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Management of Patients with Non-ST Elevation Acute Coronary Syndromes – Adult – Inpatient

Management of Patients with Non-ST Elevation Acute Coronary Syndromes – Adult – Inpatient - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Cardiovascular


1
Management of Patients with Non-ST-
Elevation Acute Coronary Syndromes –
Adult – Inpatient
Clinical Practice Guideline
Table of Contents
EXECUTIVE SUMMARY ................................................................................................ 3
SCOPE ............................................................................................................................ 4
METHODOLOGY ............................................................................................................ 4
DEFINITIONS ................................................................................................................. 5
INTRODUCTION ............................................................................................................. 5
RECOMMENDATIONS ................................................................................................... 5
ξ Initial Evaluation and Management
ξ Early Hospital Care
ξ Myocardial Revascularization
ξ Late Hospital Care, Hospital Discharge, and Posthospital Discharge Care
ξ Special Patient Groups
UW HEALTH IMPLEMENTATION.................................................................................. 6
REFERENCES ................................................................................................................ 6
CPG Contact for Content:
Name: Anne O’Connor, MD – Medicine- Cardiology
Phone Number: (608) 262-4917
Email Address: aoconnor@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
Note: Active Table of Contents -- Click to follow link
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

2
Guideline Author(s): American College of Cardiology/American Heart Association
Coordinating Team Members:
Jon Keevil, MD – Medicine- Cardiology
Amish Raval, MD – Medicine- Cardiology
Peter Mason, MD – Medicine- Cardiology
Mary Zasadil, MD – Medicine- Cardiology
Brian Sharp, MD – Emergency Medicine
Andrew Lee, MD – Emergency Medicine
Chris Francois, MD – Radiology- General
Sarah Hackenmueller, PhD, DABCC – Pathology and Laboratory Medicine
Joseph Holt, MD – Medicine- Hospitalists
Anne Rose, PharmD – Pharmacy- Inpatient Services
Katie Willenborg, PharmD – Pharmacy- Inpatient Services
Cindy Gaston, PharmD – Drug Policy Program
Stephanie Kraus, CNS – Cardiology
Kathy Wackerle, NP- Medicine- Cardiology
Rebecca Wieczorek- Heart, Vascular, Thoracic Administration
Stacey Saari- Heart, Vascular, Thoracic Administration
Brenda Larson, RN, BSN- Heart, Vascular, Thoracic Administration
Beth Gamble, NP- Heart, Vascular, Thoracic Administration
Review Individuals/Bodies:
Takushi Kohmoto, MD – Surgery- Cardiothoracic Surgery
Katherine Porter, MD – Family Medicine
Michelle Bryan, MD- Family Medicine
Mark Micek, MD- Internal Medicine
Committee Approvals/Dates:
Clinical Knowledge Management (CKM) Council (04/23/2015)
Release Date: April 2015
Next Review Date: April 2017
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

3
Executive Summary
Guideline Overview
UW Health has agreed to endorse the 2014 ACC/AHA Guideline for the Management of
Patients with Non-ST-Elevation Acute Coronary Syndromes: A Report of the American
College of Cardiology/American Heart Association Task Force on Practice Guidelines.1
Key Practice Recommendations
1. Initial Evaluation and Management
2. Early Hospital Care
3. Myocardial Revascularization
4. Late Hospital Care, Hospital Discharge, and Posthospital Discharge Care
5. Special Patient Groups
Companion Documents1,2
1. ED Chest Pain Algorithm
2. Risk Stratification of Non-ST Elevation Acute Coronary Syndrome Patients Table
3. Contraindications to Exercise Stress Testing Table
4. Stress Testing (from ED) Algorithm
5. Stress Testing Algorithm (Outpatient)
6. Non-ST Elevation Acute Coronary Syndromes Medical Therapy Algorithm
7. Non-ST Elevation Acute Coronary Syndromes Discharge Checklist
Related UW Health Clinical Practice Guidelines:
1. Unfractionated Heparin (Therapeutic Dosing) – Adult – Inpatient
2. Secondary Prevention of Atherosclerotic Cardiovascular Disease – Adult –
Inpatient/Ambulatory
3. Heart Failure- Adult- Inpatient/Ambulatory
4. Atrial Fibrillation – Adult – Inpatient/Ambulatory
Pertinent UW Health Policies & Procedures
1. UWHC Policy 1.26: Continuum of Care
2. UWHC Policy 10.24: Administration of Echocardiography Contrast Agents
Patient Resources
1. Health Information: Acute Coronary Syndrome
2. Health Information: Angina
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

4
Scope
Disease/Condition(s):
ξ Unstable angina (UA)
ξ Non-ST-elevation myocardial infarction (NSTEMI)
Clinical Specialty: Cardiology, Cardiothoracic Surgery, Hospitalists, Emergency
Medicine, Internal Medicine, Family Medicine, Pharmacy
Intended Users:
Cardiologists, Primary Care Physicians, Emergency Medicine Physicians, Pharmacists,
Registered Nurses, Cardiac Rehabilitation Therapists
CPG objective(s):
To provide recommendations for the optimal management of patients with NSTE-ACS.
Target Population:
Adult patients (18 years or older) with suspected or diagnosed NSTE-ACS.
Guideline Metrics:
CPG-derived
1. Volume of patients seen in the ED for chest pain who were discharged
2. Rate of OP stress test attendance following ED discharge
3. Amount of time between ED discharge and OP stress test
4. Volume of patients seen in the ED for chest pain who were admitted
5. Distributions of interventions performed following inpatient admission
6. 30-day and 60-day outcomes following inpatient discharge
Methodology
Methods Used to Collect/Select the Evidence:
Electronic database searches were conducted to collect evidence for review, in addition
to review of the 2014 ACC/AHA guideline.1 Expert opinion and clinical experience was
also considered during evidence review.
Methods Used to Formulate the Recommendations:
The workgroup members adopted recommendations developed by external
organizations and/or arrived at a consensus through discussion of the literature
evidence and expert experience.
Methods Used to Assess the Quality and Strength of the
Evidence/Recommendations:
Recommendations developed by external organizations (i.e., ACC/AHA) maintained the
assigned evidence grade. Recommendations internally developed during workgroup
discussions were graded using the modified grading scheme developed by AHA.
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

5
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 below)
was used to
grade each
recommendation.1
Definitions
Acute Coronary Syndrome (ACS): a spectrum of conditions compatible with acute
myocardial ischemia and/or infarction due to an abrupt reduction in coronary blood
flow.1
Introduction
In the United States, NSTE-ACS affects over 625,000 patients annually, or almost three
fourths of all patients with acute coronary syndromes.1 The median age of presentation
is 68 years. Some patients have a history of stable angina, whereas in others, ACS is
the initial presentation of coronary artery disease (CAD).1
Recommendations
Recommendations related to clinical assessment and initial evaluation, diagnosis, early
hospital care, myocardial revascularization, discharge and posthospital care can be
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

6
found in the 2014 ACC/AHA Guideline for the Management of Patients with Non-ST-
Elevation Acute Coronary Syndromes: A Report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines1 online at
http://circ.ahajournals.org/content/130/25/e344.extract.
UW Health Implementation
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. Content will be reviewed for consistency across clinical tools,
including:
Delegation Protocols
ξ Emergency Department Immediate Orders [61]
Order Sets
ξ ED – Immediate Orders – Adult [4222]
ξ ED – Chest Pain – Adult [624]
ξ ED – Nuc Med Chest Pain Treatment – Adult [2556]
ξ ED – Coronary CT Angiography Procedure – Adult [5225]
ξ IP – Coronary CT Angiography – Adult – Procedure [2236]
ξ IP – MI/Rule Out MI – Adult – Intermediate and General Care – Admission [920]
ξ IP – MI/Rule Out MI – Adult – Intensive Care – Admission [923]
ξ IP – Cardiology – Adult – Discharge [3328]
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.
References
1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of
Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of
Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation.
2014;130(25):e344-426.
2. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the
diagnosis and management of patients with stable ischemic heart disease: a report of the American
College of Cardiology Foundation/American Heart Association task force on practice guidelines, and
the American College of Physicians, American Association for Thoracic Surgery, Preventive
Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and
Society of Thoracic Surgeons. Circulation. 2012;126(25):e354-471.
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

Patient Presentation:
Chest Pain or Anginal Equivalent
with Concern for ACS
Definitive
NSTE-ACS or
Unstable Angina
STEMI
STEMI
Activation
Clinical
Concern for
NSTE-ACS?
Admit to CVM
for Medical
Management
Refer to UW Health
NSTE-ACS Medical
Therapy Algorithm
Coronary CTA or Stress Test
ED Provider Preference
(AHA Class Iia, LOE B)
Inclusion
Criteria met?
Perform CCTA
(AHA Class Iia, LOE B)
Use ED Order Set
Stress Lab
open?
CCTA
Result:
High risk/
Severe stenosis
Result:
Equivocal risk/
Moderate stenosis
Result:
Low risk/No or
Mild stenosis
Discharge
Follow-up
with PCP
Admit to CVM
ED Provider Preference
12-lead ECG (within 10 min of arrival) (AHA Class I, LOE C)
1
st
Troponin Lab (draw upon arrival) (AHA Class I, LOE A)
UW Health ED Chest Pain Algorithm
References
1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(25):e344-426.
2. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of
Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses
Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126(25):e354-471.
3. Cullen L, Mueller C, Parsonage WA, et al. Validation of high-sensitivity troponin I in a 2-hour diagnostic strategy to assess 30-day outcomes in emergency department patients with possible acute coronary
syndrome. J Am Coll Cardiol. 2013;62(14):1242-1249.
4. Than M, Aldous S, Lord SJ, et al. A 2-hour diagnostic protocol for possible cardiac chest pain in the emergency department: a randomized clinical trial. JAMA Intern Med. 2014;174(1):51-58.
2
nd
Troponin
(draw 2hrs. after onset of
symptoms)*
Change in
troponin?
Stress Test
Yes
Order Stress Test**
(AHA Class IIa, LOE A,B)
ED Management
(outside guideline scope)
No
Admit to appropriate
Medical Service for
Stress Testing***
(AHA Class IIa, LOE B)
Consider for OP Stress
Testing and Discharge
- Patient Low Risk?
- Patient Agreeable?
- PCP?
Yes
No
YesNo
CCTA Inclusion Criteria:
ξ During available hours
ξ Age < 60 yrs.
ξ No history of CAD
ξ HR < threshold or no contraindications to
beta blockade
ξ ECG with NSR, no ischemia, no arrhythmia
ξ No allergy to iodinated contrast
ξ Can hold breath for 15 seconds
ξ eGFR > 60
ξ Not taking PDE-5 inhibitor drugs (i.e., 24
hrs. since sildenafil/vardenafil dose, or 48
hrs. since tadalafil dose) (AHA Class III, LOE B)
Last Revised: 04/2015
Contact CCKM for revisions.
UW Health Management of Non-ST Elevation Acute Coronary Syndromes – Adult – Inpatient/Ambulatory Clinical Practice Guideline
*UW Health uses troponin lab with higher sensitivity.
3,4
**Stress test type will be determined by the Stress Test Lab
staff using the UW Health Stress Testing (from ED) Algorithm.
***Patients may be transferred from TAC to CSC on Fri./Sat.
1
st
Troponin
positive?
Yes
No
Yes
No
NOTE: Consider
Contraindications for
Stress Testing
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

Risk Stratification for NSTE-ACS Patients in the Emergency Department
HIGH RISK INTERMEDIATE RISK LOW RISK
At least 1 of the following: No high - risk features, but 1 of the following:
No high - or intermediate - risk features, but any
of the following:
History
Accelerating tempo of
ischemic symptoms in
preceding 48 hrs.
ξPrior MI, peripheral or cerebrovascular disease, or
CABG
ξPrior aspirin use
N/A
Characteristics of Pain Prolonged ongoing
(>20 min.) rest pain
ξProlonged (>20 min.) rest angina, now resolved, with
moderate to high likelihood of CAD
ξRest angina (>20 min.) or relieved with rest or
sublingual NTG
ξNocturnal angina
ξNew-onset or progressive CCS Class III or IV angina
in previous 2 wks. without prolonged (>20 min) rest
pain but with intermediate or high likelihood of CAD
ξIncreased angina frequency,
severity, or duration
ξAngina provoked at a lower
threshold
ξNew-onset angina with onset 2 wks.
to 2 months before presentation
Clinical Findings
ξPulmonary edema, most
likely due to ischemia
ξNew or worsening mitral
regurgitation murmur S3
or new/worsening rales
ξHypotension,
bradycardia, or
tachycardia
ξAge > 75 yrs.
Age > 70 yrs. N/A
ECG
ξAngina at rest with
transient ST-segment
changes > 0.5mm
ξBundle-branch block, new
or presumed new
ξSustained ventricular
tachycardia
ξT-wave changes
ξPathological Q waves or resting ST -depression <
1mm in multiple lead groups (anterior, inferior,
lateral)
Normal or unchanged ECG
Cardiac Markers
(UW Health Lab) TnI > 0.50 ng/mL TnI = 0.06 -0.49 ng/mL TnI = 0.00 -0.05 ng/mL
Last revised/reviewed: 04/2015 | Contact CCKM for revisions. | UW Health Non-ST-Elevation Acute Coronary Syndromes – Adult – Inpatient/Ambulatory CPG
Reference: Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the
American College of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive
Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126(25):e354-471.
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

Contraindications for Exercise Stress Testing1
Absolute
‡ $cute m\ocardial inIarction �ZitKin � days)
‡High-risk unstable angina
‡ 8ncontrolled cardiac arrK\tKmias causing symptoms or hemodynamic
compromise
‡ 6\mptomatic seYere aortic stenosis
‡ 8ncontrolled s\mptomatic Keart Iailure
‡ $cute pulmonar\ embolus or pulmonar\ inIarction
‡ $cute m\ocarditis or pericarditis
‡ $cute aortic dissection
Relative*
‡ /eIt main coronar\ stenosis
‡ Moderate stenotic YalYular Keart disease
‡ (lectrol\te abnormalities
‡Severe arterial hypertension**
‡ 7acK\arrK\tKmias or brad\arrK\tKmias
‡ +\pertropKic cardiom\opatK\ and otKer Iorms oI outIloZ tract obstruction
‡ Mental or pK\sical impairment leading to inability to exercise adequately
‡ +igK-degree atrioventricular block
*Re lative contraindications can be superseded if the benefits of exercise outweigh the risks.
**In the absence of definitive evidence, the AHA/ACC suggests systoli c blood pressure of > 200 mmHg and/or
diastolic blood pressure of > 110 mmHg. Modified from Fletcher et al. 2
Last revised/reviewed: 04/2015 | Contact CCKM for revisions.
UW Health Non-ST-Elevation Acute Coronary Syndromes – Adult – Inpatient/Ambulatory CPG
References:
1. Gibbons RJ, Balady GJ, Bricker JT, et al. ACC/AHA 2002 guideline update for exercise testing: summary article. A
report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines
(Committee to Update the 1997 Exercise Testing Guidelines). J Am Coll Cardiol. 2002;40(8):1531-1540.
2. Fletcher GF, Balady G, Froelicher VF, Hartley LH, Haskell WL, Pollock ML. Exercise standards. A statement for
healthcare professionals from the American Heart Association. Writing Group. Circulation. 1995;91(2):580-615.
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

Discharge &
Follow-up with
PCP
Stress Test Ordered
(per Cardiology)
Consider coronary
revascularization.
Admit to CVM
Contraindications
to stress testing?
Patient able
to exercise ?
No
Known CAD?
Yes
Perform Pharm Stress MPI
(AHA Class I, LOE B)
No
Resting ECG
interpretable?
No
Perform MPI with Exercise
(AHA Class I, LOE B)
Yes
Perform MPI with
Exercise
(AHA Class I, LOE B)
No
Review Test Result
Result:
High/Moderate risk
Result:
Low risk
References
1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(25):e344-426.
2. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College
of Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses
Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126(25):e354-471.
UW Health Stress Testing (from ED) Algorithm
Last Revised: 04/2015
Contact CCKM for revisions.
UW Health Management of Non-ST Elevation Acute
Coronary Syndromes – Adult – Inpatient/Ambulatory
Clinical Practice Guideline
Consider CCTA
(AHA Class Iia, LOE C)
OR
Initiate Medical Therapy
Refer to UW Health Non-STE
ACS Medical Therapy
Algorithm
Yes
Use CAD Consortium 1 Risk Calculator
Low Pretest Probability (<20 %):
Perform Standard Exercise ECG ( AHA Class IIa, LOE C)
Intermediate/ High Likelihood IHD (>20 %):
Perform MPI with Exercise ( AHA Class Iia, LOE B)
Yes
Note: Consider
Contraindications
for Stress Testing
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

Follow-up with
PCP
Stress Test Ordered
by ED
Expedited
Cardiology Evaluation
(i.e., TAC consult,
Cardiology Clinic, Stress
reader)
Admit to CVM vs.
OP cath
Contraindications
to stress testing?
Patient able
to exercise ?
No
Known CAD?
Yes
Perform Pharm Stress MPI (AHA Class I, LOE B)
OR Pharm Stress with Echo (AHA Class I, LOE B)
No
Resting ECG
interpretable?
No
Perform MPI with Exercise
(AHA Class IIa, LOE B)
OR Exercise Echo (AHA Class I, LOE B)
Yes
Perform MPI with
Exercise
(AHA Class I, LOE B)
OR
Exercise Echo
(AHA Class I, LOE B)
No
Chest Pain APP places order
Result:
High risk
Result:
Low risk
References
1. Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/
American Heart Association Task Force on Practice Guidelines. Circulation. 2014;130(25):e344-426.
2. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of
Cardiology Foundation/American Heart Association task force on practice guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses
Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. Circulation. 2012;126(25):e354-471.
UW Health Stress Testing Algorithm
For Patients Discharged from the ED for Testing
UW Health Management of Non-ST
Elevation Acute Coronary Syndromes
– Adult – Inpatient/Ambulatory
Clinical Practice Guideline
Expedited Follow-up with
the PCP or Cardiology
Clinic
Yes
Use CAD Consortium 1 Risk Calculator
Low Pretest Probability ( < 25 %):
Perform Standard Exercise ECG ( AHA Class IIa, LOE C)
Intermediate/ High Likelihood IHD (> 25 %):
Perform MPI with Exercise ( AHA Class IIa, LOE B)
OR Exercise Stress with Echo (AHA Class IIa, LOE B)
Yes
Order reviewed by
Chest Pain APP
EF < 40% or
unknown?
No
Perform MPI with Exercise
(AHA Class I, LOE B)
Yes
Result:
Moderate risk
Review Test Result
Guideline-directed
Medical Therapy for
Stable Ischemic Heart
Disease
Follow-up with PCP
(with Cardiology
referral as needed)
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

Non-STE ACS Medical Therapy Algorithm
Patient with Definite or Likely Non-ST Elevation ACS
Postadmission Medical Therapy ( Floor- CVM)
1. Continue pharmacotherapy initiated in ED
ξ Anticoagulation (enoxaparin or IV heparin ) should be continued for
duration of hospitalization or until PCI is performed
ξ Anticoagulation does not need to be held on the morning of
planned coronary angiogram
2. Administer additional pharmacotherapy:
ξ Beta Blocker (AHA Class I, LOE A)
ξ ACE-I (or ARB if into lerant) if EF < 40%, hypertension , diabetes , or
stable CKD (AHA Class I, LOE A)
ξ Aldosterone blockade (i.e., spirlactone or eplereone) if EF < 40% ,
diabetes, or heart failure and no significant renal dysfunction (Cr >
2.5 mg/dL in men or > 2.0 mg/dL in women) or hyperkalemia (K >
5.0 mEq/L) (AHA Class I, LOE A)
ξ Atorvastain (80 mg daily) (AHA Class I, LOE A)
3. Administer supplemental oxygen if saturations < 90% or in
respiratory distress (AHA Class I, LOE C)
4. Maintain nutrition status of NPO (expect medications)
5. Repeat ECG with any new symptoms
6. Complete laboratory tests (if not completed in ED):
ξ Troponin (every 6 hours until peak or 3 negative results)(AHA Class I,
LOE A)
ξ Lipid Profile (AHA Class Iia, LOE C)
ξ CBC without diffe rential
ξ BMP (Na, K, Cl, total CO2, glucose, BUN, Cr, Ca)
ξ ALT
ξ A1c
ξ PT/INR (if patient on coumadin)
7. Obtain transthoracic echocardiogram (TTE) for EF assessment to aid
risk stratification (AHA Class I, LOE C)
8. Consult Cardiac Rehabilitation
Risk Stratification to determine initial therapy strategy using TIMI
risk score and/or Grace risk model
Last Revised: 06/2015
Contact CCKM for revisions.
UW Health Management of Non-ST Elevation Acute Coronary Syndromes – Adult – Inpatient/Ambulatory Guideline
NOTE: Invasive strategy is not recommended in patients with extensive co-
morbidities (hepatic, renal (CKD stage > 4), pulmonary failure, or cancer) in whom
the risks likely outweigh the benefits of revascularization.
Confirm clopidogrel
loading dose (600 mg)
Perform PCI
Anticoagulation during
procedure to be determined by
Interventional Cardiology, with
preference for unfractionated
heparin (AHA Class I, LOE B) if low
bleed risk and bivalirudin(AHA
Class I, LOE B) if high bleed risk.
Perform CABG
1. Initiate or continue aspirin
therapy (AHA Class I, LOE B)
2. Hold ACE-I or ARB on day of
surgery
3. Refer to guideline for timing of
other antiplatelet therapy
cessation before surgery
(AHA Class I, LOE B)
Initial Medical Therapy ( ED Initiation)
1. Administer initial pharmacotherapy:
ξAspirin(325 mg STAT; 81 mg daily) (AHA Class I, LOE A)
Avoid all other NSAIDs (AHA Class III, LOE B)
ξClopidogrel (600 mg loading; 75 mg daily) (AHA Class I, LOE B)
ξEnoxaparin (1 mg/kg subcutaneous Q12 hrs) (AHA Class I, LOE A)
If CKD, administer heparin instead (60 IU/kg initial dose; 12 IU/
kg/hr infusion) (AHA Class I, LOE B)
ξNitroglycerin (0.4 mg Q5 min up to 3 doses) (AHA Class I, LOE C)
If HTN, heart failure or pain persists, consider IV. (AHA Class I, LOE
B) Do not administer if recent use of PDE-5 inhibitors (i.e., 24
hrs. since sildenafil/vardenafil dose, or 48 hrs. since tadalfil
dose) (AHA Class III, LOE B)
ξMorphine (if ischemic pain persists despite max . tolerated
nitrates) (AHA Class Iib , LOE B)
2. Administer supplemental oxygen if saturation < 90 % or
patient is in respiratory distress. (AHA Class I, LOE C)
Ischemia-guided
Strategy
Risk stratification using
noninvasive imaging
Perform diagnostic cardiac cath
Results
normal or mildly
abnormal?
Discharge
Refer to NSTE-ACS Discharge Checklist
Medical Management
Continue medications required to
control ischemia after discharge in
patients who do not undergo
coronary revascularization , patients
with incomplete/unsuccessful
revascularization, or those with
recurrent symptoms after
revascularization (AHA Class I, LOE C)
Yes No
Yes No
Invasive
strategy
warranted?
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

Non-ST Elevation Acute Coronary Syndromes
Discharge Check List
Note: This checklist does not replace individual clinical judgement and/ or consideration for patient tolerance of
specific medications or therapies.
 Aspirin 81 mg daily. ( A HA Class I, LO E A)
 Clopidogrel 75 mg daily for 12 months post NSTE-ACS (with no interruption if drug covered stent
was placed). ( AHA Class I, LOE B)
 Sublingual nitroglycerin PRN. ( AHA Class I, LO E C)
 Proton pump inhibitor if history of GI bleeding and/or requires triple therapy with vitamin K
antagonists, aspirin, and p2Y 12 receptor inhibitor. ( AHA Class I, LOE C)
 Beta blockers ( AHA Class I, LOE A)
 ACE inhibitors (or ARBs if ACE-I intolerant): EF < 40%, HTN, DM, stable CKD. ( AHA Class I, LOE A)
 Aldosterone blockage (spirlactone 25 mg daily of eplereone 50 mg daily) if EF < 40%, DM, or HF
(provided creatinine < 2.5 mg/dL for men and < 2.0 mg/dL for women and potassium is less than 5
mEq/L. ( AHA Class I, LO E A)
 High Dose Statin – atorvastatin 80 mg daily. (AHA Class I, LOE A)
 Cardiac Rehab Consult ( AHA Class I, LO E B)
 Pneumococcal Vaccine ( AHA Class I, LOE B)
 Annual influenza Vaccine ( AHA Class I, LOE C)
 Avoid NSAIDs ( AHA Class I II, LOE B)
 Follow-up with patient (AHA Class I, LOE B)
ξ UW Health recommends in 1-2 weeks with PCP and 4-6 weeks with Cardiology
 Patient Education ( AHA Class I, LOE C) to include:
ξ Warning symptoms
ξ When to seek emergency care.
ξ Medication education.
ξ CV risk Factor modification.
ξ Smoking Cessation
Last revised/reviewed: 04/2015 | Contact CCKM for revisions.
UW Health Non-ST-Elevation Acute Coronary Syndromes – Adult – Inpatient/Ambulatory CPG
Reference: Amsterdam EA, Wenger NK, Brindis RG, et al. 2014 AHA/ACC Guideline for the Management of Patients With
Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart
Association Task Force on Practice Guidelines. Circulation. 2014;130(25):e344-426.
Copyright © 2017 Univ ersity of Wisconsin Hospitals and Clinics Authority
Contact: Lee Vermeulen, CCKM@uwhealth.org Last Revised: 02/2017CCKM@uwhealth.org

CLINICAL PRACTICE GUIDELINE
2014 AHA/ACC Guideline for
the Management of Patients
With Non–ST-Elevation Acute
Coronary Syndromes
A Report of the American College of Cardiology/American Heart Association
Task Force on Practice Guidelines
Developed in Collaboration With the Society for Cardiovascular Angiography and Interventions
y
Writing
Committee
Members*
Hani Jneid, MD, FACC, FAHA, FSCAIy
Rosemary F. Kelly, MD{
Michael C. Kontos, MD, FACC, FAHA*y
yACC/AHA Representative. zACC/AHA Task Force on Practice Guidelines
Liaison. xAmerican College of Physicians Representative. kAmerican
Academy of Family Physicians Representative. {Society of Thoracic
on Performance
ngiography and
llege of Emergency Phy-
levation acute coronary
n Science Advisory and
Casey DE Jr, Ganiats TG,
ing RW, Zieman SJ. 2014
n College of Cardiology/
JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL.64,NO.24,2014
ª 2014 BY THE AMERICAN HEART ASSOCIATION, INC.,
AND THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2014.09.017
PUBLISHED BY ELSEVIER INC.
Downloa
This article is copublished in Circulation.
American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;64:e139–228.
ded From: http://co
Glenn N. Levine, MD, FACC, FAHAy
Philip R. Liebson, MD, FACC, FAHAy
Debabrata Mukherjee, MD, FACCy
Surgeons Representative. #ACC/AHA Task Force
Measures Liaison. **Society for Cardiovascular A
Interventions Representative.
The writing committee gratefully acknowledges the memory of Dr. Francis M. Fesmire (representative of the American Co
sicians), who died during the development of this document but contributed immensely to our understanding of non–ST-e
syndromes.
This document was approved by the American College of Cardiology Board of Trustees and the American Heart Associatio
Coordinating Committee in August 2014.
The American College of Cardiology requests that this document be cited as follows: Amsterdam EA, Wenger NK, Brindis RG,
Holmes DR Jr, Jaffe AS, Jneid H, Kelly RF, Kontos MC, Levine GN, Liebson PR, Mukherjee D, Peterson ED, Sabatine MS, Small
AHA/ACC guideline for the management of patients with non–ST-elevation acute coronary syndromes: a report of the America
Allan S. Jaffe, MD, FACC, FAHA*y
n
and Society of Thoracic Surgeons
Endorsed by the American Association for Clinical Chemistr
Ezra A. Amsterdam, MD, FACC, Chairy
Nanette K. Wenger, MD, MACC, FAHA, Vice Chair*y
Ralph G. Brindis, MD, MPH, MACC, FSCAIz
Donald E. Casey JR, MD, MPH, MBA, FACP, FAHAx
Theodore G. Ganiats, MDjj
David R. Holmes JR, MD, MACCy
Copies: This document is available on the World Wide Web sites of the A
Heart Association (my.americanheart.org). For copies of this document, plea
reprints@elsevier.com.
Permissions: Multiple copies, modi�cation, alteration, enhancement, and
permission of the American College of Cardiology. Requests may be co
obtainingpermission-to-re-useelsevier-material).
tent.onlinejacc.org/ on 03/27/2015
Eric D. Peterson, MD, MPH, FACC, FAHA*#
Marc S. Sabatine, MD, MPH, FACC, FAHA*y
Richard W. Smalling, MD, PHD, FACC, FSCAI***
Susan J. Zieman, MD, PHD, FACCy
*Writing committee members are required to recuse themselves from
voting on sections to which their speci�c relationships with industry
and other entities may apply; see Appendix 1 for recusal information.
merican College of Cardiology (www.cardiosource.org) and the American
se contact the Elsevier Inc. Reprint Department, fax (212) 633-3820, e-mail
/or distribution of this document are not permitted without the express
mpleted online via the Elsevier site (http://www.elsevier.com/authors/

ACC/AH
Force M
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3.2. Diagnosis o
3.2.1. Histo
3.2.2. Phys
3.2.3. Elect
3.2.4. Biom
3.2.5. Imag
t
L
Diagnosis and Risk Strati�cation ....e151
3.4.
3.4.4.
3.5. Imme
Amsterdam et al.
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2014 AHA/ACC N
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3.3.1. Ratio
Spec
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3.3.2. Estim
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rum of Risk: High, Intermediate,
ow ........................... e150
4.2.
3.3. Prognosis—Early Risk Strati�cation:
Recommendations ........................e149
mendations ...................e148
f NSTE-ACS ....................e148
ry ............................e148
ical Examination .................e148
rocardiogram ...................e149
arkers of Myocardial Necrosis ......e149
ing ............................e149
4.1.
ation of Level of Risk ............ e150
.1. History: Angina Symptoms and
Angina Equivalents ............. e150
4.3.
nejacc.org/ on 03/27/2015
4.1.2.2. Analgesic Therapy:
Recommendations .............. e158
4.1.2.3. Beta-Adrenergic Blockers:
Recommendations .............. e159
4.1.2.4. Calcium Channel Blockers:
Recommendations .............. e159
4.1.2.5. Other Anti-Ischemic Interventions . e160
4.1.2.6. Cholesterol Management ........e160
Inhibitors of the Renin-Angiotensin-Aldosterone
4.1.2. Anti-Ischemic and Analgesic Medications ..e158
4.1.2.1. Nitrates: Recommendations ...... e158
4.1.1. Oxygen: Recommendation ............ e157
3. INITIAL EVALUATION AND MANAGEMENT .....e146
3.1. Clinical Assessment and Initial Evaluation:
Recommendation .........................e146
3.1.1. ED or Outpatient Facility Presentation:
Recom
3.5.1. Discharge From the ED or Chest Pain Unit:
Recommendations ................... e156
4. EARLY HOSPITAL CARE ...................... e156
Standard Medical Therapies ................ e157
1. INTRODUCTION .............................e144
1.1. Methodology and Evidence Review ..........e144
1.2. Organization of the GWC ...................e144
1.3. Document Review and Approval .............e144
1.4. Scope of the CPG .........................e144
2. OVERVIEW OF ACS ..........................e146
2.1. De�nition of Terms ........................e146
2.2. Epidemiology and Pathogenesis .............e146
2.2.1. Epidemiology ....................... e146
2.2.2. Pathogenesis ........................ e146
BLE .................................... e142
TABLE OF CONTENTS
Judith S. Hochman, MD, FACC, FAHAyy
Robert A. Guyton, MD, FACCyy
Biykem Bozkurt, MD, PHD, FACC, FAHA
Ralph G. Brindis, MD, MPH, MACC
Lesley H. Curtis, PHD, FAHA
David DeMets, PHDyy
Lee A. Fleisher, MD, FACC, FAHA
Samuel Gidding, MD, FAHA
Nancy M. Albert, PHD, RN, FAHA
A Task
embers
Jeffrey L. Anderson, MD, FACC, FAHA, Ch
Jonathan L. Halperin, MD, FACC, FAHA, Ch
STE-ACS Guideline
Syste
Initia
Patie
3.4.3.1. Prognosis ..................... e155
CK-MB and Myoglobin Compared With
Troponin ........................... e155
diate Management ...................e156
3.4.1. Biomarkers: Diagnosis ................ e153
3.4.2. Biomarkers: Prognosis ................ e154
3.4.3. Cardiac Troponins ................... e154
Cardiac Biomarkers and the Universal De�nition
of MI: Recommendations ................... e153
m
l
n
3.3.2.5. Physical Examination ............ e153
3.3.2.3. Early Estimation of Risk ..........e151
3.3.2.4. Electrocardiogram .............. e153
3.3.2.2. Demographics and History in
yyFormer Task Force member; current member during the
writing effort.
agnus Ohman, MD, FACC
n J. Pressler, PHD, RN, FAHA
k W. Sellke, MD, FACC, FAHA
Kuang Shen, MD, FACC, FAHA
am G. Stevenson, MD, FACC, FAHAyy
inda N. Wijeysundera, MD, PHD
e W. Yancy, MD, FACC, FAHAyy
Richard J. Kovacs, MD, FACC, FAHA
DECEMBER 23, 2014:e139– 228
: Recommendations ................. e161
Antiplatelet/Anticoagulant Therapy in
ts With De�nite or Likely NSTE-ACS .... e161

