mechanism to
terminate apneas in
the same way they do
in OSA.
Relationship between
beta blocker treatment
and the severity of
CSA in chronic HF.
Tamura, A. 2007
17218566 (125)
To examine the
relationship
between use of
beta blockers and
the severity
of CSA in HF.
Cohort study 45 Chronic HF NYHA II-III
LVEF <50%.
Previous
cerebrovascular
disease,
Recent (<6 mo)
acute coronary
syndrome,
chronic
respiratory
disease
Polysomnography,
echocardiography,
plasma BNP levels
N/A Pts receiving beta blockers
compared to pts not receiving
beta blockers had:
lower AHI, lower CAI.
Negatively correlated with the
dose of carvedilol were: AHI
CAI

Multiple regression analysis
selected no use of beta blockers
as an independent factor of CAI.

In 5 pts with CAI >5 who
underwent serial sleep studies,
CAI decreased significantly after
6 mo of treatment with
carvedilol.
Small sample size.
Did not measure
central
chemosensitivity to
CO2.
In pts with chronic HF,
CAI was lower
according to the dose
of beta blockers. No
use of beta blockers
was independently
associated with CAI. 6
mo of treatment with
carvedilol decreased
CAI. These results
suggest that beta
blocker therapy may
dose-dependently
suppress CSA in pts
with chronic HF.
Influence of CRT on
different types of SDB.
Oldenburg, O. 2007
17467333 (126)
To investigate the
influence of CRT
on SDB in pts with
severe HF.
Prospective
non-
randomized
study
77 Eligible for CRT,
present with dyspnea,
NYHA III-IV
LBBB with QRS ≥150
None specified. Cardiorespiratory
polygraphy. NYHA
class, frequency of
nycturia,
N/A CSA was documented in 36
(47%) pts, OSA in 26 (34%), and
no SDB in 15 (19%).

Categorization of
hemodynamic
response based on a
novel scoring system
In pts with severe HF
eligible for CRT, CSA
is common and can be
influenced by CRT.

© American College of Cardiology Foundation and American Heart Association, Inc.        49 
 
msec, LVEDD ≥60mm,
LVEF of ≤35%,
peak VO2 during
standardized
cardiopulmonary
exercise testing, ≤18
ml/kg/min, during initial
testing of several LV-
lead positions
(posterolateral veins),
RV-stimulation sites
(apex vs. RVOT)
and LV vs. biventricular
pacing, pulse pressure
as a surrogate
parameter of
haemodynamic acute
response had to
increase by >10%.
cardiopulmonary
exercise, 6-min walk
test, and
echocardiography
parameters.
Sleep disordered parameters
improved in CSA pts only:
AHI, SaO2min, Desaturation (p<
0.001)

Daytime capillary pCO2 was
significantly lower in CSA pts
compared to those without SDB
with a trend towards increase
with CRT (p=0.02).

After classifying short term
clinical and hemodynamic CRT
effects, improved SDB
parameters in CSA occurred in
responders only (p=0.004).

not prospectively
validated.
Prospectively
followed CRT pts
without calculating
statistical power
needed
to show results for
pts without SDB,
those with OSA, or
CSA in advance.
Improvement depends
on good clinical and
hemodynamic
response to CRT.
AHI indicates apnea hypopnoea index; ANP, atrial natriuretic peptide; BNP, B-Type natriuretic peptide; CAI, central apnea index; CPAP, continuous positive airway pressure; CRT, cardiac resynchronisation therapy; CSA, central sleep apnea; DM, dilated
cardiomyopathy; EF, ejection fraction; HF, heart failure; HTN, hypertension; LBBB, left bundle branch block; LVEDD, left ventricular end diastolic diameter; LVEF, left ventricular ejection fraction; MI, myocardial infarction; N/A, not applicable; NYHA, New York
Heart Association; OSA, obstructive sleep apnea; pts, patients; QoL, quality of life; RV, right ventricular; RVOT, right ventricular outflow tract; SDB, sleep disordered breathing; UA, unstable angina.

Data Supplement 16. Cardiac Rehabilitation-Exercise (Section 7.3.1.6)
Study Name,
Author, Year
Aim of Study Study
Type
Study
Size
Patient Population Endpoints Statistical Analysis (Results) Findings/Comments
Inclusion Criteria Exclusion Criteria Primary Endpoint Secondary
Endpoint




© American College of Cardiology Foundation and American Heart Association, Inc.        50 
 
Antiremodeling
effect of long-
term exercise
training in pts
with stable
chronic HF.
Giannuzzi,
Pantaleo. 2003
12860904 (127)

To determine whether
long-term exercise
training may influence
LV volume and
function in a large
cohort of pts with
stable chronic HF.
RCT 90 HF secondary to idiopathic
DCM, IHD or valvular
disease
LVEF <35% by ECHO.
Clinical stability for at least
3 mo under optimized
therapy
NYHA II-III
Peak oxygen uptake (VO2)
< 20mL/kg/min at
ergospirometry
Echocardiographic images
of adequate quality for
quantitative analysis
Any systemic disease
limiting exercise,
hypertrophic
cardiomyopathy,
Valvular disease requiring
surgery,
Angina pectoris,
Sustained ventricular
arrhythmias,
Severe hypertension,
Excess variability >10% at
baseline cardiopulmonary
exercise test
Cardiopulmonary
exercise testing,
6MWT,
echocardiography,
and QoL.
N/A Differences from baseline to 6 mo
improved in the intervention group for:
EF (p<0.001);
Work capacity (p<0.001);
Peak VO2 (p<0.006);
Walking distance (p<0.001);
QoL (p<0.01);
LV volumes (diminished) (p<0.001);
Trend to fewer readmissions for
worsening dyspnea (p< 0.05)

LV volumes increased in control group
(p= 0.05)
In stable chronic HF,
long-term moderate
exercise training has no
detrimental effect on left
ventricular volumes and
function; rather, it
attenuates abnormal
remodeling. Furthermore,
exercise training is safe
and effective in
improving exercise
tolerance and QoL.
Combined
endurance-
resistance
training vs.
endurance
training in pts
with chronic HF:
a prospective
randomized
study. Beckers,
Paul. 2008
18515805 (128)

To compare the
effects of combined
endurance-resistance
training with
endurance
training only on
submaximal and
maximal exercise
capacity, ventilatory
prognostic
parameters, safety
issues,
and QoL in pts with
chronic HF.
Prospective
randomized
study
58 Chronic HF due to ischemic
or dilated cardiomyopathy
LVEF <40%
NYHA II-III.
Optimal and stable
pharmacological treatment
Recent ACS or
revascularization in the
past 3 mo,
actively listed on the
transplant list,
logistic problems,
exercise limited by angina
or peripheral arterial
occlusive disease,
cerebrovascular or
musculoskeletal disease
preventing exercise
training,
respiratory limitation
Steady-state workload VO
2
peak,
ventilatory
prognostic
parameters,
upper and
lower limb
strength, and
QoL
In the combined endurance-resistance
training (compared to the endurance
training group):
SSW increased: p=0.007;
Decrease in heart rate at SSW:
p=0.002;
VO
2
peak halftime was reduced:
p=0.001
Maximal strength in upper limbs
increased: p<0.001
HRQoL improved (reported decrease of
cardiac symptoms): p= 0.003; 95% CI:
1.11-12.46.
In chronic HF pts,
combined endurance-
resistance training had a
more pronounced effect
on submaximal exercise
capacity, muscle
strength, and quality of
life. The absence of
unfavorable effects on
left ventricular
remodelling and outcome
parameters is reassuring
and might facilitate
further implementation of
this particular training
modality.

© American College of Cardiology Foundation and American Heart Association, Inc.        51 
 
Comparison of
hospital-based
versus home-
based exercise
training in pts
with HF: effects
on functional
capacity, QoL,
psyhcological
symptoms, and
hemodynamic
parameters.
Karapolat, Hale.
2009
19641843 (129)

To compare the
effects of home-
based and
hospital-based
exercise programs on
exercise capacity,
QoL, psychological
symptoms, and
hemodynamic
parameters in HF pts.
Randomized
study
74 Diagnosed with HF for at
least 3 mo,
HF as a result of ischemic
and dilated
cardiomyopathy,
clinical stability for at least 3
mo, LVEF <40%
NYHA II-III, optimal and
standard pharmacological
treatment, ability to speak
and understand Turkish,
absence of psychiatric
disease, ability to remain
stable during exercise tests
Neurological, orthopedic,
peripheral vascular, or
severe pulmonary disease,
NYHA class IV,
UA pectoris,
poorly controlled or
exercise-induced cardiac
arrhythmias,
recent ACS or
revascularization (<3 mo),
significant valvular heart
disease, AF, uncontrolled
arterial HTN, performing
exercise training at regular
intervals during the
previous 6 wk.
Exercise capacity,
QoL, psychological
symptoms, and
hemodynamic
parameters
N/A After the exercise programs, significant
improvement was observed in both
groups (all p<0.05) including:
Peak VO
2;
6MWT; Subscales of
physical function, general health, and
vitality of short form 36
Beck Depression Inventory
LVEF

A comparison of the 2 exercise groups
revealed no significant differences
between them regarding the analyzed
variables.

Both the hospital-based
and home-based
exercise groups
improved significantly in
functional
capacity, QoL,
depression symptoms,
and LVEF. Based on
these results, we believe
that physicians can
recommend home-based
exercise under strict
supervision for stable HF
pts.
Endurance
exercise training
in older pts with
HF: results from
a randomized,
controlled, single-
blind trial.
Brubaker, Peter.
2009
20121952 (130)
To determine whether
exercise training
improves exercise
capacity and HRQoL
in older persons with
HFrEF.
RCT 59 Age >60 y,
diagnosed with HfrEF,
LVEF <45%
Valvular disease as the
primary etiology of HFrEF,
recent stroke or MI,
uncontrolled HTN,
any other condition limiting
exercise duration
Exercise
performance, LV
structure and function,
neuroendocrine
activation and
HRQoL.
N/A Better in Exercise Training Group:
Mean cycle ergometer distance per
session (p=0.001)
Combined walking & cycling distance
(p=0.001)
Peak exercise workload (watts)
(p=0.007)
Exercise time (seconds) on the bike
(p=0.002)
All other outcome measures did not
show significance.
Failed to produce
consistent benefits in a
cohort or elderly pts with
HFrEF that included a
significant portion of
women. Exercise time
and peak workload
increased but VO
2
peak,
the primary outcome, did
not. Exercise training
failed to provide benefits
in any of the 4 primary
endpoints.

© American College of Cardiology Foundation and American Heart Association, Inc.        52 
 
Effects of
exercise training
on health status
in pts with
chronic HF.
Flynn, Kathryn.
2009
19351942 (131)
To test the effects of
exercise training on
health status among
pts with HF.
RCT 2,331 Medically stable, HF outpt,
LVEF <35%,
NYHA II-IV,
ability and willingness to
undergo exercise training
Unable to exercise,
already exercising
regularly (>1/wk),
had experienced a major
CV event in the previous 6
wk
Health status
(assessed by the
KCCQ)
At 3 mo the KCCQ overall summary
score improved by a greater degree in
the exercise training group (p< 0.001;
95% CI: 0.84-3.01)

At 3 mo there were no further significant
changes in KCCQ score for either
group (p= 0.85), resulting in sustained,
greater improvement overall for the
exercise group (p< 0.001).

Changes from baseline to 12 mo in the
KCCQ overall summary score were
associated with changes in exercise
time:
Cardiopulmonary exercise test: (r=0.28;
p< 0.001)
Peak O2 consumption: (r=0.21; p<
0.001)

6-min walk distance (r=0.18; p<0.001)

Based on these relationships, a 49.7-m
change in distance walked corresponds
to an individual's change of 5 points on
the KCCQ overall summary score.
Exercise training
conferred modest but
statistically significant
improvements in self-
reported health status
compared with usual
care without training.
Improvements occurred
early and persisted over
time.
Resistance
training increases
6-min walk
distance in
people with
chronic HF: a
systematic
review. Hwang,
Chueh-Lung.
2010
20482475 (132)
To determine if
resistance training
improves heart
function, exercise
capacity and QoL in
people with chronic
HF more than no
intervention or usual
care.
Systematic
review with
meta-
analysis of
randomized
trials
241 pts
from 8 trials
Adults with chronic HF
Diagnosis based on clinical
signs or LVEF <40%
None specified Cardiac function,
exercise capacity,
QoL.
N/A Resistance training significantly
increased 6-min walk distance: WMD:
52m; 95% CI: 19-85
Resistance training
increased 6-min walk
distance compared to no
training, but had no other
benefits on cardiac
function, exercise
capacity, or QoL if used
along or as an adjunct to
aerobic training in people
with chronic HF.