4.3.2
4.4.
4.5.
5. MYO
5.1. Percut
5.1.1. P
R
5
5.2.
6. LAT
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6.1.
6.3.
7. SPE
7.3
7.4
7.5
7.7
7.8
7.9
7.10
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5.1.2.3. Anticoagulant Therapy in Patients
Undergoing PCI: Recommendations ..e173
Timing of Urgent CABG in Patients With NSTE-ACS
in Relation to Use of Antiplatelet Agents:
Recommendations ........................e174
E HOS
POST
Gener
Symp
m: http
.1.2.2. GP IIb/IIIa Inhibitors:
Recommendations ...............e172
5.1.2. PCI—Antiplatelet and Anticoagulant
Therapy .............................e171
5.1.2.1. Oral and Intravenous Antiplatelet
Agents: Recommendations ........e171
IAL REVASCULARIZATION .......... e171
aneous Coronary Intervention .......... e171
CI—General Considerations:
ecommendation .....................e171
4.5.2. Selection for Coronary Angiography .....e170
CARD
Recommendations ........................e170
4.5.1. Noninvasive Test Selection ............e170
4.4.6. Care Objectives .....................e169
Risk Strati�cation Before Discharge for Patients
With an Ischemia-Guided Strategy of NSTE-ACS:
t
Ischemia-Guided Strategy .............e169
4.4.4.1. Comparison of Early Versus Delayed
Angiography ................. e169
4.4.5. Subgroups: Early Invasive Strategy Versus
Early Invasive and Ischemia-Guided
Strategies: Recommendations .........e168
Strategy ...........................e166
4.4.2.1. Routine Invasive Strategy Timing . e166
4.4.3. Rationale for Ischemia-Guided Strategy . e166
4.4.4.
Strategies ...............................e166
4.4.1. General Principles ...................e166
4.4.2. Rationale and Timing for Early Invasive
De�nite NSTE-ACS: Recommendation ...e166
Ischemia-Guided Strategy Versus Early Invasive
4.3.2.4. Unfractionated Heparin ..........e165
4.3.2.5. Argatroban ...................e166
4.3.3. Fibrinolytic Therapy in Patients With
Recommendations ...................e164
4.3.2.1. Low-Molecular-Weight Heparin ...e165
4.3.2.2. Bivalirudin ....................e165
4.3.2.3. Fondaparinux .................e165
or Ischemia-Guided Strategy:
Recommendations ................... e161
4.3.1.1. Aspirin .......................e163
4.3.1.2. P2Y
12
Receptor Inhibitors ........e163
. Initial Parenteral Anticoagulant Therapy in
Patients With De�nite NSTE-ACS:
4.3.1. Initial Oral and Intravenous Antiplatelet
Therapy in Patients With De�nite or Likely
NSTE-ACS Treated With an Initial Invasive
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DECEMBER 23, 2014:e139– 228
PITAL CARE, HOSPITAL DISCHARGE,
HOSPITAL DISCHARGE CARE ........ e175
al Principles (Cardioprotective Therapy and
om Management) .................... e175
://content.onlinejacc.org/ on 03/27/2015
7.11. Vasospastic (Prinzmetal) Angina:
Recommendations .......................e192
7.12
7.13
. Women: Recommendations ................e189
. Anemia, Bleeding, and Transfusion:
Recommendations .......................e190
. Thrombocytopenia ....................... e191
. Cocaine and Methamphetamine Users:
Recommendations ....................... e191
7.6. CKD: Recommendations ...................e188
7.6.1. Antiplatelet Therapy ................ e189
7.2.1. Arrhythmias ....................... e183
7.2.2. Cardiogenic Shock: Recommendation ... e186
. Diabetes Mellitus: Recommendation .........e186
7.3.1. Adjunctive Therapy ................. e187
. Post–CABG: Recommendation ..............e187
. Perioperative NSTE-ACS Related to Noncardiac
Surgery: Recommendations ................e188
7.1. NSTE-ACS in Older Patients: Recommendations . e182
7.2. HF: Recommendations ....................e183
CIAL PATIENT GROUPS ................... e182
6.4. Plan of Care for Patients With NSTE-ACS:
Recommendations ........................ e181
6.4.1. Systems to Promote Care Coordination .. e181
.
.
6.3.6. Antioxidant Vitamins and Folic Acid:
Recommendations ................... e181
6.3.4. NSAIDs: Recommendations ............ e179
6.3.5. Hormone Therapy: Recommendation ...e180
Recommendation .................... e179
Prevention ...............................e179
6.3.1. Cardiac Rehabilitation and Physical
Activity: Recommendation ............ e179
6.3.2. Patient Education: Recommendations ... e179
6.3.3. Pneumococcal Pneumonia:
Risk Reduction Strategies for Secondary
6.2. Medical Regimen and Use of Medications at
Discharge: Recommendations ............... e175
6.2.1. Late Hospital and Posthospital Oral
Antiplatelet Therapy: Recommendations .. e175
6.2.2. Combined Oral Anticoagulant Therapy and
Antiplatelet Therapy in Patients With
NSTE-ACS .......................... e177
6.2.3. Platelet Function and Genetic Phenotype
Testing ............................ e178
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
ACS With Angiographically Normal Coronary
Arteries: Recommendation .................e193
Stress (Takotsubo) Cardiomyopathy:
Recommendations .......................e193

e142
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7.14. Obesity .................................e194
7.15. Patients Taking Antineoplastic/
Immunosuppressive Therapy ...............e194
8. QUALITY OF CARE AND OUTCOMES FOR ACS—USE
OF PERFORMANCE MEASURES AND REGISTRIES ..e194
8.1. Use of Performance Measures and Registries:
Recommendation .........................e194
9. SUMMARY AND EVIDENCE GAPS ..............e194
REFERENCES ................................. e195
APPENDIX 1
Author Relationships With Industry
and Other Entities (Relevant) ...................e216
APPENDIX 2
Reviewer Relationships With Industry
and Other Entities (Relevant) ...................e219
APPENDIX 3
Abbreviations ................................e224
APPENDIX 4
Additional Tables .............................e225
PREAMBLE
The American College of Cardiology (ACC) and the
American Heart Association (AHA) are committed to the
prevention and management of cardiovascular diseases
through professional education and research for clini-
cians,providers,andpatients.Since1980,theACCand
AHA have shared a responsibility to translate scienti�c
evidence into clinical practice guidelines (CPGs) with
recommendations to standardize and improve car-
diovascular health. These CPGs, based on systematic
methods to evaluate and classify evidence, provide a
cornerstone of quality cardiovascular care.
In response to published reports from the Institute of
Medicine (1,2) and the ACC/AHA’s mandate to evaluate
new knowledge and maintain relevance at the point of
care, the ACC/AHA Task Force on Practice Guidelines
(Task Force) began modifying its methodology. This
modernization effort is published in the 2012 Methodol-
ogy Summit Report (3) and 2014 perspective article (4).
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
The latter recounts the history of the collaboration,
changes over time, current policies, and planned initia-
tives to meet the needs of an evolving healthcare envi-
ronment. Recommendations on value in proportion to
resource utilization will be incorporated as high-quality
: http://content.onlinejacc.org/ on 03/27/2015
comparative-effectiveness data become available (5).
The relationships between CPGs and data standards,
appropriate use criteria, and performance measures are
addressed elsewhere (4).
Intended Use—CPGs provide recommendations applicable
to patients with or at risk of developing cardiovascular
disease. The focus is on medical practice in the United
States, but CPGs developed in collaboration with other
organizations may have a broader target. Although CPGs
may be used to inform regulatory or payer decisions, the
intent is to improve the quality of care and be aligned
with the patient’s best interest.
Evidence Review—Guideline writing committee (GWC)
members are charged with reviewing the literature;
weighing the strength and quality of evidence for or
against particular tests, treatments, or procedures; and
estimating expected health outcomes when data exist. In
analyzing the data and developing CPGs, the GWC uses
evidence-based methodologies developed by the Task
Force (6). A key component of the ACC/AHA CPG meth-
odology is the development of recommendations on the
basis of all available evidence. Literature searches focus
on randomized controlled trials (RCTs) but also include
registries, nonrandomized comparative and descriptive
studies, case series, cohort studies, systematic reviews,
and expert opinion. Only selected references are cited in
the CPG. To ensure that CPGs remain current, new data
are reviewed biannually by the GWCs and the Task Force
to determine if recommendations should be updated or
modi�ed. In general, a target cycle of 5 years is planned
for full revisions (1).
Guideline-Directed Medical Therapy—Recognizing ad-
vances in medical therapy across the spectrum of car-
diovascular diseases, the Task Force designated the term
“guideline-directed medical therapy” (GDMT) to repre-
sent recommended medical therapy as de�ned mainly by
Class I measures, generally a combination of lifestyle
modi�cation and drug- and device-based therapeutics. As
medical science advances, GDMT evolves, and hence
GDMT is preferred to “optimal medical therapy.” For
GDMT and all other recommended drug treatment regi-
mens, the reader should con�rmthedosagewithproduct
insert material and carefully evaluate for contraindica-
tions and possible drug interactions. Recommendations
are limited to treatments, drugs, and devices approved for
clinical use in the United States.
Class of Recommendation and Level of Evidence—Once
recommendations are written, the Class of Recommendation
(COR; i.e., the strength the GWC assigns to the recommenda-
tion, which encompasses the anticipated magnitude and
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
judged certainty of bene�t in proportion to risk) is assigned by
the GWC. Concurrently, the Level of Evidence (LOE) rates the
scienti�c evidence supporting the effect of the intervention on
the basis on the type, quality, quantity, and consistency of data

eve
e143
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TABLE 1 Applying Classi�cation of Recommendations and L
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
from clinical trials and other reports (Table 1) (4). Unless
otherwise stated, recommendations are presented in order by
the COR and then the LOE. Where comparative data exist,
preferred strategies take precedence. When more than 1 drug,
strategy, or therapy exists within the same COR and LOE and
there are no comparative data, optionsare listed alphabetically.
Relationships With Industry and Other Entities—The ACC
and AHA exclusively sponsor the work of GWCs without
commercial support, and members volunteer their time
for this activity. The Task Force makes every effort to
avoid actual, potential, or perceived con�icts of interest
that might arise through relationships with industry or
A recommendation with Level of Evidence B or C does not imply that the recommendation is w
lend themselves to clinical trials. Although randomized trials are unavailable, there may be a
*Data available from clinical trials or registries about the usefulness/ef�cacy in different sub
infarction, history of heart failure, and prior aspirin use.
†For comparative-effectiveness recommendations (Class I and IIa; Level of Evidence A and B o
of the treatments or strategies being evaluated.
ded From: http://content.onlinejacc.org/ on 03/27/2015
l of Evidence
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
other entities (RWI). All GWC members and reviewers are
required to fully disclose current industry relationships
or personal interests from 12 months before initiation
of the writing effort. Management of RWI involves
selecting a balanced GWC and requires that both the chair
and a majority of GWC members have no relevant RWI
(see Appendix 1 for the de�nition of relevance). GWC
members are restricted with regard to writing or voting
on sections to which their RWI apply. In addition, for
transparency, GWC members’ comprehensive disclosure
information is available as an online supplement.Com-
prehensive disclosure information for the Task Force is
eak. Many important clinical questions addressed in the clinical practice guidelines do not
very clear clinical consensus that a particular test or therapy is useful or effective.
populations, such as sex, age, history of diabetes mellitus, history of prior myocardial
nly), studies that support the use of comparator verbs should involve direct comparisons

JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
e144
Downloaded From
available as an additional supplement.TheTaskForce
strives to avoid bias by selecting experts from a broad
array of backgrounds representing different geographic
regions, sexes, ethnicities, races, intellectual perspec-
tives/biases,andscopesofclinicalpractice.Selectedor-
ganizations and professional societies with related
interests and expertise are invited to participate as part-
ners or collaborators.
Individualizing Care in Patients With Associated Conditions
and Comorbidities—TheACCandAHArecognizethe
complexity of managing patients with multiple condi-
tions, compared with managing patients with a single
disease, and the challenge is compounded when CPGs
for evaluation or treatment of several coexisting illnesses
are discordant or interacting (7). CPGs attempt to de�ne
practicesthatmeettheneedsofpatientsinmost,butnot
all, circumstances and do not replace clinical judgment.
Clinical Implementation—Management in accordance
with CPG recommendations is effective only when fol-
lowed; therefore, to enhance their commitment to treat-
ment and compliance with lifestyle adjustment, clinicians
should engage the patient to participate in selecting
interventions on the basis of the patient’s individual
values and preferences, taking associated conditions and
comorbidities into consideration (e.g., shared decision
making). Consequently, there are circumstances in which
deviations from these guidelines are appropriate.
The recommendations in this CPG are the of�cial policy of
the ACC and AHA until they are superseded by a published
addendum, focused update, or revised full-text CPG.
Jeffrey L. Anderson, MD, FACC, FAHA
Chair, ACC/AHA Task Force on Practice Guidelines
1. INTRODUCTION
1.1. Methodology and Evidence Review
The recommendations listed in this CPG are, whenever
possible, evidence based. An extensive evidence review was
conducted through October 2012, and other selected refer-
ences published through April 2014 were reviewed by the
GWC. Literature included was derived from research
involving human subjects, published in English, and indexed
in MEDLINE (through PubMed), EMBASE, the Cochrane
Library, Agency for Healthcare Research and Quality Reports,
and other selected databases relevant to this CPG. The rele-
vant data are included in evidence tables in the Online Data
Supplement. Key search words included but were not
limited to the following: acute coronary syndrome, anticoag-
ulant therapy, antihypertensives, anti-ischemic therapy, anti-
platelet therapy, antithrombotic therapy, beta blockers,
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
biomarkers, calcium channel blockers, cardiac rehabilitation,
conservative management, diabetes mellitus, glycoprotein IIb/
IIIa inhibitors, heart failure, invasive strategy, lifestyle modi�-
cation, myocardial infarction, nitrates, non–ST-elevation, P2Y
12
: http://content.onlinejacc.org/ on 03/27/2015
receptor inhibitor, percutaneous coronary intervention, renin-
angiotensin-aldosterone inhibitors, secondary prevention,
smoking cessation, statins, stent, thienopyridines, troponins,
unstable angina, and weight management. Additionally, the
GWC reviewed documents related to non–ST-elevation acute
coronary syndrome (NSTE-ACS) previously published by the
ACC and AHA. References selected and published in this
document are representative and not all-inclusive.
1.2. Organization of the GWC
The GWC was composed of clinicians, cardiologists, internists,
interventionists, surgeons, emergency medicine specialists,
family practitioners, and geriatricians. The GWC included
representatives from the ACC and AHA, American Academy of
Family Physicians, American College of Emergency Physi-
cians, American College of Physicians, Society for Cardiovas-
cular Angiography and Interventions (SCAI), and Society of
Thoracic Surgeons (STS).
1.3. Document Review and Approval
This document was reviewed by 2 of�cial reviewers each
nominated by the ACC and AHA; 1 reviewer each from the
American Academy of Family Physicians, American Col-
lege of Emergency Physicians, SCAI, and STS; and 37
individual content reviewers (including members of the
American Association of Clinical Chemistry, ACC Heart
Failure and Transplant Section Leadership Council, ACC
Cardiovascular Imaging Section Leadership Council, ACC
Interventional Section Leadership Council, ACC Preven-
tion of Cardiovascular Disease Committee, ACC Surgeons’
Council, Association of International Governors, and
Department of Health and Human Services). Reviewers’
RWI information was distributed to the GWC and is pub-
lished in this document (Appendix 2).
This document was approved for publication by the
governing bodies of the ACC and the AHA and endorsed
by the American Association for Clinical Chemistry, SCAI,
and the STS.
1.4. Scope of the CPG
The 2014 NSTE-ACS CPG is a full revision of the 2007 ACCF/
AHA CPG for the management of patientswith unstableangina
(UA) and non–ST-elevation myocardial infarction (NSTEMI)
and the 2012 focused update (8). The new title, “Non–ST-
Elevation Acute Coronary Syndromes,” emphasizes the con-
tinuum between UA and NSTEMI. At presentation, patients
with UA and NSTEMI can be indistinguishable and are there-
fore considered together in this CPG.
In the United States, NSTE-ACS affects >625,000
patients annually,* or almost three fourths of all patients
with acute coronary syndrome (ACS) (9). In selecting the
*Estimate includes secondary discharge diagnoses.

initial approach to care, the term “ischemia-guided
strategy” has replaced the previous descriptor, “initial
conservative management,” to more clearly convey the
physiological rationale of this approach.
The task of the 2014 GWC was to establish a contem-
porary CPG for the optimal management of patients with
NSTE-ACS. It incorporates both established and new evi-
dence from published clinical trials, as well as informa-
tion from basic science and comprehensive review
articles. These recommendations were developed to
guide the clinician in improving outcomes for patients
with NSTE-ACS. Table 2 lists documents deemed per-
tinent to this effort and is intended for use as a re-
source, thus obviating the need to repeat extant CPG
recommendations.
The GWC abbreviated the discussion sections to
include an explanation of salient information related to
the recommendations. In contrast to textbook declaratory
presentations, explanations were supplemented with
evidence tables. The GWC also provided a brief summary
TABLE 2 Associated CPGs and Statements
Title Organization
Publication Year
(Reference)
CPGs
Stable ischemic heart disease ACC/AHA/AATS/PCNA/SCAI/STS 2014 (10)*
2012 (11)
Atrial �brillation AHA/ACC/HRS 2014 (12)
Assessment of cardiovascular risk ACC/AHA 2013 (13)
Heart failure ACC/AHA 2013 (14)
Lifestyle management to reduce cardiovascular risk AHA/ACC 2013 (15)
Management of overweight and obesity in adults AHA/ACC/TOS 2013 (16)
ST-elevation myocardial infarction ACC/AHA 2013 (17)
Treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults ACC/AHA 2013 (18)
Acute myocardial infarction in patients presenting with ST-segment elevation ESC 2012 (19)
Device-based therapy ACC/AHA/HRS 2013 (20)
Third universal de�nition of myocardial infarction ESC/ACC/AHA/WHF 2012 (21)
Acute coronary syndromes in patients presenting without persistent ST-segment elevation ESC 2011 (22)
Coronary artery bypass graft surgery ACC/AHA 2011 (23)
Hypertrophic cardiomyopathy ACC/AHA 2011 (24)
Effectiveness-based guidelines for the prevention of cardiovascular disease in women AHA/ACC 2011 (25)
Percutaneous coronary intervention ACC/AHA/SCAI 2011 (26)
Secondary prevention and risk reduction therapy for patients with coronary and other
atherosclerotic vascular disease
AHA/ACC 2011 (27)
Assessment of cardiovascular risk in asymptomatic adults ACC/AHA 2010 (28)
Myocardial revascularization ESC 2010 (29)
Unstable angina and non–ST-elevation myocardial infarction NICE 2010 (30)†
par
ion,
tcom
pain
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Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care—
postcardiac arrest care
Seventh report of the joint national committee on prevention, detection, evaluat
treatment of high blood pressure
Statements
Key data elements and de�nitions for measuring the clinical management and ou
patients with acute coronary syndromes and coronary artery disease
Practical clinical considerations in the interpretation of troponin elevations
Testing of low-risk patients presenting to the emergency department with chest
Primary prevention of cardiovascular diseases in people with diabetes mellitus
Prevention and control of in�uenza
*The full-text SIHD CPG is from 2012 (11). A focused update was published in 2014 (10).
†Minor modi�cations were made in 2013. For a full explanation of the changes, see http://p
AATS indicates American Association for Thoracic Surgery; ACC, American College of Cardiolo
for Disease Control and Prevention; CPG, clinical practice guideline; ESC, European Society of C
NICE, National Institute for Health and Clinical Excellence; PCNA, Preventive Cardiovascular N
stable ischemic heart disease; STS, Society of Thoracic Surgeons; TOS, The Obesity Society; a
ded From: http://content.onlinejacc.org/ on 03/27/2015
t 9: AHA 2010 (31)
and NHLBI 2003 (32)
es of ACC/AHA 2013 (33)
ACC 2012 (34)
AHA 2010 (35)
AHA/ADA 2007 (36)
CDC 2005 (37)
ublications.nice.org.uk/unstable-angina-and-nstemi-cg94/changes-after-publication.
gy; ADA, American Diabetes Association; AHA, American Heart Association; CDC, Centers
ardiology; HRS, Heart Rhythm Society; NHLBI, National Heart, Lung, and Blood Institute;
urses Association; SCAI, Society for Cardiovascular Angiography and Interventions; SIHD,
nd WHF, World Heart Federation.

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of the relevant recommendations and references related
to secondary prevention rather than detailed reiteration.
Throughout, the goal was to provide the clinician with
concise, evidence-based contemporary recommendations
and the supporting documentation to encourage their
application.
2. OVERVIEW OF ACS
2.1. De�nition of Terms
ACS has evolved as a useful operational term that refers to
a spectrum of conditions compatible with acute myocar-
dial ischemia and/or infarction that are usually due to an
abrupt reduction in coronary blood �ow (Figure 1). A key
branch point is ST-segment elevation (ST-elevation) or
new left bundle-branch block on the electrocardiogram
(ECG), which is an indication for immediate coronary
angiography to determine if thereisanindicationfor
reperfusion therapy to open a likely completely occluded
coronary artery. Separate CPGs have been developed for
ST-elevation myocardial infarction (STEMI) (17).
The absence of persistent ST-elevation is suggestive
of NSTE-ACS (except in patients with true posterior
myocardial infarction [MI], Sections 3.3.2.4, 4.3.2,and
7.2.2). NSTE-ACS can be further subdivided on the basis of
cardiac biomarkers of necrosis (e.g., cardiac troponin,
Sections 3.2.4 and 3.4). If cardiac biomarkers are elevated
and the clinical context is appropriate, the patient is
considered to have NSTEMI (34); otherwise, the patient
is deemed to have UA. ST depression, transient ST-
elevation, and/or prominent T-wave inversions may be
present but are not required for a diagnosis of NSTEMI.
Abnormalities on the ECG and elevated troponins in
isolation are insuf�cient to make the diagnosis of ACS but
must be interpreted in the appropriate clinical context.
Thus, UA and NSTEMI are closely related conditions
whose pathogenesis and clinical presentations are similar
but vary in severity. The conditions differ primarily by
whether the ischemia is severe enough to cause myocar-
dial damage leading to detectable quantities of myocar-
dial injury biomarkers. The term “possible ACS” is often
assigned during initial evaluation if the ECG is unreveal-
ing and troponin data are not yet available. UA can pre-
sent without any objective data of myocardial ischemic
injury (normal ECG and normal troponin), in which case
the initial diagnosis depends solely on the patient’sclin-
ical history and the clinician’s interpretation and judg-
ment. However, with the increasing sensitivity of
troponin assays, biomarker-negative ACS (i.e., UA) is
becoming rarer (39). The pathogenesis of ACS is consid-
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
ered in the “Third Universal De�nition of Myocardial
Infarction” (21). This statement de�nes MI caused by a
primarycoronaryarteryprocesssuchasspontaneous
plaque rupture as MI type 1 and one related to reduced
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myocardial oxygen supply and/or increased myocardial
oxygen demand (in the absence of a direct coronary artery
process) as a MI type 2 (Appendix 4, Table A and Section
3.4 for an additional discussion on the diagnosis of MI).
2.2. Epidemiology and Pathogenesis
2.2.1. Epidemiology
In the United States, the median age at ACS presentation
is 68 years (interquartile range 56 to 79), and the male-to-
female ratio is approximately 3:2 (40).Somepatientshave
a history of stable angina, whereas in others, ACS is the
initial presentation of coronary artery disease (CAD). It is
estimated that in the United States, each year, >780,000
persons will experience an ACS. Approximately 70% of
these will have NSTE-ACS (9). Patients with NSTE-ACS
typically have more comorbidities, both cardiac and
noncardiac, than patients with STEMI.
2.2.2. Pathogenesis
The hallmark of ACS is the sudden imbalance between
myocardial oxygen consumption (MVO
2
)anddemand,
which is usually the result of coronary artery obstruction.
The imbalance may also be caused by other conditions,
including excessive myocardial oxygen demand in the
setting of a stable �ow-limiting lesion; acute coronary
insuf�ciency due to other causes (e.g., vasospastic
[Prinzmetal] angina [Section 7.11], coronary embolism,
coronary arteritis); noncoronary causes of myocardial
oxygen supply-demand mismatch (e.g., hypotension,
severe anemia, hypertension, tachycardia, hypertrophic
cardiomyopathy, severe aortic stenosis); nonischemic
myocardial injury (e.g., myocarditis, cardiac contusion,
cardiotoxic drugs); and multifactorial causes that are not
mutually exclusive (e.g., stress [Takotsubo] cardiomyop-
athy [Section 7.13], pulmonary embolism, severe heart
failure [HF], sepsis) (41).
3. INITIAL EVALUATION AND MANAGEMENT
3.1. Clinical Assessment and Initial Evaluation:
Recommendation
CLASS I
1. Patients with suspected ACS should be risk strati�ed based
on the likelihood of ACS and adverse outcome(s) to decide on
the need for hospitalization and assist in the selection of
treatment options (42–44). (Level of Evidence: B)
Patients with suspected ACS must be evaluated rapidly to
identify those with a life-threatening emergency versus
those with a more benign condition. The goal of the initial
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evaluation focuses on answering 2 questions:
1. What is the likelihood that the symptoms and signs
represent ACS?
2. What is the likelihood of adverse clinical outcome(s)?

FIGURE 1 Acute Coronary Syndromes
The top half of the �gure illustrates the progression of plaque formation and onset and complications of NSTE-ACS, with management at each stage. The
numbered section of an artery depicts the process of atherogenesis from 1) normal artery to 2) extracellular lipid in the subintima to 3) �brofatty stage to 4)
procoagulant expression and weakening of the �brous cap. ACS develops with 5) disruption of the �brous cap, which is the stimulus for thrombogenesis. 6)
Thrombus resorption may be followed by collagen accumulation and smooth muscle cell growth. Thrombus formation and possible coronary vasospasm
reduce blood �ow in the affected coronary artery and cause ischemic chest pain. The bottom half of the �gure illustrates the clinical, pathological, elec-
trocardiographic, and biomarker correlates in ACS and the general approach to management. Flow reduction may be related to a completely occlusive
thrombus (bottom half, right side) or subtotally occlusive thrombus (bottom half, left side). Most patients with ST-elevation (thick white arrow in bottom
panel) develop QwMI, and a few (thin white arrow) develop NQMI. Those without ST-elevation have either UA or NSTEMI (thick red arrows), a distinction
based on cardiac biomarkers. Most patients presenting with NSTEMI develop NQMI; a few may develop QwMI. The spectrum of clinical presentations
including UA, NSTEMI, and STEMI is referred to as ACS. This NSTE-ACS CPG includes sections on initial management before NSTE-ACS, at the onset of NSTE-
ACS, and during the hospital phase. Secondary prevention and plans for long-term management begin early during the hospital phase. Patients with
noncardiac etiologies make up the largest group presenting to the ED with chest pain (dashed arrow).
*Elevated cardiac biomarker (e.g., troponin), Section 3.4.
ACS indicates acute coronary syndrome; CPG, clinical practice guideline; Dx, diagnosis; ECG, electrocardiogram; ED, emergency department; MI, myocardial
infarction; NQMI, non–Q-wave myocardial infarction; NSTE-ACS, non–ST-elevation acute coronary syndromes; NSTEMI, non–ST-elevation myocardial
infarction; QwMI, Q-wave myocardial infarction; STEMI, ST-elevation myocardial infarction; and UA, unstable angina.
Modi�ed with permission from Libby et al. (38).
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Risk assessment scores and clinical prediction algorithms
using clinical history, physical examination, ECG, and
cardiac troponins have been developed to help identify
patients with ACS at increased risk of adverse outcome(s).
Common risk assessment tools include the TIMI (Throm-
bolysis In Myocardial Infarction) risk score (42),thePUR-
SUIT (Platelet Glycoprotein IIb/IIIa in Unstable Angina:
Receptor Suppression Using Integrilin Therapy) risk score
(43),theGRACE(GlobalRegistryofAcuteCoronary
Events) risk score (44),andtheNCDR-ACTION(National
Cardiovascular Data Registry-Acute Coronary Treatment
and Intervention Outcomes Network) registry (https://
www.ncdr.com/webncdr/action/). These assessment tools
havebeenappliedwithvariableef�cacy to predict out-
comes in patients presenting to the emergency depart-
ment (ED) with undifferentiated chest pain (“pain”
encompasses not only pain, but also symptoms such as
discomfort, pressure, and squeezing) (45–48). The Sanchis
score (49),Vancouverrule(50),Heart(History,ECG,Age,
Risk Factors, and Troponin) score (51),HEARTS
3
score (52),
and Hess prediction rule (53) were developed speci�cally
for patients in the ED with chest pain. Although no
de�nitive study has demonstrated the superiority of risk
assessment scores or clinical prediction rules over clinician
judgment, determination of the level of risk on initial
evaluation is imperative to guide patient management,
including the need for additional diagnostic testing and
treatment. See Section 3.2.2 for a discussion of risk strat-
i�cation variables.
See Online Data Supplement 1 for additional information
on clinical assessment and initial evaluation.
3.1.1. ED or Outpatient Facility Presentation: Recommendations
CLASS I
1. Patients with suspected ACS and high-risk features such as
continuing chest pain, severe dyspnea, syncope/presyncope,
or palpitations should be referred immediately to the ED and
transported by emergency medical services when available.
(Level of Evidence: C)
CLASS IIb
1. Patients with less severe symptoms may be considered for
referral to the ED, a chest pain unit, or a facility capable of
performing adequate evaluation depending on clinical
circumstances. (Level of Evidence: C)
Patients with suspected ACS and high-risk features should be
transported to the ED by emergency medical services when
available. Hospitals and outpatient facilities should provide
clearly visible signage directing patients transported by
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
private vehicle to the appropriate triage area. Outpatient
facilities should have the capacity for ECG and cardiac
troponin measurements with immediate ED referral for
those considered to have ACS.
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3.2. Diagnosis of NSTE-ACS
Differential diagnosis of NSTE-ACS includes (41):
� Nonischemic cardiovascular causes of chest pain
(e.g., aortic dissection, expanding aortic aneurysm,
pericarditis, pulmonary embolism)
� Noncardiovascular causes of chest, back, or upper
abdominal discomfort include:
o Pulmonary causes (e.g., pneumonia, pleuritis,
pneumothorax)
o Gastrointestinal causes (e.g., gastroesophageal re-
�ux,esophagealspasm,pepticulcer,pancreatitis,
biliary disease)
o Musculoskeletal causes (e.g., costochondritis, cervi-
cal radiculopathy)
o Psychiatric disorders
o Other etiologies (e.g., sickle cell crisis, herpes zoster)
In addition, the clinician should differentiate NSTE-ACS from
acute coronary insuf�ciency due to a nonatherosclerotic
cause and noncoronary causes of myocardial oxygen supply-
demand mismatch (41) (Section 2.2.2).
3.2.1. History
NSTE-ACS most commonly presents as a pressure-type
chest pain that typically occurs at rest or with minimal
exertion lasting $10 minutes (41). The pain most
frequently starts in the retrosternal area and can radiate
to either or both arms, the neck, or the jaw. Pain may also
occur in these areas independent of chest pain. Patients
with NSTE-ACS may also present with diaphoresis, dys-
pnea, nausea, abdominal pain, or syncope. Unexplained
new-onset or increased exertional dyspnea is the most
common angina equivalent. Less common presentations
include nausea and vomiting, diaphoresis, unexplained
fatigue, and syncope. Factors that increase the probability
of NSTE-ACS are older age, male sex, positive family his-
tory of CAD, and the presence of peripheral arterial
disease, diabetes mellitus, renal insuf�ciency, prior MI,
and prior coronary revascularization. Although older pa-
tients ($75 years of age) and women usually present with
typical symptoms of ACS, the frequency of atypical pre-
sentations is increased in these groups as well as in patients
with diabetes mellitus, impaired renal function, and
dementia (54,55). Atypical symptoms, including epigastric
pain, indigestion, stabbing or pleuritic pain, and increasing
dyspnea in the absence of chest pain should raise concern
for NSTE-ACS (56). Psychiatric disorders (e.g., somatoform
disorders, panic attack, anxiety disorders) are noncardiac
causes of chest pain that can mimic ACS (57).
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3.2.2. Physical Examination
The physical examination in NSTE-ACS can be normal, but
signs of HF should expedite the diagnosis and treatment