© American College of Cardiology Foundation and American Heart Association, Inc.        53 
 
A randomized
trial of the
addition of home-
based exercise to
specialist HF
nurse care: the
Birmingham
Rehabilitation
Uptake
Maximization
study for pts with
CHF (BRUM-
CHF) study.
Jolly, Kate. 2009
19168520 (133)
To assess the
effectiveness of a
home-based exercise
program in addition to
specialist HF nurse
care.
RCT 169 LVEF <40% on ECHO;
had a severity of at least
NYHA II in the previous 24
mo;
clinically stable for 4 wk; in
receipt of optimal medical
treatment and in the care of
a specialist HF nurse team
from 2 acute hospital trusts
and 1 primary care trust in
the West-Midlands region,
UK;
not considered high-risk for
a home-based exercise
program.
NYHA IV
MI;
revascularization within the
past 4 mo;
hypotension;
UA;
ventricular or symptomatic
arrhythmias;
obstructive aortic valvular
disease;
COPD;
hypertrophic obstructive
cardiomyopathy;
severe musculoskeletal
problems preventing
exercise;
case-note reported
dementia;
current severe psychiatric
disorder
Disease-specific QoL
measured by the
MLHFQ
Composite
outcome of
death or
admission with
HF or
myocardial
infarction.
Psychological
wellbeing, self-
reported
physical
activity, blood
pressure,
generic
HRQoL, and
health care
utilization.
At 6 mo, there was no between-group
difference in the disease-specific QoL
MLHFQ (95% CI: -7.87-2.80)

At 12 mo, there was no between-group
difference in the disease-specific QoL
MLHFQ (95% CI: -5.87-4.76)


The only secondary outcomes
significant for exercise group:
Higher generic QoL scores at 6 mo
(95% CI: 0.04-0.18)
Lower hospital anxiety and depression
scale score at 12 mo (95% CI: -2.00 - -
0.14)

At 6 mo, the control group showed
deterioration in physical activity,
exercise capacity and generic QoL.
This study failed to
demonstrate a benefit
from the addition of a
home-based exercise
program in a community-
based HF population.
Further evidence is
needed to assess the
suitability
of home-based exercise
programs in this
population.
Exercise training
in older pts with
HF and
preserved EF.
Kitzman, Dalane.
2010
20852060 (134)
To test the hypothesis
that supervised
exercise training in
older pts with HFpEF
would improve the
primary
outcome of peak
exercise VO
2
and the
secondary outcome of
disease-specific QoL.
RCT 53 Stable with no medication
changes for >6 wk;
HFpEF defined as history,
symptoms and signs of HF
Preserved LVEF (>50%);
no evidence of significant
coronary, valvular or
pulmonary disease or any
other medical condition that
could mimic HF symptoms.
Contraindication to
exercise testing or training;
unable to perform a
valid baseline exercise
test;
currently exercising
regularly;
had known cancer;
significant renal
dysfunction;
substance abuse;
uncontrolled diabetes;
dementia,
History of noncompliance;
any other disorder that
would preclude
participation in the
intervention and follow-up.
Peak exercise oxygen
uptake
QoL; LV
morphology
and function,
and
neuroendocrine
function
Peak exercise oxygen uptake increased
significantly in the exercise treatment
group compared to the control group
(p= 0.0002).

There were significant improvements in
peak power output, exercise time, 6-
minute walk distance, and ventilatory
anaerobic
threshold (all p< 0.002).

There was improvement in the physical
quality of life score (but not in the total
score) (p= 0.03).
This randomized,
controlled, single-blind
study showed that
16 wk of exercise training
was safe and
significantly improved
peak and submaximal
exercise performance in
older pts with
HFpEF. These results
suggest that this
nonpharmacological
intervention may be a
worthwhile consideration
for pts with this common
and increasingly
prevalent disorder.

© American College of Cardiology Foundation and American Heart Association, Inc.        54 
 
Effects of
exercise training
in pts with HF:
the exercise
rehabilitation trial
(EXERT).
McKelvie,
Robert. 2002
12094184 (135)
To examine the
effects of exercise
training on functional
capacity in pts with
HF.
RCT 181 Documented clinical signs
and symptoms of HF
LVEF <40%,
NYHA I-III,
6MWT distance <500
meters
Inability to attend regular
exercise training sessions;
exercise testing limited by
angina or leg claudication;
abnormal blood pressure
response to exercise
testing;
cerebrovascular or
musculoskeletal
disease preventing
exercise testing or training;
respiratory limitation;
poorly controlled
cardiac arrhythmias;
any noncardiac condition
affecting regular exercise
training or decreasing
survival.
6MWT Peak oxygen
uptake,
dynamic
muscle
strength, QoL,
and cardiac
function
Significant increase in 6-min walk
distance at 3 and 12 mo (p= 0.026) but
no between-group differences (p=
0.081).

Incremental peak oxygen uptake
increased in the exercise group
compared with control group:
At 3 mo: (p=0.014);
At 12 mo: (p=0.014)

At 3 mo, compared with the control
group, increases were seen in exercise
group for:
Arm Curl and
Knee Extension: (p=0.014)

No significant changes observed in
cardiac function or QoL.
Exercise training
improves peak oxygen
uptake and strength
during supervised
training. Over the final
9 mo of the study, there
was little further
improvement, suggesting
that some supervision is
required for these pts.
There were no adverse
effects on cardiac
function or clinical
events.

© American College of Cardiology Foundation and American Heart Association, Inc.        55 
 
Combined
endurance and
muscle strength
training in female
and male pts with
chronic HF.
Miche, Eckart.
2008
18432395 (136)
To evaluate the effect
of a combined
endurance and
muscle strength
training program on
clinical performance
data and health-
related psychosocial
factors in women and
men.
Non-
randomized
study of men
vs. women.
285 Stable chronic HF;
LVEF <45%;
Peak VO2 <20 ml/min/kg;
capable of answering
questions on HRQoL and
psychological well-being.
Severe pulmonary
disorders;
neurological deficits;
cognitive disorders and
physical disabilities which
prevented pts from
participating in a training
program.
LVEF,
cardiopulmonary
performance, QoL
N/A Women had a diagnosis of non-IHD
and valvular heart disease more
commonly than men.

LVEF increased:
Female: p<0.001
Male: p<0.001

LVEDV decreased:
Female: p<0.05
Male: p<0.05

LVESV:
Female: p<0.001
Male: p<0.001

Peak VO2:
Female: p NS
Male: p<0.001

Wattmax (W):
Female: p<0.001
Male: p<0.001

6MWT (m):
Female: p<0.001
Male: p<0.001

Muscle strength training:
Female: p<0.001
Male: p<0.001

Physical Health:
Female: p<0.001
Male: p<0.001

Mental Health:
Female: p<0.01
Male: p<0.05
The results of our study
confirm the feasibility of a
combined endurance and
resistance program,
especially for women.
Our findings show a
considerably reduced
cardiopulmonary
performance, negatively
affecting physical health.
In contrast, no essential
restrictions were reported
by our groups regarding
mental health. This
underlines the
importance of a physical
training program and its
continuation at home
following the hospital
stay in order to influence
performance data
favorably.

© American College of Cardiology Foundation and American Heart Association, Inc.        56 
 
Long-term effects
of a group-based
high-intensity
aerobic interval-
training program
in pts with
chronic HF.
Nilsson, Birgitta.
2008
18940296 (137)
To evaluate the long-
term effects of a 4-
mo, group-based,
high-intensity aerobic
interval training
program on functional
capacity and the QoL
in pts with chronic HF.
RCT 80 Stable chronic HF;
NYHA II-IIIB;
receiving optimal medical
treatment;
LVEF <40% or >40% with
clinical symptoms of
diastolic HF
Acute MI within 4 wk; UA
pectoris;
serious rhythm
disturbance;
symptomatic peripheral
vascular disease;
severe obstructive
pulmonary disease;
6MWT <550 m;
workload on the cycle
ergometer test >110 W;
significant comorbidities
that would prevent study
entry due to terminal
disease or an inability to
exercise In a long-term
care establishment
Functional capacity,
evaluated by 6-min
walking distance.
QoL After 4 mo, in the exercise group:
Functional capacity improved
(p<0.001),
QoL improved (p<0.001).

After 12 mo, in the exercise group:
Functional capacity still improved
(p<0.001).
QoL still improved (p=0.003).
The results support
the implementation of a
group-based aerobic
interval training program
to improve long-term
effects on functional
capacity and the QoL in
pts with chronic HF.
Efficacy and
safety of exercise
training in pts
with chronic HF.
O'Connor,
Christopher.
2009
19351941 (138)
To test the efficacy
and safety of exercise
training among pts
with HF.
RCT 2331 HF
LVEF <35%,
NYHA II-IV,despite optimal
HF therapy for at least 6 wk
Major comorbidities or
limitations that could
interfere with exercise
training, recent or planned
major CV events or
procedures,
performance of regular
exercise training,
use of devices that limited
the ability to achieve target
heart rates.
Composite of all-
cause mortality or all-
cause hospitalization.
All-cause
mortality, the
composite
of CV mortality
or CV
hospitalization,
and the
composite of
CV mortality
or HF
hospitalization.
NS reductions in primary or secondary
endpoints.

In prespecificed supplementary
analyses adjusting for highly prognostic
baseline characteristics there were
reductions in the exercise training group
for:
All-cause mortality or hospitalization:
(p=0.03; 95% CI: 0.81-0.99)

CV mortality or HF hospitalization:
(p=0.03; 95% CI: 0.74-0.99)


Regular exercise training
in pts with systolic HF
was safe. In the protocol-
specified primary
analysis, exercise
training resulted in
nonsignificant reductions
in the primary endpoint of
all-cause mortality or
hospitalization and in
secondary endpoints.
After adjustment for
highly prognostic
predictors of the primary
endpoint, exercise
training was associated
with modest significant
reductions for both all-
cause mortality or
hospitalization and CV
mortality or HF
hospitalization.

© American College of Cardiology Foundation and American Heart Association, Inc.        57 
 
Exercise training
meta-analysis of
trials in pts with
chronic HF
(ExTraMATCH).
Piepoli. 2004
14729656 (139)
To determine the
effect of exercise
training on survival in
pts with HF due to LV
systolic dysfunction.
Collaborativ
e meta-
analysis
801 pts
from 9 trials
Randomized parallel group
controlled trials,
evaluate exercise training
without any other
simultaneous intervention,
study pts with stable HF (3
mo or more of stability) due
to left systolic ventricular
dysfunction (LVEF <50%),
have an exercise program
lasting 8 wks or more,
utilize training involving at
least both legs, have
survival follow up of ≥3 mo.
Trials of arm or single leg
training were excluded
Time to death. Death or time
to admission to
hospital.
Exercise training significantly reduce
mortality (p=0.0015; 95% CI: 0.46-0.92)

Exercise training significantly reduced
death or admission to hospital (p=0.01
95% CI: 0.56-0.93).
Meta-analysis of
randomized trials gives
no evidence that properly
supervised medical
training programs for pts
with HF might be
dangerous, and indeed
there is clear evidence of
an overall reduction in
mortality.
Randomized trial
of progressive
resistance
training to
counteract the
myopathy of
chronic HF. Pu,
Charles. 2001
11356801 (140)
To evaluate whether
strength training in
elderly pts with
chronic HF would be
well tolerated and
result in improved
overall exercise
performance without
changes in central
cardiac function.
RCT 96 (16 HF
80 control)
Community-dwelling,
female,
age >65
mild to moderate, stable
systolic HF,
NYHA I-III,
resting LVEF <45%
NYHA class IV,
MI within 6 mo,
hospitalization for chronic
HF within 2 mo,
change of HF therapy
within 1 mo,
UA pectoris, fixed
ventricular rate pacemaker,
abdominal aortic aneurysm
>4 cm, major limb
amputation, symptomatic
abdominal or inguinal
hernias
Folstein mini-mental state
examination score <23,
significant abnormalities on
maximal treadmill testing
or screening strength
testing
Overall exercise
capacity (6-min walk
distance) and muscle
function.
Muscle
metabolism
and histology,
body
composition,
maximal
oxygen
consumption,
and cardiac
function,
Women with chronic HF had
significantly lower muscle strength than
women without chronic HF (p<0.0001).

In resistance trainers (vs. controls):
Strength improved (p<0.0001);
Muscle endurance improved
(p<0.0001);
6-minute walk distance increased
(p<0.0003).

Increases in type 1 fiber area and
citrate synthase activity in skeletal
muscle were independently predictive
of improved 6-min walk distance (r
2
=
0.78; p=0.0024).
High-intensity
progressive resistance
training improves
impaired skeletal muscle
characteristics and
overall exercise
performance in older
women with chronic HF.
These gains are largely
explained by skeletal
muscle and not resting
cardiac adaptations.

© American College of Cardiology Foundation and American Heart Association, Inc.        58 
 
The effects of
physical training
on workload,
upper leg muscle
function and
muscle areas in
pts with chronic
HF. Senden, Jeff.
2005
15823638 (141)
To investigate the
effect of physical
training on upper leg
muscle area, muscle
strength and muscle
endurance expressed
as upper leg muscle
function in relation to
exercise
performance.
RCT 77 Chronic HF for at least 6
mo,
NYHA II-III,
clinically stable for at least
3 mo,
received optimal medical
therapy,
physically able to visit the
outpt clinic,
LVEF <35%
Interfering disease such as
COPD,
fasting glucose <7.0
mmol/L (DM),
neuromuscular disorders,
HTN

LVEF, body
composition, daily
physical activity,
exercise performance,
upper leg muscle area
and isokinetic leg
muscle variables.
N/A Workload and peak oxygen
consumption decreased in the control
group and increased in the training
group (p<0.05).

Hamstrings area decreased in the
control group and did not change in the
training group (p<0.05).

Upper leg muscle function improved in
the training group and did not change in
the control group (p<0.05).