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of this condition. Acute myocardial ischemia may cause a
S
4
, a paradoxical splitting of S
2
, or a new murmur of mitral
regurgitation due to papillary muscle dysfunction. How-
ever, these signs may also exist without NSTE-ACS and
thus are nonspeci�c.Thecouplingofpainonpalpation
suggesting musculoskeletal disease or in�ammation with
a pulsatile abdominal mass suggesting abdominal aortic
aneurysm raises concern for nonischemic causes of NSTE-
ACS. The physical examination can indicate alternative
diagnoses in patients with chest pain, several of which are
life threatening. Aortic dissection is suggested by back
pain, unequal palpated pulse volume, a difference of $15
mm Hg between both arms in systolic blood pressure (BP),
or a murmur of aortic regurgitation. Acute pericarditis is
suggested by a pericardial friction rub. Cardiac tampo-
nade can be re�ected by pulsus paradoxus. Pneumo-
thorax is suspected when acute dyspnea, pleuritic chest
pain, and differential breath sounds are present. A pleural
friction rub may indicate pneumonitis or pleuritis.
3.2.3. Electrocardiogram
A 12-lead ECG should be performed and interpreted within
10 minutes of the patient’s arrival at an emergency facility
to assess for cardiac ischemia or injury (21).Changeson
ECG in patients with NSTE-ACS include ST depression,
transient ST-elevation, or new T-wave inversion (21,58).
Persistent ST-elevation or anterior ST depression indica-
tive of true posterior MI should be treated according to the
STEMI CPG (17). The ECG can be relatively normal or
initially nondiagnostic; if this is the case, the ECG should
be repeated (e.g., at 15- to 30-minute intervals during the
�rst hour), especially if symptoms recur (21).AnormalECG
does not exclude ACS and occurs in 1% to 6% of such pa-
tients (59–61). A normal ECG may also be associated with
left circum�ex or right coronary artery occlusions, which
can be electrically silent (in which case posterior electro-
cardiographic leads [V
7
to V
9
] may be helpful). Right-sided
leads (V
3
RtoV
4
R) are typically performed in the case of
inferior STEMI to detect evidence of right ventricular
infarction. Left ventricular (LV) hypertrophy, bundle-
branch blocks with repolarization abnormalities, and
ventricular pacing may mask signs of ischemia/injury (62).
3.2.4. Biomarkers of Myocardial Necrosis
Cardiac troponins are the most sensitive and speci�c
biomarkers for NSTE-ACS. They rise within a few hours of
symptom onset and typically remain elevated for several
days (but may remain elevated for up to 2 weeks with a
large infarction). A negative cardiac troponin obtained
with more sensitive cardiac troponin assays on admission
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confers a>95% negative predictive value for MI compared
with high-sensitivity assays that confer a negative pre-
dictive value $99% (63–65).SeeSection 3.4 for a detailed
review of biomarkers for the diagnosis of MI.
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3.2.5. Imaging
A chest roentgenogram is useful to identify potential
pulmonary causes of chest pain and may show a widened
mediastinum in patients with aortic dissection. Com-
puted tomography (CT) of the chest with intravenous
contrast can help exclude pulmonary embolism and aortic
dissection. Transthoracic echocardiography can identify a
pericardial effusion and tamponade physiology and may
also be useful to detect regional wall motion abnormal-
ities. Transesophageal echocardiography can identify a
proximal aortic dissection. In low-risk patients with chest
pain, coronary CT angiography can result in a more rapid,
more cost-effective diagnosis than stress myocardial
perfusion imaging (66).
3.3. Prognosis—Early Risk Strati�cation: Recommendations
See Table 4 for a summary of recommendations from this
section.
CLASS I
1. In patients with chest pain or other symptoms suggestive of
ACS, a 12-lead ECG should be performed and evaluated for
ischemic changes within 10 minutes of the patient’s arrival at
an emergency facility (21). (Level of Evidence: C)
2. If the initial ECG is not diagnostic but the patient remains
symptomatic and there is a high clinical suspicion for ACS,
serial ECGs (e.g., 15- to 30-minute intervals during the �rst
hour) should be performed to detect ischemic changes.
(Level of Evidence: C)
3. Serial cardiac troponin I or T levels (when a contemporary
assay is used) should be obtained at presentation and 3 to 6
hours after symptom onset (see Section 3.4,ClassI,#3
recommendation if time of symptom onset is unclear) in
all patients who present with symptoms consistent with
ACS to identify a rising and/or falling pattern of values
(21,64,67–71). (Level of Evidence: A)
4. Additional troponin levels should be obtained beyond
6 hours after symptom onset (see Section 3.4,ClassI,#3
recommendation if time of symptom onset is unclear) in
patients with normal troponin levels on serial examination
when changes on ECG and/or clinical presentation confer an
intermediate or high index of suspicion for ACS (21,72–74).
(Level of Evidence: A)
5. Risk scores should be used to assess prognosis in patients
with NSTE-ACS (42–44,75–80). (Level of Evidence: A)
CLASS IIa
1. Risk-strati�cationmodelscanbeusefulinmanagement
(42–44,75–81). (Level of Evidence: B)
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
2. It is reasonable to obtain supplemental electrocardiographic
leads V
7
to V
9
in patients whose initial ECG is nondiagnostic
and who are at intermediate/high risk of ACS (82–84). (Level
of Evidence: B)

CLASS IIb
1. Continuous monitoring with 12-lead ECG may be a reason-
able alternative in patients whose initial ECG is non-
diagnostic and who are at intermediate/high risk of ACS
(85,86). (Level of Evidence: B)
2. Measurement of B-type natriuretic peptide or N-terminal pro–
B-type natriuretic peptide may be considered to assess risk in
patients with suspected ACS (87–91). (Level of Evidence: B)
3.3.1. Rationale for Risk Strati�cation and Spectrum of Risk:
High, Intermediate, and Low
TIMI Risk Recurrent Ischemia Requiring Urgent Revascularization
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Score Through 14 d After Randomization, %
0–1 4.7
2 8.3
3 13.2
4 19.9
5 26.2
6–7 40.9
*The TIMI risk score is determined by the sum of the presence of 7 variables at
admission; 1 point is given for each of the following variables: $65 y of age; $3 risk
Assessment of prognosis guides initial clinical evaluation
and treatment and is useful for selecting the site of
care (coronary care unit, monitored step-down unit, or
outpatient monitored unit), antithrombotic therapies
(e.g., P2Y
12
inhibitors, platelet glycoprotein [GP] IIb/IIIa
inhibitors [Sections 4.3.1.2 and 5.1.2.2]), and invasive
management (Sections 4.4.2.1, 4.3.1, 4.4, 4.4.4, 4.4.5).
There is a strong relationship between indicators of
ischemia due to CAD and prognosis (Table 3 and Figure 2).
Patients with a high likelihood of ischemia due to CAD are
atgreaterriskofamajoradversecardiacevent(MACE)
than patients with a lower likelihood of ischemia due to
CAD. Risk is highest at the time of presentation but re-
mainselevatedpasttheacutephase.By6months,NSTE-
ACS mortality rates may equal or exceed those of STEMI
(58). By 12 months, rates of death, MI, and recurrent
instability in contemporary registries are >10%. Early
events are related to the ruptured coronary plaque and
thrombosis, and later events are more closely associated
with the pathophysiology of chronic atherosclerosis and
LV systolic function (92–98).
3.3.2. Estimation of Level of Risk
At initial presentation, the clinical history, anginal
symptoms and equivalents, physical examination, ECG,
TABLE 3 TIMI Risk Score* for NSTE-ACS
All-Cause Mortality, New or Recurrent MI, or Severe
factors for CAD; prior coronary stenosis $50%; ST deviation on ECG; $2 anginal events
in prior 24 h; use of aspirin in prior 7 d; and elevated cardiac biomarkers.
CAD indicates coronary artery disease; ECG, electrocardiogram; MI, myocardial
infarction; NSTE-ACS, non–ST-elevation acute coronary syndromes; and TIMI, Throm-
bolysis In Myocardial Infarction.
Modi�ed with permission from Antman et al. (42).
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renal function, and cardiac troponin measurements can
be integrated into an estimation of the risk of death and
nonfatal cardiac ischemic events (Table 3 and Figure 2)
(42,78).
3.3.2.1. History: Angina Symptoms and Angina Equivalents
In patients with or without known CAD, clinicians must
determine whether the presentation is consistent with
acute ischemia, stable ischemic heart disease, or an
alternative etiology. Factors in the initial clinical history
related to the likelihood of acute ischemia include age,
sex, symptoms, prior history of CAD, and the number of
traditional risk factors (99–105).
The characteristics of angina include deep, poorly
localized chest or arm pain that is reproducibly associated
with exertion or emotional stress (106). Angina is relieved
promptly (i.e., in <5 minutes) with rest and/or short-
acting nitroglycerin. Patients with NSTE-ACS may have
typical or atypical anginal symptoms, but episodes are
more severe and prolonged, may occur at rest, or may be
precipitated by less exertion than the patient previously
experienced. Some patients have no chest pain but pre-
sent solely with dyspnea or with arm, shoulder, back, jaw,
neck, epigastric, or ear discomfort (107–109).
Features not characteristic of myocardial ischemia
include:
� Pleuritic pain (sharp or knifelike pain provoked by
respiration or cough);
� Primary or sole location of discomfort in the middle or
lower abdomen;
� Pain localized by the tip of 1 �nger, particularly at the
LV apex or costochondral junction;
� Pain reproduced with movement or palpation of the
chest wall or arms;
� Brief episodes of pain lasting a few seconds or less;
� Pain that is of maximal intensity at onset; and
� Pain that radiates into the lower extremities.
Evaluation should include the clinician’s impression of
whether the pain represents a high, intermediate, or low
likelihood of acute ischemia.
Although typical characteristics increase the probability
of CAD, atypical features do not exclude ACS. In the
Multicenter Chest Pain Study, acute ischemia was diag-
nosed in 22% of patients who presented to the ED with
sharp or stabbing pain and in 13% of those with pleuritic
pain (110). Seven percent of patients whose pain was
reproduced with palpation had ACS. The ACI-TIPI (Acute
Cardiac Ischemia Time-Insensitive Predictive Instrument)
project found that older age, male sex, chest or left arm
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pain, and chest pain or pressure were the most important
�ndings, and each increased the likelihood of ACS (111,112).
The relief of chest pain with nitroglycerin is not pre-
dictive of ACS. One study reported that sublingual

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10 m
tic p
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nset
ond
itial
ACS
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nitroglycerin relieved symptoms in 35% of patients with
documented ACS compared with 41% of patients without
ACS (113).Thereliefofchestpainby“gastrointestinal
cocktails” (e.g., mixtures of liquid antacids, and/or
viscous lidocaine, and/or anticholinergic agents) does not
predict the absence of ACS (114).
3.3.2.2. Demographics and History in Diagnosis and Risk
TABLE 4 Summary of Recommendations for Prognosis: Earl
Recommendations
Perform rapid determination of likelihood of ACS, including a 12-lead ECG within
emergency facility, in patients whose symptoms suggest ACS
Perform serial ECGs at 15- to 30-min intervals during the �rst hour in symptoma
nondiagnostic ECG
Measure cardiac troponin (cTnI or cTnT) in all patients with symptoms consistent
Measure serial cardiac troponin I or T at presentation and 3–6 h after symptom o
symptoms consistent with ACS
Use risk scores to assess prognosis in patients with NSTE-ACS
Risk-strati�cation models can be useful in management
Obtain supplemental electrocardiographic leads V
7
to V
9
in patients with initial n
intermediate/high risk for ACS
Continuous monitoring with 12-lead ECG may be a reasonable alternative with in
in patients at intermediate/high risk for ACS
BNP or NT–pro-BNP may be considered to assess risk in patients with suspected
*See Section 3.4, Class I, #3 recommendation if time of symptom onset is unclear.
ACS indicates acute coronary syndromes; BNP, B-type natriuretic peptide; COR, Class of
LOE, Level of Evidence; N/A, not available; NSTE-ACS, non�ST-elevation acute coronar
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DECEMBER 23, 2014:e139– 228
Strati�cation
A prior history of MI is associated with a high risk of
obstructive and multivessel CAD (115).Womenwithsus-
pected ACS are less likely to have obstructive CAD than
men. When obstructive CAD is present in women, it tends
to be less severe than it is in men (116). It has been
suggested that coronary microvascular disease and endo-
thelial dysfunction play a role in the pathophysiology of
NSTE-ACS in patients with nonobstructive CAD (116).Older
adults have increased risks of underlying CAD (117,118),
multivessel CAD, and a worse prognosis (Section 7.1).
A family history of premature CAD is associated with
increased coronary artery calcium scores (119) and
increased risk of 30-day cardiac events in patients with ACS
(120,121). Diabetes mellitus, extracardiac (carotid, aortic, or
peripheral) arterial disease, and hypertension are major
risk factors for poor outcomes in patients with ACS (Section
6.2)withbothSTEMI(122) and NSTE-ACS (92).
The current or prior use of aspirin at presentation is
associated with increased cardiovascular risk (42),likely
re�ecting the greater probability that patients who have
been prescribed aspirin have an increased cardiovascular
risk pro�le and/or prior vascular disease. Smoking is
associated with a lower risk of death in ACS (42,123,124),
primarily because of the younger age of smokers with ACS
ded From: http://content.onlinejacc.org/ on 03/27/2015
and less severe CAD. Overweight and/or obesity at ACS
presentation are associated with lower short-term risk of
death. The “obesity paradox” may be a function of
younger age at presentation, referral for angiography at
an earlier stage of disease, and more aggressive manage-
ment of ACS (123). These individuals, especially those
with severe obesity (body mass index >35), have a higher
long-term total mortality risk (124–129).
sk Strati�cation
COR LOE References
in of arrival at an IC (21)
atients with initial I C N/A
h ACS* IA(21,64,67–71)
* in all patients with IA (21,72–74)
I A (42–44,75–80)
IIa B (42–44,75–81)
iagnostic ECG at IIa B (82–84)
nondiagnostic ECG IIb B (85,86)
IIb B (87–91)
ommendation; cTnI, cardiac troponin I; cTnT, cardiac troponin T; ECG, electrocardiogram;
dromes; and NT–pro-BNP, N-terminal pro–B-type natriuretic peptide.
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
Cocaine use can cause ACS by inducing coronary
vasospasm, dissection, thrombosis, positive chronotropic
and hypertensive actions, and direct myocardial toxicity
(Section 7.10) (130). Methamphetamines are also associ-
ated with ACS (131). Urine toxicology screening should be
considered when substance abuse is suspected as a cause
of or contributor to ACS, especially in younger patients
(<50 years of age) (132).
3.3.2.3. Early Estimation of Risk
The TIMI risk score is composed of 7, 1-point risk
indicators rated on presentation (Table 3) (42).Thecom-
posite endpoints increase as the score increases. The TIMI
risk score has been validated internally within the TIMI
11B trial and in 2 separate cohorts of patients from the
ESSENCE (Ef�cacy and Safety of Subcutaneous Enox-
aparin in Non–Q-Wave Coronary Event) trial (133).The
TIMI risk score calculator is available at www.timi.org.
The TIMI risk index is useful in predicting 30-day
and 1-year mortality in patients with NSTE-ACS (134).
For patients with a TIMI risk score of 0 and normal
high-sensitivity cardiac troponin 2 hours after presenta-
tion, accelerated diagnostic protocols have been devel-
oped that predict a very low rate of 30-day MACE
(Section 3.4.3) (65).

FIGURE 2 Global Registry of Acute Coronary Events Risk Calculator for In-Hospital Mortality for Acute Coronary Syndrome
Amsterdam et al.
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2014 AHA/ACC NSTE-ACS Guideline
DECEMBER 23, 2014:e139– 228
e152
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The GRACE risk model predicts in-hospital and post-
discharge mortality or MI (44,78,79,81).TheGRACEtool
was developed from 11,389 patients in GRACE and vali-
datedinsubsequentGRACEandGUSTO(Global
Utilization of Streptokinase and Tissue Plasminogen
Activator for Occluded Coronary Arteries) IIb cohorts. The
sum of scores is applied to a reference nomogram to
determine all-cause mortality from hospital discharge to
6 months. The GRACE clinical application tool is a
web-based downloadable application available at http://
www.outcomes-umassmed.org/grace/ (Figure 2) (44,135).
Among patients with a higher TIMI risk score (e.g., $3),
there is a greater bene�t from therapies such as low-
molecular-weight heparin (LMWH) (133,136),plateletGP
IIb/IIIa inhibitors (137), and an invasive strategy (138).
Similarly, the GRACE risk model can identify patients who
would bene�t from an early invasive strategy (139).
Patients with elevated cardiac troponin bene�tfrommore
aggressive therapy, whereas those without elevated
cardiac troponins may not (140).Thisisespeciallytruefor
women in whom some data suggest adverse effects from
invasive therapies in the absence of an elevated cardiac
troponin value (141). Although B-type natriuretic peptide
and N-terminal pro–B-type natriuretic peptide are not
useful for the diagnosis of ACS per se (but rather HF,
which has many etiologies), they add prognostic value
(87–91).
3.3.2.4. Electrocardiogram
The 12-lead ECG is pivotal in the decision pathway for the
evaluation and management of patients presenting with
symptoms suggestive of ACS (58,59,85). Transient ST
changes ($0.5 mm [0.05 mV]) during symptoms at rest
strongly suggest ischemia and underlying severe CAD.
Patients without acute ischemic changes on ECG have a
reduced risk of MI and a very low risk of in-hospital life-
threatening complications, even in the presence of
confounding electrocardiographic patterns such as LV
hypertrophy (143–145). ST depression (especially horizon-
tal or downsloping) is highly suggestive of NSTE-
ACS (21,146,147). Marked symmetrical precordial T-wave
inversion ($2 mm [0.2 mV]) suggests acute ischemia,
particularly due to a critical stenosis of the left anterior
descending coronary artery (148,149); it may also be seen
with acute pulmonary embolism and right-sided ST-T
changes.
Nonspeci�c ST-T changes (usually de�ned as ST devi-
ation of<0.5 mm [0.05 mV] or T-wave inversion of <2mm
[0.2 mV]) are less helpful diagnostically. Signi�cant Q
waves are less helpful, although by suggesting prior MI,
JACC VOL. 64, NO. 24, 2014
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they indicate a high likelihood of signi�cant CAD. Isolated
Q waves in lead 3 are a normal �nding. A completely
normal ECG in a patient with chest pain does not exclude
ACS, because 1% to 6% of such patients will have a MI,
ded From: http://content.onlinejacc.org/ on 03/27/2015
and at least 4% will have UA (59–61). Fibrinolytic therapy
is contraindicated for patients with ACS without ST-
elevation, except for those with electrocardiographic
evidence of true posterior MI (i.e., ST-elevation in pos-
terior chest leads [V
7
to V
9
]).Thiscanbeevaluatedwhen
acute myocardial infarction (AMI) is suspected but elec-
trocardiographic changes are modest or not present
(82–84); a transthoracic echocardiogram to evaluate for
posterior wall motion abnormalities may also be helpful
in this setting.
Alternative causes of ST-T changes include LV aneu-
rysm, pericarditis, myocarditis, bundle-branch block, LV
hypertrophy, hyperkalemia, Prinzmetal angina, early
repolarization, apical LV ballooning syndrome (Takotsubo
cardiomyopathy, Section 7.13), and Wolff-Parkinson-
White conduction. Central nervous system events and
therapy with tricyclic antidepressants or phenothiazines
can cause deep T-wave inversion.
3.3.2.5. Physical Examination
The physical examination is helpful in assessing the
hemodynamic impact of an ischemic event. Patients with
suspected ACS should have vital signs measured (BP in
both arms if dissection is suspected) and should undergo
a thorough cardiovascular examination. Patients with
evidence of LV dysfunction on examination (e.g., rales, S
3
gallop) or acute mitral regurgitation have a higher likeli-
hood of severe underlying CAD and are at high risk of a
poor outcome. In the SHOCK (Should we Emergently
Revascularize Occluded Coronaries for Cardiogenic
Shock) study, NSTEMI accounted for approximately 20%
of cardiogenic shock complicating MI (150). Other trials
have reported lower percentages (92,151).Thephysical
examination may also help identify comorbid conditions
(e.g., occult GI bleeding) that could impact therapeutic
risk and decision making.
See Online Data Supplement 2 for additional information
on risk strati�cation.
3.4. Cardiac Biomarkers and the Universal De�nition of MI:
Recommendations
See Table 5 for a summary of recommendations from this
section and Online Data Supplement 3 for additional in-
formation on cardiac injury markers and the universal
de�nition of AMI.
3.4.1. Biomarkers: Diagnosis
CLASS I
1. Cardiac-speci�c troponin (troponin I or T when a contem-
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
porary assay is used) levels should be measured at presen-
tation and 3 to 6 hours after symptom onset in all patients
who present with symptoms consistent with ACS to identify
a rising and/or falling pattern (21,64,67–71,152–156). (Level
of Evidence: A)

kers
er sy
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for
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easo
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MI, myocardial infarction.
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2. Additional troponin levels should be obtained beyond
6 hours after symptom onset in patients with normal tro-
ponins on serial examination when electrocardiographic
changes and/or clinical presentation confer an intermediate
or high index of suspicion for ACS (21,72–74,157). (Level of
Evidence: A)
3. If the time of symptom onset is ambiguous, the time of
presentation should be considered the time of onset for
assessing troponin values (67,68,72). (Level of Evidence: A)
CLASS III: NO BENEFIT
1. With contemporary troponin assays, creatine kinase myocar-
TABLE 5 Summary of Recommendations for Cardiac Biomar
Recommendations
Diagnosis
Measure cardiac-speci�c troponin (troponin I or T) at presentation and 3—6 h aft
patients with suspected ACS to identify pattern of values
Obtain additional troponin levels beyond 6 h in patients with initial normal seria
electrocardiographic changes and/or intermediate/high risk clinical features
Consider time of presentation the time of onset with ambiguous symptom onset
With contemporary troponin assays, CK-MB and myoglobin are not useful for dia
Prognosis
Troponin elevations are useful for short- and long-term prognosis
Remeasurement of troponin value once on d 3 or 4 in patients with MI may be r
infarct size and dynamics of necrosis
BNP may be reasonable for additional prognostic information
ACS indicates acute coronary syndromes; BNP, B-type natriuretic peptide; CK-MB, creatin
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
dial isoenzyme (CK-MB) and myoglobin are not useful for
diagnosis of ACS (158–164). (Level of Evidence: A)
3.4.2. Biomarkers: Prognosis
CLASS I
1. The presence and magnitude of troponin elevations are
useful for short- and long-term prognosis (71,73,165,166).
(Level of Evidence: B)
CLASS IIb
1. It may be reasonable to remeasure troponin once on day 3 or
day 4 in patients with MI as an index of infarct size and
dynamics of necrosis (164,165). (Level of Evidence: B)
2. Use of selected newer biomarkers, especially B-type natriuretic
peptide, may be reasonable to provide additional prognostic
information (87,88,167–171). (Level of Evidence: B)
Cardiac troponins are the mainstay for diagnosis of ACS and
for risk strati�cation in patients with ACS. The primary
diagnostic biomarkers of myocardial necrosis are cardiac
troponin I and cardiac troponin T. Features that favor tro-
ponins for detection of ACS include high concentrations of
troponins in the myocardium; virtual absence of troponins in
: http://content.onlinejacc.org/ on 03/27/2015
nonmyocardial tissue; high-release ratio into the systemic
circulation (amount found in blood relative to amount
depleted from myocardium); rapid release into the blood in
proportion to the extent of myocardial injury; and the ability
to quantify values with reproducible, inexpensive, rapid, and
easily applied assays. The 2012 Third Universal De�nition of
MI provides criteria that classify 5 clinical presentations of MI
on the basis of pathological, clinical, and prognostic factors
(21). In the appropriate clinical context, MI is indicated by a
rising and/or falling pattern of troponin with $1 value above
the 99th percentile of the upper reference level and evidence
for serial increases or decreases in the levels of troponins
and the Universal De�nition of MI
COR LOE References
mptom onset in all IA(21,64,67–71,152–156)
ponins with IA(21,72–74,157)
assessing troponin values I A (67,68,72)
sis of ACS III: No Bene�tA (158–164)
I B (71,73,165,166)
nable as an index of IIb B (164,165)
IIb B (87,88,167–171)
ase myocardial isoenzyme; COR, Class of Recommendation; LOE, Level of Evidence; and
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
(67,68,156). The potential consequences of emerging high-
sensitivity troponin assays include increases in the diag-
nosis of NSTEMI (152,172,173) in�uenced by the de�nition of
an abnormal troponin (67,153,174,175). The recommenda-
tions in this section are formulated from studies predicated
on both the new European Society of Cardiology/ACC/AHA/
World Health Organization criteria (21) and previous criteria/
rede�nitions of MI based on earlier-generation troponin
assays (Appendix 4, Table A).
3.4.3. Cardiac Troponins
See Online Data Supplement 4 for additional information
on cardiac troponins.
Of the 3 troponin subunits, 2 subunits (troponin I and
troponin T) are derived from genes speci�cally expressed
in the myocardium. Cardiac troponin measurements
provide highly sensitive results speci�cfordetecting
cardiomyocyte necrosis (34,173). Highly sensitive assays
can identify cardiac troponin not only in the blood of
patients with acute cardiac injury, but also in the blood of
most healthy people (64,68,70,166,176,177).Asassay
sensitivity increases, a greater proportion of patients will
have detectable long-term elevations in troponin, thus

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requiring consideration of serial changes for the diagnosis
of MI. Clinicians should be aware of the sensitivity of the
tests used for troponin evaluation in their hospitals and
cutpoint concentrations for clinical decisions. Markedly
elevated values are usually related to MI, myocarditis,
rare analytical factors, or chronic elevations in patients
with renal failure and in some patients with HF.
CPGs endorse the 99th percentile of the upper refer-
ence level as the appropriate cutpoint for considering
myocardial necrosis (21,22). For the diagnosis of acute
myocardial necrosis, it is important to determine not only
the peak troponin value, but also serial changes:
1. A troponin value above the 99th percentile of the upper
reference level is required. Additionally, evidence for a
serial increase or decrease $20% is required if the
initial value is elevated (21,178).
2. For any troponin values below or close to the 99th
percentile, evidence for acute myocardial necrosis is
indicated by a change of $3 standard deviations of the
variation around the initial value as determined by the
individual laboratory (21,179).
3. Clinical laboratory reports should indicate whether
signi�cant changes in cardiac troponin values for the
particular assay have occurred.
Absolute changes in nanograms per liter of high-sensitivity
cardiac troponin T levels appear to have a signi�cantly
higher diagnostic accuracy for AMI than relative changes and
may distinguish AMI from other causes of high-sensitivity
cardiac troponin T elevations (71). This has also been sug-
gested for some contemporary assays (71). Troponins are
elevated in MI as early as 2 to 4 hours after symptom onset
(64,70), and many medical centers obtain troponins at 3
hours. Depending on the assay, values may not become
abnormal for up to 12 hours. In the vast majority of patients
with symptoms suggestive of ACS, MI can be excluded or
con�rmed within 6 hours, because very few patients present
immediately after symptom onset. In high-risk patients,
measurements after 6 hours may be required to identify ACS.
Solitary elevations of troponin cannot be assumed
to be due to MI, because troponin elevations can be
due to tachyarrhythmia, hypotension or hypertension,
cardiac trauma, acute HF, myocarditis and pericarditis,
acute pulmonary thromboembolic disease, and severe
noncardiac conditions such as sepsis, burns, respiratory
failure, acute neurological diseases, and drug toxicity
(including cancer chemotherapy). Chronic elevations can
result from structural cardiac abnormalities such as LV
hypertrophy or ventricular dilatation and are also com-
mon in patients with renal insuf�ciency (34).Patients
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DECEMBER 23, 2014:e139– 228
with end-stage renal disease and no clinical evidence of
ACS frequently have elevations of cardiac troponin
(180–182). With conventional assays, this is more common
with cardiac troponin T than with cardiac troponin I (180).
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In the diagnosis of NSTEMI, cardiac troponin values must
manifest an acute pattern consistent with the clinical
events, including ischemic symptoms and electrocardio-
graphic changes. Troponin elevations may persist for up
to 14 days or occasionally longer. There is a paucity of
guidelines for establishment of reinfarction during the
acute infarct period on the basis of troponin measure-
ments. References suggest that an increase of >20% of
previous troponin levels or an absolute increase of high-
sensitivity cardiac troponin T values (e.g., >7ng/Lover
2 hours) may indicate reinfarction (183–185).
During pregnancy, troponin values are within the
normal range in the absence of cardiovascular morbid-
ities. There is controversy as to whether troponin levels
are elevated in pre-eclampsia, eclampsia, or gestational
hypertension (186–189).Whenpresent,cardiactroponin
elevations re�ect myocardial necrosis.
Point-of-care troponin values may provide initial
diagnostic information, although their sensitivity is sub-
stantially below that of central laboratory methods
(154,155,190–192). In addition, the rigorous quantitative
assay standardization needed for routine diagnosis favors
central laboratory testing.
3.4.3.1. Prognosis
Troponin elevations convey prognostic assessment
beyond that of clinical information, the initial ECG, and
the predischarge stress test (71). In addition, troponin
elevations may provide information to direct therapy.
Patients with cardiac troponin elevations are at high risk
and bene�t from intensive management and early revas-
cularization (193–195). High risk is optimally de�ned by
the changing pattern as described in Section 3.4.3.Cardiac
troponin elevations correlate with estimation of infarct
size and risk of death; persistent elevation 72 to 96 hours
after symptom onset may afford relevant information in
this regard (164). Elevations of cardiac troponin can occur
for multiple reasons other than MI. In these cases, there is
often substantial risk of adverse outcomes, as troponin
elevation indicates cardiomyocyte necrosis (181).
3.4.4. CK-MB and Myoglobin Compared With Troponin
Previously, CK-MB was used for early evidence of myo-
cardial injury. Because myoglobin is a relatively small
molecule, it is rapidly released from infarcted myocar-
dium. CK-MB is much less sensitive for detection of
myocardial injury than troponin, and substantially more
tissue injury is required for its detection. With the
availability of cardiac troponin, CK-MB, myoglobin, and
other diagnostic biomarkers are no longer necessary
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
(158,160–163,196–198).CK-MBmaybeusedtoestimateMI
size. Detection of MI after percutaneous coronary inter-
vention (PCI) remains an area of controversy. Because of
the increased sensitivity of cardiac troponin, the

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prognostic value associated with varying degrees of
elevation remains unclear.
See Online Data Supplements 5, 6, and 7 for additional
information on cardiac injury markers.
3.5. Immediate Management
3.5.1. Discharge From the ED or Chest Pain Unit:
Recommendations
CLASS IIa
1. It is reasonable to observe patients with symptoms con-
sistent with ACS without objective evidence of myocardial
ischemia (nonischemic initial ECG and normal cardiac
troponin) in a chest pain unit or telemetry unit with serial
ECGs and cardiac troponin at 3- to 6-hour intervals
(196,197,199–201). (Level of Evidence: B)
2. It is reasonable for patients with possible ACS who have
normal serial ECGs and cardiac troponins to have a
treadmill ECG (200–202) (Level of Evidence: A),stress
myocardial perfusion imaging (200), or stress echocardiog-
raphy (203,204) before discharge or within 72 hours after
discharge. (Level of Evidence: B)
3. In patients with possible ACS and a normal ECG, normal
cardiac troponins, and no history of CAD, it is reasonable to
initially perform (without serial ECGs and troponins) coro-
nary CT angiography to assess coronary artery anatomy
(205–207) (Level of Evidence: A) or rest myocardial perfu-
sion imaging with a technetium-99m radiopharmaceutical
to exclude myocardial ischemia (208,209). (Level of
Evidence: B)
4. It is reasonable to give low-risk patients who are referred for
outpatient testing daily aspirin, short-acting nitroglycerin,
and other medication if appropriate (e.g., beta blockers),
with instructions about activity level and clinician follow-up.
(Level of Evidence: C)
The majority of patients presenting to the ED with chest
pain do not have ACS (Figure 1), and most are at low risk for
major morbidity and mortality (35). Low-risk patients are
usually identi�ed by an absence of history of cardiovascular
disease, normal or near-normal initial ECG, normal initial
troponin, and clinical stability (35,202). The utility of an
accelerated diagnostic protocol for detecting patients with
benign conditions versus those who require admission for
serious disease has been established (35). At minimum,
these protocols involve serial ECGs and troponin measure-
ments, both of which can be performed in the ED, a sepa-
rate chest pain unit, or a telemetry unit. A 30-day negative
predictive value >99% for ACS has been reported for pa-
tients presenting to the ED with chest pain who undergo a
2-hour accelerated diagnostic protocol composed of a TIMI
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
risk score of 0, normal ECG, and normal high-sensitivity
troponin at 0 hours and 2 hours (assuming appropriate
follow-up care) (65,210). Some protocols also call for
a functional or anatomic test (e.g., treadmill test, rest
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scintigraphy, coronary CT angiography, stress imaging).
Coronary CT angiography is associated with rapid assess-
ment, high negative predictive value, decreased length of
stay, and reduced costs (205–207); however, in the latter
studies, it increased the rate of invasive coronary angiog-
raphy and revascularization with uncertain long-term
bene�ts in low-risk patients without ECG or troponin al-
terations (211). Accelerated diagnostic protocols are also
potentially applicable in intermediate-risk patients, whose
presentation includes a history of cardiovascular disease,
diabetes mellitus, chronic kidney disease (CKD), and/or
advanced age (202).
See Online Data Supplement 8 for additional informa-
tion on discharge from the ED or chest pain unit.
4. EARLY HOSPITAL CARE
The standard of care for patients who present with
NSTE-ACS, including those with recurrent symptoms,
ischemic electrocardiographic changes, or positive car-
diac troponins, is admission for inpatient management.
The goals of treatment are the immediate relief of
ischemia and the prevention of MI and death. Initially,
stabilized patients with NSTE-ACS are admitted to an
intermediate (or step-down) care unit. Patients undergo
continuous electrocardiographic rhythm monitoring and
observation for recurrent ischemia. Bed or chair rest is
recommended for patients admitted with NSTE-ACS.
Patients with NSTE-ACS should be treated with anti-
anginal (Section 4.1.2.5), antiplatelet, and anticoagulant
therapy (Section 4.3). Patients are managed with either
an early invasive strategy or an ischemia-guided strategy
(Section 4.4).
Patients with continuing angina, hemodynamic insta-
bility, uncontrolled arrhythmias, or a large MI should be
admitted to a coronary care unit. The nurse-to-patient
ratio should be suf�cient to provide 1) continuous elec-
trocardiographic rhythm monitoring, 2) frequent assess-
ment of vital signs and mental status, and 3) ability to
perform rapid cardioversion and de�brillation. These
patients are usually observed in the coronary care unit for
at least 24 hours. Those without recurrent ischemia, sig-
ni�cant arrhythmias, pulmonary edema, or hemodynamic
instability can be considered for admission or transfer to
an intermediate care or telemetry unit.
An assessment of LV function is recommended because
depressedLVfunctionwilllikelyin�uence pharmaco-
logical therapies (e.g., angiotensin-converting enzyme
[ACE] inhibitors for depressed left ventricular ejection
fraction [LVEF]), may suggest the presence of more
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DECEMBER 23, 2014:e139– 228
extensive CAD, and may in�uence the choice of revascu-
larization (PCI versus coronary artery bypass graft surgery
[CABG]). Because signi�cant valvular disease may also
in�uence the type of revascularization, echocardiography

rather than ventriculography is often preferred for
assessment of LV function.
4.1. Standard Medical Therapies.
See Table 6 for a summary of recommendations from this
section.
4.1.1. Oxygen: Recommendation
CLASS I
1. Supplemental oxygen should be administered to patients
with NSTE-ACS with arterial oxygen saturation less than
90%, respiratory distress, or other high-risk features of
hypoxemia. (Level of Evidence: C)
Patients with cyanosis, arterial oxygen saturation <90%,
respiratory distress, or other high-risk features of hypoxemia
are treated with supplemental oxygen. The 2007 UA/
NSTEMI CPG recommended the routine administration of
supplemental oxygen to all patients with NSTE-ACS during
the �rst 6 hours after presentation on the premise that it is
safe and may alleviate hypoxemia (212). The bene�tof
routine supplemental oxygen administration in normoxic
patients with NSTE-ACS has never been demonstrated. At
the time of GWC deliberations, data emerged that routine
use of supplemental oxygen in cardiac patients may have
untoward effects, including increased coronary vascular
resistance, reduced coronary blood �ow, and increased risk
of mortality (213–215).
TABLE 6 Summary of Recommendations for Early Hospital Care
Recommendations COR LOE References
Oxygen
Administer supplemental oxygen only with oxygen saturation <90%, respiratory distress, or other high-risk
features for hypoxemia
I C N/A
Nitrates
Administer sublingual NTG every 5 min � 3 for continuing ischemic pain and then assess need for IV NTG I C (216–218)
Administer IV NTG for persistent ischemia, HF, or hypertension I B (219–224)
Nitrates are contraindicated with recent use of a phosphodiesterase inhibitor III: Harm B (225–227)
Analgesic therapy
IV morphine sulfate may be reasonable for continued ischemic chest pain despite maximally tolerated anti-ischemic
medications
IIb B (232,233)
NSAIDs (except aspirin) should not be initiated and should be discontinued during hospitalization for NSTE-ACS
because of the increased risk of MACE associated with their use
III: Harm B (234,35)
Beta-adrenergic blockers
Initiate oral beta blockers within the �rst 24 h in the absence of HF, low-output state, risk for cardiogenic shock, or
other contraindications to beta blockade
IA(240–242)
Use of sustained-release metoprolol succinate, carvedilol, or bisoprolol is recommended for beta-blocker therapy with I C N/A
catio
tion
and
erva
fter
ssfu
y sp
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Amsterdam et al.
DECEMBER 23, 2014:e139– 228
2014 AHA/ACC NSTE-ACS Guideline
e157
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concomitant NSTE-ACS, stabilized HF, and reduced systolic function
Re-evaluate to determine subsequent eligibility in patients with initial contraindi
It is reasonable to continue beta-blocker therapy in patients with normal LV func
IV beta blockers are potentially harmful when risk factors for shock are present
CCBs
Administer initial therapy with nondihydropyridine CCBs with recurrent ischemia
in the absence of LV dysfunction, increased risk for cardiogenic shock, PR int
third-degree atrioventricular block without a cardiac pacemaker
Administer oral nondihydropyridine calcium antagonists with recurrent ischemia a
the absence of contraindications
CCBs are recommended for ischemic symptoms when beta blockers are not succe
unacceptable side effects*
Long-acting CCBs and nitrates are recommended for patients with coronary arter
Immediate-release nifedipine is contraindicated in the absence of a beta blocker
Cholesterol management
Initiate or continue high-intensity statin therapy in patients with no contraindications
Obtain a fasting lipid pro�le, preferably within 24 h
*Short-acting dihydropyridine calcium channel antagonists should be avoided.
CCB indicates calcium channel blocker; COR, Class of Recommendation; HF, heart failure; IV
event; N/A, not available; NSAIDs, nonsteroidal anti-in�ammatory drugs; NSTE-ACS, non–ST
ded From: http://content.onlinejacc.org/ on 03/27/2015
ns to beta blockers I C N/A
with NSTE-ACS IIa C (241,243)
III: Harm B (244)
contraindications to beta blockers
l >0.24 s, or second- or
IB(248–250)
use of beta blocker and nitrates in I C N/A
l, are contraindicated, or cause I C N/A
asm I C N/A
III: Harm B (251,252)
I A (269–273)
IIa C N/A
, intravenous; LOE, Level of Evidence; LV, left ventricular; MACE, major adverse cardiac
-elevation acute coronary syndromes; and NTG, nitroglycerin.

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4.1.2. Anti-Ischemic and Analgesic Medications
4.1.2.1. Nitrates: Recommendations
CLASS I
1. Patients with NSTE-ACS with continuing ischemic pain
should receive sublingual nitroglycerin (0.3 mg to 0.4 mg)
every 5 minutes for up to 3 doses, after which an assessment
should be made about the need for intravenous nitroglycerin
if not contraindicated (216–218). (Level of Evidence: C)
2. Intravenous nitroglycerin is indicated for patients with
NSTE-ACS for the treatment of persistent ischemia, HF, or
hypertension (219–224). (Level of Evidence: B)
CLASS III: HARM
1. Nitrates should not be administered to patients with NSTE-
ACS who recently received a phosphodiesterase inhibitor,
especially within 24 hours of sildena�lorvardena�l, or
within 48 hours of tadala�l (225–227). (Level of Evidence: B)
Nitrates are endothelium-independent vasodilators with
peripheral and coronary vascular effects. By dilating the
capacitance vessels, nitrates decrease cardiac preload and
reduce ventricular wall tension. More modest effects on the
arterial circulation result in afterload reduction and further
decrease in MVO
2
. This may be partially offset by re�ex
increases in heart rate and contractility, which counteract the
reduction in MVO
2
unless a beta blocker is concurrently
administered. Nitrates also dilate normal and atherosclerotic
coronary arteries and increase coronary collateral �ow.
Nitrates may also inhibit platelet aggregation (228).
RCTs have not shown a reduction in MACE with nitrates.
The rationale for nitrate use in NSTE-ACS is extra-
polated from pathophysiological principles and extensive
(although uncontrolled) clinical observations, experi-
mental studies, and clinical experience. The decision to
administer nitrates should not preclude therapy with other
proven mortality-reducing interventions such as beta
blockers.
Intravenous nitroglycerin is bene�cial in patients
with HF, hypertension, or symptoms that are not
relieved with sublingual nitroglycerin and administra-
tion of a beta blocker (219,221–224). Patients who require
intravenous nitroglycerin for >24 hours may require
periodic increases in the infusion rate and use of
nontolerance-producing regimens (e.g., intermittent
dosing) to maintain ef�cacy. In current practice, most
patients who require continued intravenous nitroglyc-
erin for the relief of angina undergo prompt coronary
angiography and revascularization. Topical or oral ni-
trates are acceptable alternatives to intravenous nitro-
2014 AHA/ACC NSTE-ACS Guideline
glycerin for patients who do not have refractory or
recurrent ischemia (229,230). Side effects of nitrates
include headache and hypotension. Nitrates should
not be administered to patients with hypotension or to
: http://content.onlinejacc.org/ on 03/27/2015
occur in >20% of patients, hypotension and respiratory
depression are the most serious complications of exces-
sive use of morphine. Naloxone (0.4 mg to 2.0 mg IV) may
be administered for morphine overdose with respiratory
or circulatory depression.
those who received a phosphodiesterase inhibitor and
are administered with caution to patients with right
ventricular infarction (231).
See Online Data Supplement 9 for additional infor-
mation on nitrates.
4.1.2.2. Analgesic Therapy: Recommendations
CLASS IIb
1. In the absence of contraindications, it may be reasonable to
administer morphine sulfate intravenously to patients with
NSTE-ACS if there is continued ischemic chest pain despite
treatment with maximally tolerated anti-ischemic medica-
tions (232,233). (Level of Evidence: B)
CLASS III: HARM
1. Nonsteroidal anti-in�ammatory drugs (NSAIDs) (except
aspirin) should not be initiated and should be discontinued
during hospitalization for NSTE-ACS because of the
increased risk of MACE associated with their use (234,235).
(Level of Evidence: B)
The role of morphine sulfate was re-evaluated for this CPG
revision, including studies that suggest the potential for
adverse events with its use (232). Morphine sulfate has
potent analgesic and anxiolytic effects, as well as hemody-
namic actions, that are potentially bene�cial in NSTE-ACS. It
causes venodilation and produces modest reductions in
heart rate (through increased vagal tone) and systolic BP. In
patients with symptoms despite antianginal treatment,
morphine (1 mg to 5 mg IV) may be administered during
intravenous nitroglycerin therapy with BP monitoring. The
morphine dose may be repeated every 5 to 30 minutes to
relieve symptoms and maintain the patient’s comfort. Its use
should not preclude the use of other anti-ischemic therapies
with proven bene�ts in patients with NSTE-ACS. To our
knowledge, no RCTs have assessed the use of morphine in
patients with NSTE-ACS or de�ned its optimal adminis-
tration schedule. Observational studies have demonstrated
increased adverse events associated with the use of
morphine sulfate in patients with ACS and acute decom-
pensated HF (232,233,236). Although these reports were
observational, uncontrolled studies limited by selection bias,
they raised important safety concerns.
DECEMBER 23, 2014:e139– 228
Traditional NSAIDs and selective cyclooxygenase
(COX)-2 inhibitors markedly block endothelial prostacy-
clin production, which leads to unopposed platelet
aggregation by platelet-derived thromboxane A
2
.Both

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typesofNSAIDspreventthebene�cial actions of aspirin
and interfere with the inhibition of COX-1, thromboxane
A
2
production, and platelet aggregation. Because of
their inhibitory activity on the ubiquitous COXs, NSAIDs
have an extensive adverse side effect pro�le, particularly
renal and gastrointestinal. The increased cardio-
vascular hazards associated with NSAIDs have been
observed in several studies of patients without ACS
(234,235,237,238). The PRECISION (Prospective Random-
ized Evaluation of Celecoxib Integrated Safety Versus
Ibuprofen Or Naproxen) trial, in progress at the time of
publication, is the �rst study of patients with high car-
diovascular risk who are receiving long-term treatment
with a selective COX-2 inhibitor or traditional NSAIDs.
PRECISION will examine the relative cardiovascular
safety pro�les of celecoxib, ibuprofen, and naproxen in
patients without ACS (239).
See Online Data Supplement 10 for additional infor-
mation on analgesic therapy.
4.1.2.3. Beta-Adrenergic Blockers: Recommendations
CLASS I
1. Oral beta-blocker therapy should be initiated within the �rst
24 hours in patients who do not have any of the following:
1) signs of HF, 2) evidence of low-output state, 3) increased
risk for cardiogenic shock, or 4) other contraindications to
beta blockade (e.g., PR interval >0.24 second, second- or
third-degree heart block without a cardiac pacemaker, active
asthma, or reactive airway disease) (240–242). (Level of
Evidence: A)
2. In patients with concomitant NSTE-ACS, stabilized HF,
and reduced systolic function, it is recommended to continue
beta-blocker therapy with 1 of the 3 drugs proven to
reduce mortality in patients with HF: sustained-release
metoprolol succinate, carvedilol, or bisoprolol. (Level of
Evidence: C)
3. Patients with documented contraindications to beta blockers
in the �rst 24 hours of NSTE-ACS should be re-evaluated to
determine their subsequent eligibility. (Level of Evidence: C)
CLASS IIa
1. It is reasonable to continue beta-blocker therapy in patients
with normal LV function with NSTE-ACS (241,243). (Level of
Evidence: C)
CLASS III: HARM
1. Administration of intravenous beta blockers is potentially
harmful in patients with NSTE-ACS who have risk factors for
shock (244). (Level of Evidence: B)
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DECEMBER 23, 2014:e139– 228
Beta blockers decrease heart rate, contractility, and BP,
resulting in decreased MVO
2
. Beta blockers without
increased sympathomimetic activity should be administered
orally in the absence of contraindications. Although early
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indicated in the absence of active bronchospasm. Beta-1
selective beta blockers are preferred and should be initiated
at a low dosage.
See Online Data Supplement 11 for additional informa-
tion on beta blockers, including risk factors for shock.
4.1.2.4. Calcium Channel Blockers: Recommendations
CLASS I
1. In patients with NSTE-ACS, continuing or frequently recurring
ischemia, and a contraindication to beta blockers, a non-
dihydropyridine calcium channel blocker (CCB) (e.g., verap-
amil or diltiazem) should be given as initial therapy in the
absence of clinically signi�cant LV dysfunction, increased risk
for cardiogenic shock, PR interval greater than 0.24 second,
or second- or third-degree atrioventricular block without a
cardiac pacemaker (248–250). (Level of Evidence: B)
2. Oral nondihydropyridine calcium antagonists are recom-
mended in patients with NSTE-ACS who have re-
current ischemia in the absence of contraindications, after
appropriate use of beta blockers and nitrates. (Level of
Evidence: C)
3. CCBsy are recommended for ischemic symptoms when beta
blockers are not successful, are contraindicated, or cause
unacceptable side effects. (Level of Evidence: C)
4. Long-acting CCBs and nitrates are recommended in patients
with coronary artery spasm. (Level of Evidence: C)
administration does not reduce short-term mortality
(241,244), beta blockers decrease myocardial ischemia,
reinfarction, and the frequency of complex ventricular dys-
rhythmias (240,245), and they increase long-term survival.
Early beta blockade, particularly if given intravenously, can
increase the likelihood of shock in patients with risk factors.
Risk factors for shock include patients >70 years of age, heart
rate >110 beats per minute, systolic BP <120 mm Hg, and late
presentation (244). In patients with LV dysfunction
(LVEF <0.40) with or without pulmonary congestion, beta
blockers are strongly recommended before discharge. Beta
blockers should be used prudently with ACE inhibitors or
angiotensin-receptor blockers (ARBs) in patients with HF.
Renin-angiotensin-aldosterone system blocking agents
should be cautiously added in patients with decompensated
HF (246). Beta blockers without intrinsic sympathomimetic
activity should be used, especially beta-1 blockers such as
sustained-release metoprolol succinate, bisoprolol, or car-
vedilol, a beta-1 and alpha-1 blocker. This is because of their
mortality bene�t in patients with HF and systolic dysfunc-
tion (246,247). In patients with chronic obstructive lung
yShort-acting dihydropyridine calcium channel antagonists should be avoided.

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CLASS III: HARM
1. Immediate-release nifedipine should not be administered to
patients with NSTE-ACS in the absence of beta-blocker
therapy (251,252). (Level of Evidence: B)
CCBs include dihydropyridines and nondihydropyridines.
The dihydropyridines (nifedipine and amlodipine) produce
the most marked peripheral vasodilation and have little
direct effect on contractility, atrioventricular conduction,
and heart rate. The nondihydropyridines (diltiazem and
verapamil) have signi�cant negative inotropic actions and
negative chronotropic and dromotropic effects. All CCBs
cause similar coronary vasodilation and are preferred in
vasospastic angina (253). They also alleviate ischemia due
to obstructive CAD by decreasing heart rate and BP.
Verapamil and diltiazem decreased reinfarction in patients
without LV dysfunction in some (248,249,254) but not all
studies (255,256). Verapamil may be bene�cial in reducing
long-term events after AMI in hypertensive patients
without LV dysfunction (250) and in patients with MI and
HF receiving an ACE inhibitor (257). Immediate-release
nifedipine causes a dose-related increase in mortality in
patients with CAD and harm in ACS and is not recom-
mended for routine use in patients with ACS (251,258).
Long-acting preparations may be useful in older patients
with systolic hypertension (259). There are no signi�cant
trial data on ef�cacy of amlodipine or felodipine in pa-
tients with NSTE-ACS.
See Online Data Supplement 12 for additional infor-
mation on CCBs.
4.1.2.5. Other Anti-Ischemic Interventions
Ranolazine
Ranolazine is an antianginal medication with minimal
effects on heart rate and BP (260,261). It inhibits the
late inward sodium current and reduces the deleterious
effects of intracellular sodium and calcium overload
that accompany myocardial ischemia (262).Ranolazine
is currently indicated for treatment of chronic angina.
The MERLIN-TIMI (Metabolic Ef�ciency With Ranola-
zine for Less Ischemia in Non–ST-Elevation Acute Cor-
onary Syndromes-Thrombosis In Myocardial Infarction)
36 trial examined the ef�cacy and safety of ranolazine
in 6,560 patients with NSTE-ACS who presented within
48 hours of ischemic symptoms (263).Inaposthoc
analysis in women, ranolazine was associated with a
reduced incidence of the primary endpoint (cardiovas-
cular death, MI, or recurrent ischemia), principally
owing to a 29% reduction in recurrent ischemia (116).In
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
the subgroup with prior chronic angina (n¼3,565),
ranolazine was associated with a lower primary com-
posite endpoint, a signi�cant reduction of worsening
angina, and increased exercise duration (264).Because
the primary endpoint of the original MERLIN-TIMI
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36 trial was not met, all additional analyses should be
interpreted with caution. The recommended initial dose
is 500 mg orally twice daily, which can be uptitrated to
a maximum of 1,000 mg orally twice daily. Ranolazine
is usually well tolerated; its major adverse effects are
constipation, nausea, dizziness, and headache. Ranola-
zine prolongs the QTc interval in a dose-related
manner, but QTc prolongation requiring dose reduc-
tion was comparable with ranolazine and placebo in the
MERLIN-TIMI 36 trial (263).
See Online Data Supplement 13 for additional infor-
mation on ranolazine.
Intra-Aortic Balloon Pump (IABP) Counterpulsation
IABP counterpulsation may be used in patients with
NSTE-ACS to treat severe persistent or recurrent
ischemia, especially in patients awaiting invasive angi-
ography and revascularization, despite intensive medical
therapy. In experimental studies, IABP counterpulsation
increases diastolic BP and coronary blood �ow and
potentially augments cardiac output while diminishing
LV end-diastolic pressure. The use of IABP for refractory
ischemia dates back several decades, and its current
application is predominantly driven by clinical experi-
ence and nonrandomized observational studies (265).
When studied in rigorous RCTs, IABP counterpulsation
failed to reduce MACE in high-risk elective PCI (266),
decrease infarct size after primary PCI for acute STEMI
(267), or diminish early mortality in patients with
cardiogenic shock complicating AMI (268).
4.1.2.6. Cholesterol Management
CLASS I
1. High-intensity statin therapy should be initiated or
continued in all patients with NSTE-ACS and no contraindi-
cations to its use (269–273). (Level of Evidence: A)
CLASS IIa
1. It is reasonable to obtain a fasting lipid pro�le in patients
with NSTE-ACS, preferably within 24 hours of presentation.
(Level of Evidence: C)
Therapy with statins in patients with NSTE-ACS reduces the
rate of recurrent MI, coronary heart disease mortality, need for
myocardial revascularization, and stroke. High-risk patients,
such as those with NSTE-ACS, derive more bene�t in reducing
these events from high-intensity statins, such as atorvastatin
which lower low-density lipoprotein cholesterol levels
by $50% as in the PROVE IT-TIMI 22 (Pravastatin or Ator-
vastatin Evaluation and Infection Therapy-Thrombolysis In
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DECEMBER 23, 2014:e139– 228
Myocardial Infarction) and MIRACL (Myocardial Ischemia
Reduction With Acute Cholesterol Lowering) trials (273,274),
than from moderate- or low-intensity statins (18,272). These
�ndings provide the basis for high-intensity statin therapy

may result in an increase in adverse events (277,278).Ina
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after stabilization of patients with NSTE-ACS. In addition,
early introduction of this approach can promote improved
compliance with this regimen.
4.2. Inhibitors of the Renin-Angiotensin-Aldosterone System:
Recommendations
CLASS I
1. ACE inhibitors should be started and continued
inde�nitely in all patients with LVEF less than 0.40 and in
those with hypertension, diabetes mellitus, or stable CKD
(Section 7.6), unless contraindicated (275,276). (Level of
Evidence: A)
2. ARBs are recommended in patients with HF or MI with LVEF
less than 0.40 who are ACE inhibitor intolerant (277,278).
(Level of Evidence: A)
3. Aldosterone blockade is recommended in patients post–MI
without signi�cant renal dysfunction (creatinine >2.5 mg/dL
in men or >2.0 mg/dL in women) or hyperkalemia (Kþ >5.0
mEq/L) who are receiving therapeutic doses of ACE inhibitor
and beta blocker and have a LVEF 0.40 or less, diabetes
mellitus, or HF (279). (Level of Evidence: A)
CLASS IIa
1. ARBs are reasonable in other patients with cardiac or other
vascular disease who are ACE inhibitor intolerant (280).
(Level of Evidence: B)
CLASS IIb
1. ACE inhibitors may be reasonable in all other patients with
cardiac or other vascular disease (281,282). (Level of
Evidence: B)
ACE inhibitors reduce mortality in patients with recent MI,
primarily those with LV dysfunction (LVEF <0.40) with or
without pulmonary congestion (283–285). In patients with
normal LV function (including patients with diabetes mel-
litus), total mortality and MACE (including HF) are reduced.
It has been found that approximately 15% of patients with
NSTEMI develop HF during hospitalization, with the rate
increasing to 24% of patients 1 year later (286). A meta-
analysis demonstrated a small but signi�cant (0.48%) ab-
solute bene�t of early initiation of an ACE inhibitor on
survival at 30 days, with bene�t seen as early as 24 hours
after admission for AMI (283). An ACE inhibitor should be
used cautiously in the �rst 24 hours of AMI, because it may
result in hypotension or renal dysfunction (283). It may be
prudent to initially use a short-acting ACE inhibitor, such as
captopril or enalapril, in patients at increased risk of these
adverse events. In patients with signi�cant renal dysfunc-
tion, it is sensible to stabilize renal function before initi-
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DECEMBER 23, 2014:e139– 228
ating an ACE inhibitor or an ARB, with re-evaluation of
creatinine levels after drug initiation. An ARB may be
substituted for an ACE inhibitor with similar bene�ts on
survival (277,278). Combining an ACE inhibitor and an ARB
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study in which patients with AMI with LV dysfunction
(LVEF <0.40) with or without HF were randomized 3 to 14
days after AMI to receive eplerenone (a selective aldoste-
rone blocker), eplerenone was ef�cacious as an adjunct to
ACE inhibitors and beta blockers in decreasing long-term
mortality (279,287). In a study of patients with HF,
>50% of whom had an ischemic etiology, spironolactone
(a nonselective aldosterone inhibitor) was bene�cial (279);
however, RCT data on MI are not available.
See Online Data Supplement 14 for additional informa-
tion on inhibitors of the renin-angiotensin-aldosterone
system.
4.3. Initial Antiplatelet/Anticoagulant Therapy in Patients With
De�nite or Likely NSTE-ACS
4.3.1. Initial Oral and Intravenous Antiplatelet Therapy in
Patients With De�nite or Likely NSTE-ACS Treated With an
Initial Invasive or Ischemia-Guided Strategy:
Recommendations
See Table 7 for a summary of recommendations from this
section and Online Data Supplement 15 for additional infor-
mation on initial oral and intravenous antiplatelet therapy
in patients with de�nite or likely NSTE-ACS treated with
an early invasive or an ischemia-guided strategy.
CLASS Iz
1. Non–enteric-coated, chewable aspirin (162 mg to 325 mg)
should be given to all patients with NSTE-ACS without
contraindications as soon as possible after presentation,
and a maintenance dose of aspirin (81 mg/d to 325 mg/d)
should be continued inde�nitely (288–290,293,391). (Level
of Evidence: A)
2. In patients with NSTE-ACS who are unable to take aspirin
because of hypersensitivity or major gastrointestinal intol-
erance, a loading dose of clopidogrel followed by a daily
maintenance dose should be administered (291). (Level of
Evidence: B)
3. A P2Y
12
inhibitor (either clopidogrel or ticagrelor) in addition
to aspirin should be administered for up to 12 months to all
patients with NSTE-ACS without contraindications who are
treated with either an early invasivex or ischemia-guided
strategy. Options include:
� Clopidogrel: 300-mg or 600-mg loading dose, then 75
mg daily (289,292) (Level of Evidence: B)
� Ticagrelork: 180-mg loading dose, then 90 mg twice daily
(293,294) (Level of Evidence: B)
zSee Section 5.1.2.1 for recommendations at the time of PCI.
xSee Section 4.3.1.2 for prasugrel indications in either an early invasive or
ischemia-guided strategy.
kThe recommended maintenance dose of aspirin to be used with ticagrelor is
81 mg daily (290).

let
sing
325
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TABLE 7
Summary of Recommendations for Initial Antiplate
NSTE-ACS and PCI
Recommendations Do
Aspirin
� Non–enteric-coated aspirin to all patients promptly after 162 mg–
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
CLASS IIa
1. It is reasonable to use ticagrelor in preference to clopidogrel
for P2Y
12
treatment in patients with NSTE-ACS who undergo
an early invasive or ischemia-guided strategy (293,294).
(Level of Evidence: B)
CLASS IIb
1. In patients with NSTE-ACS treated with an early in-
vasive strategy and dual antiplatelet therapy (DAPT)
with intermediate/high-risk features (e.g., positive troponin),
presentation
� Aspirin maintenance dose continued inde�nitely 81 mg/d–325
P2Y
12
inhibitors
� Clopidogrel loading dose followed by daily maintenance
dose in patients unable to take aspirin
75 mg
� P2Y
12
inhibitor, in addition to aspirin, for up to 12 mo for
patients treated initially with either an early invasive or
initial ischemia-guided strategy:
� Clopidogrel
� Ticagrelor*
300-mg or 6
then 75 m
180-mg load
� P2Y
12
inhibitor therapy (clopidogrel, prasugrel, or ticagrelor)
continued for at least 12 mo in post–PCI patients treated with
coronary stents
N/A
� Ticagrelor in preference to clopidogrel for patients treated
with an early invasive or ischemia-guided strategy
N/A
GP IIb/IIIa inhibitors
� GP IIb/IIIa inhibitor in patients treated with an early invasive
strategyandDAPTwithintermediate/high-risk features
(e.g., positive troponin)
Preferred op
tiro�ban
Parenteral anticoagulant and �brinolytic therapy
� SC enoxaparin for duration of hospitalization or until PCI
is performed
� 1 mg/kg
1 mg/kg/
<30 mL/
� Initial 30
in select
� Bivalirudin until diagnostic angiography or PCI is performed
in patients with early invasive strategy only
� Loading
followed
� Only pro
in patien
� SC fondaparinux for the duration of hospitalization or until
PCI is performed
2.5 mg SC d
� Administer additional anticoagulant with anti-IIa activity if
PCI is performed while patient is on fondaparinux
N/A
� IV UFH for 48 h or until PCI is performed � Initial lo
4,000 IU
(max 1,0
� Adjusted
� IV �brinolytic treatment not recommended in patients with
NSTE-ACS
N/A
See Section 5.1.2.1 for recommendations on antiplatelet/anticoagulant therapy at the time o
*The recommended maintenance dose of aspirin to be used with ticagrelor is 81 mg daily (2
aPTT indicates activated partial thromboplastin time; BID, twice daily; COR, Class of Recomm
IV, intravenous; LOE, Level of Evidence; max, maximum; N/A, not available; NSTE-ACS, non
subcutaneous; and UFH, unfractionated heparin.
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/Anticoagulant Therapy in Patients With De�nite or Likely
and Special Considerations COR LOE References
mg I A (288–290)
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
a GP IIb/IIIa inhibitor may be considered as part of initial an-
tiplatelet therapy. Preferred options are epti�batide or tir-
o�ban (43,94,295). (Level of Evidence: B)
Despite the large number of new antiplatelet and antith-
rombotic agents, aspirin, which targets COX and subsequent
thromboxane A
2
inhibition, is the mainstay of antiplatelet
therapy. Multiple other pathways of platelet activation can be
targeted by agents that inhibit the platelet P2Y
12
receptor,
including thienopyridine prodrug agents, such as clopidogrel
mg/d* IA(288–290,
293,391)
I B (291)
IB
00-mg loading dose,
g/d
(289,292)
ing dose, then 90 mg BID (293,294)
I B (293,296,302,
330,331)
IIa B (293,294)
tions are epti�batide or IIb B (43,94,295)
SC every 12 h (reduce dose to
d SC in patients with CrCl
min)
mg IV loading dose
ed patients
IA(133,136,309)
dose 0.10 mg/kg loading dose
by 0.25 mg/kg/h
visional use of GP IIb/IIIa inhibitor
ts also treated with DAPT
IB(292,293,
310,311)
aily I B (312–314)
I B (313–315)
ading dose 60 IU/kg (max
) with initial infusion 12 IU/kg/h
00 IU/ h)
to therapeutic aPTT range
IB(316–322)
III: Harm A (93,329)
f PCI and Sections 6.2.1 and 6.3 for recommendations on posthospital therapy.
90).
endation; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; GP, glycoprotein;
–ST-elevation acute coronary syndromes; PCI, percutaneous coronary intervention; SC,