At baseline and after intervention nearly
60% of the variance in maximal
workload was explained by upper leg
muscle function and quadriceps muscle
area.
In chronic HF pts, home-
based training in
conjunction with a
supervised strength and
endurance training
program is safe, feasible
and effective and does
not require complex
training equipment.
Physical training
prevented loss of
hamstrings muscle mass
and improved exercise
performance by
enhancing muscle
strength and endurance.
Antiremodeling
effect of long-
term exercise
training in pts
with stable
chronic HF.
Giannuzzi,
Pantaleo. 2003
12860904 (127)

To determine whether
long-term exercise
training may influence
LV volume and
function in a large
cohort of pts with
stable CHF.
RCT 90 HF secondary to idiopathic
DCM, IHD or valvular
disease,
LVEF <35% by ECHO,
clinical stability for at least 3
mo under optimized
therapy,
NYHA II-III,
peak oxygen uptake (VO
2
)
<20mL/kg/min at
ergospirometry,
echocardiographic images
of adequate quality for
quantitative analysis
Any systemic disease
limiting exercise,
hypertrophic
cardiomyopathy,
valvular disease requiring
surgery,
angina pectoris,
sustained ventricular
arrhythmias,
severe HTN,
excess variability >10% at
baseline cardiopulmonary
exercise test
Cardiopulmonary
exercise testing,
6MWT, ECHO, and
QoL.
N/A Differences from baseline to 6 mo
improved in the intervention group for:
EF (p<0.001),
Work capacity (p<0.001),
Peak VO
2
(p<0.006),
Walking distance (p<0.001),
QoL (p<0.01),
LV volumes (diminished) (p<0.006),
Trend to fewer readmissions for
worsening dyspnea (EDV p<0.05 ESV)

LV volumes increased in control group
(p<0.0.01 EDV ESV)
In stable chronic HF,
long-term moderate
exercise training has no
detrimental effect on LV
volumes and function;
rather, it attenuates
abnormal remodeling.
Furthermore, exercise
training is safe and
effective in improving
exercise tolerance and
QoL.

© American College of Cardiology Foundation and American Heart Association, Inc.        59 
 
Exercise training
reduces
circulating
adiponectin
levels in pts with
chronic HF. Van
Berendoncks,
An. 2010
19656085 (142)

To assess circulating
adiponectin
concentrations in
chronic HF pts,
compare with
controls, and evaluate
the effects of a 4-mo
exercise training
program.
Prospective,
non-
randomized
trial
80 LVEF <30%,
NYHA II-III,
symptoms had been stable
on medical treatment for at
least 1 mo prior to inclusion
Recent ACS or
revascularization,
valvular disease requiring
surgery,
exercise-induced
myocardial ischemia or
malignant ventricular
arrhythmia, acute
myocarditis or pericarditis,
cerebrovascular or
musculoskeletal disease
preventing exercise testing
or training,
acute or chronic infections,
allergies, cancer or
inflammatory disease, DM.
Circulating
adiponectin
concentrations,
exercise capacity,
anthropometric data
and NT-proBNP
levels.
N/A At baseline, adiponectin levels were
significantly higher in chronic HF pts
compared with healthy subjects
(p=0.015).

At baseline, stratification of pts
according to tertiles of NT-proBNP
revealed an increase in adiponectin
with disease severity (p<0.001).

Exercise training significantly reduced
circulating adiponectin levels in the
trained chronic HF group (compared to
sedentary chronic HF group) (p=0.008)
Circulating adiponectin
concentrations
are higher in chronic HF
pts compared with
healthy subjects and
increase with disease
severity.
Exercise training for 4
mo lowers circulating
adiponectin levels. The
present findings, together
with those from other
studies, suggest that
dysregulation of the
adiponectin pathway
contributes to the
observed metabolic
impairment in chronic HF
Effects of
exercise training
on cardiac
performance,
exercise capacity
and QoL in pts
with HF. Van Tol,
Benno. 2006
16713337 (143)
To determine the
effect of exercise
training in pts with
chronic HF on cardiac
performance,
exercise capacity and
HRQoL.
Meta-
analysis of
RCTs
35 trials RCTs,
included pts with chronic
HF in the control and in the
intervention group
(diagnosis based
on clinical findings or LVEF
<40%), included at least 1
treatment group receiving
exercise training and 1
control group which
received standard medical
treatment w/o additional
exercise training,
evaluated outcome
measures in terms of
cardiac performance,
exercise capacity and/or
HRQoL, exercise training
had to include at least one
of the following training
modalities: walking, cycling
or resistive training of
peripheral muscles.
Studies in which only
respiratory muscles or one
isolated muscle group was
trained.
Cardiac performance,
exercise capacity and
HRQoL.
N/A During maximal exercise, significant
summary effect sizes were found for:
SBP (p=0.03),
Heart rate (p=0.011),
Cardiac output (p=0.004),
Peak oxygen uptake (p=0.00),
Anaerobic threshold (p=0.00),
6MWT (p=0.00).

The MLHFQ improved by an average of
9.7 points (p=0.00).
Exercise training has
clinically important
effects on exercise
capacity and health-
related quality of life, and
may have small positive
effects on cardiac
performance during
exercise.
6MWT indicates 6 minute walk test; ACS acute coronary syndrome; AF, atrial fibrillation; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; CV, cardiovascular; DCM, dilated cardiomyopathy; DM, diabetes mellitus; ECHO,
echocardiography; EF, ejection fraction; EXERT, Exercise Rehabilitation Trial; HF, heart failure; HFpEF, heart failure with preserved ejection fraction; HFrEF, heart failure with reduced ejection fration; HRQoL, health related quality of life; HTN,

© American College of Cardiology Foundation and American Heart Association, Inc.        60 
 
hypertension; IHD, ischemic heart disease; KCCQ, Kansas City Cardiomyopathy Questionnaire; LV, left ventricular; LVEDV, left ventricular end-diastolic volume; LVEF, left ventricular ejection fraction; LVESV, left ventricular end-systolic volume; MI,
myocardial infarction; MLHFQ, Minnesota Living with Heart Failure Questionaire; N/A, not applicatble; NT-proBNP, N-terminal pro-B-Type natriuretic peptide; N/A, not applicable; NS, not significant; O2, oygen; pt, patient; QoL, quality of life; r
2
,

coefficient
of determination; RCT, randomized control trial; SSW, Stead-state workload; UA, unstable angina; UK, United Kingdom; and VO2, oxygen volume.

Data Supplement 17. Diuretics Versus Ultrafiltration in Acute Decompensated HF (Section 7.3.2.1)
Study Name,
Author, Year
Aim of Study Study
Type
Study
Size
Patient Population Endpoints Statistical Analysis (Results) Study
Limitations
Findings/
Comments
Diuretic
studies
Inclusion Criteria Exclusion Criteria Primary Endpoint Secondary
Endpoint

DOSE-AHF,
Felker, 2011
21366472
(144)
To compare high and
low doses of diuretics
administered over
longer and shorter
periods of time to
determine the safest
and most effective
combination.
RCT 308 Prior clinical
diagnosis of HF
that was treated
with daily oral loop
diuretics for at
least 1 mo;
current diagnosis
of HF, as defined
by the presence of
at least 1 symptom
(dyspnea,
orthopnea, or
edema) and 1 sign
(rales on
auscultation,
peripheral edema,
ascites, pulmonary
vascular
congestion on
chest
radiography);
daily oral dose of
furosemide 80 mg-
240 mg (or
equivalent);
identified within 24
h of hospital
admission;
current treatment
plan includes IV
loop diuretics for at
least 48 h
BNP <250 mg/mL or NT-proBNP
<1000 mg/mL; IV vasoactive
treatment or ultrafiltration therapy
since initial presentation; treatment
plan includes IV vasoactive
treatment or ultra-filtration;
substantial diuretic response to
prerandomization diuretic dosing
such that higher doses of diuretics
would be medically inadvisable;
SBP <90 mm Hg; SCr >3.0 mg/dL
at baseline or currently undergoing
renal replacement therapy;
hemodynamically significant
arrhythmias; ACS within 4 wk prior
to study entry; active myocarditis;
hypertrophic obstructive
cardiomyopathy; severe stenotic
valvular disease; restrictive or
constrictive cardiomyopathy;
complex congenital heart disease;
constrictive pericarditis;. non-
cardiac pulmonary edema; clinical
evidence of digoxin toxicity; need
for mechanical hemodynamic
support; sepsis; terminal illness
(other than HF) with expected
survival time of <1 y; history of
adverse reaction to the study
drugs; use of IV iodinated
radiocontrast material within 72 h
prior to study entry or planned
during hospitalization; enrollment
Pt well-being, as
determined by VAS;
change in SCr
Weight loss;
Proportion of pt
free of congestion;
change in the
bivariate
relationship of
creatinine vs.
weight loss;
dyspnea, as
determined by
VAS; pt global
assessment, as
determined by
VAS; change in
SCr; Change in
cystatin C;
worsening or
persistent HF,
defined as a need
for rescue therapy;
development of
cardio-renal
syndrome, defined
as an increase in
the SCr level >0.3
mg/dL; net fluid
loss; time from
study entry to
discharge during
index
hospitalization;
death or total days
hospitalized for
Comparison of bolus vs. continuous
infusion: no significant difference in
either
pts' global assessment of symptoms
(mean AUC, 4236±1440 in the bolus vs
4373±1404 in the infusion group,
p=0.47)
Mean change in creatinine level
(0.05±0.3 mg/dL in the bolus vs
0.07±0.3 mg/dL in the infusion group,
p=0.45)
Secondary Endpoints: No significant
differences, including SCr and cystatin
C levels during index hospitalization and
at 60 d. Comparison of high-dose vs.
low-dose strategy: no significant
difference in pts' global assessment of
symptoms, although there was a
nonsignificant trend toward greater
improvement in the high-dose group
(mean AUC, 4430±1401 vs.
4171±1436; p=0.06; mean change in
creatinine level (0.08±0.3 mg/dL with
the high-dose strategy and 0.04±0.3
mg/dL with the low-dose strategy,
p=0.21). Secondary
endpoints: The high-dose strategy was
associated with greater diuresis (net
fluid loss and weight loss) and greater
relief from dyspnea but also with
transient worsening of renal function
(occured in 23% of pts in the high-dose
vs 14% in the low-dose group, p=0.04)
N/A N/A

© American College of Cardiology Foundation and American Heart Association, Inc.        61 
 
or planned enrollment in another
clinical trial during hospitalization;
inability to comply with planned
study procedures
HF; death or re-
hospitalization
Clinical composite endpoint of death,
rehospitalization, or ED visit during the
60-d follow-up period: HR with
continuous infusion: 1.15; 95% CI: 0.83-
1.60; p=0.41, HR with high-dose
strategy, 0.83; 95% CI: 0.60-1.16;
p=0.28
PROTECT,
Massie, 2010
20925544
(145)
Rolofylline, an
adenosine A1-receptor
antagonist, would
improve dyspnea,
reduce the risk of
WRF, and lead to a
more favorable clinical
course in pt with acute
HF
RCT 2,033 Persistent dyspnea
at rest or with
minimal activity,
impaired renal
function (an
estimated CrCl of
20-80 mL/min with
the use of the
Cockcroft−Gault
equation), a BNP
level of ≥500
pg/mL or more or
an NT-pBNP level
≥2000 pg/mL,
ongoing IV loop-
diuretic therapy,
and enrollment
within 24 h after
admission.
Pregnant or breast feeding; acute
contrast induced nephropathy,
sepsis, serum potassium
<3.5mEq/L; ongoing or planned IV
therapy for acute HF with positive
inotropic agents, vasopressors,
vasodilators, or mechanical
support, with the exception of IV
nitrates, BNP<500; ongoing or
planned UF, hemofiltration or
dialysis; severe pulmonary
disease; significant stenotic
valvular disease, heart transplant
recipient or admitted for cardiac
transplantation
Primary end point was
treatment success,
treatment failure, or no
change in the pt's condition.
Success defined as pt-
reported moderate or
marked improvement in
dyspnea both 24 and 48 h
after administration of the
study drug, in the absence
of any criterion for failure.
Failure defined as the
occurrence of any of the
following: death or
readmission for HF through
d 7, worsening symptoms
and signs of HF occurring
>24 h after the initiation of
the study drug requiring
intervention by d 7 or
discharge (if earlier), or
persistent WRF, defined as
an increase in the SCr level
≥0.3 mg/dL (26.5 μmolL)
from randomization to d 7,
confirmed at d 14, or the
initiation of hemofiltration or
dialysis during the period
from initiation of the study
drug through d 7. Pts were
classified as having
unchanged treatment status
if they met neither the
criteria for treatment
success nor the criteria for
treatment failure.
Two secondary
outcomes were
prespecified: death
from any cause or
rehospitalization
for cardiovascular
or renal causes
through d 60 and
the proportion of
pts with persistent
renal impairment,
defined as an
increase in the SCr
level ≥0.3 mg/dL
by d 7, confirmed
at d 14; the
initiation of
hemofiltration or
dialysis through d
7; or death by d 7.
Rolofylline did not provide a benefit with
respect to the primary endpoint (OR:
0.92; 95% CI: 0.78-1.09; p=0.35).
Persistent renal impairment developed
in 15% of pts in the rolofylline group and
in 13.7% of pts in the placebo group
(OR: 1.11; 95% CI: 0.85-1.46; p=0.44).
By 60 d, death or readmission for
cardiovascular or renal causes had
occurred in similar proportions of pts
assigned to rolofylline, 386 of 1356 pts
(Kaplan–Meier estimate, 30.7%; 95%
CI: 27.8-33.6) as compared with 195 of
677 pts assigned to placebo (Kaplan–
Meier estimate: 31.9%; 95% CI: 27.4-
36.4) (HR: 0.98; 95% CI: 0.83-1.17;
p=0.86). AE rates were similar overall;
however, only pts in the rolofylline group
had seizures, a known potential adverse
effect of A1-receptor antagonists1.
Post hoc
selection of the
best of 3 dose
groups from the
pilot trial with
multiple small
treatment groups
carries the risk
that an apparent
superiority may
be the play of
chance and may
have resulted in
the inability to
replicate pilot
study findings in
this more
definitive, larger
study. Also,
clinical relevance
of endpoints has
been questioned
Rolofylline did
not have a
favorable effect
with respect to
the primary
clinical
composite end
point, nor did it
improve renal
function or 60-
d outcomes. It
does not show
promise in the
treatment of
acute HF with
renal
dysfunction

© American College of Cardiology Foundation and American Heart Association, Inc.        62 
 