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and prasugrel, which require conversion into molecules that
bind irreversibly to the P2Y
12
receptor. Additional pyrimidine
derivatives, including ticagrelor, do not require biotransfor-
mation and bind reversibly to the P2Y
12
receptor, antagonizing
adenosine diphosphate platelet activation. In addition to these
oral agents, intravenous GP IIb/IIIa receptor inhibitors,
including abciximab, epti�batide, and tiro�ban, target the �nal
common pathway of platelet aggregation. In the EARLY ACS
(Early Glycoprotein IIb/IIIa Inhibition in Patients With Non–ST-
Segment Elevation Acute Coronary Syndrome) trial, patients
were randomly assigned to either early, pre–PCI double-bolus
epti�batide or delayed, provisional epti�batide. Seventy-�ve
percent of the patients received upstream, preprocedure clo-
pidogrel. The risk of TIMI major bleeding in the early epti�-
batide group was 2.6% compared with 1.8% (p¼0.02) in the
delayed provisional group (295).IntheGUSTOIV-ACS(Global
Use of Strategies To Open Occluded Coronary Arteries IV-
Acute Coronary Syndromes) trial, there was no clinical
bene�t of abciximab in this population; in troponin-negative
patients, mortality was 8.5% compared with 5.8% in controls
(p¼0.002) (288,289,296,297).
4.3.1.1. Aspirin
Aspirin is the established �rst-line therapy in patients
with NSTE-ACS and reduces the incidence of recurrent MI
and death (288,289). A loading dose of non–enteric-
coated aspirin 162 mg to 325 mg is the initial antiplatelet
therapy. The subsequent maintenance dose is 81 mg per
day to 162 mg per day; in special circumstances, a higher
maintenancedoseupto325mgdailyhasbeenused(391).
The lower dose is favored and all patients treated with
ticagrelor should receive only 81 mg per day (290).In
other countries, available low-dose aspirin formations
may include 75 mg and 100 mg. High-dose ($160 mg)
versus low-dose (<160mg)aspirinisassociatedwith
increased bleeding risk in the absence of improved
outcomes (298).MostNSAIDsreversiblybindtoCOX-1,
preventing inhibition by aspirin and by COX-2 and
may cause prothrombotic effects. Enteric-coated aspirin
should be avoided initially because of its delayed and
reduced absorption (299).
4.3.1.2. P2Y
12
Receptor Inhibitors
Three P2Y
12
receptor inhibitors are approved in the United
States for treatment of ischemic myocardial disorders,
including NSTE-ACS. For discontinuation before surgery,
see Section 5.
Clopidogrel
Administration of clopidogrel with aspirin was superior
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to administration of aspirin alone in reducing the inci-
dence of cardiovascular death and nonfatal MI or
stroke both acutely and over the following 11 months
(289,296). There was a slight increase in major bleeding
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events with clopidogrel, including a nonsigni�cant in-
crease in life-threatening bleeding and fatal bleeding
(289). An initial loading dose of 300 mg to 600 mg is
recommended (289,296,300). A 600-mg loading dose re-
sults in a greater, more rapid, and more reliable platelet
inhibition compared with a 300-mg loading dose (301).
Use of clopidogrel for patients with NSTE-ACS who are
aspirin intolerant is based on a study in patients with
stable ischemic heart disease (291). When possible, dis-
continue clopidogrel at least 5 days before surgery (301).
Prasugrel
The metabolic conversion pathways of prasugrel produce
more rapid and consistent platelet inhibition than
clopidogrel (300). In patients with NSTE-ACS and de�ned
coronary anatomy undergoing planned PCI, a 60-mg
loading dose of prasugrel followed by 10 mg daily was
compared with a 300-mg loading dose and 75 mg daily of
clopidogrel. The composite primary endpoint (cardiovas-
culardeath,nonfatalMI,andstroke)wasreducedin
patients treated with prasugrel (hazard ratio [HR]: 0.81;
p¼0.001). This was driven by a risk reduction for MI and
stent thrombosis with no difference in mortality (302).
Counterbalancing the salutary effects of prasugrel was a
signi�cant increase in spontaneous bleeding, life-
threatening bleeding, and fatal bleeding in the patients
treated with prasugrel compared with patients treated
with clopidogrel. There was net harm in patients with a
history of cerebrovascular events and no clinical bene�t
in patients >75 years of age or those with low body weight
(<60 kg) (302).InpatientswithNSTE-ACStreatedwithan
ischemia-guided strategy, 1 RCT comparing aspirin and
either clopidogrel or prasugrel evaluated the primary
endpoint of death from cardiovascular causes, MI, or stroke
for up to 30 months; there were similar bleeding rates and
no bene�t of treatment with prasugrel when compared
with treatment with clopidogrel (303). The ACCOAST (A
Comparison of Prasugrel at the Time of Percutaneous Cor-
onary Intervention or as Pretreatment at the Time of
Diagnosis in Patients With Non–ST-Elevation Myocardial
Infarction) RCT of high-risk patients with NSTE-ACS
scheduled to undergo early coronary angiography found
that a strategy of administration of prasugrel at the time of
randomization before angiography did not lead to a
reduction in the composite primary endpoint when
compared with a strategy of administration of prasugrel
only at the time of PCI; however, it did lead to an increase in
bleeding complications (304). On the basis of TRITON (Trial
to Assess Improvement in Therapeutic Outcomes by Opti-
mizing Platelet Inhibition with Prasugrel) study design
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
and the results of TRILOGY ACS (Targeted Platelet Inhibi-
tion to Clarify the Optimal Strategy to Medically Manage
Acute Coronary Syndromes) and ACCOAST, prasugrel is
not recommended for “upfront” therapy in patients with

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NSTE-ACS. The use of prasugrel in patients undergoing
PCI is addressed in Section 5.
Ticagrelor
Ticagrelor is an oral, reversibly binding P2Y
12
inhibitor
with a relatively short plasma half-life (12 hours).
Compared with clopidogrel, ticagrelor has a more rapid
and consistent onset of action and, because it is revers-
ible, it has a faster recovery of platelet function. The
loading dose of ticagrelor for patients treated either
invasively or with an ischemia-guided strategy is 180 mg
followed by a maintenance dose of 90 mg twice daily
(293,294).InpatientswithNSTE-ACStreatedwithtica-
grelor compared with clopidogrel, there was a reduction in
the composite outcome of death from vascular causes, MI,
orstroke(reduction:11.7%to9.8%;HR:0.84;p<0.001)
(293). The mortality rate was also lower in those patients
treated with ticagrelor. Although overall major bleeding
was not increased with ticagrelor, a modest increase in
major bleeding and non–procedure-related bleeding
occurred in the subgroup of patients who did not undergo
CABG (major bleeding: 4.5% versus 3.8%; p¼0.02; non-
procedure major bleeding: 3.1% versus 2.3%; p¼0.05);
however, there was no difference in blood transfusion or
fatal bleeding (305). Side effects unique to ticagrelor
include dyspnea (which occurs in up to 15% of patients
within the �rst week of treatment but is rarely severe
enough to cause discontinuation of treatment) (293) and
bradycardia. The bene�t of ticagrelor over clopidogrel was
limited to patients taking 75 mg to 100 mg of aspirin (290).
The short half-life requires twice-daily administration,
which could potentially result in adverse events in non-
compliant patients, particularly after stent implantation.
When possible, ticagrelor should be discontinued at least
5daysbeforesurgery(306). Although ticagrelor has not
been studied in the absence of aspirin, its use in aspirin-
intolerant patients is a reasonable alternative.
Intravenous GP IIb/IIIa Receptor Inhibitors
The small molecule GP IIb/IIIa receptor antagonists,
tiro�ban and epti�batide, bind reversibly to the GP
IIb/IIIa receptor. Because the drug-to-receptor ratio is
high, platelet infusion is not effective in cases of severe
bleeding after use of epti�batide or tiro�ban, and they
must be cleared from the circulation to reduce bleeding.
In contrast, with abciximab, the drug-to-receptor ratio is
low, and platelet infusion may be effective.
Several large RCTs evaluated the impact of GP IIb/IIIa
receptor inhibitors in patients with NSTE-ACS who were
committed to an invasive strategy (295,296,306).The
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
ACUITY (Acute Catheterization and Urgent Intervention
Triage Strategy) trial evaluated unfractionated heparin
(UFH) versus bivalirudin with or without GP IIb/IIIa in-
hibitors (295,307). The rates of composite ischemia
: http://content.onlinejacc.org/ on 03/27/2015
(death, MI, unplanned revascularization) in patients who
received bivalirudin alone compared with those who
received UFH plus GP IIb/IIIa inhibitors were similar (9%
versus 8%; p¼0.45) (307). Fewer patients experienced
major bleeding with bivalirudin alone than did with
heparin plus GP IIb/IIIa inhibitors (4% versus 7%; relative
risk [RR]: 0.52; 95% con�dence interval [CI]: 0.40 to 0.66;
p<0.0001) (307). The ACUITY Timing trial evaluated the
bene�t of upstream GP IIb/IIIa receptor antagonist
comparedwithitsdeferreduse,testingthehypothesis
that earlier administration of GP IIb/IIIa inhibitors in pa-
tients destined for PCI would be superior (308).Com-
posite ischemia at 30 days occurred in 7.9% of patients
assigned to deferred use compared with 7.1% assigned to
upstream administration (RR: 1.12; 95% CI: 0.97 to 1.29;
p¼0.044 for noninferiority; p¼0.13 for superiority). De-
ferred GP IIb/IIIa inhibitors reduced the 30-day rates of
major bleeding compared with upstream use (4.9% versus
6.1%; p<0.001) (308). Similar results were reported by the
EARLY ACS investigators, who evaluated epti�batide
given upstream versus delayed, provisional admini-
stration in >9,000 patients with NSTE-ACS (295).
The composite endpoint of death, MI, recurrent
ischemia requiring urgent revascularization, or throm-
botic complications occurred in 9.3% of patients in the
early-epti�batide group compared with 10% in the
delayed-epti�batide group (odds ratio [OR]: 0.92; 95% CI:
0.80 to 1.06; p¼0.23) (308). As in the ACUITY Timing trial,
the early-epti�batide group had signi�cantly higher rates
of bleeding and red cell transfusions (295,308).
4.3.2. Initial Parenteral Anticoagulant Therapy in Patients With
De�nite NSTE-ACS: Recommendations
See Table 7 for a summary of recommendations regarding
antiplatelet/anticoagulant therapy in patients with de�-
nite or likely NSTE-ACS and Online Data Supplement 16
for additional information on combined oral anticoagu-
lant therapy and antiplatelet therapy in patients with
de�nite NSTE-ACS.
CLASS Iz
1. In patients with NSTE-ACS, anticoagulation, in addition to
antiplatelet therapy, is recommended for all patients irre-
spective of initial treatment strategy. Treatment options
include:
� Enoxaparin: 1 mg/kg subcutaneous (SC) every 12 hours
(reduce dose to 1 mg/kg SC once daily in patients with
creatinine clearance [CrCl]<30 mL/min), continued for the
duration of hospitalization or until PCI is performed. An
initial intravenous loading dose of 30 mg has been used
in selected patients (133,136,309). (Level of Evidence: A)
zSee Section 5.1.2.1 for recommendations at the time of PCI.

require routine monitoring. The dose of enoxaparin is
1
in
se
fu
�n
1
be
pr
Q-
in
si
te
En
In
tr
ni
th
m
ap
se
bl
en
PC
e165
Downloade
mg/kg SC every 12 hours for NSTE-ACS; an initial
travenous loading dose of 30 mg has been used in
lected patients. In the presence of impaired renal
nction (CrCl <30 mL per minute), which is a common
ding in older patients, the dose should be reduced to
mg/kg SC once daily, and strong consideration should
given to UFH as an alternative. Calculation of CrCl is
udent in patients considered for enoxaparin therapy.
In the ESSENCE trial, in patients with UA or non–
wave MI, the rates of recurrent ischemic events and
vasive diagnostic and therapeutic procedures were
gni�cantly reduced by enoxaparin therapy in the short
rm, and bene�t was sustained at 1 year (324).
In the SYNERGY (Superior Yield of the New Strategy of
oxaparin, Revascularization and Glycoprotein IIb/IIIa
hibitors) trial of high-risk patients with NSTE-ACS
eated with an early invasive strategy, there was no sig-
�cant difference in death or MI at 30 days between
ose randomized to enoxaparin versus UFH. There was
ore TIMI major bleeding in those treated with enox-
� Bivalirudin: 0.10 mg/kg loading dose followed by 0.25
mg/kg per hour (only in patients managed with an early
invasive strategy), continued until diagnostic angiography
or PCI, with only provisional use of GP IIb/IIIa inhibitor,
provided the patient is also treated with DAPT
(292,293,310,311). (Level of Evidence: B)
� Fondaparinux: 2.5 mg SC daily, continued for the duration
of hospitalization or until PCI is performed (312–314).
(Level of Evidence: B)
� If PCI is performed while the patient is on fondaparinux, an
additional anticoagulant with anti-IIa activity (either UFH
or bivalirudin) should be administered because of the risk
of catheter thrombosis (313–315). (Level of Evidence: B)
� UFH IV: initial loading dose of 60 IU/kg (maximum
4,000 IU) with initial infusion of 12 IU/kg per hour
(maximum 1,000 IU/h) adjusted per activated partial
thromboplastin time to maintain therapeutic anti-
coagulation according to the speci�c hospital protocol,
continued for 48 hours or until PCI is performed
(316–322). (Level of Evidence: B)
4.3.2.1. Low-Molecular-Weight Heparin
LMWHs have a molecular weight approximately one
third that of UFH and have balanced anti-Xa and anti-IIa
activity. LMWHs are readily absorbed after subcutane-
ous administration and have less platelet activation
(323). The anticoagulant activity of LMWH does not
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DECEMBER 23, 2014:e139– 228
arin without statistically signi�cant increase in GUSTO
vere bleeding or transfusion. Some of the increased
eeding may have been related to patients randomized to
oxaparin who received additional UFH at the time of
I (325,326).
d From: http://content.onlinejacc.org/ on 03/27/2015
4.3.2.2. Bivalirudin
The direct thrombin inhibitor bivalirudin is administered
intravenously. Bivalirudin was evaluated in the ACUITY
trial, a randomized open-label trial, in 13,819 moderate- to
high-risk patients with NSTE-ACS with a planned invasive
strategy. Three treatment arms were tested, including
UFH or LMWH with a GP IIb/IIIa receptor inhibitor, biva-
lirudin with a GP IIb/IIIa receptor inhibitor, or bivalirudin
alone. The majority of patients received clopidogrel (300
mg) before intervention, in addition to aspirin, anticoag-
ulants, and GP IIb/IIIa inhibitors. Bivalirudin alone was
noninferior to the standard UFH/LMWH combined with
GP IIb/IIIa inhibitor (composite ischemia endpoint 7.8%
versus7.3%;HR:1.08;p¼0.32), but there was a signi�-
cantly lower rate of major bleeding with bivalirudin (3.0%
versus 5.7%; HR: 0.53; p<0.001) (310). The anticoagulant
effect of bivalirudin can be monitored in the catheteri-
zation laboratory by the activated clotting time.
4.3.2.3. Fondaparinux
Fondaparinux is a synthetic polysaccharide molecule and
the only selective inhibitor of activated factor X available
for clinical use. Fondaparinux is well absorbed when
given subcutaneously and has a half-life of 17 hours,
enabling once-daily administration. Because it is excreted
by the kidneys, it is contraindicated if CrCl is <30 mL per
minute. Monitoring of anti-Xa activity is not required,
and fondaparinux does not affect usual anticoagulant
parameters such as activated partial thromboplastin time
or activated clotting time. In NSTE-ACS, the dose of fon-
daparinux is 2.5 mg SC administered daily and continued
for the duration of hospitalization or until PCI is per-
formed (312–314). In the OASIS (Organization to Assess
Strategies in Ischemic Syndromes)-5 study, patients with
NSTE-ACS were randomized to receive 2.5 mg SC fonda-
parinux daily or enoxaparin 1 mg/kg SC twice daily for 8
days. The incidence of the primary composite ischemic
endpoint at 9 days was similar between fondaparinux and
enoxaparin, but major bleeding was signi�cantly less
frequent with fondaparinux. To avert catheter thrombosis
when fondaparinux is used alone in patients undergoing
PCI, an anticoagulant with anti-IIa activity is also
administered (313–315). One regimen is 85 IU/kg of UFH
loading dose at the time of PCI (reduced to 60 IU/kg if a GP
IIb/IIIa inhibitor is used concomitantly) (314).
4.3.2.4. Unfractionated Heparin
Studies supporting the addition of a parenteral anti-
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
coagulant to aspirin in patients with NSTE-ACS were
performed primarily on patients with a diagnosis of
“unstable angina” in the era before DAPT and early
catheterization and revascularization. In general, those
studies found a strong trend for reduction in composite

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adverse events with the addition of parenteral UFH to
aspirin therapy (316–322).
Clinical trials indicate that a weight-adjusted dosing
regimen of UFH can provide more predictable anti-
coagulation (327) than a �xed initial dose (e.g., 5,000 IU
loading dose, 1,000 IU/h initial infusion). The recom-
mended weight-adjusted regimen is an initial loading
dose of 60 IU/kg (maximum 4,000 IU) and an initial
infusion of 12 IU/kg/h (maximum 1,000 IU/h), adjusted
using a standardized nomogram.
4.3.2.5. Argatroban
Argatroban, a direct thrombin inhibitor, is indicated for
prophylaxis or treatment of thrombosis in patients with
heparin-induced thrombocytopenia, including those un-
dergoing PCI (328). Steady state plasma concentrations
are achieved in 1 to 3 hours after intravenous adminis-
tration. Because of its hepatic metabolism, argatroban can
be used in patients with renal insuf�ciency. The usual
dose is 2 mcg/kg per minute by continuous intravenous
infusion, adjusted to maintain the activated partial
thromboplastin time at 1.5 to 3 times baseline (but not
>100 s).
4.3.3. Fibrinolytic Therapy in Patients With De�nite NSTE-ACS:
Recommendation
CLASS III: HARM
1. In patients with NSTE-ACS (i.e., without ST-elevation, true
posterior MI, or left bundle-branch block not known to be
old), intravenous �brinolytic therapy should not be used
(93,329). (Level of Evidence: A)
There is no role for �brinolytic therapy in patients with
NSTE-ACS. Fibrinolysis with or without subsequent PCI in
patients with NSTE-ACS was evaluated by the Fibrinolytic
Trialists and TIMI investigators (93,329). There was no
bene�t for mortality or MI. Intracranial hemorrhage and fatal
and nonfatal MI occurred more frequently in patients treated
with �brinolytic therapy.
See Online Data Supplement 17 for additional in-
formation on parenteral anticoagulant and �brinolytic
therapy in patients with de�nite NSTE-ACS.
4.4. Ischemia-Guided Strategy Versus Early Invasive Strategies
See Figure 3 for the management algorithm for ischemia-
guided versus early invasive strategy.
4.4.1. General Principles
Two treatment pathways have emerged for all patients
with NSTE-ACS. The invasive strategy triages patients to
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
an invasive diagnostic evaluation (i.e., coronary angiog-
raphy). In contrast, the initial ischemia-guided strategy
calls for an invasive evaluation for those patients who
1) fail medical therapy (refractory angina or angina at rest
: http://content.onlinejacc.org/ on 03/27/2015
or with minimal activity despite vigorous medical
therapy), 2) have objective evidence of ischemia (dyna-
mic electrocardiographic changes, myocardial perfusion
defect) as identi�ed on a noninvasive stress test, or
3) have clinical indicators of very high prognostic risk (e.g.,
highTIMIorGRACEscores).Inbothstrategies,patients
should receive optimal anti-ischemic and antithrombotic
medical therapy as outlined in Section 4.1.Asubgroupof
patients with refractory ischemic symptoms or hemody-
namic or rhythm instability are candidates for urgent
coronary angiography and revascularization.
4.4.2. Rationale and Timing for Early Invasive Strategy
This strategy seeks to rapidly risk stratify patients by
assessing their coronary anatomy. The major advantages
of invasive therapy when appropriate are 1) the rapid and
de�nitive nature of the evaluation, 2) the potential for
earlier revascularization in appropriate patients that
might prevent occurrence of further complications of ACS
that could ensue during medical therapy, and 3) facilita-
tion of earlier discharge from a facility.
4.4.2.1. Routine Invasive Strategy Timing
The optimal timing of angiography has not been con-
clusively de�ned. In general, 2 options have emerged:
early invasive (i.e., within 24 hours) or delayed invasive
(i.e., within 25 to 72 hours). In most studies using the
invasive strategy, angiography was deferred for 12 to
72 hours while antithrombotic and anti-ischemic thera-
pies were intensi�ed (138,332–337). The concept of de-
ferred angiography espouses that revascularization may
be safer once plaque is stabilized with optimal antith-
rombotic and/or anti-ischemic therapies. Conversely,
early angiography facilitates earlier risk strati�ca-
tion and consequently speeds revascularization and
discharge but can place greater logistic demands on a
healthcare system.
4.4.3. Rationale for Ischemia-Guided Strategy
The ischemia-guided strategy seeks to avoid the routine
early use of invasive procedures unless patients experi-
ence refractory or recurrent ischemic symptoms or
develop hemodynamic instability. When the ischemia-
guided strategy is chosen, a plan for noninvasive evalu-
ation is required to detect severe ischemia that occurs at a
low threshold of stress and to promptly refer these pa-
tients for coronary angiography and revascularization as
indicated. The major advantage offered by the ischemia-
guided strategy is that some patients’ conditions stabi-
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
lize during medical therapy and will not require coronary
angiography and revascularization. Consequently, the
ischemia-guided strategy may potentially avoid costly
and possibly unnecessary invasive procedures.

FIGURE 3 Algorithm for Management of Patients With De�nite or Likely NSTE-ACS*
*See corresponding full-sentence recommendations and their explanatory footnotes.
†In patients who have been treated with fondaparinux (as upfront therapy) who are undergoing PCI, an additional anticoagulant with anti-IIa activity should be
administered at the time of PCI because of the risk of catheter thrombosis.
ASA indicates aspirin; CABG, coronary artery bypass graft; cath, catheter; COR, Class of Recommendation; DAPT, dual antiplatelet therapy; GPI, glycoprotein IIb/IIIa
inhibitor; LOE, Level of Evidence; NSTE-ACS, non–ST-elevation acute coronary syndrome; PCI, percutaneous coronary intervention; pts, patients; and UFH,
unfractionated heparin.
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DECEMBER 23, 2014:e139– 228
2014 AHA/ACC NSTE-ACS Guideline
e167
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Several studies (93,138,334–337) and meta-analyses (141,340)
have concluded that a strategy of routine invasive therapy is
generally superior to an ischemia-guided strategy or selec-
tively invasive approach. One study reported that the routine
invasive strategy resulted in an 18% relative reduction in
death or MI, including a signi�cant reduction in MI alone
(341). The routine invasive arm was associated with higher
in-hospital mortality (1.8% versus 1.1%), but this disadvan-
tage was more than compensated for by a signi�cant
reduction in mortality between discharge and the end of
follow-up (3.8% versus 4.9%). The invasive strategy was also
associated with less angina and fewer rehospitalizations.
Patients undergoing routine invasive treatment also had
improved quality of life. In an analysis of individual patient
data (340) that reported 5-year outcomes from the FRISC
(Framingham and Fast Revascularization During Instability
in Coronary Artery Disease)-II trial (339), ICTUS (Invasive
Versus Conservative Treatment in Unstable Coronary Syn-
dromes) trial (338), and RITA (Randomized Trial of a Con-
servative Treatment Strategy Versus an Interventional
Treatment Strategy in Patients with Unstable Angina)-3 trial
(334), 14.7% of patients (389 of 2,721) randomized to a routine
GRACE risk score 109–140; TIMI score $2
CABG indicates coronary artery bypass graft; EF, ejection fraction; GFR, glomerular
�ltration rate; GRACE, Global Registry of Acute Coronary Events; HF, heart failure; LV,
left ventricular; NSTE-ACS, non–ST-elevation acute coronary syndrome; PCI, percuta-
neous coronary intervention; TIMI, Thrombolysis In Myocardial Infarction; Tn, troponin;
VF, ventricular �brillation; and VT, ventricular tachycardia.
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
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4.4.4. Early Invasive and Ischemia-Guided Strategies:
Recommendations
CLASS I
1. An urgent/immediate invasive strategy (diagnostic angiog-
raphy with intent to perform revascularization if appropriate
based on coronary anatomy) is indicated in patients (men
and women
{
) with NSTE-ACS who have refractory angina or
hemodynamic or electrical instability (without serious
comorbidities or contraindications to such procedures)
(42,44,138,338). (Level of Evidence: A)
2. An early invasive strategy (diagnostic angiography with
intent to perform revascularization if appropriate based on
coronary anatomy) is indicated in initially stabilized patients
with NSTE-ACS (without serious comorbidities or contrain-
dications to such procedures) who have an elevated risk for
clinical events (Table 8) (42,44,138,333,334,338,339).
(Level of Evidence: B)
CLASS IIa
1. It is reasonable to choose an early invasive strategy (within
24 hours of admission) over a delayed invasive strategy
(within 25 to 72 hours) for initially stabilized high-risk pa-
tients with NSTE-ACS. For those not at high/intermediate
risk, a delayed invasive approach is reasonable (139). (Level
of Evidence: B)
CLASS IIb
1. In initially stabilized patients, an ischemia-guided strategy
may be considered for patients with NSTE-ACS (without
serious comorbidities or contraindications to this approach)
who have an elevated risk for clinical events (333,334,338).
(Level of Evidence: B)
2. The decision to implement an ischemia-guided strategy in
initially stabilized patients (without serious comorbidities or
contraindications to this approach) may be reasonable after
considering clinician and patient preference. (Level of
Evidence: C)
CLASS III: NO BENEFIT
1. An early invasive strategy (i.e., diagnostic angiography with
intent to perform revascularization) is not recommended in
patients with:
a. Extensive comorbidities (e.g., hepatic, renal, pulmonary
failure; cancer), in whom the risks of revascularization and
comorbid conditions are likely to outweigh the bene�ts of
revascularization. (Level of Evidence: C)
b. Acute chest pain and a low likelihood of ACS who
are troponin-negative (Level of Evidence: C),especially
women (141). (Level of Evidence: B)
{See Section 7.7 for additional information on women.
: http://content.onlinejacc.org/ on 03/27/2015
TABLE 8
Factors Associated With Appropriate Selection
of Early Invasive Strategy or Ischemia-Guided
Strategy in Patients With NSTE-ACS
Immediate invasive
(within 2 h)
Refractory angina
Signs or symptoms of HF or new or worsening mitral
regurgitation
Hemodynamic instability
Recurrent angina or ischemia at rest or with low-level
activities despite intensive medical therapy
Sustained VT or VF
Ischemia-guided
strategy
Low-risk score (e.g., TIMI [0 or 1], GRACE [<109])
Low-risk Tn-negative female patients
Patient or clinician preference in the absence of
high-risk features
Early invasive
(within 24 h)
None of the above, but GRACE risk score >140
Temporal change in Tn (Section 3.4)
New or presumably new ST depression
Delayed invasive
(within 25�72 h)
None of the above but diabetes mellitus
Renal insuf�ciency (GFR <60 mL/min/1.73 m
2
)
Reduced LV systolic function (EF <0.40)
Early postinfarction angina
PCI within 6 mo
Prior CABG
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invasive strategy experienced cardiovascular death or
nonfatal MI versus 17.9% of patients (475 of 2,746) in the
selective invasive strategy (HR: 0.81; 95% CI: 0.71 to 0.93;
p¼0.002). The most marked treatment effect was on MI

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(10.0% routine invasive strategy versus 12.9% selective
invasive strategy), and there were consistent trends for fewer
cardiovascular deaths (HR: 0.83; 95% CI: 0.68 to 1.01;
p¼0.068) and all-cause mortality (HR: 0.90; 95% CI: 0.77 to
1.05). There were absolute reductions of 2.0% to 3.8% in
cardiovascular death or MI in the low- and intermediate-risk
groups and an 11.1% absolute risk reduction in the highest-
risk patients. The invasive strategy demonstrated its great-
est advantage in the highest-risk stratum of patients with no
signi�cant bene�t on mortality over the noninvasive
approach in moderate- and low-risk patients (342).An
ischemia-guided strategy has been used with favorable
results in initially stabilized patients with NSTE-ACS at
elevated risk for clinical events, including those with positive
troponin levels (338). One limitation of these studies is the
absence of adherence to optimal medical therapy in non-
invasively treated patients during long-term management. In
addition, in FRISC-II, invasive management was delayed and
patients with markedly positive stress tests (up to 2.9-mm
exercise-induced ST depression) were randomized to
noninvasive or invasive therapy (338).
See Online Data Supplement 18 for additional infor-
mation on comparison of early invasive strategy and
ischemia-guided strategy.
4.4.4.1. Comparison of Early Versus Delayed Angiography
In some studies, early angiography and coronary inter-
vention have been more effective in reducing ischemic
complications than delayed interventions, particularly in
patients at high risk (de�ned by a GRACE score >140)
(139,336). A more delayed strategy is also reasonable in
low- to intermediate-risk patients. The advantage of
early intervention was achieved in the context of
intensive background antithrombotic and anti-ischemic
therapy. However, this question was also assessed by a
meta-analysis of 11 trials (7 RCTs and 4 observational
studies) (343). Meta-analysis of the RCTs was inconclu-
sive for a survival bene�t of the early invasive strategy
(OR:0.83[95%CI:0.64to1.09];p¼0.180), and there
were no signi�cant differences in MI or major bleeding;
a similar result was found with the observational
studies. These data are limited by the small sample size
of the individual trials, low event rates, inconsistency in
timing of intervention, and heterogeneous patient
pro�les.
See Online Data Supplement 19 for additional infor-
mation on comparison of early versus delayed angiography.
4.4.5. Subgroups: Early Invasive Strategy Versus
Ischemia-Guided Strategy
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The TACTICS-TIMI (Treat Angina With Tiro�ban and
Determine Cost of Therapy With an Invasive or Conser-
vative Strategy-Thrombolysis In Myocardial Infarction)
18 trial demonstrated a reduction in the 6-month
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endpoint of death or MI in older adults with ACS (138).
Controversy exists over revascularization treatment dif-
ferences between men and women with ACS. The FRISC-
II trial showed a bene�t of revascularization in men for
death or MI that was not observed for women (344).In
contrast, death, MI, or rehospitalization rates were
reducedforbothmenandwomeninTACTICS-TIMI18
(138). RITA-3 showed that the routine strategy of inva-
sive evaluation resulted in a bene�cial effect in high-risk
men that was not seen in women (342). A meta-analysis
suggests that in NSTE-ACS, an invasive strategy has a
comparable bene�tinmenandhigh-riskwomenfor
reducing the composite endpoint of death, MI, or reho-
spitalization (141,345,346). In contrast, an ischemia-
guided strategy is preferred in low-risk women (141).
Another collaborative meta-analysis of randomized trials
reported that an early invasive strategy yielded similar
RR reductions in overall cardiovascular events in pa-
tients with and without diabetes mellitus (347).How-
ever, an invasive strategy appeared to reduce recurrent
nonfatal MI to a greater extent in patients with diabetes
mellitus.
4.4.6. Care Objectives
Coronary angiography is designed to provide detailed
information about the size and distribution of coronary
vessels, the location and extent of atherosclerotic
obstruction, and the suitability for revascularization.
The LV angiogram, usually performed with coronary
angiography, provides an assessment of the extent of
focal and global LV dysfunction and of the presence and
severity of coexisting disorders (e.g., valvular or other
associated lesions). Patients with NSTE-ACS can be
divided into risk groups on the basis of their initial
clinical presentation. The TIMI, PURSUIT, and GRACE
scores are useful tools for assigning risk to patients with
NSTE-ACS.
Risk strati�cation identi�es patients who are most
likely to bene�tfromsubsequentrevascularization.
Patients with left main disease or multivessel CAD with
reduced LV function are at high risk for adverse outcomes
and are likely to bene�t from CABG. Clinical evaluation
and noninvasive testing aid in the identi�cation of most
patients at high risk because they often have $1ofthe
following high-risk features: advanced age (>70 years
of age), prior MI, revascularization, ST deviation, HF,
depressed resting LV function (i.e., LVEF #0.40) on
noninvasive study, or noninvasive stress test �ndings,
including magnetic resonance imaging (348).Anyofthese
riskfactorsordiabetesmellitusmayaidintheidenti�-
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
cation of high-risk patients who could bene�tfroman
invasive strategy.
Some patients with NSTE-ACS are not in the very high-
risk group and do not have �ndings that portend a high

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risk for adverse outcomes. They are not likely to receive
thesamedegreeofbene�t from routine revascularization
afforded to high-risk patients, and an invasive study is
optional for those at lower risk and can be safely deferred
pending further clinical evidence. Decisions about coro-
nary angiography in patients who are not at high risk
according to �ndings on clinical examination and nonin-
vasive testing can be individualized on the basis of
patient preferences and/or symptoms.
4.5. Risk Strati�cation Before Discharge for Patients With an
Ischemia-Guided Strategy of NSTE-ACS: Recommendations
CLASS I
1. Noninvasive stress testing is recommended in low- and
intermediate-risk patients who have been free of ischemia at
rest or with low-level activity for a minimum of 12 to 24
hours (349–353). (Level of Evidence: B)
2. Treadmill exercise testing is useful in patients able to ex-
ercise in whom the ECG is free of resting ST changes that
may interfere with interpretation (349–352). (Level of
Evidence: C)
3. Stress testing with an imaging modality should be used in
patients who are able to exercise but have ST changes on
resting ECG that may interfere with interpretation. In pa-
tients undergoing a low-level exercise test, an imaging
modality can add prognostic information (349–352). (Level
of Evidence: B)
4. Pharmacological stress testing with imaging is recom-
mended when physical limitations preclude adequate exer-
cise stress. (Level of Evidence: C)
5. A noninvasive imaging test is recommended to evaluate LV
function in patients with de�nite ACS (349–352). (Level of
Evidence: C)
The management of patients with NSTE-ACS requires
continuous risk strati�cation. Important prognostic infor-
mation is derived from initial assessment, the patient’s
course during the early days of management, and the
response to anti-ischemic and antithrombotic therapy. The
choice of stress test is based on the patient’s resting ECG and
ability to exercise, local expertise, and available technolo-
gies. The exercise intensity of the treadmill test (low level or
symptom-limited) is used at the discretion of the attending
clinician based on individual patient assessment. For inva-
sively managed patients with residual nonculprit lesions,
additional evaluation may be indicated to ascertain the
signi�cance of such lesions. Refer to the PCI CPG for addi-
tional details (26).
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
4.5.1. Noninvasive Test Selection
The goals of noninvasive testing in patients with a low or
intermediate likelihood of CAD and high-risk patients
who did not have an early invasive strategy are to detect
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ischemia and estimate prognosis. This information guides
further diagnostic steps and therapeutic measures.
Because of its simplicity, lower cost, and widespread
familiarity with its performance and interpretation, the
standard low-level exercise electrocardiographic stress
test remains the most reasonable test in patients who are
able to exercise and who have a resting ECG that is
interpretable for ST shifts. There is evidence that imaging
studies are superior to exercise electrocardiographic
evaluation in women for diagnosis of CAD (350).How-
ever, for prognostic assessment in women, treadmill ex-
ercise testing has provided comparable results to stress
imaging (354). Patients with an electrocardiographic
pattern that would interfere with interpretation of the ST
segment (baseline ST abnormalities, bundle-branch block,
LV hypertrophy with ST-T changes, intraventricular con-
duction defect, paced rhythm, pre-excitation, and
digoxin) should have an exercise test with imaging.
Patients who are unable to exercise should have a
pharmacological stress test with imaging. Low- and
intermediate-risk patients with NSTE-ACS may undergo
symptom-limited stress testing, provided they have been
asymptomatic and clinically stable at 12 to 24 hours for
those with UA and 2 to 5 days for patients at similar risk
with NSTEMI (349).Theoptimaltestingstrategyin
womenislesswellde�nedthaninmen.
4.5.2. Selection for Coronary Angiography
In contrast to noninvasive tests, coronary angiography
provides detailed structural information for assessment
of prognosis and appropriate management. When com-
binedwithLVangiography,italsoprovidesanassess-
ment of global and regional LV function. Coronary
angiography is usually indicated in patients with NSTE-
ACS who have recurrent symptoms or ischemia despite
adequate medical therapy or who are at high risk as
categorized by clinical �ndings (HF, serious ventricular
arrhythmias), noninvasive test �ndings (signi�cant LV
dysfunction with EF <0.40, large anterior or multiple
perfusion defects or wall motion abnormalities on
echocardiography, high-risk Duke treadmill score #�11),
high-riskTIMIorGRACEscores,ormarkedlyelevated
troponin levels. Patients with NSTE-ACS who have had
previous PCI or CABG should also be considered for early
coronary angiography, unless prior coronary angiography
data indicate that no further revascularization is
feasible.
The general indications for coronary angiography and
revascularization should be tempered by individual
patient characteristics and preferences (a patient-
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centered approach). Patient and clinician judgments
about risks and bene�ts are important for patients who
might not be candidates for coronary revascularization,
such as very frail older adults and those with serious

40% of patients with NSTE-ACS will undergo PCI (365).As
discussed previously, in patients with NSTE-ACS, a strategy
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
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comorbid conditions (e.g., severe hepatic, pulmonary,
or renal failure; active or inoperable cancer).
See Online Data Supplement 20 for additional infor-
mation on risk strati�cation.
5. MYOCARDIAL REVASCULARIZATION
Recommendations about coronary artery revasculariza-
tion indications, bene�ts, and choice of revascularization
procedure (PCI or CABG) for all anatomic subsets have
been published in the 2011 PCI CPG (26), the 2011 CABG
CPG (23),andthe2012stableischemicheartdiseaseCPG
and its 2014 focused update (10,11). The main difference
between management of patients with stable ischemic
heart disease and NSTE-ACS is a stronger impetus for
revascularization in those with NSTE-ACS. Myocardial
ischemia in ACS may progress to MI and is potentially life
threatening. In addition, in patients with ACS, angina
(including recurrent angina) is more likely to be reduced
by revascularization than by medical therapy (26).
A “heart team” approach to revascularization de-
cisions, involving an interventional cardiologist and
cardiothoracic surgeon, is used in patients with unpro-
tected left main or complex CAD. Calculation of SYNTAX
(Synergy Between Percutaneous Coronary Intervention
With TAXUS and Cardiac Surgery) and STS scores is
reasonable in these patients to guide the choice of
revascularization (23,26,355).
Factors that in�uence the choice of revascularization
procedure include the extent and complexity of CAD;
short-term risk and long-term durability of PCI; operative
mortality (which can be estimated by the STS score);
diabetes mellitus; CKD; completeness of revasculariza-
tion; LV systolic dysfunction; previous CABG; and the
ability of the patient to tolerate and comply with DAPT. In
general, the greater the extent and complexity of the
multivessel disease, the more compelling the choice of
CABG over multivessel PCI (23,26,356–358).Inpatients
with NSTE-ACS, PCI of a culprit unprotected left main
coronary artery lesion is an option if the patient is not a
candidate for CABG (23,26).
See Online Data Supplements 21 and 22 for additional
information on myocardial revascularization.
5.1. Percutaneous Coronary Intervention
5.1.1. PCI—General Considerations: Recommendation
CLASS IIb
1. A strategy of multivessel PCI, in contrast to culprit
lesion�only PCI, may be reasonable in patients undergoing
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DECEMBER 23, 2014:e139– 228
coronary revascularization as part of treatment for NSTE-
ACS (330,359–364). (Level of Evidence: B)
Approximately half of all PCI procedures are performed in
patients with UA or NSTEMI, and approximately 32% to
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of early angiography and revascularization (primarily with
PCI) results in lower rates of recurrent UA, recurrent reho-
spitalization, MI, and death (366,367). Although PCI of a
nonculprit lesion is not advocated in patients with STEMI
(26), there is less agreement on whether nonculprit lesions
should undergo intervention at the time of culprit-lesion
PCI for NSTE-ACS. Most reports (359–364), but not all
(330), comparing culprit lesion�only PCI with multivessel
PCI (e.g., PCI of multiple vessels performed at the same
time) in patients with NSTE-ACS did not �nd an increased
risk of MACE with multivessel PCI and found a reduction in
the need for repeat revascularization. However, the data
consist predominantly of post hoc analysis of non-
randomized data with variable duration of follow-up. This
question has not been resolved and is an area of current
investigation.
5.1.2. PCI—Antiplatelet and Anticoagulant Therapy
5.1.2.1. Oral and Intravenous Antiplatelet Agents:
Recommendations
CLASS I
1. Patients already taking daily aspirin before PCI should take
81 mg to 325 mg non–enteric-coated aspirin before PCI
(26,368–370). (Level of Evidence: B)
2. Patients not on aspirin therapy should be given non–enteric-
coated aspirin 325 mg as soon as possible before PCI
(26,368–370). (Level of Evidence: B)
3. After PCI, aspirin should be continued inde�nitely at a dose
of 81 mg to 325 mg daily (27,288,371). (Level of Evidence: B)
4. A loading dose of a P2Y
12
receptor inhibitor should be given
before the procedure in patients undergoing PCI with
stenting (26,293,302,331,372–375). (Level of Evidence: A)
Options include:
a. Clopidogrel: 600 mg (331,372–374,376–378) (Level of
Evidence: B) or
b. Prasugrel#:60mg(302) (Level of Evidence: B) or
c. Ticagrelork:180mg(293) (Level of Evidence: B)
5. In patients with NSTE-ACS and high-risk features (e.g.,
elevated troponin) not adequately pretreated with clopi-
dogrel or ticagrelor, it is useful to administer a GP IIb/IIIa
inhibitor (abciximab, double-bolus epti�batide, or high-dose
bolus tiro�ban)atthetimeofPCI(379–382). (Level of
Evidence: A)
#Patients should receive a loading dose of prasugrel, provided that they were
not pretreated with another P2Y
12
receptor inhibitor.
kThe recommended maintenance dose of aspirin to be used with ticagrelor is
81 mg daily (290).

6. In patients receiving a stent (bare-metal stent or drug-
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
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eluting stent [DES]) during PCI for NSTE-ACS, P2Y
12
inhibi-
tor therapy should be given for at least 12 months (330).
Options include:
a. Clopidogrel: 75 mg daily (296,331) (Level of Evidence: B) or
b. Prasugrel#:10mgdaily(302) (Level of Evidence: B) or
c. Ticagrelork: 90 mg twice daily (293) (Level of Evidence: B)
CLASS IIa
1. It is reasonable to choose ticagrelor over clopidogrel for
P2Y
12
inhibition treatment in patients with NSTE-ACS
treated with an early invasive strategy and/or coronary
stenting (293,294). (Level of Evidence: B)
2. It is reasonable to choose prasugrel over clopidogrel for
P2Y
12
treatmentinpatientswithNSTE-ACSwhoundergoPCI
who are not at high risk of bleeding complications
(302,303). (Level of Evidence: B)
3. In patients with NSTE-ACS and high-risk features (e.g.,
elevated troponin) treated with UFH and adequately pre-
treated with clopidogrel, it is reasonable to administer a GP
IIb/IIIa inhibitor (abciximab, double-bolus epti�batide, or
high-bolus dose tiro�ban)atthetimeofPCI(195,383,384).
(Level of Evidence: B)
4. After PCI, it is reasonable to use 81 mg per day of aspirin in
preference to higher maintenance doses (331,368,385–388).
(Level of Evidence: B)
5. If the risk of morbidity from bleeding outweighs the antici-
pated bene�tofarecommendeddurationofP2Y
12
inhibitor
therapy after stent implantation, earlier discontinuation
(e.g., <12 months) of P2Y
12
inhibitor therapy is reasonable
(330). (Level of Evidence: C)
CLASS IIb
1. Continuation of DAPT beyond 12 months may be con-
sidered in patients undergoing stent implantation. (Level of
Evidence: C)
CLASS III: HARM
1. Prasugrel should not be administered to patients with a prior
history of stroke or transient ischemic attack (302). (Level of
Evidence: B)
Comprehensive recommendations on the use of antiplatelet
and anticoagulant therapy in patients with NSTE-ACS under-
going PCI are given in the 2011 PCI CPG (26). Aspirin reduces
the frequency of ischemic complications after PCI and is
ideally administered at least 2 hours, and preferably 24 hours,
#Patients should receive a loading dose of prasugrel, provided that they were
not pretreated with another P2Y
12
receptor inhibitor.
kThe recommended maintenance dose of aspirin to be used with ticagrelor is
81 mg daily (290).
: http://content.onlinejacc.org/ on 03/27/2015
before PCI (26,368,369). DAPT, consisting of aspirin and a
P2Y
12
inhibitor, in patients treated with coronary stents re-
duces the risk of stent thrombosis and composite ischemic
events (296,331,372–375,389,390). Compared with a loading
dose of 300 mg of clopidogrel, a loading dose of 600 mg of
clopidogrel in patients undergoing PCI achieves greater
platelet inhibition with fewer low responders and decreases
the incidence of MACE (376–378). In patients with ACS who
have undergone coronary stenting, treatment with prasugrel
or ticagrelor, compared with treatment with clopidogrel, re-
sults in a greater reduction in composite ischemic events and
the incidence of stent thrombosis, although at a risk of
increased non–CABG bleeding (293,302). The optimal duration
of DAPT therapy in patients treated with DES is not well
established (26). However, aspirin is continued inde�nitely in
all patients managed with a bare-metal stent or DES, and
DAPT is an option for >12 months in patients who have
received a DES. This determination should balance the risks of
stent thrombosis and ischemic complications versus bleeding
and should be jointly made by the clinician and the patient.
Loading and short-term maintenance doses of clopi-
dogrel were studied in CURRENT–OASIS (Clopidogrel
Optimal Loading Dose Usage to Reduce Recurrent Events–
Organization to Assess Strategies in Ischemic Syndromes)
7,whichdemonstratedapotentialbene�tofhigher-dose
clopidogrel (600-mg loading dose, 150 mg daily for
6 days, 75 mg daily thereafter) in patients with NSTE-ACS
undergoing an invasive management strategy (292,391).
Although the overall trial (292) failed to demonstrate a
signi�cant difference in the primary endpoint between the
clopidogrel and aspirin groups (4.2% versus 4.4%), the PCI
subset (n¼17,263) showed signi�cant differences in the
clopidogrel arm (391). Notably, the higher-dose clopidogrel
therapy increased major bleeding in the entire group (2.5%
versus 2.0%; p¼0.012) and the PCI subgroup (1.1% versus
0.7%; p¼0.008). In addition, during the period of several
hours required for conversion of clopidogrel to its active
metabolite, there is reduced effectiveness. However,
ef�cacy is restored following conversion.
Patients undergoing PCI who have previously received
a loading dose of 300 mg of clopidogrel and are on a 75-mg
daily maintenance dose should receive another 300-mg
loading dose (315). There are no data appropriate for
prasugrel because this drug is administered before PCI.
For ticagrelor, there are no data on additional loading.
5.1.2.2. GP IIb/IIIa Inhibitors: Recommendations
CLASS I
1. In patients with NSTE-ACS and high-risk features (e.g.,
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DECEMBER 23, 2014:e139– 228
elevated troponin) who are not adequately pretreated with
clopidogrel or ticagrelor, it is useful to administer a GP IIb/
IIIa inhibitor (abciximab, double-bolus epti�batide, or high-
dose bolus tiro�ban) at the time of PCI (379–382). (Level of
Evidence: A)

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CLASS IIa
1. In patients with NSTE-ACS and high-risk features (e.g.,
elevated troponin) treated with UFH and adequately pre-
treated with clopidogrel, it is reasonable to administer a GP
IIb/IIIa inhibitor (abciximab, double-bolus epti�batide, or
high-dose bolus tiro�ban)atthetimeofPCI(195,383).
(Level of Evidence: B)
GP IIb/IIIa receptor antagonist therapy in patients with
NSTE-ACS undergoing PCI reduced the incidence of com-
posite ischemic events, primarily through a decrease in
documented MI, although in some trials this is counter-
balanced by an increased rate of bleeding (193,195,310,379–
382,392). Most, but not all, randomized trials of the use of
GP IIb/IIIa inhibitor were conducted in the era before clopi-
dogrel therapy (193,195,310,379–383,392). Abciximab, double-
bolus epti�batide, and high-bolus dose tiro�ban result in a
high degree of platelet inhibition, reduce ischemic compli-
cations in patients undergoing PCI, and appear to afford
comparable angiographic and clinical outcomes (26). As trials
of the GP IIb/IIIa inhibitors generally excluded patients at
high risk of bleeding, recommendations for the use of GP IIb/
IIIa inhibitors are best understood as applying to patients not
at high risk of bleeding complications. Although GP IIb/IIIa
inhibitors were used in 27% and 55% of patients, respec-
tively, in the PLATO (Platelet Inhibition and Patient Out-
comes) and TRITON studies of ticagrelor and prasugrel, there
are insuf�cient data (293,302,393) (and no RCT data) from
which to make speci�c recommendations about GP IIb/IIIa
inhibitor use in patients treated with either of these P2Y
12
inhibitors.
See Online Data Supplement 21 for additional informa-
tion on GP IIb/IIIa inhibitors.
5.1.2.3. Anticoagulant Therapy in Patients Undergoing PCI:
Recommendations
CLASS I
1. An anticoagulant should be administered to patients with
NSTE-ACS undergoing PCI to reduce the risk of intracoronary
and catheter thrombus formation. (Level of Evidence: C)
2. Intravenous UFH is useful in patients with NSTE-ACS
undergoing PCI. (Level of Evidence: C)
3. Bivalirudin is useful as an anticoagulant with or without prior
treatment with UFH in patients with NSTE-ACS undergoing
PCI (310,394–398). (Level of Evidence: B)
4. An additional dose of 0.3 mg/kg IV enoxaparin should be
administered at the time of PCI to patients with NSTE-ACS
who have received fewer than 2 therapeutic subcutaneous
doses (e.g., 1 mg/kg SC) or received the last subcutaneous
enoxaparin dose 8 to 12 hours before PCI (309,399–403).
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(Level of Evidence: B)
5. If PCI is performed while the patient is on fondaparinux, an
additional 85 IU/kg of UFH should be given intravenously
immediately before PCI because of the risk of catheter
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thrombosis (60 IU/kg IV if a GP IIb/IIIa inhibitor used with
UFH dosing based on the target-activated clotting time)
(26,313–315,404). (Level of Evidence: B)
6. In patients with NSTE-ACS, anticoagulant therapy should be
discontinued after PCI unless there is a compelling reason to
continue such therapy. (Level of Evidence: C)
CLASS IIa
1. In patients with NSTE-ACS undergoing PCI who are at
high risk of bleeding, it is reasonable to use bivalirudin
monotherapy in preference to the combination of UFH
and a GP IIb/IIIa receptor antagonist (310,396). (Level of
Evidence: B)
CLASS IIb
1. Performance of PCI with enoxaparin may be reasonable in
patients treated with upstream subcutaneous enoxaparin for
NSTE-ACS (26,309,399–402,405,406). (Level of Evidence: B)
CLASS III: HARM
1. Fondaparinux should not be used as the sole anticoagulant
to support PCI in patients with NSTE-ACS due to an
increased risk of catheter thrombosis (26,313–315). (Level of
Evidence: B)
Anticoagulant therapy prevents thrombus formation at the
site of arterial injury, on the coronary guide wire, and in
the catheters used for PCI (26,407). With rare exceptions,
all PCI studies have used some form of anticoagulant at
the time of PCI (26). Intravenous UFH and bivalirudin both
have Class I recommendations in patients undergoing
PCI in the 2011 PCI CPG (26). Patients who have received
multiple doses of subcutaneously-administered enoxaparin
who undergo PCI within 8 hours of the last subcutaneous
dose generally have received adequate anticoagulation to
undergo PCI, but the degree of anticoagulation may
diminish 8 to 12 hours after the last subcutaneous dose. In
such patients, as well as in patients who have received
fewer than 2 subcutaneous doses of enoxaparin, the
addition of enoxaparin (0.3 mg/kg IV) at the time of
PCI provides additional anticoagulation and has become
standard practice (26,309,399–403). Patients who undergo
PCI >12 hours after the last subcutaneous dose of enox-
aparin are usually treated with full-dose de novo anti-
coagulation with an established regimen (e.g., full-dose
UFH or bivalirudin). Fondaparinux as the sole anticoagu-
lant during PCI has been associated with catheter throm-
bosis, and use of an anticoagulant with anti-IIa activity is
recommended when patients treated with fondaparinux
undergo PCI (313–315). One suggested regimen is UFH 85
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
IU/kg IV if no GP IIb/IIIa inhibitor is used and 60 IU/kg IV
if a GP IIb/IIIa inhibitor is used with UFH dosing based on
the target-activated clotting time (314,404) (Table 9)
(26,313–315).

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5.2. Timing of Urgent CABG in Patients With NSTE-ACS in
Relation to Use of Antiplatelet Agents: Recommendations
TABLE 9 Dosing of Parenteral Anticoagulants During PCI
Drug*
In Patients Who Have Received
Prior Anticoagulant Therapy
Enoxaparin � For prior treatment with enoxaparin, if last SC dose was
administered 8�12 h earlier or if <2 therapeutic SC dos
of enoxaparin have been administered, an IV dose of en
0.3 mg/kg should be given
� If the last SC dose was administered within prior 8 h,
no additional enoxaparin should be given
Bivalirudin � For patients who have received UFH, wait 30 min, then
give 0.75 mg/kg IV loading dose, then 1.75 mg/kg/h IV
� For patients already receiving bivalirudin infusion, give
additional
loading dose 0.5 mg/kg and increase infusion to 1.75 m
during PCI
Fondaparinux � For prior treatment with fondaparinux, administer addit
treatment with anticoagulant possessing anti-IIa activit
whether GPI receptor antagonists have been administer
UFH � IV GPI planned: additional UFH as needed (e.g., 2,000–
achieve ACT of 200–250 s
� No IV GPI planned: additional UFH as needed (e.g., 2,00
to achieve ACT of 250–300 s for HemoTec, 300–350 s
*Drugs presented in order of the COR and then the LOE as noted in the Preamble. When m
are listed alphabetically.
ACT indicates activated clotting time; COR, Class of Recommendation; GPI, glycopr
percutaneous coronary intervention; SC, subcutaneous; and UFH, unfractionated heparin
Modi�ed from Levine et al. (26).
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
CLASS I
1. Non–enteric-coated aspirin (81 mg to 325 mg daily) should
be administered preoperatively to patients undergoing
CABG (408–410). (Level of Evidence: B)
2. In patients referred for elective CABG, clopidogrel and
ticagrelor should be discontinued for at least 5 days before
surgery (23,411–413) (Level of Evidence: B) and prasugrel for
at least 7 days before surgery (8,414). (Level of Evidence: C)
3. In patients referred for urgent CABG, clopidogrel and tica-
grelor should be discontinued for at least 24 hours to reduce
major bleeding (8,412,415–417). (Level of Evidence: B)
4. In patients referred for CABG, short-acting intravenous GP
IIb/IIIa inhibitors (epti�batide or tiro�ban) should be dis-
continued for at least 2 to 4 hours before surgery (418,419)
and abciximab for at least 12 hours before to limit blood loss
and transfusion (389). (Level of Evidence: B)
CLASS IIb
1. In patients referred for urgent CABG, it may be rea-
sonable to perform surgery less than 5 days after clopi-
dogrel or ticagrelor has been discontinued and less than 7 days
after prasugrel has been discontinued. (Level of Evidence: C)
In-hospital CABG is performed in 7% to 13% of patients hospi-
talized with NSTE-ACS (420–422). Approximately one third of
patients with NSTEMI undergo CABG within 48 hours of hos-
pital admission (421). In these patients, CABG was performed
at a median time of 73 hours after admission (interquartile
: http://content.onlinejacc.org/ on 03/27/2015
range: 42 to 122 hours) (421). In-hospital mortality in patients
with NSTEMI undergoing CABG is approximately 3.7% (421).
In Patients Who Have Not Received
Prior Anticoagulant Therapy
arin
� 0.5 mg/kg–0.75 mg/kg IV loading dose
sion
/h
� 0.75 mg/kg loading dose, 1.75 mg/kg/h IV infusion
l IV
nsidering
N/A
0 U) to
,000 U)
emochron
� IV GPI planned: 50–70 U/kg loading dose to achieve
ACT of 200–250 s
� No IV GPI planned: 70–100 U/kg loading dose to achieve
target ACT of 250–300 s for HemoTec, 300–350 s
for Hemochron
han 1 drug exists within the same LOE, and there are no comparative data, then the drugs
IIb/IIIa inhibitor; IV, intravenous; LOE, Level of Evidence; N/A, not applicable; PCI,
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
Recommendations for management of patients treated
with oral and intravenous antiplatelet agents who undergo
CABGaregiveninthe2011CABGCPG(23).Preoperative
aspirin reduces operative morbidity and mortality, and
CABG can be performed safely in patients on aspirin ther-
apy with only a modest increase in bleeding risk (23,408–
410).TheuseofP2Y
12
inhibitors in patients with NSTE-
ACS is associated with an increase in post–CABG bleeding
and the need for transfusion (293,302,411,413,423–425).
Although it is recommended that clopidogrel and ticagrelor
be discontinued at least 5 days before surgery and prasu-
grel at least 7 days before surgery in patients referred for
elective CABG (23,411–413), the timing of CABG in patients
with NSTE-ACS treated with a P2Y
12
inhibitor (330) should
re�ect a balance of the potential increase in bleeding
against the potential bene�ts of not delaying surgery 5 to 7
days. The risk of major bleeding complications is
increased when CABG is performed <24 hours after
discontinuation of clopidogrel (23,416,417).Inpatients
who undergo CABG 1 to 4 days after discontinuation of
clopidogrel, it appears that the incidence of life-
threatening bleeding is not signi�cantly increased, but
an increase in blood transfusions is likely
(23,415,416,425,426). In the TRITON-TIMI 38 trial (302),
the incidence of CABG-related major bleeding was higher
in patients treated with prasugrel than in patients treated
with clopidogrel (23,386).InthePLATOtrial,theratesof
major bleeding and transfusion requirements were similar

dose, frequency, side effects, and duration of use (429).
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
e175
Downloa
between patients treated with ticagrelor and patients
treatedwithclopidogrel(294). The more rapid recovery of
platelet function in pharmacokinetic studies of ticagrelor
did not translate to a lower risk of bleeding or lessen the
need for transfusion compared with clopidogrel when
CABG was performed early (i.e., <5days)afterdrug
discontinuation (23,293,412).
See Online Data Supplements 21 and 22 for more
information on myocardial revascularization.
6. LATE HOSPITAL CARE, HOSPITAL DISCHARGE,
AND POSTHOSPITAL DISCHARGE CARE
6.1. General Principles (Cardioprotective Therapy and
Symptom Management)
The goals of therapy after NSTE-ACS are to restore the patient
to normal activities to the extent possible and to use the
acute event to re-evaluate the plan of care, particularly life-
style and risk factor modi�cation. Aggressive risk factor
modi�cations that can prolong survival should be the main
goal of long-term management of patients with stable CAD.
Patients presenting with NSTE-ACS represent a high-risk
cohort in whom secondary cardiovascular disease preven-
tion is likely to be particularly effective (Table 10). Clinicians
have an opportunity to provide evidence-based care to this
high-risk cohort and to aggressively treat the underlying
atherosclerotic process through lifestyle modi�cation and
effective pharmacological therapies (427).Inmostcases,the
inpatient anti-ischemic medical regimen should be
continued after discharge, and the antiplatelet/anticoagulant
medications should be changed to an outpatient regimen.
The goals for continued medical therapy after discharge
relate to potential prognostic bene�ts (primarily shown for
antiplatelet agents, beta blockers, statins, and inhibitors of
the renin-angiotensin aldosterone system, especially for
LVEF <0.40). Added bene�ts are control of ischemic symp-
toms (nitrates, beta blockers, CCBs, and ranolazine) and
treatment of major risk factors such as smoking, hyperten-
sion, dyslipidemia, physical inactivity, obesity, and diabetes
mellitus (427). Selection of a medical regimen should be
individualized to each patient on the basis of in-hospital
�ndings, risk factors for CAD, drug tolerability, and recent
procedural interventions. The mnemonic “ABCDE” (Aspirin,
Antianginals, and ACE Inhibitors; Beta Blockers and BP;
Cholesterol and Cigarettes; Diet and Diabetes Mellitus;
Education and Exercise) is useful in guiding treatment (428).
6.2. Medical Regimen and Use of Medications at Discharge:
Recommendations
CLASS I
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DECEMBER 23, 2014:e139– 228
1. Medications required in the hospital to control ischemia
should be continued after hospital discharge in patients with
NSTE-ACS who do not undergo coronary revascularization,
patients with incomplete or unsuccessful revascularization,
ded From: http://content.onlinejacc.org/ on 03/27/2015
(Level of Evidence: C)
5. For patients who are post–NSTE-ACS and have initial
angina lasting more than 1 minute, nitroglycerin (1 dose
sublingual or spray) is recommended if angina does not
subside within 3 to 5 minutes; call 9-1-1 immediately
to access emergency medical services (429).(Levelof
Evidence: C)
6. If the pattern or severity of angina changes, suggesting
worsening myocardial ischemia (e.g., pain is more frequent
or severe or is precipitated by less effort or occurs at rest),
patients should contact their clinician without delay to
assess the need for additional treatment or testing (429).
(Level of Evidence: C)
7. Before discharge, patients should be educated about
modi�cation of cardiovascular risk factors (428). (Level of
Evidence: C)
6.2.1. Late Hospital and Posthospital Oral Antiplatelet Therapy:
Recommendations
CLASS I
1. Aspirin should be continued inde�nitely. The maintenance
dose should be 81 mg daily in patients treated with tica-
grelor and 81 mg to 325 mg daily in all other patients
(288–290). (Level of Evidence: A)
2. In addition to aspirin, a P2Y
12
inhibitor (either clopidogrel or
ticagrelor) should be continued for up to 12 months in all
patients with NSTE-ACS without contraindications who are
treated with an ischemia-guided strategy. Options include:
� Clopidogrel: 75 mg daily (289,296) (Level of Evidence: B) or
� Ticagrelork:90mgtwicedaily(293,294) (Level of
Evidence: B)
and patients with recurrent symptoms after revasculariza-
tion. Titration of the doses may be required (427,428).
(Level of Evidence: C)
2. All patients who are post–NSTE-ACS should be given sub-
lingual or spray nitroglycerin with verbal and written
instructions for its use (429). (Level of Evidence: C)
3. Before hospital discharge, patients with NSTE-ACS should
be informed about symptoms of worsening myocardial
ischemia and MI and should be given verbal and written
instructions about how and when to seek emergency care for
such symptoms (429). (Level of Evidence: C)
4. Before hospital discharge, patients who are post–NSTE-ACS
and/or designated responsible caregivers should be pro-
vided with easily understood and culturally sensitive verbal
and written instructions about medication type, purpose,
kThe recommended maintenance dose of aspirin to be used with ticagrelor is
81 mg daily (290).