DAD-HF,
Giamouzis,
2010
21111980
(146)
Evaluate the effect of
low-dose dopamine
and furosemide on
diuresis and renal
function in pts with
acute decompensated
HF
RCT 60 Age >18 y; history
of HF;
deterioration of HF,
symptoms of
recent onset (<6
h), dyspnea at
rest, orthopnea,
and paroxysmal
nocturnal dyspnea,
accompanied by
signs of
congestion (third
heart sound,
jugular venous
distension,
pulmonary rales)
on physical
examination; levels
of serum BNP
>400 pg/mL or NT
pBNP >1,500
pg/mL; and oxygen
saturation <90%
on admission.
Acute de novo HF; severe renal
failure (admission SCr >215
mmol/L [2.5 mg/dL] or eGFR <30
mL min 1 1.73 m
2
); admission SBP
<90 mm Hg; severe valvular
disease; known adverse reactions
to furosemide or dopamine; HF
secondary to congenital heart
disease; a scheduled procedure
with a need for IV contrast dye in
the present hospitalization; and a
scheduled cardiac surgery within 2
mo.
Incidence of WRF during
the first 24 h from
randomization. 2
definitions were used for
WRF: 1) >0.3 mg/dL rise in
SCr level from baseline to
24 h; and 2) >20%
decrease in eGFR from
baseline to 24 h
Changes in SCr,
urea, potassium,
and eGFR during
the first 24 h from
randomization;
incidence of WRF
over the course of
hospitalization;
total length of stay;
and 60-d mortality
or rehospitalization
rate (all-cause,
cardiovascular,
and worsening of
HF).
Mean hourly excreted urine volume
(272±149mL in high-dose furosemide
vs 278±186mL in LDFD plus low-dose
dopamine group; p=.965) and changes
in dyspnea score (Borg index: 4.4±2.1
in high-dose furosemide group vs
4.7±2.0 in LDFD group; p=.575) during
the 8 h of protocol treatment were
similar in the two groups. WRF was
more frequent in the high-dose
furosemide (n=9; 30%) than in the
LDFD group (n=2; 6.7%; p=.042).
Serum potassium changed from
4.3±0.5 to 3.9±0.4mEq/L at 24 h
(p=.003) in the high-dose furosemide
group and from4.4±0.5 to
4.2±0.5mEq/L at 24 hours (p=.07) in the
LDFD group. Length of stay and 60-d
mortality or rehospitalization rates (all-
cause, cardiovascular, and worsening
HF).
Relatively small
study, 2 groups
did not receive
the same dose of
furosemide and
did not include a
low-dose
furosemide only
group.
This study
shows that
LDFD infusions
are as effective
as high-dose
furosemide
infusions in
terms of clinical
and diuretic
response in pts
hospitalized for
acute
decompensate
d HF.
Moreover,
LDFD infusion
was associated
with
significantly
lower rates of
WRF than
high-dose
furosemide,
suggesting a
renoprotective
effect in this pt
population.

© American College of Cardiology Foundation and American Heart Association, Inc.        63 
 
Pilot
continuous
vs bolus
infusion
(Duke), L
Allen, 2010
20538132
(147)
Pilot study of
furosemide by
continuous infusion vs
twice-d bolus injection.
Hypothesis that
continuous dosing of
IV furosemide
provides gradual
diuresis with less
neurohormonal
activation, which
would manifest as less
renal dysfunction,
compared to bolus
dosing in the treatment
of acute
decompensated HF
with volume overload
RCT 41 Primary diagnosis
of acute
decompensated
HF; evidence of
volume overload;
could be
randomized <24 h
from hospital
presentation
End-stage renal disease or
anticipated need for renal
replacement therapy; were not
expected to survive hospitalization;
pregnant
Change in SCr from
admission to hospital d 3 or
hospital discharge
Cumulative urine
output and other
electrolyte
changes from
admission to
hospital d 3 as well
as hospital length
of stay
None of the outcomes showed a
statistically significant difference
between bolus and continuous dosing
from admission to hospital d 3.
Nonsignificant trend toward
improvement in the bolus dosing arm.
Decreases in serum potassium, serum
sodium, and SBP showed nonsignificant
trends in favor of continuous infusion

Smaller study No statistically
significant
differences
noted between
bolus and
continuous
infusion
Pilot
continuous
vs bolus
infusion
(MUSC),
Thomson,
2010
20206891
(148)
Pilot study comparing
the effectiveness of
continuous IV with
intermittent IV infusion
of furosemide in pt
with acute
decompensated HF
RCT 56 Admission
diagnosis of acute
decompensated
HF
Pts who had received >2 doses of
IV fruosemide before
randomization
Net daily urine output Net daily urine
output normalized
for amount of
furosemide
received, total
daily urine output
normalized for
amount of
furosemide
received, weight
loss during the
study, need for
additional HF
therapy, duration
of study drug
dministration,
length of
hospitalization
Mean urine output in 24 h was
2,098±1,132 mL in pt receiving
continuous vs 1,575±1100 mL in the
bolus group (p=0.086). Total urine
output was 3726±1121 mL/24 h in the
continuous group vs 2,955±1,267
mL/24 h in bolus group (p=0.019).
Length of hospital stay was 6.9±3.7 d in
the continuous group vs 10.9±8.3 d in
the bolus group (p=0.006)

Smaller study LOS shorter
and mean
urine output
greater in the
continuous
infusion group
vs bolus group
ADHERE,
Peacock,
2008
18480204
(149)
To determine the
clinical and renal
outcomes associated
with lower vs higher IV
loop diuretic dose in
pts hospitalized with
acute decompensated
Registry 82,540 Pts in the
ADHERE registry
who received IV
diuretics during a
hospitalization for
acute
decompensated
Pts receiving vasoactive drugs or
dialysis. Those who received
multiple types of diuretics. Pts with
SCr values >6 mg/dL or
hospitalizations with LOS <4 h
were excluded from the analysis of
change in SCr and dialysis
Increase from baseline to
last available SCr > 0.5
mg/dL;
decrease in GFR >10
mL/min from baseline to
discharge; initiation of
dialysis during
Inhospital
mortality, ICU
admission, ICU
LOS >3 d, and
hospital LOS >4 d
Both before and after risk and
propensity adjustments, an increase in
SCr >0.5 mg/dL occurred less
frequently in LDD admissions than in
HDD admissions (both p<0.0001). The
prevalence of a >10 mL/min decrease in
GFR from baseline to discharge was
ADHERE registry
data were
retrospective and
observational so
should be
regarded as
hypothesis
Among pts in
the ADHERE
registry, After
covariate and
propensity
adjustments,
the inhospital

© American College of Cardiology Foundation and American Heart Association, Inc.        64 
 
HF. This study
analyzed data from the
ADHERE registry to
look at the impact of
diuretic dosing. 62,866
pt receiving <160 mg
and 19,674 pts ≥160
mg of furosemide were
analyzed.
HF. initiation. Pt with SCr values >6
mg/dL, GFR values >200 mL/min,
or hospitalizations with LOS <24 h
were excluded from the analysis of
change in GFR.
hospitalization. significantly lower in LDD vs HDD
admissions (p <0.0001). Significant
differences between cohorts present
after risk and propensity adjustments.
LDD treatment was associated with
lower prevalence of prolonged ICU LOS
(nonsignificant differences).
After covariate and propensity
adjustments: in-hospital mortality risk of
LDD was significantly lower compared
to HDD. AUC for adjusted model was
0.78.
Unadjusted mortality OR 0.875; 95% CI:
0.787–0.973; p =0.01.
After adjustment for covariates known to
be associated with mortality – age,
BUN, SBP, DBP, sodium, creatinine,
heart rate and dyspnea at rest –
adjusted OR was 0.888: 95% CI: 0.795–
0.993; p =0.0364
generating.
Clinical reasons
for initiation of IV
diuretics was not
collected and
therefore not
considered in
analysis.
mortality risk of
pts who
received LDD
was
significantly
lower
compared to
those receiving
HDD.
Cohort study
high vs. low
dose
(Brigham and
Women's)
Mielniczuk,
2008
18514930
(150)
This study was a
prospective
observational analysis
of pts in an advanced
HF clinic stratified at
baseline by diuretic
dose (low dose ≤80
mg, high dose >80 mg
furosemide equivalent)
to evaluate the effect
of high/low (or no)
diuretic doses on
outcomes.
Cohort 183 Eligible pts had to
have a primary
diagnosis of
chronic HF and be
followed by a
specialist in a
tertiary care HF
clinic. Pts with
either preserved or
reduced systolic
function were
included
Pts were excluded if they required
renal replacement therapy, had a
concurrent noncardiac diagnosis
expected to limit life expectancy to
less than 1 y, or were unable to
participate in repeat clinical
assessments
All pts were followed for 1
y. The primary outcome for
the analysis was time to
first HF event of HF
admission, cardiac
transplant, MCS, or death
Secondary
outcomes included
individual
components of the
HF composite and
WRF, which was
defined as an
increase in SCr
>0.3 mg/dL from
baseline
Compared with pts taking LDD (113 pts
[62%]), pts taking HDD (70 pts[38%])
had more markers of increased
cardiovascular risk (older, ischemic
cardiomyopathy, DM and HTN) and
were more likely to have a history of
recent instability (33% vs 4.4% in low
dose, p< .001). SCr significantly higher
in pts receiving HDD vs. LDD (1.4 ± 0.5
mg/dL vs 1.1 ± 0.5 mg/dL, respectively,
p < .001).
1 y cumulative HF event rates
significantly greater in pts taking HDD
when to low-dose/no diuretics (HF
composite, 29% vs 4.5%, p<.01; HF
hospitalization, 26% vs 4.5%, p< .01;
MCS or transplant, 7.1% vs 2.7%, P =
.02; death, 2.9% vs 0.9%, p= .4; high vs
low dose for all).
Among pts taking HDD, those with a
history of instability had significantly
greater HF event rates during a 1-y
period compared with pts with recent
Smaller study,
observational,
single-center
HDD may be
more of a
marker than a
cause of
instability. A
history of HF
stability during
the past 6 mo
is associated
with an 80%
lower risk of an
HF event
during the next
y,
independently
of baseline
diuretic dose.

© American College of Cardiology Foundation and American Heart Association, Inc.        65 
 
clinical stability (HF composite, 47% vs
18%, p =.013) Independently of diuretic
dose, pts with a history of clinical
stability had an 80% lower risk of
developing an HF event . HDD were a
strong univariate predictor of
subsequent HF events (HR: 3.83, 95%
CI: 1.82-8.54); however, after
adjustment for clinical stability, diuretic
dose no longer remained significant
(HR: 1.53, 95% CI: 0.58-4.03).
PROTECT
pilot, Cotter,
2008
18926433
(151)
Pilot study was
designed to identify an
efficacious dose while
refining inclusion
criteria and endpoints
RCT 301 Hospitalized for
acute HF with an
estimated CrCl of
20-80 mL/min and
elevated natriuretic
peptide levels
were enrolled
within 24 h of
presentation
SBP <95 or >160 mm Hg; fever
>38°C; acute contrast-induced
nephropathy; resistant
hypokalemia; ongoing or planned
IV therapy with positive inotropic
agents, vasopressors, vasodilators
with the exception of IV nitrates, or
mechanical support (intra-aortic
balloon pump, endotracheal
intubation, or ventricular assist
device); severe pulmonary
disease; significant stenotic
valvular disease; previous heart
transplant or admission for cardiac
transplantation; clinical evidence of
ACS <2 wk before screening; and
acute HF caused by significant
arrhythmias; pts at high risk of
seizures
The prespecified primary
analysis for this pilot phase
was a trichotomous
classification of pts as
”success,” “unchanged,” or
”failure” based on their
changes in symptoms and
renal function. This pilot
phase was not powered to
demonstrate statistically
significant changes. The
major objective was to
evaluate the performance
of this novel endpoint and
refine it on the basis of real-
world experience.
Treatment success was
defined as an improvement
in dyspnea (reported by the
pt using a 7-point Likert
scale as moderately or
markedly better compared
with study start) determined
at 24 and 48 h after the
start of study drug (d 2 and
3) or d of discharge if
earlier, as long as the pt did
not meet any of the criteria
for treatment failure.
Treatment failure was
defined as death, early HF
readmission (occurring
Composite of
death or all-cause
readmission within
60 d
Pts treated with rolofylline more likely to
achieve success, as evidenced by
improved dyspnea (52.7% vs 37.2%),
and less likely to experience failure
(manifested by worsening HF, death, or
renal impairment) compared with pts
treated with placebo (16.2% vs 28.2%).
By comparing rolofylline 30 mg with
placebo, the OR estimated from the
proportional odds model was 0.51 (95%
CI: 0.28–0.94). In the prespecified
subgroup of pts with higher natriuretic
peptide levels, pretreatment BNP level
≥500, or NT pro-BNP ≥2000 pg/mL,
most likely representing more severe
acute HF, the OR from the proportional
odds model was 0.59 (95% CI 0.30–
1.17). SCr increased in pts receiving
placebo and remained stable or tended
to decrease in those receiving
rolofylline. On d 14 the absolute
differences between placebo and
rolofylline for change in creatinine
increased with increasing rolofylline
dose, reflecting the lesser increase in
creatinine in rolofylline-treated pt (r = -
0.12, p=.030). Treatment with 30 mg,
the dose selected for the pivotal trials,
was associated with a trend toward
reduced 60-d mortality or readmission
for cardiovascular or renal cause (HR:
0.55; 95% CI: 0.28-1.04).
Limited by the
study size and
number of
treatment groups.
Study was not
powered to
quantitatively
distinguish
between the 3
active doses,
although trends
emerged
suggesting a
dose-related
preservation of
renal function and
increase in
diuresis, as well
as a greater
effect on the
composite
endpoint at the 30
mg dose.
The
preservation of
renal function
associated with
rolofylline, a
selective renal
vasodilator, is
the first
evidence that
an intervention
to prevent
renal
impairment
may positively
affect acute
symptoms and
60-d outcome
in pts with
acute HF;
however,
results were
not confirmed
in the phase III
trial.