TABLE 10 Plan of Care for Patients With NSTE-ACS
Plan of Care Resources/References
Medications
Antithrombotic therapies � Sections 6.2.1 and 6.2.2
Beta blockers � Section 4.1.2.3
ACE inhibitors/ARBs/aldosterone antagonists � Section 4.2
CCBs � Section 4.1.2.4
Statins � 2013 Blood cholesterol CPG (18)
Discontinuation of antithrombotic therapies for elective surgical and
medical procedures with increased risk of bleeding
� 2014 SIHD focused update (10)
� 2012 SIHD CPG (11)
� 2012 Management of AMI in patients with persistent STEMI CPG (19)
� 2011 Secondary prevention CPG (27)
� 2007 Science Advisory on the prevention of premature discontinuation of DAPT in
patients with coronary artery stents (504)
Inappropriate use of analgesics (NSAIDs) � 2010 Expert consensus document on PPIs and thienopyridines (430)
Use of PPIs � 2011 PCI CPG (26)
Risk factor modi�cation/lifestyle interventions and physical activity/cardiac rehabilitation
Smoking cessation � Tobacco cessation toolkit (505)
Diet nutrition � 2013 Lifestyle CPG (15)
Physical activity � 2013 Lifestyle CPG (15)
� 2011 Secondary prevention CPG (27)
Cardiorespiratory �tness (MET capacity) � 2011 Secondary prevention CPG (27)
� 2010 Performance measures on cardiac rehabilitation (454)
� 2012 Scienti�c statement on sexual activity and cardiovascular disease (231)
Management of comorbidities
Overweight/obesity � 2013 Obesity CPG (16)
� 2011 Secondary prevention CPG (27)
Statins � 2013 Lifestyle CPG (15)
� 2013 Blood cholesterol CPG (18)
Hypertension � 2014 Report on high BP (501)
� 2013 Science advisory on high BP control (506)
Diabetes mellitus � 2013 Position statement on standards of medical care in diabetes (507)
HF � 2013 HF CPG (14)
Arrhythmia/Arrhythmia risk � 2012 Focused update incorporated into the 2008 DBT CPG (20)
� 2014 AF CPG (12)
Psychosocial factors
Sexual activity � 2012 Scienti�c statement on sexual activity and cardiovascular disease (231)
� 2013 Consensus document on sexual counseling for individuals with cardiovascular
disease and their partners (508)
Gender-Speci�c issues � 2007 Cardiovascular disease prevention in women CPG (475)
Depression, stress, and anxiety � 2008 Science advisory on depression and coronary heart disease (509)
Alcohol use � 2011 Secondary prevention CPG (27)
Culturally sensitive issues � 2009 Consensus report on a comprehensive framework and preferred practices for
measuring and reporting cultural competency (510)
Return to work schedule
Clinician follow-up
Cardiologist � 2011 Secondary prevention CPG (27)
� 2013 Hospital to Home Quality Initiative (511)
Primary care clinician
Advanced practice nurse/physician assistant
Pharmacists � 2013 Discharge counseling for patients with HF or MI (512)
Other relevant medical specialists
Electronic personal health records
In�uenza vaccination � 2005 Recommendations for prevention and control of in�uenza (37)
Continued on the next page
Amsterdam et al.
JACC VOL. 64, NO. 24, 2014
2014 AHA/ACC NSTE-ACS Guideline
DECEMBER 23, 2014:e139– 228
e176
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0 C
e—p
3 ST
ectiv
diov
ial in
anti
l infa
or; SIHD, stable ischemic heart disease; and STEMI, ST-elevation myocardial infarction.
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
e177
Downloa
3. In patients receiving a stent (bare-metal stent or DES) during
PCI for NSTE-ACS, P2Y
12
inhibitor therapy should be given
for at least 12 months (330). Options include:
TABLE 10 Continued
Plan of Care
Patient/family education
Plan of care for AMI � 201
car
� 201
Recognizing symptoms of MI
Activating EMS, signs and symptoms for urgent vs.
emergency evaluations
CPR training for family members
Risk assessment and prognosis
Advanced directives
Social networks/social isolation
Socioeconomic factors
Access to health insurance coverage
Access to clinicians � Eff
Disability � Car
Social services
Community services
ACE indicates angiotensin-converting enzyme; AF, atrial �brillation; AMI, acute myocard
blocker; CPG, clinical practice guideline; CPR, cardiopulmonary resuscitation; DAPT, dual
emergency medical services; HF, heart failure; MET, metabolic equivalent; MI, myocardia
coronary syndromes; PCI, percutaneous coronary intervention; PPI, protein pump inhibit
� Clopidogrel: 75 mg daily (296,331) (Level of Evidence: B) or
� Prasugrel#:10mgdaily(302) (Level of Evidence: B) or
� Ticagrelork:90mgtwicedaily(293) (Level of Evidence: B)
CLASS IIa
1. It is reasonable to use an aspirin maintenance dose of 81 mg per
day in preference to higher maintenance doses in patients with
NSTE-ACS treated either invasively or with coronary stent
implantation (26,331,368,385–388). (Level of Evidence: B)
2. It is reasonable to use ticagrelor in preference to clopidogrel
for maintenance P2Y
12
treatment in patients with NSTE-ACS
who undergo an early invasive or ischemia-guided strategy
(293,294). (Level of Evidence: B)
3. It is reasonable to choose prasugrel over clopidogrel for
maintenance P2Y
12
treatment in patients with NSTE-ACS
who undergo PCI who are not at high risk for bleeding
complications (302,303). (Level of Evidence: B)
4. If the risk of morbidity from bleeding outweighs the antici-
pated bene�tofarecommendeddurationofP2Y
12
inhibitor
therapy after stent implantation, earlier discontinuation
(e.g., <12 months) of P2Y
12
inhibitor therapy is reasonable
(330). (Level of Evidence: C)
#Patients should receive a loading dose of prasugrel, provided they were not
pretreated with another PY
12
receptor inhibitor.
kThe recommended maintenance dose of aspirin to be used with ticagrelor is 81
mg daily (290).
ded From: http://content.onlinejacc.org/ on 03/27/2015
CLASS IIb
1. Continuation of DAPT beyond 12 months may be considered in
patients undergoing stent implantation. (Level of Evidence: C)
Resources/References
PG for cardiopulmonary resuscitation and emergency cardiovascular
art 9: postcardiac arrest care (31)
EMI CPG (17)
e communication and care coordination (513)
ascular disability: updating Social Security listings (514)
farction; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel
platelet therapy; DBT, device-based therapy; ECC, emergency cardiovascular care; EMS,
rction; NSAID, nonsteroidal anti-in�ammatory drug; NSTE-ACS, non–ST-elevation acute
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
6.2.2. Combined Oral Anticoagulant Therapy and Antiplatelet
Therapy in Patients With NSTE-ACS
CLASS I
1. The duration of triple antithrombotic therapy with a
vitamin K antagonist, aspirin, and a P2Y
12
receptor inhibitor
in patients with NSTE-ACS should be minimized to the
extent possible to limit the risk of bleeding. (Level of
Evidence: C)
2. Proton pump inhibitors should be prescribed in patients
with NSTE-ACS with a history of gastrointestinal bleeding
who require triple antithrombotic therapy with a vitamin
K antagonist, aspirin, and a P2Y
12
receptor inhibitor
(26,430,431). (Level of Evidence: C)
CLASS IIa
1. Proton pump inhibitor use is reasonable in patients with
NSTE-ACS without a known history of gastrointestinal
bleeding who require triple antithrombotic therapy with a
vitamin K antagonist, aspirin, and a P2Y
12
receptor inhibitor
(26,430,431). (Level of Evidence: C)
CLASS IIb
1. Targeting oral anticoagulant therapy to a lower international
normalized ratio (INR) (e.g., 2.0 to 2.5) may be reasonable in
patients with NSTE-ACS managed with aspirin and a P2Y
12
inhibitor. (Level of Evidence: C)

thrombotic events compared with those randomized
e178
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The combination of oral antiplatelet therapy and oral
anticoagulant therapy signi�cantly increases the risk of
bleeding. This risk varies widely, but on average, the
addition of a single antiplatelet agent increased the risk
of bleeding from a range of 2% to 3% to a range of 4%
to 6%, whereas the addition of DAPT to oral antico-
agulant therapy (“triple therapy”) increased the risk of
bleeding from a range of 4% to 6% to a range of 10% to
14% (432–435). This risk was also related to the duration of
triple therapy.
In patients with NSTE-ACS in whom there are in-
dications for triple therapy, the bene�tofsuchtherapy
in terms of prevention of stent thrombosis, thrombo-
embolic events, and recurrent MI must be weighed
against the risk of bleeding complications. Similarly,
DAPT, in addition to anticoagulant therapy, requires
consideration of the increased risk of bleeding. It is
essential that therapeutic decision making in this crit-
ical area include discussion with the patient about
the options, advantages, and limitations of available
approaches.
Recommendations about the management of pa-
tients treated with triple therapy have been pub-
lished in ACC/AHA CPGs and by other organizations
(17,26,430,433,436). Although some organizations have
recommended a target INR of 2.0 to 2.5 in patients with
atrial �brillation (AF) who requiretripletherapy(437),
others continue to recommend a target INR of 2.0 to
3.0 (12,436). The HAS-BLED (Hypertension, Abnormal
Renal/Liver Function, Stroke, Bleeding History or
Predisposition, Labile INR, Elderly, Drugs/Alcohol
Concomitantly) score has relevance in these delibera-
tions (439). No prospective study to date has demon-
strated that a target INR of 2.0 to 2.5 reduces bleeding
complications.
Whenever possible, shorter durations of triple ther-
apy are favored in preference to longer durations of
triple therapy. In patients with NSTE-ACS who require
oral anticoagulation for AF, mechanical heart valve,
deep venous thrombosis, or other conditions, a bare-
metal stent may offer the advantages of lower
bleeding risk over a DES because of the potentially
shorter duration of triple antithrombotic therapy. The
WOEST (What is the Optimal Antiplatelet and Antico-
agulant Therapy in Patients With Oral Anticoagulation
and Coronary Stenting) trial is the �rst published
study to address the question of optimal antiplatelet
therapy in patients taking oral anticoagulant medication
(440).WOESTwasarandomized,open-labeltrialof
563 patients (approximately 25% of whom had NSTE-
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
ACS) receiving oral anticoagulant therapy and under-
going coronary stenting. Patients randomized to single
antiplatelet treatment with clopidogrel had signi�cantly
fewer bleeding complications and no increase in
: http://content.onlinejacc.org/ on 03/27/2015
to DAPT with aspirin and clopidogrel. Larger clinical
trials are needed to compare double versus triple ther-
apy in the setting of coronary stenting and NSTE-ACS.
One such study that has been initiated is PIONEER
AF-PCI (an Open-Label, Randomized, Controlled,
Multicenter Study Exploring two Treatment Strategies
of Rivaroxaban and a Dose-Adjusted Oral Vitamin K
Antagonist Treatment Strategy in Subjects With
Atrial Fibrillation who Undergo Percutaneous Coronary
Intervention).
Although there are some data on therapy with aspirin,
clopidogrel, and warfarin, there is sparse information on
the use of newer P2Y
12
inhibitors (prasugrel, ticagrelor),
direct thrombin inhibitor (dabigatran), or factor-Xa in-
hibitors (rivaroxaban, apixaban) in patients receiving
triple therapy. Prasugrel (302) and ticagrelor (412) pro-
duce a greater degree of platelet inhibition than clopi-
dogrel and are associated with greater rates of bleeding
(300,302,412,441). These are important potential disad-
vantages in patients requiring triple therapy, a group in
which the inherent risks of bleeding are signi�cantly
increased. (Overall bleeding risk was not increased with
ticagrelor, although there was increased bleeding in
certain subgroups on this drug (412)). Because there are
no well-established therapies to reverse the anticoagu-
lant effects of the newer oral antiplatelet agents,
cautionisrequiredwhenconsideringtheuseofthese
agents in patients who require triple therapy and are
at signi�cantly increased risk of bleeding. This admo-
nition is especially important in elderly patients, a
group in which bleeding risk is inherently increased
(Section 7.1).
Proton pump inhibitors decrease the risk of gastroin-
testinal bleeding in patients treated with DAPT (431) and
are used in patients treated with DAPT who have a history
of gastrointestinal bleeding and those at increased risk of
bleeding, which is associated with oral anticoagulation
therapy even if there is no history of gastrointestinal
bleeding (430). On the basis of these results, proton pump
inhibitors are also used in patients receiving triple
antithrombotic therapy who have a history of gastroin-
testinal bleeding. Although the clinical evidence that
omeprazole and esomeprazole diminish the antiplatelet
ef�cacy of clopidogrel is weak (430), the U.S. Food and
Drug Administration has issued a warning to avoid
concomitant use of these 2 proton pump inhibitors with
clopidogrel (442).
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
6.2.3. Platelet Function and Genetic Phenotype Testing
Although higher platelet reactivity has been associated
with a greater incidence of adverse events in patients
undergoing stent implantation, a strategy of adjusting

vaccine is recommended for all adults $65 years of age.
e179
Downloa
antiplatelet therapy based on routine platelet function
testing has not been bene�cial in reducing ischemic
complications (26,443–445). Similarly, a strategy of
routine genetic phenotype testing has also not been
bene�cialandthusisnotrecommended(26,446–448).A
more detailed discussion of these issues and current
recommendations about platelet function testing and
genetic testing are in the 2011 PCI CPG (26).
6.3. Risk Reduction Strategies for Secondary Prevention
Secondary prevention is a critical aspect of the manage-
ment of care for the survivor of NSTE-ACS. It has been
clearly established that in this high-risk cohort, subse-
quent cardiovascular morbidity and mortality can be
reduced by a comprehensive approach to favorably
modifying patients’ risk pro�les (27).
Secondary prevention comprises lifestyle changes, risk
factor education, medical therapy, and, where appro-
priate, revascularization. These elements are discussed in
Section 6.4. Despite the proven utility of secondary pre-
vention, its implementation remains suboptimal, and
enhanced application is a major goal in this patient
population.
See Online Data Supplement 23 for additional infor-
mation on risk reduction strategies.
6.3.1. Cardiac Rehabilitation and Physical Activity:
Recommendation
CLASS I
1. All eligible patients with NSTE-ACS should be referred to a
comprehensive cardiovascular rehabilitation program either
before hospital discharge or during the �rst outpatient visit
(449–452). (Level of Evidence: B)
The U.S. Public Health Service emphasizes comprehensive
cardiac rehabilitation programs (449), and the 2011 sec-
ondary prevention CPG underscores referral to cardiac
rehabilitation for survivors of ACS (27). Since 2007, referral
to these programs has been designated a quality perfor-
mance measure (453–455). Barriers to referral can be obvi-
ated by discussion with the patient and referral by the
patient’s primary care clinician and/or cardiovascular care-
giver. These comprehensive programs provide patient ed-
ucation, enhance regular exercise, monitor risk factors, and
address lifestyle modi�cation (456). Aerobic exercise
training can generally begin 1 to 2 weeks after discharge in
patients treated with PCI or CABG (457). Mild-to-moderate
resistance training can be considered and started 2 to
4 weeks after aerobic training (458). Unsupervised exercise
may target a heart rate range of 60% to 75% of maximum
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
age-predicted heart rate based on the patient’s exercise
stress test. Supervised training may target a higher heart
rate (70% to 85% of age-predicted maximum) (457). Addi-
tional restrictions apply when residual ischemia is present.
ded From: http://content.onlinejacc.org/ on 03/27/2015
Adults of any age who are at increased risk, including
smokers and those with asthma, should also be given the
vaccine. Immunocompromised adults should receive the
13-valent conjugate vaccine in addition to the 23-valent
vaccine (464–466). The in�uenza vaccine is discussed in
Section 6.4.
6.3.4. NSAIDs: Recommendations
CLASS I
1. Before hospital discharge, the patient’s need for treatment
of chronic musculoskeletal discomfort should be assessed,
Daily walking can be encouraged soon after discharge for
most patients. Resource publications on exercise prescrip-
tion in cardiovascular patients are available (456,457). Reg-
ular physical activity reduces symptoms in patients with
cardiovascular disease, enhances functional capacity, im-
proves other risk factors such as insulin resistance and
glucose control, and is important in weight control (456).
Questionnaires and nomograms for cardiac patients have
been developed to guide exercise prescription if an exercise
test is unavailable (459–462). See Section 6.4 and Table 10 for
more information.
6.3.2. Patient Education: Recommendations
CLASS I
1. Patients should be educated about appropriate cholesterol
management, BP, smoking cessation, and lifestyle manage-
ment (15,16,18). (Level of Evidence: C)
2. Patients who have undergone PCI or CABG derive bene�t
from risk factor modi�cation and should receive counseling
that revascularization does not obviate the need for lifestyle
changes (463). (Level of Evidence: C)
Results of testing should be discussed with the patient, the
patient’s family, and/or the patient’s advocate in an under-
standable manner. Test results should be used to help
determine the advisability of coronary angiography, the need
for adjustments in the medical regimen, and the speci�cs for
secondary prevention measures. See Section 6.4 and Table 10
for more information on plan of care.
6.3.3. Pneumococcal Pneumonia: Recommendation
CLASS I
1. The pneumococcal vaccine is recommended for patients 65
years of age and older and in high-risk patients with car-
diovascular disease (464–466). (Level of Evidence: B)
Vaccination with the 23-valent pneumococcal polysaccharide
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
and a stepped-care approach should be used for selection of
treatments. Pain treatment before consideration of NSAIDs
should begin with acetaminophen, nonacetylated salicylates,
tramadol, or small doses of narcotics if these medications are
not adequate (17,237). (Level of Evidence: C)

CLASS IIa
1. It is reasonable to use nonselective NSAIDs, such as nap-
roxen, if initial therapy with acetaminophen, nonacetylated
salicylates, tramadol, or small doses of narcotics is insuf�-
cient (237). (Level of Evidence: C)
CLASS IIb
1. NSAIDs with increasing degrees of relative COX-2 selectivity
may be considered for pain relief only for situations in which
intolerable discomfort persists despite attempts at stepped-
care therapy with acetaminophen, nonacetylated salicylates,
tramadol, small doses of narcotics, or nonselective NSAIDs.
In all cases, use of the lowest effective doses for the shortest
possible time is encouraged (234,235,237,467). (Level of
Evidence: C)
CLASS III: HARM
1.43) for other NSAIDs (234). There were dose-related in-
creases in risk of death and non–dose-dependent trends for
rehospitalization for MI for all drugs (234,467). An AHA sci-
enti�c statement on the use of NSAIDs concluded that the
risk of cardiovascular events is proportional to COX-2 selec-
tivity and the underlying risk in the patient (237). Non-
pharmacological approaches were recommended as the �rst
line of treatment, followed by the stepped-care approach to
pharmacological therapy, as shown in Figure 4.
6.3.5. Hormone Therapy: Recommendation
CLASS III: HARM
1. Hormone therapy with estrogen plus progestin, or estrogen
alone, should not be given as new drugs for secondary pre-
vention of coronary events to postmenopausal women after
NSTE-ACS and should not be continued in previous users un-
less the bene�ts outweigh the estimated risks (17,470–472).
(Level of Evidence: A)
ulos
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1. NSAIDs with increasing degrees of relative COX-2 selectivity
should not be administered to patients with NSTE-ACS and
chronic musculoskeletal discomfort when therapy with
acetaminophen, nonacetylated salicylates, tramadol, small
doses of narcotics, or nonselective NSAIDs provide accept-
able pain relief (234,235,237,467). (Level of Evidence: B)
Selective COX-2 inhibitors and other nonselective NSAIDs
have been associated with increased cardiovascular risk, and
the risk appears to be ampli�ed in patients with established
cardiovascular disease (17,234,235,467,469). In a large Danish
observational study of patients with �rst MI (n¼58,432), the
HR and 95% CI for death were 2.80 (2.41 to 3.25) for rofe-
coxib, 2.57 (2.15 to 3.08) for celecoxib, 1.50 (1.36 to 1.67) for
ibuprofen, 2.40 (2.09 to 2.80) for diclofenac, and 1.29 (1.16 to
FIGURE4 Stepped-Care Approach to Pharmacological Therapy for Musc
Factors for Ischemic Heart Disease
ASA indicates aspirin; COX-2, cyclooxygenase-2; GI, gastrointestinal; NSAIDs, no
Modi�ed from Jneid et al. (8).
: http://content.onlinejacc.org/ on 03/27/2015
Although prior observational data suggested a protective
effect of hormone therapy for coronary events, a randomized
trial of hormone therapy for secondary prevention of death
and MI (the HERS [Heart and Estrogen/Progestin Replace-
ment] study) failed to demonstrate a bene�cial effect (473).
There was an excess risk for death and MI early after initia-
tion of hormone therapy. The Women’s Health Initiative
included randomized primary prevention trials of estrogen
plus progestin and estrogen alone (472). Both trials were
stopped early owing to an increased risk related to hormone
therapy that was believed to outweigh the potential bene�ts
of further study (470–472). It is recommended that post-
menopausal women receiving hormone therapy at the time
keletal Symptoms in Patients With Known Cardiovascular Disease or Risk
nsteroidal anti-in�ammatory drugs; and PPI, proton-pump inhibitor.

gies for secondary prevention in the posthospital phase of
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of a cardiovascular event discontinue its use and that hor-
mone therapy should not be initiated for the primary or
secondary prevention of coronary events. However, there
may be other permissible indications for hormone therapy in
postmenopausal women (e.g., treatment of perimenopausal
symptoms such as �ushing or prevention of osteoporosis) if
the bene�ts are believed to outweigh the increased cardio-
vascular risk. Postmenopausal women who are >1 to 2 years
past the initiation of hormone therapy who wish to continue
such therapy for another compelling indication should weigh
the risks and bene�ts, recognizing the greater risk of car-
diovascular events and breast cancer (combination therapy)
or stroke (estrogen) (473).
6.3.6. Antioxidant Vitamins and Folic Acid: Recommendations
CLASS III: NO BENEFIT
1. Antioxidant vitamin supplements (e.g., vitamins E, C, or beta
carotene) should not be used for secondary prevention in
patients with NSTE-ACS (474,475). (Level of Evidence: A)
2. Folic acid, with or without vitamins B
6
and B
12
, should not be
usedforsecondarypreventioninpatientswithNSTE-ACS
(476,477). (Level of Evidence: A)
Although there is an association of elevated homocysteine
blood levels and CAD, a reduction in homocysteine levels
with routine folate supplementation did not reduce the risk
of CAD events in 2 trials (the NORVIT [Norwegian Vitamin
Trial] and the HOPE [Heart Outcomes Prevention Evaluation]
study) that included post–MI or high-risk stable patients
(476–478) and produced poorer outcomes in another study
(479). Additionally, in the NORVIT trial, there was a trend
toward increased cardiovascular events (95% CI: 1.00 to 1.50;
p¼0.05) in the cohort receiving the combination of folic acid,
vitamin B6, and vitamin B12; the authors cautioned against
using the treatment for secondary prevention (476). Simi-
larly, experience in large clinical trials with antioxidant
vitamins has failed to demonstrate bene�t for primary or
secondary prevention (474,475,480).
See Online Data Supplement 23 for additional infor-
mation on antioxidant vitamins and folic acid.
6.4. Plan of Care for Patients With NSTE-ACS:
Recommendations
CLASS I
1. Posthospital systems of care designed to prevent hospital
readmissions should be used to facilitate the transition to
effective, coordinated outpatient care for all patients with
NSTE-ACS (481–485). (Level of Evidence: B)
2. An evidence-based plan of care (e.g., GDMT) that promotes
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medication adherence, timely follow-up with the healthcare
team, appropriate dietary and physical activities, and
compliance with interventions for secondary prevention
should be provided to patients with NSTE-ACS. (Level of
Evidence: C)
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3. In addition to detailed instructions for daily exercise, pa-
tients should be given speci�c instruction on activities (e.g.,
lifting, climbing stairs, yard work, and household activities)
that are permissible and those to avoid. Speci�cmention
should be made of resumption of driving, return to work, and
sexual activity (452,486,487). (Level of Evidence: B)
4. An annual in�uenza vaccination is recommended for patients
with cardiovascular disease (27,488). (Level of Evidence: C)
Education of patients with NSTEMI and their families is
critical and often challenging, especially during transitions of
care. Failure to understand and comply with a plan of care
may account for the high rate of AMI rehospitalization rates
in the United States (489,490). An important intervention to
promote coordination is to provide patients and caregivers
with a comprehensive plan of care and educational materials
during the hospital stay that support compliance with
evidence-based therapies (491–493). The posthospitalization
plan of care for patients with NSTE-ACS (Table 10) should
address in detail several complex issues, including medica-
tion adherence and titration, timely follow-up, dietary
interventions, physical and sexual activities, cardiac reha-
bilitation, compliance with interventions for secondary pre-
vention, and reassessment of arrhythmic and HF risks. In
addition, clinicians should pay close attention to psychoso-
cial and socioeconomic issues, including access to care, risk
of depression, social isolation, and healthcare disparities
(494–496).
6.4.1. Systems to Promote Care Coordination
There has been improved understanding of the system
changes necessary to achieve safer care (497).Thisin-
cludes adoption by all U.S. hospitals of a standardized set
of “Safe Practices” endorsed by the National Quality
Forum (498), which overlap with the National Patient
Safety Goals espoused by The Joint Commission (499).
Examples of patient safety standards for all patients after
AMI include improved communication among clinicians,
nurses, and pharmacists; medication reconciliation;
careful transitions between care settings; and consistent
documentation. The National Quality Forum has also
endorsed a set of patient-centered “Preferred Practices for
Care Coordination” (500), which detail comprehensive
speci�cations that are necessary to achieve successful
care coordination for patients and their families. Systems
of care designed to support patients with NSTE-ACS,
STEMI, and other cardiac diseases can result in signi�-
cant improvement in patient outcomes. Table 10 provides
reference documents for multiple risk-reduction strate-
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
NSTE-ACS. These include the 2013 ACC/AHA CPGs on
management of blood cholesterol (18),obesity(16),and
lifestyle (15) and the 2014 recommendations for manage-
ment of hypertension (501), which were published during

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the development of this CPG. To provide the in-
terventions and services listed in Table 10, appropriate
resources must be used so that patients with MI have full
access to evidence-based therapies and follow-up care.
There is a growing emphasis on penalizing hospitals for
avoidable hospital readmissions. It is imperative for
health systems to work with clinicians, nurses, pharma-
cists, communities, payers, and public agencies to sup-
port the interventions that achieve comprehensive care.
Several patient characteristics have been predictors of
readmission after AMI (502,503).
7. SPECIAL PATIENT GROUPS
See Table 11 for summary of recommendations for this
section.
7.1. NSTE-ACS in Older Patients: Recommendations
CLASS I
1. Older patients** with NSTE-ACS should be treated with
GDMT, an early invasive strategy, and revascularization as
appropriate (515–519). (Level of Evidence: A)
2. Pharmacotherapy in older patients** with NSTE-ACS should
be individualized and dose adjusted by weight and/or CrCl to
reduce adverse events caused by age-related changes in
pharmacokinetics/dynamics, volume of distribution, comor-
bidities, drug interactions, and increased drug sensitivity
(515,520–522). (Level of Evidence: A)
3. Management decisions for older patients** with NSTE-ACS
should be patient centered, and consider patient prefer-
ences/goals, comorbidities, functional and cognitive status,
and life expectancy (515,523–525). (Level of Evidence: B)
CLASS IIa
1. Bivalirudin, rather than a GP IIb/IIIa inhibitor plus UFH, is
reasonable in older patients** with NSTE-ACS, both initially
and at PCI, given similar ef�cacy but less bleeding risk
(396,526–528). (Level of Evidence: B)
2. It is reasonable to choose CABG over PCI in older patients**
with NSTE-ACS who are appropriate candidates, particularly
those with diabetes mellitus or complex 3-vessel CAD
(e.g., SYNTAX score >22), with or without involvement of
the proximal LAD artery, to reduce cardiovascular disease
events and readmission and to improve survival (529–534).
(Level of Evidence: B)
In this CPG, “older adults” refers to patients $75 years of age
(515). Older adults have the highest incidence, prevalence,
and adverse outcomes of NSTE-ACS (9,515–517,535,536).
Older age is accompanied by comorbidities, polypharmacy,
and age- and disease-related physiological changes that
**Those $75 years of age (see text).
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adversely impact NSTE-ACS presentation, management,
and outcome. As older patients are under-represented
in clinical trials, the recommendations in this CPG are
largely supported by registry data and meta-analyses
(516,537).
Older patients with NSTE-ACS primarily present with
chest pain but frequently have atypical symptoms. ECGs
may be less diagnostic than in younger patients (517,538).
Older patients with NSTE-ACS derive the same or greater
bene�t from pharmacological therapies, interventional
therapies, and cardiac rehabilitation as younger patients,
but older patients receive signi�cantly less GDMT than
younger patients, even when adjusted for comorbidities
(515–517,535,538,539). In the ACSIS (Acute Coronary Syn-
drome Israeli Survey) registry, patients >80 years of age
referred for early coronary angiography, compared with
no angiography, had lower 30-day and 1-year mortality
rates (540).
Age-related pharmacokinetics and pharmacodynamic
changes can alter drug dosing, ef�cacy, and safety of
many NSTE-ACS therapies, as can drug–drug interactions
(Appendix 4, Table B) (515,520,521,541,542).CrClor
glomerular �ltration rate (GFR) should be estimated
initially and throughout care for all older patients with
NSTE-ACS, and pharmaceutical agents should be renally
and weight dose-adjusted to limit drug toxicity (espe-
cially bleeding risk), given the unreliability of serum
creatinine to assess age-related renal dysfunction
(515,522,526,543–545) (Appendix 4, Table C). Bleeding in
older patients with NSTE-ACS is multifactorial, resulting
in narrower therapeutic windows (541,542,544,546,547).
In the CRUSADE (Can Rapid Risk Strati�cation of
Unstable Angina Patients Suppress Adverse Outcomes
With Early Implementation of the American College of
Cardiology/American Heart Association Guidelines) study,
excessive doses of UFH, LMWH, and GP IIb/IIIa inhibitors
accountedfor15%ofmajorbleeding, longer lengths of
stay, and increased mortality (522,548). Aspirin should be
maintained at 81 mg per day (after initial stent implanta-
tion). Owing to excess bleeding without clinical bene�t,
the U.S. Food and Drug Administration lists a Black Box
warning that does not recommend administration of pra-
sugrel to patients with NSTE-ACS who are$75 years of age
or weigh <60 kg except in those at very high risk. A meta-
analysis of 6 RCTs about the use of GP IIb/IIIa inhibitors in
patients with NSTE-ACS reported no signi�cant age-
treatment interaction, although older women had signi�-
cantly more adverse events (549). Bivalirudin appears
safer for older patients with NSTE-ACS � PCI than GP
IIb/IIIa inhibitors plus UFH, with less bleeding and similar
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ef�cacy (526,550). AF is more common in older patients
with NSTE-ACS, and triple therapy (DAPT and warfarin)
entails a marked bleeding risk (551). In the WOEST (What is
the Optimal Antiplatelet and Anticoagulant Therapy in

developed within 48 hours after admission (575).Risk
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Patients With Oral Anticoagulation and Coronary Stenting)
study, it was found that in patients taking oral coagulants
who required PCI, use of clopidogrel without aspirin was
associated with a signi�cant reduction in bleeding com-
plications and no increase in thrombotic events (440).
Nonetheless, practice should not be changed on the basis
of this limited study alone.
Older patients with NSTE-ACS bene�tasmuchor
more than younger patients from an early invasive
strategy compared with an ischemia-guided strategy
(340,341,515,518,519). In a 5-year follow-up meta-analysis
of FRISC-II and RITA-3, an early invasive strategy versus
an ischemia-guided strategy was associated with a sig-
ni�cant reduction in death/MI and MI in patients $75
years of age but not in patients <65 years of age (518).
Although the highest risk reduction in death/MI with an
early invasive strategy occurred in those $75 years of age,
this strategy was associated with a 3-fold bleeding risk
(552). However, despite the overall favorable evidence for
an early invasive strategy in older patients, age is the
strongest risk factor for this group not undergoing an
early invasive strategy (553).
PCI has increased in older patients, including the very
elderly ($90 years of age), with success rates similar to
younger patients and declining complication rates,
including major bleeding (515,517,526–528,554). Several
large registries report a greater RR reduction in mortality
of older patients treated with revascularization versus
medical therapy compared with those #65 years of age,
despite increased comorbidities (517,540,554–556).
Operative mortality rates for CABG in patients $80
years of age with NSTE-ACS range from 5% to 8% (11% for
urgent cases) and increase to approximately 13% at $90
years of age. Complications occur more frequently in
older patients with CABG (557,558).Lengthofstayaver-
ages 6 days longer in older patients than in patients <50
years of age, and discharge (to home [52%]) is less
frequent than in younger patients (557).Inameta-
analysis, off-pump CABG appeared to offer a potentially
safer and more effective revascularization technique
compared with on-pump CABG in older patients with
NSTE-ACS (559). Older patients with NSTE-ACS with dia-
betes mellitus had a greater survival advantage with
CABG (529). Evaluation tools can help identify older
patients with NSTE-ACS whose risk and comorbidity
pro�le predict mortality within 6 to 12 months and
possibly guide a palliative approach (524).
See Online Data Supplement 24 for additional informa-
tion on older patients.
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7.2. HF: Recommendations
CLASS I
1. Patients with a history of HF and NSTE-ACS should be treated
according to the same risk strati�cation guidelines and
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recommendations for patients without HF (14,42–44,75–81).
(Level of Evidence: B)
2. Selection of a speci�c revascularization strategy should be
based on the degree, severity, and extent of CAD; associated
cardiac lesions; the extent of LV dysfunction; and the history
of prior revascularization procedures (14,138,141,333,334,
337,341,560,561). (Level of Evidence: B)
In patients with HF and NSTE-ACS, the plan of care should be
implemented as in patients without HF using medical ther-
apy and an early invasive approach, because patients with
abnormal LV function are at increased risk of mortality and
morbidity (562). HF itself may be associated with elevated
serum troponin in the presence or absence of obstructive
CAD. After angiography, risk strati�cation can be used to
select revascularization strategies. The effect of surgical
revascularization on improving survival has been most
clearly demonstrated in patients with both extensive CAD
and LV dysfunction (356,357,563–567). Such patients should
undergo testing to identify the severity and extent of
ischemia and should in general be referred for coronary
angiography. In selected patients with appropriate anatomy,
PCI has been used (23,568). In patients who have already
undergone CABG or in whom the anatomy is not favorable
for CABG, PCI has been performed using CPG-based PCI
performance strategies if speci�c targeted areas that are
amenable to PCI can be identi�ed (26). If there is a large
amount of ischemic territory and very poor LV function,
percutaneous ventricular assist devices or, in less severe
cases, an IABP can be used for support during the procedure
(266,569–573).
See Online Data Supplement 25 for additional informa-
tion on HF.
7.2.1. Arrhythmias
Ventricular arrhythmias are common early after onset of
NSTE-ACS, and not all require intervention. The mech-
anisms for these arrhythmias include continuing
ischemia, hemodynamic and electrolyte abnormalities,
reentry, and enhanced automaticity. Approximately 5%
to 10% of hospitalized patients may develop ventricular
tachycardia (VT)/ventricular �brillation (VF), usually
within 48 hours of presentation (574). The incidence of
VF in otherwise uncomplicated AMI appears to have
decreased within the past few years from >4% to <2%,
of which 59% of patients had non–Q-wave MI (574).A
study of 277 consecutive patients with NSTE-ACS who
underwent cardiac catheterization within 48 hours
found VT/VF occurring in 7.6% of patients, 60% of which
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
factors for VT/VF include HF, hypotension, tachycardia,
shock, and low TIMI �ow grade. Treatment consists of
immediate de�brillation or cardioversion for VF or
pulseless sustained VT. Early administration of beta