© American College of Cardiology Foundation and American Heart Association, Inc.        66 
 
within 7 d of study drug
initiation), worsening HF as
defined daily by the
physician assessment by d
7, or persistent renal
impairment as defined
above.
Unchanged pts were
classified as unchanged if
neither criteria for success
or failure were met.
DIG, Ahmed,
2008
17532064
(152)
The objective of this
propensity-matched
study was to
determine the effect of
diuretics on mortality
and hospitalizations in
HF pts ≥65 y.
Registry 7,788 Pts who were at
≥21 y of age were
eligible for the
main trial if they
had HF, a LVEF
≤45%, were in
normal sinus
rhythm, and did
not meet any of 20
easily determined,
not overly
restrictive
exclusion criteria
Age <21 yrs; baseline EF not
available; MI, cardiac surgery or
PTCA within 4 wk; unstable or
refractory angina <1 month; II-III
AV block without pacemaker; AF or
flutter; cor pulmonale; constrictive
pericarditis; acute myocarditis;
hypertrophic cardiomyopathy;
amyloid cardiomyopathy; complex
CHD; tx with IV inotropic agents;
K+ < 3.2 mmol/L or >5.5 mmol/L;
on heart transplant list; noncardiac
cause of HF; Creatinine >3.0
mg/dL or severe liver disease;
unlikely to comply
All-cause mortality and all-
cause hospitalization during
36.7 mo of median follow-
up
Mortality and
hospitalizations
due to
cardiovascular
causes and HF
All-cause mortality occurred in 173 pts
not receiving diuretics and 208 pts
receiving diuretics respectively during
2,056 and 1,943 person-y of follow-up
(HR:1.36; 95% CI: 1.08-1.71; p=0.009).
All-cause hospitalizations occurred in
413 pts not receiving and 438 pts
receiving diuretics respectively during
1,255 and 1,144 person-y of follow-up
(HR: 1.18; 95% CI: 0.99-1.39; p=0.063).
Diuretic use was associated with
significant increased risk of
cardiovascular mortality (HR:1.50; 95%
CI:1.15-1.96; p=0.003) and HF
hospitalization (HR:1.48; 95% 95% CI:
1.13-1.94; p=0.005).
Beta blockers
were not
approved for HF
during the DIG
trial and data on
beta blocker use
were not
collected
Diuretic use
associated with
increased
mortality
among elderly
in the DIG trial
EVEREST,
Gheorghiade,
2007
17384438
(153)
To evaluate short-term
effects of tolvaptan
when added to
standard therapy in pts
hospitalized with HF
RCT 2,048
(trial A)
and
2,085
(trial B)
Age ≥18 y with a
history of chronic
HF (requiring
treatment for a
minimum of 30 d
before
hospitalization)
who had been
hospitalized
primarily for
worsening CHF
and had a LVEF
≤40% (measured
at any point within
1 y of admission).
Entry required HF
Cardiac surgery within 60 d of
enrollment, cardiac mechanical
support, biventricular pacemaker
placement within the last 60 d,
comorbid conditions with an
expected survival of less than 6
mo, acute MI at the time of
hospitalization, hemodynamically
significant uncorrected primary
cardiac valvular disease, refractory
end-stage HF, hemofiltration or
dialysis, supine systolic arterial
blood pressure of less than 90 mm
Hg, SCr concentration >3.5 mg/dL
(>309.4 μmol/L), serum potassium
concentration > 5.5 mEq/L, and
Composite of changes in
global clinical status based
on a visual analog scale
and body weight at d 7 or
discharge if earlier
Dyspnea (d 1),
global clinical
status (d 7 or
discharge), body
weight (d 1 and 7
or discharge), and
peripheral edema
(d 7 or discharge).
Rank sum analysis of the composite
primary endpoint showed greater
improvement with tolvaptan vs placebo
(trial A, mean [+SD], 1.06 [0.43] vs 0.99
[0.44]; and trial B, 1.07 [0.42] vs 0.97
[0.43]; both trials p<.001). Mean (+SD)
body weight reduction was greater with
tolvaptan on d 1 (trial A, 1.71 [1.80] vs
0.99 [1.83] kg; p<.001; and trial B, 1.82
[2.01] vs 0.95 [1.85] kg; p<.001) and
day 7 or discharge (trial A, 3.35 [3.27]
vs 2.73 [3.34] kg; p<.001; and trial B,
3.77 [3.59] vs 2.79 [3.46] kg; p<.001).
Improvements in global clinical status
were not different between groups.
More pts receiving tolvaptan (684
N/A In pts
hospitalized
with HF, oral
tolvaptan in
addition to
standard
therapy
including
diuretics
improved
many, though
not all, HF
signs and
symptoms,
without serious
AE.

© American College of Cardiology Foundation and American Heart Association, Inc.        67 
 
symptoms at rest
or minimal exertion
and signs of
congestion (≥2 of
the following:
dyspnea, jugular
venous distention,
or peripheral
edema) at time of
randomization.
hgb of less than 9 g/dL [76.7%] and 678 [72.1%] for trial A and
trial B, respectively) vs pts receiving
placebo (646 [70.6%] and 597 [65.3%],
respectively) reported improvement in
dyspnea at d 1 (both trials p<.001).
Edema at d 7 or discharge improved
significantly with tolvaptan in trial B (p
=0.02) but did not reach significance in
trial A (p=0.07). Serious AE frequencies
were similar between groups, without
excess renal failure or hypotension
EVEREST,
Konstam,
2007
17384437
(154)
To investigate the
effects of tolvaptan
initiated in pts
hospitalized with HF
RCT 4,133 Pts age ≥18 y with
reduced LVEF
≤40%, signs of
volume expansion,
NYHA class III/IV
symptoms, and
hospitalization for
exacerbation of
chronic HF no
more than 48 h
earlier were
eligible for the
study
Cardiac surgery within 60 d of
enrollment, cardiac mechanical
support, biventricular pacemaker
placement within the last 60 d,
comorbid conditions with an
expected survival of <6 mo, acute
MI at the time of hospitalization,
hemodynamically significant
uncorrected primary cardiac
valvular disease, refractory end-
stage HF, hemofiltration or dialysis,
supine systolic arterial bp < 90 mm
Hg, SCr >3.5 mg/dL (309 μmol/L),
K+ level greater than 5.5 mEq/L,
and hgb <9 g/dL.
Dual primary endpoints
were all-cause mortality
(superiority and
noninferiority) and
cardiovascular death or
hospitalization for HF
(superiority only)
Composite of
cardiovascular
mortality or
cardiovascular
hospitalization;
incidence of
cardiovascular
mortality; and
incidence of
clinical worsening
of HF (death,
hospitalization for
HF, or
unscheduled visit
for HF). Additional
secondary
endpoints included
changes from
baseline in body
weight at d 1,
serum sodium
level at d 7 or
discharge in pts
with a baseline
serum sodium
<134 mEq/L,
edema score at d
7 or discharge for
those with edema
at baseline, pt-
assessed dyspnea
at d 1 for those
During a median follow-up of 9.9 mo,
537 pts (25.9%) in tolvaptan group and
543 (26.3%) in placebo group died HR
for mortality: 0.98; 95% CI, 0.87-1.11;
p=.68). Kaplan-Meier estimates of
mortality at 1 y were 25.0% in the
tolvaptan group and 26.0% in the
placebo group.
Composite cardiovascular death or
hospitalization for HF: 871 tolvaptan
group (42.0%) and 829 placebo group
(40.2%) HR: 1.04; 95% CI: 0.95-1.14;
p=.55).
Secondary endpoints of CV mortality,
CV death or hospitalization, and
worsening HF were also not different.
Tolvaptan significantly improved
secondary endpoints of d 1 pt-assessed
dyspnea (p<.001), with 74.3% of the
tolvaptan group and 68.0% of the
placebo group demonstrating an
improvement in dyspnea score, as well
as d 1 body weight, and d 7 edema. In
pts with hyponatremia, serum sodium
levels significantly increased. The
KCCQ overall summary score was not
improved at outpt wk 1, but body weight
and serum sodium effects persisted
long after discharge.
N/A Tolvaptan
initiated for
acute
treatment of
pts hospitalized
with HF had no
effect on long-
term mortality
or HF-related
morbidity.

© American College of Cardiology Foundation and American Heart Association, Inc.        68 
 
with dyspnea at
baseline, and
KCCQ overall
summary score at
outpt wk 1.
DIG, Ahmed
(UAB), 2006
16709595
(155)
Non-potassium-
sparing diuretics are
commonly used in HF.
They activate the
neurohormonal
system, and are
potentially harmful.
Yet, the long-term
effects of chronic
diuretic use in HF are
largely unknown. This
study retrospectively
analysed the DIG data
to determine the
effects of diuretics on
HF outcomes. Effects
of diuretics on
mortality and
hospitalization at 40
mo of median follow-
up were assessed
using matched Cox
Registry 2,782 The DIG trial
enrolled 7,788
ambulatory chronic
systolic (LVEF
≤45%; n=6800)
and diastolic
(LVEF >45%;
n=988) HF pts in
normal sinus
rhythm, of whom
6,076 (78%) were
receiving diuretics
Age <21 y; baseline EF
unavailable; MI, cardiac surgery or
PTCA within 4 wk; unstable or
refractory angina <1 mo; II-III AV
block without pacemaker; AF or
flutter; cor pulmonale; constrictive
pericarditis; acute myocarditis;
hypertrophic cardiomyopathy;
amyloid cardiomyopathy; complex
CHD; tx with IV inotropic agents;
K+ < 3.2 mmol/L or > 5.5 mmol/L;
on heart transplant list; noncardiac
cause of HF; Creatinine > 3.0
mg/dL or severe liver disease;
unlikely to comply
All-cause mortality Mortality from
worsening HF, and
hospitalizations
due to all causes
and worsening HF
Propensity scores for diuretic use were
calculated for each of the 7,788 DIG
participants using a non-parsimonious
multivariable logistic regression model,
and were used to match 1,391 (81%)
no-diuretic pts with 1,391 diuretic pts.
Mean survival times for diuretic vs. no-
diuretic pts: 47 (95% CI: 46–48) and 50
(95% CI: 49–51) mo.
All-cause mortality was 21% for no-
diuretic pts and 29% for diuretic pts
(HR: 1.31; 95% CI: 1.11-1.55; p=0.002).
HF hospitalizations occurred in 18% of
no-diuretic pts and 23% of diuretic pts
(HR: 1.37; 95% CI: 1.13-1.65; p=0.001).
Mortality due to HF occurred in 6% of
pts in the no-diuretic group and 9% of
those in the diuretic group (HR: 1.36;
95% CI 0.99–1.87; p=0.056).
Compared with 8% deaths among pts
never receiving diuretics during the first
24 mo of follow-up, 19% of those who
Based on non-
randomized
findings,
retrospective.
Beta-blockers
were not
approved for HF
during the DIG
trial and data on
beta-blocker use
were not
collected
Chronic
diuretic use
was associated
with increased
long-term
mortality and
hospitalizations
in a wide
spectrum of
ambulatory
chronic systolic
and diastolic
HF pts

© American College of Cardiology Foundation and American Heart Association, Inc.        69 
 
regression models always received diuretics during the
same time died from all causes
(multivariable adjusted HR: 1.81; 95%
CI 1.38–2.38; p<0.0001).
DIG,
Domanski,
2006
16762792
(156)
Investigate the
associations between
death, cardiovascular
death, death from
worsening HF, SCD,
and HF hospitalization
among those taking a
PSD, NPSD, or no
diuretic in the DIG trial
Registry 6,797 HF and LVEF
≤45% enrolled in
the DIG trial. The
DIG randomly
assigned 6800 pts
with HF and LVEF
≤45% to digoxin or
placebo in a
double-blinded
controlled trial
Age <21 y; baseline EF not
available; MI, cardiac surgery or
PTCA within 4 wk; unstable or
refractory angina <1 mo; II-III AV
block without pacemaker; AF or
flutter; cor pulmonale; constrictive
pericarditis; acute myocarditis;
hypertrophic cardiomyopathy;
amyloid cardiomyopathy; complex
CHD; tx with IV inotropic agents;
K+ < 3.2 mmol/L or > 5.5 mmol/L;
on heart transplant list; noncardiac
cause of HF; Creatinine > 3.0
mg/dL or severe liver disease;
unlikely to comply
All-cause death,
cardiovascular death, death
from progressive HF, SCD,
and HF hospitalization
N/A For death from HF or SCD, the incident
rates were not significantly different
between the pts taking the PSD only
versus no-diuretic group (p=.06, and
p=.7, respectively); for the other 4
events (hosp for HF, death from CVD,
death from all causes, hosp or death
from HF), the incidence rates were all
significantly lower in the no-diuretic
group than in the PSD-only group
(p≤.01). For all 6
events, the incidence rates for the
NPSD only group were significantly
higher than the PSD-only group (p≤.02).
The incidence rates for the NPSD-only
group and both-diuretic groups were
comparable and not significantly
different with the p- values ranging from
.07 to .6 (date not shown).
After multivariate analysis, the risks of
all 6 endpoints were increased in pts
taking a NPSD, whether or not they
were taking a PSD after adjusting for
known covariates. There was no
significant difference in the risk of any of
these events for pts taking only PSD
and those taking no diuretics.
Compared with not taking diuretic, risk
of death (RR: 1.36, 95% CI: 1.17–1.59,
p<.0001), cardiovascular death (RR:
1.38, 95% CI: 1.17–1.63; p=.0001),
progressive HF death (RR: 1.41, 95%
CI: 1.06–1.89, p= .02), SCD (RR: 1.67,
95% CI 1.23–2.27, p=.001), and HF
hospitalization (RR: 1.68, 95% CI: 1.41–
Post-hoc study
and doses of
diuretics were not
available for
analysis. Also, did
not analyze
effects of
treatment over
time. Beta-
blockers were not
approved for HF
during the DIG
trial and data on
beta blocker use
were not
collected
Among pts in
the DIG trial,
compared with
pts not taking
any diuretic or
taking a PSD,
pts taking non-
PSD had a
higher RR of
death.

© American College of Cardiology Foundation and American Heart Association, Inc.        70 
 
1.99, p< .0001) were increased with
NPSD.
There was no significant difference in
any endpoint for pts taking only PSD
compared to no diuretic. PSD only
subjects were less likely than NPSD
subjects to be hospitalized for HF (RR:
0.71, 95% CI: 0.52–0.96, p=.02).
Cohort study
low vs. high
dose (Cedars
Sinai/ UCLA),
Eshaghian,
2006
16765130
(157)
This study sought to
determine the dose-
dependent relation
between loop diuretic
use and HF prognosis
Cohort 1,354 Study population
consisted of 1,354
consecutive pts
with advanced
systolic HF
referred to a single
university medical
center for HF
management
and/or transplant
evaluation from
1985 to 2004
Pts with LVEF >40%, those with
HF due to valvular disease, and
those aged <18 y were excluded
from the analysis
All-cause mortality The composite
endpoint of death
or urgent
transplant (status
IA) was analyzed
as a secondary
endpoint
Pts with HF in the highest diuretic dose
quartile were found to have significantly
impaired survival compared with pts in
the lowest quartile.
Survival estimates at 1 y were 91%,
88%, 80%, and 69% for quartiles 1, 2,
3, and 4, respectively (p <0.0001).
Survival estimates at 2 y were 83%,
81%, 68%, and 53%, respectively (p
<0.0001). Death from any cause: HR:
3.4, 95% CI: 2.4-4.7
death and urgent transplantation: HR
2.7, 95% CI 2.0-3.5
death from progressive HF: HR: 3.8;
95% CI 2.1-6.8
sudden death: HR: 3.6; 95% CI: 1.9-6.8
Univariate analysis- compared with the
lowest quartile, increasing loop diuretic
dose quartiles were associated with a
progressive increase in mortality
(second quartile, HR: 1.2; 95% CI: 0.8-
1.7; third quartile, HR: 2.1, 95% CI 1.5-
2.9; and fourth quartile, HR: 3.4; 95% CI
2.4-4.7). Diuretic dose quartiles were
associated with increased mortality
independent of other covariates. After
adjustment the highest diuretic quartile
remained a significant predictor of
increased mortality at 1 y (HR: 4.2; 95%
CI: 1.5-11.3) and at 2 y (HR: 4.0; 95%
CI 1.9-8.4)

Possible selection
bias. Diuretic
dose was
examined at only
a single point in
time, without
considering
chnages in doses
over time.
Baseline
characteristics
and other HF
treatments
different among
the diuretic dose
quartiles. With
adjustment for
multiple
covariates, larger
loop diuretic
doses could still
be a surrogate for
other measured
and unmeasured
variables that
reflect more
severe HF.
Serum potassium
and magnesium
level information
was unavailable.
Propensity
matching was not
performed. So the
relation between
This study
suggests that
in pts with
advanced
systolic HF, the
use of higher
doses of loop
diuretics is
associated with
significantly
increased all-
cause
mortality.
Although it may
appear obvious
that pts with
HF requiring
higher loop
diuretic doses
to prevent fluid
retention and
control
symptoms
might be sicker
than pts
receiving lower
doses, the
powerful and
independent
association
with mortality
warrants
further
consideration.

© American College of Cardiology Foundation and American Heart Association, Inc.        71 
 
loop diuretic dose
and increased
mortality is
causative.
Cochrane
review, 2005
16034890
(158)
To compare the
effects and adverse
effects of continuous
IV infusion of loop
diuretics with those of
bolus IV administration
among pts with HF
class III-IV
Meta-
analysis
254 RCTs comparing
the efficacy of
continuous IV
infusion versus
bolus IV
administration of
loop diuretics in HF
in a total of 8
RCTs.
N/A (7 studies) urine output,
cc/24 h;
Electrolyte disturbances
(hypokalemia,
hypomagnesemia); adverse
effects (tinnitus and hearing
loss); (single
study) duration of hospital
stay and cardiac
mortality; (2 studies) all
cause mortality
N/A Urine output: the output (as measured
in cc/24 h) was noted to be greater in
pts given continuous infusion with a
WMD of 271 cc/24 h (95%CI: 93.1-449;
p<0.01). Electrolyte
disturbances were not significantly
different in the two
treatment groups : RR 1.47; 95%CI:
0.52-4.15; p=0.5.
Less adverse effects (tinnitus and
hearing loss) were noted with
continuous infusion: RR 0.06; 95%CI:
0.01- 0.44; p=0.005.
Duration of hospital stay was
significantly shortened by 3.1 d with
continuous infusion WMD -3.1; 95%CI -
4.06 to -2.20; p<0.0001; while cardiac
mortality was significantly different in
the two treatment groups, RR: 0.47;
95% CI: 0.33 to 0.69; p<0.0001.
All-cause mortality was significantly
different in the two treatment groups,
RR: 0.52; 95% CI: 0.38- 0.71; p<0.0001.
Available data
were insufficient
to confidently
assess the merits
of the 2 methods
of giving IV
diuretics. The
existing data did
not allow
definitive
recommendations
for clinical
practice
Based on small
and relatively
heterogeneous
studies, this
review showed
greater diuresis
and a better
safety profile
when loop
diuretics were
given as
continuous
infusion.
SOLVD,
Domanski,
2003
12932605
(159)
Study sought to
determine whether
NPSDs in the absence
of a PSD may result in
progressive HF.
Registry 6,797 Symptomatic and
asymptomatic pts
with a LVEF
fraction <0.36 were
randomly assigned
to double-blinded
treatment with
enalapril or
placebo.
Only drug class was ascertained;
specific medications were not
recorded.
Rates of hospitalization for
HF, death from
cardiovascular disease,
death from all causes, and
either hospitalization or
death due to worsening HF
N/A The risk of hospitalization from
worsening HF in those taking a PSD
relative to those taking only a non-PSD
was 0.74; 95% CI 0.55-0.99; p= 0.047.
The RR for cardiovascular death was
0.74; 95% CI 0.59-0.93; p=0.011), for
death from all causes 0.73; 95% CI:
0.59-0.90; p=0.004), and for
hospitalization for, or death from, HF
0.75; 95% CI: 0.58-0.97; p=0.030).
Compared with pts not taking any
diuretic, the risk of hospitalization or
death due to worsening HF in pts taking
This study is
retrospective and,
therefore, not
definitive proof
that NPSDs
cause
progressive HF.
Because the
diuretic dosage
was not available,
we cannot draw
conclusions about
a dose-response
This study
shows that in
pts with
moderate or
severe LV
dysfunction,
the use of a
PSD is
associated with
a reduced risk
of death or
hospitalization
due to

© American College of Cardiology Foundation and American Heart Association, Inc.        72 
 
non-PSDs alone was significantly
increased (RR:1.31: 95% CI: 1.09-1.57;
p=0.0004); this was not observed in pts
taking PSDs with or without a NPSD
(RR: 0.99; 95% CI: 0.76- 1.30; p=0.95).
relationship. Also,
baseline data
were used, and
diuretic treatment
status may have
changed over
time
progressive
HF, relative to
pts taking only
a non-PSD.
PRAISE,
Neuberg,
2002
12094185
(152)
The prognostic
importance of diuretic
resistance (as
evidenced by a high-
dose requirement) was
retrospectively
evaluated in pts with
advanced HF who
were enrolled in the
PRAISE.
Registry 1,153 LVEF <30% and
NYHA functional
class IIIb/IV HF
despite mandatory
background
treatment with
digoxin, diuretics,
and ACE inhibitors.
Pts were excluded if their serum
potassium level was <3.5 or >5.5
mmol/L and if their SCr level was
>3.0 mg/dL (270 >mol/L), and/or if
they met other standard exclusion
criteria
Death or cardiac
transplantation
N/A HDD were independently associated
with mortality, sudden death, and pump
failure death (aHR: 1.37 (p=.004), aHR:
1.39 (p=.042), and aHR: 1.51 (p=.034),
respectively.
Use of metolazone was an independent
predictor of total mortality (aHR: 1.37;
p=.016) but not of cause-specific
mortality. In quartiles of loop diuretic
dose, total mortality increased
progressively without a clear risk
threshold, more than doubling from the
lowest-dose group to the highest-dose
group (p=.001). Unadjusted mortality
rates were 20.7% (n=152), 30.7%
(n=313), 36.8% (n=304), and 44.8%
(n=84) for increasing dose of
furosemide (40 mg, 40-80 mg, 80-120
mg, and 120 mg daily) or bumetanide
(1 mg, 1-2 mg, 2-3 mg, and 3 mg daily),
respectively. By proportional hazard
regression, high diuretic dose was an
independent predictor of total mortality
(aHR: 1.37; p=0.004), sudden death (a
HR: 1.39, p=0.042), and pump failure
death (aHR: 1.51, p=0.034).
Retrospectiveolde
r study as pts
enrolled in
PRAISE were not
on beta blockers.
Found that
high doses of
loop diuretic
(>80mg of
furosemide or
>2mg of
buetanide
daily) were
independently
associated with
mortality in pts
with advanced
HF. When
degree of
congestion was
considered
together with
its treatment,
the associated
risks were
additive,
suggesting that
diuretic
resistance
should be
considered an
indicatior of
prognosis in
chronic HF.
However,
retrospective
analysis does
not establish
harm, nor rule
out a long-term

© American College of Cardiology Foundation and American Heart Association, Inc.        73 
 
benefit of
diuretic
therapy.
Ultrafiltration
UNLOAD
substudy
(Maryland),
Rogers,
2008
18226766
(160)

This study was
designed to evaluate
the consequences of
UF and standard IV
diuretic (furosemide)
therapy on GFR and
renal plasma flow in pts
with acute
decompensated HF.
RCT 19 Pts hospitalized for acute
decompensated HF with
an EF <40% and ≥2
signs of hypervolemia
based on at least 2 of the
following findings: ≥2+
pitting edema of the
lower extremities, jugular
venous pressure ≥10 cm
H
2
O, pulmonary edema
or pleural effusion on
chest radiograph
consistent with
decompensated
congestive HF, ascites,
paroxysmal nocturnal
dyspnea, or ≥2 pillow
orthopnea.
Pts with ACS, SCr >3.0
mg/dL, SBP ≤ 90 mm Hg,
hematocrit >45%, inability to
obtain venous access, or
clinical instability likely to
require IV nitroprusside or IV
pressors, history of
administration of IV diuretics
and/or vasoactive drugs
during the present
hospitalization (except for a
single dose of IV diuretics
administered in the ED
before hospitalization), use
of iodinated radiocontrast
material, contraindication to
the use of anticoagulation,
systemic infection, or
hemodialysis were excluded
from the substudy.
Urine output, GFR
(as measured by
iothalamate), and
renal plasma flow (as
measured by para-
aminohippurate)
were assessed
before fluid removal
and after 48 h.
N/A 19 pts (59 +/- 16 y, 68% were male)
were randomized to receive UF (n= 9)
or IV diuretics (n= 10). The change in
GFR (-3.4 +/- 7.7 mL/min vs -3.6 +/-
11.5 mL/min; p= .966), renal plasma
flow (26.6 +/- 62.7 mL/min vs 16.1 +/-
42.0 mL/min; p= .669), and filtration
fraction (-6.9 +/- 13.6 mL/min vs -3.9 +/-
13.6 mL/min; p= .644) after treatment
were not significantly different between
the UF and furosemide treatment
groups. No significant
difference in net 48-h fluid removal
between the groups (-3211 +/- 2345 mL
for UF and -2725 +/- 2330 mL for
furosemide, p= .682). UF removed 3666
+/- 2402 mL.
Urine output during 48 h was
significantly greater in the furosemide
group (5786 +/- 2587 mL) compared
with the UF group (2286 +/- 915 mL, p<
.001).
Small single
center study.
Pts receiving
UF tended to
have worse
GFR at
baseline.
Renal
hemodynamic
outcomes
were
measured
during acute
fluid removal
(48 h).
Unknown as
to when
changes in
GFR or RPF
occur. The
present study
does not
assess any
chronic
effects of UF
or diuresis.
During a 48-h
period, UF did not
cause any
significant
differences in renal
hemodynamics
compared with the
standard treatment
of IV diuretics
UNLOAD,
MR
Costanzo,
2007
17291932
(161)
To compare the safety
and efficacy of
venovenous UF and
standard IV diruetic
therapy for
hypervolemic HF pts
RCT 200 Pts hospitalized with
primary diagnosis of
acute decompensated
congestive HF; evidence
of fluid overload as
indicated by: pitting
edema (2+) of lower
extremities; jugular
venous distension;
pulmonary edema or
pleural effusion; ascites;
ACS; creatinine >3.0; SBP
<90 mmHg; hematocrit
>45%; prior administration of
IV vasoactive drugs in the
ED; clinical instability
requiring pressors during
hospitalization; recent use of
iodinated contrast material;
severe concomitant disease
expected to prolong
hospitalization; sepsis; on or
Total weight loss
during first 48 h;
change in dyspnea
score during first 48
h.
Change in global
assessment; change in
QoL (living with HF);
changes in BNP;
changes in 6 min walk
test; total fluid loss during
first 48 h; changes in
BUN and creatinine;
changes in renin and
aldosterone; rate of
hospitalizations and
Primary efficacy endpoints:
Weight loss was greater in the UF than
in the standard-care group (5.0 ± 3.1 kg
vs. 3.1 ± 3.5 kg; p=0.0001)
Dyspnea scores were similarly
improved in the UF and standard-care
group at both 8 and 48 h.
Primary safety endpoints:
Changes in SCr were similar in the 2
groups throughout the study and % of
pts with rise in SCr >0.3 mg/dL were
Population
not
representative
of HF pts
(better renal
function, and
excluded pts
with
hypotention);
industry
sponsored;
While weight loss
was greater and
rehospitalization at
90 d was lower in
the UF arm, data
not available on
long-term effects
on renal function
or resource
utilization. The pts
in trial represented

© American College of Cardiology Foundation and American Heart Association, Inc.        74 
 
paroxysmal nocturnal
dyspnea or 2-pillow
orthopnea

requires renal dialysis;
history of cardiac transplant;
heparin allergy.
unscheduled clinic and
ED visits in the wk after
inpt treatment
similar in both groups at 24 h, 48 h and
at discharge
Serum potassium <3.5 mEq/l occurred
in 1% of the UF group and 12% of
diuretics group (p=0.018)
small trial;
usual care
group not
very
aggressively
treated
hemodynamically
stable/congested
HF pts that
respond very well
to diuretics and
have better
outcomes vs. HF
population in
general.
Case-series
(Mayo
clinic),
Liang, 2006
17174232
(162)
Present data on UF
from a series of pts
treated at the Mayo
clinic who were
generally sicker and
had failed at least 1 IV
treatment
Case-
series
11 HF pts admitted to Mayo
clinic who have failed at
least 1 IV diuresis
treatment
Contraindication to UF Change in creatinine;
fluid loss;
complications from
UF
N/A 5 pts had significant rise in creatinine,
5 required dialysis, overall 6-mo
mortality 55%, bleeding and
complications related to positional flow
were common.
Small study;
single
institution; pts
with much
worse
prognosis vs
general HF
population
In high risk
populations, (mean
GFR of 38 mL/min)
UF may not be the
most appropriate
choice.
RAPID-CHF,
Bart, 2005
16325039
(163)
Pilot study which
compared a single 8-h
UF intervention to usual
care in pts admitted
with decompensated
HF
RCT 40 Hospitalized with primary
diagnosis of HF; at least
2+ edema of the lower
extremities and at least
either JVP >10,
pulmonary edema or
pleural effusion on CXR,
pulmonary rales,
pulmonary wedge or
LVEDP >20, ascites, or
pre-sacral edema
Severe stenotic valvular
disease; ACS; SBP <90;
hematocrit >40%
5. poor peripheral venous
access; hemodynamic
instability; use of iodinated
radiocontrast within 72 h of
consent or anticipated use;
severe concomitant disease
24-h weight loss Total volume removal at
24 and 48 h; global HF
and dyspnea
assessments; serum
electrolytes; and length
of hospital stay
No difference in 24-h weight loss
(p=0.240), significantly more fluid
removal with UF (4,650 mL in UF group
vs. 2,838 mL in usual care group,
(p=0.001) and improved dyspnea
scores (p=0.039) and no change in
creatinine. Trend toward greater weight
loss at 24 h in the UF group
Small study,
pilot
UF group had
more fluid
removed, with no
significant change
in creatinine,
however no
difference in 24 h
weight loss.
EUPHORIA,
Costanzo,
2005
16325040
(164)

Compared UF to
historical controls in
order to determine if
use of UF before any IV
diuretics in pts with
decompensated HF and
modest renal
dysfunction
reestablishes euvolemia
and permits hospital
discharge in ≤3 d,
without hypotension, a
≥25% increase in SCr.
or other AEs.
Observat
ional
study
20 Volume overload;
modest degree of renal
dysfunction or diuretic
resistance (chronic daily
PO furosemide ≥80 mg,
or torsemide ≥ 40mg, or
bumetamide ≥ 2mg and
SCr ≥1.5 mg/dl),
relatively high diuretic
requirement at baseline;
<12 h since
hospitalization, given no
vasoactive drugs and <1
dose IV diuretic
Hematocrit >40%;. end-
stage renal disease requiring
dialysis; Hypercoagulability;
SBP <85 mm Hg;
Requirement for IV
inotropes; Participation in
another research study or
previously in this trial
Weight loss; hospital
length of stay
Increase in creatinine
>25%, hypotension; BNP
levels
An average of 8,367 ± 4,232 mL were
removed with 2.6 ± 1.2, 8 h UF courses.
Of the 19 pts 12 (68%) were discharged
in ≤3 d
Small
observational
study; Single-
center series
Concluded that UF
decreases length
of stay and
readmissions.
compared the
treatment period
with the pre-
treatment period,
rather than with a
randomized control
cohort.

© American College of Cardiology Foundation and American Heart Association, Inc.        75 
 
Agostoni,
1994
8154506
(165)
Investigated the
mechanisms involved in
the regulation of salt
and water metabolism
in pt with HF.
Extracorporeal UF was
utilized as a
nonpharmacologic
method for withdrawal
of body fluid.
RCT 16 Treated with a
combination of
digoxin, oral furosemide,
and ACE inhibitor
(captopril
or enalapril) for chronic;
sinus rhythm; NYHA II-III
Pts with acute MI (<1 y),
angina pectoris, primary
valvular disease, intermittent
claudication, fibrotic or
primary vascular lung
diseases, sinus or
atrioventricular node
dysfunction, effort-induced
severe ventricular
arrhythmias or an artificial
pacemaker
Scores of lung water;
exercise test
parameters; plasma
renin, aldosterone
and norepinephrine
3 mo after UF or IV diuretic, the
hemodynamic variables examined at
rest had returned to the control values
in the diuretic group, but not the UF
group. In the UF group, right atrial
pressure, pulmonary artery pressure
and wedge pressure were still as
reduced as they had been 24 h after
UF. (p<0.01, only figures displayed).
Small older
study
After UF, improved
functional capacity
continued for 3 mo
after the procedure
Pepi, 1993
8038023
(166)
To investigate the
pathophysiological
(cardiac function and
physical performance)
significance of clinically
silent interstitial lung
water accumulation in
pts with moderate HF;
to use isolated UF as a
means of extravascular
fluid reabsorption
RCT 24 NYHA functional class II-
III HF and clinically silent
by radiologically evident
increased lung water;
sinus rhythm and EF
<35%
Severe tricuspid or mitral
regurgitation; pleural,
pericardial or abdominal
effusion
LVSF (from
ultrasonography);
Doppler evaluation of
mitral, tricuspid, and
aortic flow and echo-
Doppler
determination of
cardiac output;
radiological score of
extravascular lung
water; R/LV filling
pressures; oxygen
consumption at peak
exercise and
exercise tolerance
time in
cardiopulmonary
tests.
UF decreased radiological score of
extravascular lung water (from 15(1)-
9(1)) and of right (from 7.1 (2.3)-2.3
(1.7) mm Hg) and left (from 17.6 (8.8)-
9.5 (6.4) mm Hg) ventricular filling
pressures; an increase in oxygen
consumption at peak exercise (from
15.8 (3.3) to 17.6 (2) mL/min/kg) and of
tolerance time (from 444 (138) to 508
(134) s); decrease in atrial and
ventricular dimensions; no changes in
the systolic function of the left ventricle;
a reduction of the early to late filling
ratio in both ventricles (mitral valve from
2 (2) to 1.1 (1.1)); (tricuspid valve from
1.3 (1.3) to 0.69 (0.18)) and an increase
in the deceleration time of mitral and
tricuspid flow, reflecting a redistribution
of filling to late diastole. Variations in the
ventricular filling pattern, lung water
content, and functional performance
persisted for 3mo in all cases. None of
these changes was detected in the
control group.
Small older
study; single
institution
Pathophysiological
study involving UF
and hemodynamic
outcomes.
Agostoni,
1993
8426008
(167)
The aim of this study
was to evaluate
whether UF is beneficial
in pts with moderate
congestive HF.
RCT 36 NYHA functional classes
II and III; stable clinical
condition; receiving drug
treatment (stable over
last 6 mo) optimized to
prevent development of
edema and maintain a
stable body weight (+/- 1
Pts with acute MI (<1 y),
angina pectoris, primary
valvular disease, intermittent
claudication, fibrotic or
primary vascular lung
diseases, sinus or
atrioventricular node
dysfunction, effort-induced
Functional
performance was
assessed with
cardiopulmonary
exercise tests
Plasma norepinephrine
levels
Significant reductions in UF group right
atrial pressure (from 8 ± 1 - 3.4 ± 0.7
mm Hg, pulmonary wedge pressure
(from 18 ± 2.5 - 10 ± 1.9 mm Hg) and
cardiac index (from 2.8 ± 0.2 -2.3± 0.2
L/min). During the follow-up period,
lung function improved, extravascular
lung water (X-ray score) decreased and
Small older
study
Pathophysiological
study involving UF
and hemodynamic
outcomes.

© American College of Cardiology Foundation and American Heart Association, Inc.        76 
 
kg in last 6 mo);
therapeutic digoxin level
(if on digoxin)
severe ventricular
arrhythmias or an artificial
pacemaker
peak oxygen consumption (mL/min per
kg) increased from 15.5 ± 1 (d -1) to
17.6 ± 0.9 (d 4), to 17.8 ±0.9 (d 30), to
18.9 ±1 (d 90) and to 19.1 ±1 (d 180).
Oxygen consumption at anaerobic
threshold (mL/min per kg) also
increased from 11.6 ±0.8 (d -1) to 13
±0.7 (d 4), to 13.7 ± 0.5 (d 30), to 15.5
± 0.8 (d 90) and to 15.2 ± 0.8 (d 180).
These changes were associated with
increased ventilation, tidal volume and
dead space/tidal volume ratio at peak
exercise. Improvement in exercise
performance was associated with a
decrease in norepinephrine at rest, a
downward shift of norepinephrine
kinetics at submaximal exercise and an
increase in norepinephrine during
orthostatic tilt. None of these changes
were recorded in group B.
ACS indicates acute coronary syndrome; ADHERE, Acute Decompensated Heart Failure National Registry; AE, adverse event; AUC, area under the curve; BNP, B-Type natriuretic peptide; BUN, blood urea nitrogen; CHD, chronic heart disease; CHF, congestive
heart failure; CrCl, creatinine clearance; CV, cardiovascular; DAD-HF, Dopamine in Acute Decompensated Heart Failure; DBP, diastolic blood pressure; DIG, Digitalis Investigation Group; DM, diabetes mellitus; ED, emergency department; eGFR, glomerular
filtration rate; EUPHORIA, Early Ultrafiltration Therapy in Patients with Decompensated Heart Failure and Observed Resistance to Intervention with Diuretic Agents; EVEREST, Efficacy of Vasopressin Antagonism in hEart failuRE: Outcome Study With Tolvaptan;
HDD, high dose diuretics; HF, heart failure; Hgb, hemoglobin; HTN, hypertension; ICU, intensive care unit; IV, intravenous; KCCQ, Kansas City Cardiomyopathy Questionnaire; LDD, low dose diuretics; LDFD, low-dose furosemide; LOS, length of stay; LVEF, left
ventricular ejection fraction; MCS, mechanical cardiac support; N/A, not applicable; NPSD, nonpotassium-sparing diuretics; NT-pBNP, N-terminal pro-B-Type natriuretic peptide; PO, per oral; PRAISE, Prospective Randomized Amlodipine Survival Evaluation;
PROTECT, Placebo-controlled Randomized study of the selective A(1) adenosine receptor antagonist rolofylline for patients hospitalized with acute heart failure and volume Overload to assess Treatment Effect on Congestion and renal function; PTCA,
percutaneous transluminal coronary angioplasty; PSD, potassium-sparing diuretics; pts, patients; RAPID-HF, Relief for Acutely Fluid-Overloaded Patients With Decompensated Congestive Heart Failure; RCT, randomized control trial; SBP, systolic blood pressure;
SCD, sudden cardiac death; SCr, serum creatinine; SOLVD, Studies of left ventricular dysfunction; Tx, treatment; UF, ultrafiltration; UNLOAD, Ultrafiltration Versus Intravenous Diuretics for Patients Hospitalized for Acute Decompensated Heart Failure; VAS, visual
analog scale, WMD, weighted mean difference; and WRF, worsening renal function.
 
Data Supplement 18. ACE Inhibitors (Section 7.3.2.2)
Study Name,
Author, Year
Aim of Study Study Type Background
Therapy
Study Size Etiology Patient Population Endpoints Mortality Trial
Duration
(Years)
Absolute
Benefit
P Values & 95% CI:
Pre-trial
standard
treatment.
N (Total)
n (Experimental)
n (Control)
Ischemic/
Non-Ischemic
Inclusion
Criteria
Exclusion
Criteria
Primary
Endpoint
Secondary
Endpoint
1st Year
Mortality


© American College of Cardiology Foundation and American Heart Association, Inc.        77 
 
CONSENSUS
1987
2883575 (168)

To Evaluate
influence of
enalapril on
prognosis of
NYHA class lV
HF
RCT Diuretics
(spironolactone
53%, mean dose
80mg), digitalis
(93%), other
vasodilators,
except ACEI (ie
nitrates 46%)
253; 127;126

CAD 73% Severe
HF/symptoms at
rest/NYHA class
lV;
Increased heart
size >600 ml;
BP: 120/75;
HR: 80; AF
50%
APE;
hemodynamicall
y import
aortic/MV
stenosis;
MI w/in prior 2
mo
Unstable
angina; planned
cardiac surgery;
right HF b/c of
pulm disease;
Cr>300 umol/L
Mortality Change in NYHA-
FC, LV size, Cr
level
52% placebo
group and
36% enalapril
group (6 mo
mortality:
26% in
enalpril group
and 44% in
placebo
group)
0.51 y N/A Crude mortality at end of
6 mo (primary endpoint),
26% in enalapril group
and 44% in placebo
group—40% reduction (p
=0.002).
Mortality was reduced by
31% at 1 y (p=0.001)
10 y FU of
CONSENSUS
1999
10099910
(169)
Report on the
survival at the
10-y follow up
of the pts
randomized in
CONSENSUS.
(1st study to
show
prognostic
improvement
by an ACEI.
Pts in NYHA
class IV HF
treated with
enalapril or
placebo. After
study
completion all
pts were
offered open-
label enalapril
therapy).
10-y open-
label follow-up
study (via
completion of a
questionnaire)
on the survival
status of pts in
CONSENSUS
-a RCT.
All pts were
offered open-
label enalapril
therapy
315; 77; 58 253 randomized
pts included in
analysis of time
from
randomization to
death;
Survivors (135)
of the double-
blind period
included in
analysis of the
time from end of
double-blind
period to death;
Severe, NYHA
lV
Mortality 10 y 5 pts, all in the enalapril
group, were long-term
survivors (p=0.004).
Averaged over the trial
(double-blind plus open-
label extension) risk
reduction was 30%
(p=0.008), 95% CI: 11%
- 46%.
At end of double-blind
study period, mortality
considerably higher
among pts not receiving
open ACEI therapy

© American College of Cardiology Foundation and American Heart Association, Inc.        78 
 
SOLVD 1991
2057034 (170)
Study the effect
of enalapril on
mortality and
hospitalization
in pts with
chronic HF and
EF <35%
RCT Diuretics +
Digoxin
2569; 1285; 1284 Ischemic heart
disease 72%
LVEF <35%;
Mild to severe
(11% class
l/<2% class lV);
LVEF 25%; BP:
125/77; HR:
80; AF: 8-12%
Age >80 y;
Unstable
angina; MI w/in
past mo; Cr>2.0
mg/dL

Mortality Hospitalizations;
Incidence of MI;
Mortality by
specific causes;
Combined
mortality and
morbidity from
both
SOLVD+/SOLVD-
15.70% 3.45 y Treating
1000
SOLVD+
pts with
enalapril
for ~3 y
would
save ~50
premature
deaths
and 350
hospitaliz
ations.
Reduced mortality by
16%; (95% CI, 5-26%;
p=0.0036)
SOLVD 1992
1463530 (90)

Study effect of
ACEIs on total
mortality and
mortality from
CV causes, the
development of
HF, and
hospitalization
for HF in pts
with EF <35%
RCT No drug
treatment for HF
4228; 2111; 2117 History of
ischemic heart
disease 85%
EF <35%;
Asymptomatic;
NYHA class I
(67%) + ll;
EF: 28%; BP:
126/78; HR:
75; AF: 4%
As per SOLVD+ Mortality;
Combined
mortality and
the
incidence of
HF and rate
of
hospitalizatio
n for HF
Incidence of HF
and rate of
hospitalization for
HF
3.12 y Reduced mortality:
p=0.30; 95% CI: -8-21%
SOLVD F/U
2003
12788569 (91)
12-y FU of
SOLVD to
establish if the
mortality
reduction with
enalapril
among pts with
HF was
sustained, and
whether a
subsequent
reduction in
mortality would
emerge among
those with
asymptomatic
ventricular
dysfunction.
12 y f/u of
RCTs
[SOLVD+ and
SOLVD-]
N/A 6784; 3391; 3393 N/A Participation in
SOLVD+ and
SOLVD-
Asymptomatic to
severe;
NYHA l-lV
N/A Mortality N/A N/A N/A Enalapril
extended
median
survival
by 9.4 mo
in the
combined
trials
(95% CI:
2.8–16.5,
p=0.004).
In the prevention trial,
50.9% of the enalapril
group had died c/w
56.4% of the placebo
group (p=0.001).
In the treatment trial,
79.8% of the enalapril
group had died c/w
80.8% of the placebo
group (p=0.01).
Combined prevention
and treatment trials: HR
for death was 0.90 for
the enalapril group c/w
placebo group (95% CI:
0.84–0.95, p=0.0003).


© American College of Cardiology Foundation and American Heart Association, Inc.        79 
 
ATLAS
1999
10587334
(171)

To compare
the efficacy
and safety of
low and high
doses of ACEI
on the risk of
death and
hospitalization
in chronic HF.
than the large
doses that
have been
shown to
reduce
morbidity and
mortality in pts
with HF.
AIM:
Investigate if
low doses and
high doses of
ACEIs have
similar benefits.
RCT N/A 3164;
1596 to the low-
dose strategy and
1568 to the high-
dose strategy.

CAD 65% LVEF <=30%;
NYHA class II,
III, or IV, despite
treatment with
diuretics for ≥2
mo
(Treatment for
HF in ED or
hospital within 6
mo required for
pts in class II);
Prior use of
digitalis, ACEIs,
or vasodilators
allowed but not
mandated;
NYHA ll-lV
(mainly class ll);
LVEF 23%;
SBP 126 mmHg;
HR 80; NYHA
class: lll (few ll
and lV)
Acute coronary
ischemic event
or
revascularizatio
n procedure
within 2 mo;
History of
sustained or
symptomatic
ventricular
tachycardia;
Intolerant of
ACEIs;
SCr >2.5 mg/dL
Mortality
from all
causes
Combined risk of
all-cause
mortality and
hospitalization for
any reason;
CV mortality, CV
hospitalizations;
All-cause
mortality
combined with
CV
hospitalizations;
CV mortality
combined with
CV
hospitalizations;
Combined risk of
fatal and nonfatal
MI plus
hospitalization for
unstable angina

5 y High-dose group had 8%
lower risk of all-cause
mortality (p=0.128) and
10% lower risk of CV
mortality (p=0.073) than
low-dose group.
Death or hospitalization
for any reason, high-
dose group had 12%
lower risk than low-dose
group, p=0.002.
Total number of
hospitalizations: high-
dose group 13% fewer
hospitalizations for any
reason (p=0.021), 16%
fewer hospitalizations for
CV reason (p=0.05), and
24% fewer
hospitalizations for HF
(p=0.002).
Post-MI ACEI Use

© American College of Cardiology Foundation and American Heart Association, Inc.        80 
 
SAVE, 1992
1386652 (89)

To test the
hypothesis that
the long-term
administration
of captopril to
survivors of
acute MI who
had baseline
LV dysfunction
but did not
have overt HF
requiring
vasodilator
therapy would
reduce
mortality,
lessen
deterioration in
cardiac
performance,
and improve
clinical
outcome.
RCT Beta-blockers
36%;
Digitalis 26%;
Nitrates 51%
2231; 1115; 1116 Ischemic
100%
Alive 3 d after
MI;
LVEF <40%;
>21 y of age,
but <80;
Killip class I —
60%
(60% of the ps
did not have
even transient
pulmonary
congestion at
baseline/the
time of their
acute MI;
EF 31%;
BP 113/70;
HR 78;
Failure to
undergo
randomization
within 16 d after
the MI;
Relative
contraindication
to the use of an
ACEIs or the
need for such an
agent;
SCr > 2.5 mg/dl
Mortality from
all causes
Mortality from
CV causes;
Mortality
combined with a
decrease in the
EF of at least 9
units in surviving
pts;
CV morbidity
(development of
severe CHF or
the recurrence
of MI);
Combination of
CV mortality and
morbidity;
2 endpoints of
severe HF
(treatment
failure): 1st,
development of
overt HF
necessitating
treatment with
ACEI and 2nd,
hospitalization to
treat CHD.
3.5 y Mortality from all causes
was significantly reduced
in the captopril group
(228 deaths, or 20%) as
c/w the placebo group
(275 deaths, or 25%); the
RR:19% (95% CI, 3-
32%; p= 0.019).
RR:21% (95% CI, 5 -
35%; p = 0.014) for
death from CV causes,
37% (95% CI, 20-50%;
p<0.001) for the
development of severe
HF, 22% (95% CI, 4-
37%; p= 0.019) for CHF
requiring hospitalization,
and 25% (95% CI, 5-
40%; p= 0.015) for
recurrent MI.

© American College of Cardiology Foundation and American Heart Association, Inc.        81 
 
AIRE 1993
8104270 (172)

Investigated
the effect of
therapy with
ACEI ramipril,
on survival in
pts who had
shown clinical
evidence of HF
at any time
after an acute
MI. Also, to
compare the
incidences of
progression to
severe or
resistant HF,
nonfatal re-
infarction and
stroke between
the 2 groups.
RCT 2006; 1014; 992 Aged ≥18 y,
with a definite
acute MI 3-10 d
before
randomization;
Clinical
evidence of HF
at any time
since acute MI
Use of an ACEI
considered to be
mandatory
Mortality from
all causes
1.3 y Mortality from all causes
was significantly lower
for pts on ramipril
compared to pts on
placebo. RR: 27%; 95%
Cl: 11-40%; p = 0.002.
Prespecified secondary
outcomes: risk reduction
of 19% for the 1st
validated outcome—
namely, death,
severe/resistant HF, MI,
or stroke (95% CI: 5% -
31%; p=0.008).
TRACE 1995
7477219 (173)

To determine
whether pts
who LV
dysfunction
soon after MI
benefit from
long-term oral
ACE inhibition.
RCT Beta blocker 16%;
Calcium antagonist
28%; Diuretic
66%; Nitrates
53%; Digoxin
28%.
1749; 876; 873 Ischemic
100%
Consecutive pts
>18 y
hospitalized with
MI;
Criteria for MI:
chest pain or
electrocardiogra
phic changes,
accompanied by
>2X increase in
one or more
cardiac
enzymes;
LV dysfunction
(EF <35%);
NYHA class 1 -
41%;
BP 121/76; HR
81
Contraindication
to ACEI or a
definite need for
them;
Severe,
uncontrolled DM;
Hyponatremia
(<125 mmol/L);
Elevated SCr
level (2.3 mg/dL)
Death from
any cause
Death from a CV
cause, sudden
death;
Progression to
severe HF
(hospital
admission for
HF, death due to
progressive HF,
or HF
necessitating
open-label
ACEI);
Recurrent
infarction (fatal
or nonfatal);
Change in the
wall-motion
index (EF)
The mortality
from all causes
at 1 y was
24%.
24 lives
were
saved
after one
mo of
treating
1000 pts
During the study period,
304 pts in the trandolapril
group died (34.7%), as
did 369 in the placebo
group (42.3%). RR: 0.78
(95% CI, 0.67 - 0.91;
p=0.001).
In every subgroup,
treatment with
trandolapril was
associated with a
reduction in risk.
ACEI indicates angiotensin-converting-enzyme inhibitor; AF, atrial fibrillation; AIRE, Acute Infarction Ramipril Efficacy; APE, acute pulmonary embolism; ATLAS, Assessment of Treatment with Lisinopril and Survival; BP, blood pressure; CAD, coronary artery disease;
CHD, chronic heart disease; CHF, congestive heart failure; CONSENSUS Cooperative North Scandinavian Enalapril Survival Study; Cr, creatinine; CV, cardiovascular; C/W, compared with; DM, diabetes mellitus; ED, emergency department; FU, follow-up; HF, heart

© American College of Cardiology Foundation and American Heart Association, Inc.        82 
 
failure; HR, heart rate; LV, left ventricular; MI, myocardial infarction; MV, mitral valve; N/A, not applicable; NYHA, New York Heart Association; pts, patients; SAVE, survival and ventricular enlargement trial; SBP, systolic blood pressure; SOLVD, Studies Of Left
Ventricular Dysfunction; RCT, randomized control trial; SCr, serum creatinine; and TRACE, Trandolapril Cardiac Evaluation.
Data Supplement 19. ARBs (Section 7.3.2.3)
Study
Name,
Author,
Year
Aim of
Study
Study
Type
Background
Therapy Study Size Etiology Patient Population Severity Endpoints Mortality
Trial
Duration
(Y) Statistical Results
Pre-trial
standard
treatment.
N (Total)
n (Experimental)
n (Control)
Ischemic/
Non-Ischemic
Inclusion
Criteria
Exclusion
Criteria
Primary
Endpoint
Secondary
Endpoint 1st Y Mortality
CHARM
Alternative;
Granger et
al; (2003)
13678870
(174)
Discover
whether
ARB could
improve
outcome in
pts not
taking an
ACEI
(intolerant)
RCT Diuretics,
Beta-blockers
(55%),
spironolacton
e 24%,
Digoxin 45-
46%
2028; 1013;
1015
Ischemic 67-70% Symptomatic
HF, EF <40%,
no ACEI (b/c
of intolerance)
NYHA ll-lV; mild to
severe (<4% class
lV); EF: 30%; BP:
130/70; HR: 74-
75; AF: 25-26%
Composite of
CV death or
hospital
admission for
CHF
CV death,
hospital
admission for
CHF or non-fatal
MI; CV death,
CHF admission,
non-fatal MI, non-
fatal stroke; CV
death, CHF
admission, non-
fatal MI, non-fatal
stroke, coronary
revascularization;
Death (any
cause); New DM
2.8 y Absolute reduction of 7 major
events per 100 pts threated -
NNT 14 pts to prevent 1 CV
death or hospitalization.
HR: 0.77 (95% CI: 0.67-0.89);
p=0.0004
CHARM-
ADDED;
McMurray
et al;
(2003)
13678869
(175)

To
investigate
if ARB +
ACEI in pts
with chronic
HF improve
clincal
outcomes
RCT Beta blocker-
55%;
spironolacton
e 17%;
Digoxin 58-
59%
2548; 1276;
1272
Ischemic 62-63% Symptomatic
HF; EF <40%;
Treatment with
ACEI; Age >18
y
NYHA class ll-lV;
mild to seve