TABLE 11 Summary of Recommendations for Special Patient Groups
Recommendations COR LOE References
NSTE-ACS in older patients
Treat older patients ($75 y of age) with GDMT, early invasive strategy, and revascularization as appropriate I A (515–519)
Individualize pharmacotherapy in older patients, with dose adjusted by weight and/or CrCl to reduce
adverse events caused by age-related changes in pharmacokinetics/dynamics, volume of distribution,
comorbidity, drug interactions, and increased drug sensitivity
IA(515,520–522)
Undertake patient-centered management for older patients, considering patient preferences/goals,
comorbidities, functional and cognitive status, and life expectancy
IB(515,523–525)
Bivalirudin rather than GP IIb/IIIa inhibitor plus UFH is reasonable for older patients ($75 y of age), given
similar ef�cacy but less bleeding risk
IIa B (396,526–528)
It is reasonable to choose CABG over PCI in older patients, particularly those with DM or multivessel disease,
because of the potential for improved survival and reduced CVD events
IIa B (529–534)
HF
Treat patients with a history of HF according to the same risk strati�cation guidelines and recommendations
for patients without HF
IB(14,42–44,75–81)
Select a revascularization strategy based on the extent of CAD, associated cardiac lesions, LV dysfunction,
and prior revascularization
IB(14,138,141,333,334,
337,341,560,561)
Cardiogenic shock
Recommend early revascularization for cardiogenic shock due to cardiac pump failure I B (560,588,589)
DM
Recommend medical treatment and decisions for testing and revascularization similar to those for patients
without DM
IA(138,339,601)
Post�CABG
Recommend GDMT antiplatelet and anticoagulant therapy and early invasive strategy because of increased
risk with prior CABG
IB(67,68,141,340–342)
Perioperative NSTE-ACS
Administer GDMT to perioperative patients with limitations imposed by noncardiac surgery I C (626,627)
Direct management at underlying cause of perioperative NSTE-ACS I C (21,626–634)
CKD
Estimate CrCl and adjust doses of renally cleared medications according to pharmacokinetic data I B (649,650)
Administer adequate hydration to patients undergoing coronary and LV angiography I C N/A
Invasive strategy is reasonable in patients with mild (stage 2) and moderate (stage 3) CKD IIa B (649–652)
Women
Manage women with the same pharmacological therapy as that for men for acute care and secondary
prevention, with attention to weight and/or renally calculated doses of antiplatelet and anticoagulant
agents to reduce bleeding risk
IB(669–673)
Early invasive strategy is recommended in women with NSTE-ACS and high-risk features (troponin positive) I A (141,345,346,561)
Myocardial revascularization is reasonable for pregnant women if ischemia-guided strategy is ineffective for
management of life-threatening complications
IIa C (674)
Women with low-risk features (Section 3.3.1) should not undergo early invasive treatment because of lack of
bene�t and the possibility of harm
III: No Bene�tB (141,345,346)
Anemia, bleeding, and transfusion
Evaluate all patients for risk of bleeding I C N/A
Recommend that anticoagulant and antiplatelet therapy be weight-based where appropriate and adjusted for
CKD to decrease the risk of bleeding
IB(522,697,698)
There is no bene�t of routine blood transfusion in hemodynamically stable patients with hemoglobin levels >8 g/dL III: No Bene�tB (699–703)
Cocaine and methamphetamine users
Manage patients with recent cocaine or methamphetamine use similarly to those without cocaine- or
methamphetamine-related NSTE-ACS. The exception is in patients with signs of acute intoxication
(e.g., euphoria, tachycardia, and hypertension) and beta-blocker use unless patients are receiving
coronary vasodilator therapy
I C N/A
It is reasonable to use benzodiazepines alone or in combination with NTG to manage hypertension and
tachycardia and signs of acute cocaine or methamphetamine intoxication
IIa C (741–744)
Do not administer beta blockers to patients with recent cocaine or methamphetamine use who have signs
of acute intoxication due to risk of potentiating coronary spasm
III: Harm C N/A
Continued on the next page
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TABLE 11 Continued
Recommendations
Vasospastic (Prinzmetal) angina
Recommend CCBs alone or in combination with nitrates
Recommend HMG-CoA reductase inhibitor, cessation of tobacco use, and atheros
Recommend coronary angiography (invasive or noninvasive) for episodic chest pa
ST-elevation to detect severe CAD
Provocative testing during invasive coronary angiography* may be considered fo
angina when clinical criteria and noninvasive assessment fail to determine dia
ACS with angiographically normal coronary arteries
Invasive physiological assessment (coronary �ow reserve measurement) may be
coronary arteries if endothelial dysfunction is suspected
Stress (Takotsubo) cardiomyopathy
Consider stress-induced cardiomyopathy in patients with apparent ACS and nono
Perform ventriculography, echocardiography, or MRI to con�rm or exclude diagn
Treat with conventional agents (ACE inhibitors, beta blockers, aspirin, and diuret
Administer anticoagulant therapy for LV thrombi
It is reasonable to administer catecholamines for symptomatic hypotension in th
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
blockers has been associated with reduction in incidence
of VF (576). The prophylactic use of lidocaine is not
recommended. Although VT/VF is associated with higher
90-day mortality risk, premature ventricular contractions
not associated with hemodynamic compromise and
accelerated ventricular rhythms do not confer higher
mortality risks and do not require speci�ctherapyother
than maintaining electrolyte balance. NSTE-ACS non-
sustained VT occurring >48 hours after admission in-
dicates an increased risk of cardiac and sudden death,
especially when associated with accompanying myocar-
dial ischemia (577). Life-threatening ventricular ar-
rhythmias that occur >48 hours after NSTE-ACS are
usually associated with LV dysfunction and signify poor
prognosis. RCTs in patients with ACS have shown
consistent bene�t of implantable cardioverter-
de�brillator therapy for survivors of VT or VF arrest
(578–582). For other at-risk patients, especially those
with signi�cantly reduced LVEF, candidacy for primary
prevention of sudden cardiac death with an implantable
cardioverter-de�brillator should be readdressed $40
days after discharge (583).Alifevestmaybeconsidered
in the interim.
tract obstruction
It is reasonable to use IABP for refractory shock
It is reasonable to use beta blockers and alpha-adrenergic agents for LV out�ow trac
Prophylactic anticoagulation may be considered to prevent LV thrombi
*Provocative testing during invasive coronary angiography (e.g., using ergonovine, acetylch
manner by experienced operators. However, sustained spasm, serious arrhythmias, and even d
in patients with signi�cant left main disease, advanced 3-vessel disease, presence of high-grad
advanced HF.
ACE indicates angiotensin-converting enzyme; ACS, acute coronary syndrome; CABG, corona
chronic kidney disease; COR, Class of Recommendation; CrCl, creatinine clearance; CVD, cardi
glycoprotein; HF, heart failure; IABP, intra-aortic balloon pump; LOE, Level of Evidence;
non–ST-elevation acute coronary syndrome; NTG, nitroglycerin; PCI, percutaneous coronary
ded From: http://content.onlinejacc.org/ on 03/27/2015
COR LOE References
I B (753–758)
sis risk factor modi�cation I B (759–763)
ith transient I C N/A
pected vasospastic
sis
IIb B (764–767)
idered with normal IIb B (629,773–776)
uctive CAD I C N/A
I B (795–798)
if hemodynamically stable I C N/A
I C N/A
ence of LV out�ow IIa C N/A
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
AF, atrial �utter, and other supraventricular arrhyth-
mias may be triggered by excessive sympathetic stimu-
lation,atrialstressduetovolumeoverload,atrial
infarction, pericarditis, electrolyte abnormalities, hypox-
ia, or pulmonary disease. AF is the most common of these
arrhythmias and may develop in >20% of patients. AF is
associated with shock, HF, stroke, and increased 90-day
mortality (584). Management of AF requires rate control
and adequate anticoagulation according to the 2014 AF
CPG (12). For hemodynamically unstable patients and
those with continuing ischemia, treatment should be
implemented according to the 2010 advanced cardiac life
support CPGs (585).
Sinus bradycardia is especially common with inferior
NSTEMI. Symptomatic or hemodynamically signi�cant
sinus bradycardia should be treated with atropine and, if
not responsive, temporary pacing. The incidence of
complete heart block is 1.0% to 3.7% in NSTEMI, based on
anterior or posterior/inferior location, respectively (586).
Atrioventricular block and bundle-branch block develop
inapproximately5%ofpatients(587). High-degree
atrioventricular block or bundle-branch block in anterior
NSTEMI is more ominous because of a greater extent of
IIa C N/A
t obstruction IIa C N/A
IIb C N/A
oline, methylergonovine) is relatively safe, especially when performed in a controlled
eath can also occur but very infrequently. Therefore, provocative tests should be avoided
e obstructive lesions, signi�cant valvular stenosis, signi�cant LV systolic dysfunction, and
ry artery bypass graft; CAD, coronary artery disease; CCB, calcium channel blocker; CKD,
ovascular disease; DM, diabetes mellitus; GDMT, guideline-directed medical therapy; GP,
LV, left ventricular; MRI, magnetic resonance imaging; N/A, not available; NSTE-ACS,
intervention; and UFH, unfractionated heparin.

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myocardial injury and involvement of the conduction
system (587).
First-degree atrioventricular block does not require
treatment. High-grade atrioventricular block after inferior
NSTEMI usually is transient, with a narrow QRS complex
and a junctional escape rhythm that can be managed with
an ischemia-guided strategy. Prophylactic placement of a
temporary pacemaker is recommended for high-grade
atrioventricular block, new bundle-branch block, or
bifascicular block with anterior infarction. Indications for
permanent pacing are reviewed in the 2012 device-based
therapy CPG (20).
7.2.2. Cardiogenic Shock: Recommendation
CLASS I
1. Early revascularization is recommended in suitable patients
with cardiogenic shock due to cardiac pump failure after
NSTE-ACS (560,588,589). (Level of Evidence: B)
AMI is the leading cause of cardiogenic shock. Early revas-
cularization is a mainstay in the treatment of cardiogenic
shock (560,589). Compared with medical therapy, early
revascularization is associated with improved 6-month
mortality (560) and 13% absolute mortality reduction at 6
years (588). Urgent revascularization with CABG may be
indicated for failed PCI, coronary anatomy not amenable to
PCI, and at the time of surgical repair of a mechanical defect
(e.g., septal, papillary muscle, free-wall rupture). Age alone is
not a contraindication to urgent revascularization for
cardiogenic shock (589,590). Mortality after cardiogenic
shock has steadily improved (591), including in older adults
(589,590), with 30-day mortality ranging from approximately
40% with milder forms of shock (268) to >45% with re-
fractory shock (592). Approximately 30% of patients in the
IABP-SHOCK (Intra-Aortic Balloon Pump in Cardiogenic
Shock) II trial presented with NSTEMI (268), and 22% of pa-
tients in the TRIUMPH (Tilarginine Acetate Injection in a
Randomized International Study in Unstable Acute Myocar-
dial Infarction Patients With Cardiogenic Shock) trial had ST
depression on presentation (592). Of the 23% of patients with
ACS who had NSTEMI in the GRACE registry, 4.6% of pa-
tients experienced cardiogenic shock (593). Of the 2,992
patients in shock, 57% underwent cardiac catheterization,
and in-hospital revascularization was performed in 47% of
this group.
In-hospital mortality of all patients with shock was
59% (594). Patients with NSTEMI developed cardiogenic
shock later than patients with STEMI, and had higher-risk
clinical characteristics, more extensive CAD, and more
recurrent ischemia and infarction before developing
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
shockcomparedwithpatientswithSTEMI,andshock
developed later in patients with NSTEMI (151).Patients
with NSTEMI constituted >17% of those in the SHOCK trial
registry (595). They were also older and had more
: http://content.onlinejacc.org/ on 03/27/2015
comorbidities but had comparable mortality to patients
with STEMI. The left circum�ex coronary artery was the
culprit vessel in 30% of patients with NSTEMI, suggesting
thepresenceoftrueposteriorMI(595). Dopamine in pa-
tients with cardiogenic shock may be associated with
increased mortality compared with norepinephrine (596).
The use of percutaneous ventricular assist devices has
been hampered by the need for interventional expertise,
cost, and lack of supportive evidence (597). IABP has been
used for decades (265,598), and it may facilitate inter-
vention in patients who are hemodynamically unstable,
but it did not reduce mortality or secondary endpoints
in 1 RCT of 598 patients with cardiogenic shock
complicating AMI (268). Newer devices with higher levels
of support have provided better hemodynamic support
but without improved clinical outcomes compared with
IABP (599,600).
See Online Data Supplement 26 for additional information
on cardiogenic shock.
7.3. Diabetes Mellitus: Recommendation
CLASS I
1. Medical treatment in the acute phase of NSTE-ACS and decisions
to perform stress testing, angiography, and revascularization
should be similar in patients with and without diabetes mellitus
(138,339,601). (Level of Evidence: A)
CAD accounts for 75% of deaths in patients with diabetes
mellitus; >30% of patients with NSTE-ACS have diabetes
mellitus; and patients with NSTE-ACS and diabetes mellitus
have more adverse outcomes (e.g., death, MI, readmission
with ACS, or HF) during follow up (593,602,603). The latter
may be related to increased plaque instability and comor-
bidities, including hypertension, LV hypertrophy, cardio-
myopathy, HF, and autonomic dysfunction (603–605).
Patients with diabetes mellitus and ACS have longer delays
from symptom onset to presentation (593,606,607), which
may be attributable to their atypical symptoms.
There is a U-shaped relationship between glucose levels
and mortality in patients with diabetes mellitus and ACS
(543). Both hyperglycemia and hypoglycemia have similar
adverse effects on in-hospital and 6-month mortality. The
urgency to aggressively control blood glucose has been
moderated by the results of the NICE-SUGAR (Normoglyce-
mia in Intensive Care Evaluation and Survival Using Glucose
Algorithm Regimen) trial (608). In this study of patients
admitted to medical and surgical intensive care units,
intensive glucose control (target 81 mg/dL to 108 mg/dL)
resulted in increased all-cause mortality and hypoglycemia
compared with moderate glucose control (target <180 mg/dL).
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Blood glucose should be maintained at <180 mg/dL while
avoiding hypoglycemia. There is no established role for the
administration of glucose-insulin-potassium infusions in
NSTE-ACS (609–611).

prior CABG and more adverse follow-up outcomes,
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Although patients with diabetes mellitus and NSTE-
ACS are at higher risk for in-hospital and longer-term
events, they undergo less frequent revascularization
procedures. In a multinational study of 6,385 patients
with ACS, 25% of whom had diabetes mellitus, those with
diabetes mellitus had more adverse risk pro�les, more
atypical presentations, longer treatment delays, more
HF, and renal insuf�ciency but underwent less angiog-
raphy and revascularization (607).IntheGRACERegistry
(593) and other studies (606), patients with diabetes
mellitus and NSTE-ACS in the United Kingdom (603) and
Finland (612) had higher baseline risk pro�les but
received effective medical cardiac therapies and revas-
cularization less frequently.
Although there are no RCTs of patients speci�cally
diagnosedwithdiabetesmellitusandACS,thereare
ample data on patients with diabetes mellitus treated
with PCI or CABG (564,565,613–615).ThelargestRCT,
the FREEDOM (Future Revascularization Evaluation in
Patients With Diabetes Mellitus: Optimal Management
of Multivessel Disease) trial (616),evaluated1,900
patients (approximately 30% with “recent” [interval
unspeci�ed] ACS) with 2- or 3-vessel CAD randomized
to a DES or CABG. At 5 years, there was a signi�cant
decrease in all-cause mortality (p¼0.049; MI: p<0.001)
associated with CABG. There was no speci�canalysis
of outcomes in patients with “recent” (interval un-
speci�ed) ACS. CABG was also superior to PCI in
reducing MACE in other trials (564,613–615) (Appendix
4, Table D).
The importance of the severity and complexity of CAD
was underscored in the SYNTAX trial, in which those with
less severe and complex CAD had similar outcomes with
PCIandCABGcomparedwiththose with more severe and
complex disease, in which CABG improved outcomes,
including survival (355,565).
7.3.1. Adjunctive Therapy
A meta-analysis (6 trials: 23,072 patients without dia-
betes mellitus, 6,458 patients with diabetes mellitus) of
the effect of GP IIb/IIIa platelet receptor inhibitors
(abciximab, epti�batide, and tiro�ban) on mortality in
NSTEMI revealed that for the entire patient group, a GP
IIb/IIIa inhibitor was associated with reduced 30-day
mortality (6.2% to 4.6%; p¼0.007) (392).Thisbene�t
was particularly large in the 1,279 patients with diabetes
mellitus who underwent PCI (4.0% to 1.2%; p¼0.002).
The ACUITY trial in ACS (13,819 patients, 3,852 with
diabetes mellitus) reported that 30-day adverse clinical
outcomes (death, MI, or unplanned revascularization) or
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DECEMBER 23, 2014:e139– 228
major bleeding were increased in patients with diabetes
mellitus (12.9% versus 10.6%; p<0.001) (617). Bivalirudin
plus a GP IIb/IIIa inhibitor resulted in increased similar
rates of the composite ischemia compared with heparin
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including increased mortality, but had a bene�twith
epti�batide similar to those without prior CABG (622).
Patients with prior CABG are less likely to undergo early
catheterization after NSTEMI. In the Get With The
Guidelines study of patients with NSTEMI, 18.5% had
prior CABG and a lower likelihood of early invasive eval-
uation but had higher rates of guideline-recommended
clopidogrel and bivalirudin therapy and lower rates of
GP IIb/IIIa and anticoagulant therapy (625).Inpatients
with prior CABG who develop NSTE-ACS that is related to
an ungrafted native coronary vessel, treatment should
follow GDMT (26).
Because patients with prior CABG presenting with
ACS are a high-risk group with increased comorbid char-
acteristics and high-risk anatomy, a strategy of early
angiography should be implemented (unless clinically
plus a GP IIb/IIIa inhibitor. Bivalirudin alone was asso-
ciated with a similar increased rate of composite
ischemia but less major bleeding (3.7% versus 7.1%;
p<0.001).
Several studies evaluated the bene�t of oral antiplate-
let therapy during ACS in patients with diabetes mellitus.
In TRITON-TIMI 38, patients with diabetes mellitus had a
greater reduction in ischemic events without an observed
increase in TIMI major bleeding with prasugrel compared
with clopidogrel (618).InPLATO,ticagrelorcompared
with clopidogrel reduced ischemic events irrespective of
diabetic status and glycemic control, without an increase
in major bleeding (619).
See Online Data Supplement 27 for additional infor-
mation on diabetes mellitus.
7.4. Post–CABG: Recommendation
CLASS I
1. Patients with prior CABG and NSTE-ACS should receive
antiplatelet and anticoagulant therapy according to GDMT
and should be strongly considered for early invasive strategy
because of their increased risk (67,68,141,340–342). (Level
of Evidence: B)
Although CABG reduces morbidity and mortality in selected
patients with complex CAD, they remain at risk for devel-
opment of disease progression of ungrafted native vessels or
signi�cant atherothrombotic disease in saphenous vein
grafts and subsequent ACS. These patients constitute a
higher-risk group because they have already undergone
CABG, typically for more extensive CAD, and they have more
comorbidities (620–624).
In the PURSUIT trial, 12% (1,134) of the patients had
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
contraindicated), and these patients should receive
optimal antiplatelet and anticoagulant therapy.
See Online Data Supplement 28 for additional informa-
tion on post-CABG.

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7.5. Perioperative NSTE-ACS Related to Noncardiac Surgery:
Recommendations
CLASS I
1. Patients who develop NSTE-ACS following noncardiac sur-
gery should receive GDMT as recommended for patients in
the general population but with the modi�cations imposed
by the speci�c noncardiac surgical procedure and the
severity of the NSTE-ACS (626,627). (Level of Evidence: C)
2. In patients who develop NSTE-ACS after noncardiac surgery,
management should be directed at the underlying cause
(21,626–634). (Level of Evidence: C)
Patients with NSTE-ACS following noncardiac surgery should
be managed according to the guidelines for patients in the
general population, with risk strati�cation and guideline-
based pharmacological and invasive management directed
at the etiology (e.g., hypertension, tachycardia, HF, hypo-
tension, sepsis, and anemia) with modi�cations based on the
severity of NSTE-ACS and the limitations imposed by the
noncardiac surgical procedure.
The de�nition of ACS has a substantial effect on re-
ported incidence (178,184,635–644).Somepatientsmay
not be able to give a history of ischemic symptoms because
of the noncardiac surgery. The criteria in the 2012 Third
Universal De�nition of MI should be applied (21).Inpa-
tients at risk of ACS following noncardiac surgery, routine
monitoring of troponins and ECGs may be performed. As
the sensitivity of troponin assays improves, the frequency
of identifying perioperative MI will increase. In the POISE
(Perioperative Ischemic Study Evaluation) trial (645),of
8,351 patients randomized to extended-release metoprolol
versus placebo, 5.7% of patients in the control group had a
perioperative MI typically occurring within 48 hours and
often not associated with ischemic symptoms.
ACS in the setting of noncardiac surgery is associated
with increased mortality. Several risk scores have been
developed to determine the probability of mortality
(646–648). A meta-analysis of the prognostic value of
troponin and CK-MB after noncardiac surgery that included
14 studies enrolling 3,318 patients demonstrated that
elevated troponin after surgery was an independent pre-
dictor of mortality both in the hospital and at 1-year follow-
up (639). Markedly elevated troponins are associated
with increased mortality compared with minimal troponin
elevation, even though the latter still indicates a post-
operative MI (184,639,641,642).InpatientswithUAinwhom
the risks of bleeding with antiplatelet therapy outweigh the
bene�ts, GDMT with beta blockers, nitrates, and ACE in-
hibitors should be optimized to achieve symptom control. In
patients with a relative or absolute contraindication to
2014 AHA/ACC NSTE-ACS Guideline
antiplatelet or anticoagulant therapy, coronary angiography
may be helpful to identify anatomy requiring revasculari-
zation after recovery from the noncardiac surgery.
: http://content.onlinejacc.org/ on 03/27/2015
7.6. CKD: Recommendations
CLASS I
1. CrCl should be estimated in patients with NSTE-ACS, and
doses of renally cleared medications should be adjusted
according to the pharmacokinetic data for speci�cmedica-
tions (649,650). (Level of Evidence: B)
2. Patients undergoing coronary and LV angiography should
receive adequate hydration. (Level of Evidence: C)
CLASS IIa
1. An invasive strategy is reasonable in patients with mild
(stage 2) and moderate (stage 3) CKD (649–652). (Level of
Evidence: B)
CKD is a major risk factor for poor outcomes in patients
with NSTEMI (652–657). Patients with impaired renal func-
tion have additional adverse baseline characteristics,
including older age, a history of prior HF, and peripheral
arterial disease. It is prudent to omit LV angiography
in patients with CKD and assess LV function with
echocardiography.
In an analysis from 3 ACS trial databases of 19,304 pa-
tients with NSTEMI, 42% (8,152 patients) had abnormal
renal function on the basis of serum creatinine and
calculated CrCl; total mortality and mortality/MI were
increasedat30daysand180days.CrClwasindepen-
dently associated with mortality (HR: 0.81) and the risk of
mortality/MI (HR: 0.93) (656). The VALIANT (Valsartan in
Acute Myocardial Infarction) trial included 14,527 high-
risk patients with AMI with LV dysfunction or HF and a
serum creatinine level $1.5 mg/dL (658,659).TheModi-
�cation of Diet in Renal Disease equation was used, and
patients were analyzed based on their estimated GFR.
There was an increasing adjusted HR for both death
and the composite endpoint of cardiovascular death,
reinfarction, HF, stroke, or resuscitation after cardiac ar-
rest with decreasing estimated GFR. For death, with a
GFR <45.0 mL per minute/1.73 m
2
,theadjustedHRwas
1.70 compared with patients with a GFR of 60.0 mL per
minute/1.73 m
2
to 74.9 mL per minute/1.73 m
2
in whom
the adjusted HR was 1.14. There are insuf�cient data on
the bene�t-to-risk ratio of an invasive strategy in patients
withNSTE-ACSandadvancedCKD(stages4and5)
(652). There is also less evidence-based medical therapy
and revascularization data in patients with CKD because
of the risk for contrast-induced nephropathy, increased
need for dialysis, and increased mortality. Multiple
studies have evaluated radiographic agents, including
ionic versus nonionic media and isosmolar or low-osmolar
agents.
DECEMBER 23, 2014:e139– 228
The strength and consistency of relationships between
speci�c isosmolar or low-osmolar agents and contrast-
induced nephropathy or renal failure are insuf�cient

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for selection of low-osmolar and isosmolar media. Limi-
tation of the risk of contrast-induced nephropathy is
based on reduced contrast volume (660) and adequate
hydration (661).
A recent meta-analysis of 5 RCTs evaluated 1,453
patients with NSTE-ACS and CKD, all with GFR <60 mL
per minute/1.73 m
2
(651). Patients were analyzed ac-
cording to baseline renal function: stage 3a, 3b, and 4 to
5. An invasive strategy was associated with a nonsig-
ni�cant reduction in all-cause mortality and the com-
posite of death or nonfatal MI. An early invasive
strategy in patients with CKD and ACS reduced reho-
spitalization and resulted in a trend toward lower
mortality and nonfatal reinfarction. The increased risk
of mortality associated with mild, moderate, and
severe CKD is evident across studies, and risks are
increased as the gradient of renal dysfunction worsens
(649–651,662).
See Online Data Supplement 29 for additional infor-
mation on CKD.
7.6.1. Antiplatelet Therapy
Patients with CKD with ACS are at increased risk for
ischemic complications, including stent thrombosis and
post–PCI ischemic events (663). They are also predisposed
to higher bleeding complications, which, in addition to
the lack of clinical trial data, result in their undertreat-
ment with antiplatelet therapy. Patients with advanced
CKD exhibit high residual platelet reactivity despite
treatment with clopidogrel independent of the presence
of diabetes mellitus (664). Hyporesponsiveness to thie-
nopyridines is associated with increased adverse cardio-
vascular outcomes, including cardiovascular mortality
(665), and higher dosing regimens of clopidogrel do not
appear to further suppress adenosine diphosphate-
induced platelet aggregation (664,666).
Although prasugrel may be more ef�cient than
doubling the dose of clopidogrel in achieving adequate
platelet inhibition (667), no clinical studies have
demonstrated its ef�cacy in patients with CKD with ACS.
Ticagrelor, however, was studied in a prespeci�ed anal-
ysis from the PLATO trial (668).Inpatientswithan
estimated GFR <60 mL per minute (nearly 21% of pa-
tients in PLATO with available central laboratory serum
creatinine levels), ticagrelor signi�cantly reduced the
primary cardiovascular endpoint (17.3% versus 22.0%;
HR: 0.77; 95% CI: 0.65 to 0.90) compared with clopi-
dogrel (667). Notably, this was associated with a 4% ab-
solute risk reduction in all-cause mortality favoring
DECEMBER 23, 2014:e139– 228
ticagrelor and with no differences in major bleeding,
fatal bleeding, and non–CABG-related major bleeding
events, demonstrating its utility in patients with renal
insuf�ciency.
ded From: http://content.onlinejacc.org/ on 03/27/2015
7.7. Women: Recommendations
CLASS I
1. Women with NSTE-ACS should be managed with the same
pharmacological therapy as that for men for acute care and
for secondary prevention, with attention to weight and/or
renally calculated doses of antiplatelet and anticoagulant
agents to reduce bleeding risk (669–673). (Level of
Evidence: B)
2.WomenwithNSTE-ACSandhigh-risk features (e.g., troponin
positive) should undergo an early invasive strategy
(141,345,346,561). (Level of Evidence: A)
CLASS IIa
1. Myocardial revascularization is reasonable in pregnant
womenwithNSTE-ACSifanischemia-guidedstrategyis
ineffective for management of life-threatening complica-
tions (674). (Level of Evidence: C)
CLASS III: NO BENEFIT
1. Women with NSTE-ACS and low-risk features (see Section
3.3.1) should not undergo early invasive treatment because
of the lack of bene�t (141,345,346) and the possibility of
harm (141). (Level of Evidence: B)
Women of all ages have higher rates of in-hospital and long-
term complications of NSTE-ACS than men, including
bleeding, HF, cardiogenic shock, acute renal failure, recur-
rent MI, stroke, and readmissions (670,675,676).
Women present later after symptom onset of NSTE-ACS
and have higher rates of inappropriate discharges from
the ED (671,677,678). Women more commonly report
atypical symptoms than men (675,679). Women present-
ing with chest pain are more likely than men to have
either a noncardiac cause or cardiac causes other than
obstructive epicardial coronary disease (108,677,680,681).
Women with NSTE-ACS with no apparent obstructive
epicardial disease have a 2% risk of death or MI within 30
days and require secondary prevention and symptom
management (682).
Women derive the same treatment bene�tasmenfrom
aspirin, clopidogrel, anticoagulants, beta blockers, ACE
inhibitors, and statins (385,670–672,675,676,683,684).
Despite worse outcomes, women with NSTE-ACS are
underprescribed guideline-directed pharmacological
therapy, both during the acute illness and at discharge
(538,685,686). The basis for pharmacotherapy for women
with NSTE-ACS with abnormal biomarkers and/or func-
tional tests, but without signi�cant obstructive epicardial
disease, remains unclear (Section 7.13). In addition to risk
2014 AHA/ACC NSTE-ACS Guideline
factor modi�cation, some studies support the bene�tof
imipramine, ranolazine, beta blockers, and/or ACE in-
hibitors to reduce adverse outcomes (687).Womenwith
NSTE-ACS incur a higher rate of bleeding complications

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(672,673) (Section 7.8) and renal failure. A risk score has
been developed to attempt to reduce the bleeding risk in
women with NSTE-ACS (688).
The decision for an early invasive versus an
ischemia-guided strategy in women with NSTE-ACS is
based on a meta-analysis (366) and post hoc gender
analyses of clinical trials, including FRISC II, RITA-3,
and TACTICS-TIMI 18 (344,346,689).TheAgencyfor
Healthcare Research and Quality analysis of an early
invasive versus ischemia-guided strategy (345) provides
further evidence that an early invasive strategy should
be reserved for women with positive troponins, as
showninTACTICS-TIMI18(346).Suchwomenhada
signi�cant reduction of death and MI at 1 year with an
early invasive versus ischemia-guided strategy. Women
with NSTE-ACS and no elevation in troponin who un-
derwent an early invasive strategy had a nonsigni�cant
increase in events, as did women with a low-risk TIMI
score (OR: 1.59 for early invasive versus ischemia-guided
strategy), prompting the Class III recommendation in
this CPG.
The NCDR-ACTION registry reported increased com-
plication rates of myocardial revascularization in women
(https://www.ncdr.com/webncdr/action/). Women also
have higher rates of contrast-induced nephropathy and
vascular complications (673,690,691).Despitehaving
fewer high-risk angiographic lesions, a higher percentage
of normal LV function, and up to 25% angiographically
normal coronary arteries, women with NSTE-ACS have a
paradoxically higher rate of persistent angina, rein-
farction, functional decline, and depression after PCI
(141,675,677,680,682).Clinicaltrials(692,693),anda
meta-analysis (694) of DES for NSTE-ACS reported no
gender differences in short- and long-term (up to 5
years) outcome, including target vessel revasculariza-
tion, MACE, cardiac death, or MI. However, women
were older and had more comorbidities than men at
enrollment.
Women with NSTE-ACS referred for CABG are older
with more comorbidities, which is re�ected by higher
periprocedural mortality, HF, bleeding, MI, and renal
failure (686,695,696). Women required more periproce-
duralIABP,vasopressors,mechanicalventilation,dial-
ysis, and blood products and had longer stays in the
intensive care unit and hospital, higher rates of wound
infection, depression, and longer recovery (549,677).
An Agency for Healthcare Research and Quality meta-
analysis of 10 RCTs through December 2011 reported no
ef�cacy or safety difference between PCI and CABG for
NSTE-ACS in men or women in 30-day or 1-year MACE
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
(death/MI/stroke). At 2 years, the procedural success
remained equal in women but favored CABG in men
(p¼0.002) (345,564). The Agency for Healthcare Research
and Quality reported similar outcomes in women with
: http://content.onlinejacc.org/ on 03/27/2015
diabetes mellitus with PCI and CABG for NSTE-ACS at
7 years, but men with diabetes mellitus had fewer events
with CABG. A prespeci�ed gender analysis of the
FREEDOM trial favored CABG over PCI for women with
diabetes mellitus, although the difference was not as
signi�cant as it was for men (616).
Consistent with the European Society of Cardiology
recommendations, myocardial revascularization should be
reserved for pregnant women with NSTE-ACS and very serious
complications unresponsive to medical therapy (674).
See Online Data Supplement 30 for more information
on women.
7.8. Anemia, Bleeding, and Transfusion: Recommendations
CLASS I
1. All patients with NSTE-ACS should be evaluated for the risk
of bleeding. (Level of Evidence: C)
2. Anticoagulant and antiplatelet therapy should be weight-
based where appropriate and should be adjusted when
necessary for CKD to decrease the risk of bleeding in patients
with NSTE-ACS (522,697,698). (Level of Evidence: B)
CLASS III: NO BENEFIT
1. A strategy of routine blood transfusion in hemodynamically
stable patients with NSTE-ACS and hemoglobin levels
greater than 8 g/dL is not recommended (699–703). (Level
of Evidence: B)
Anemia in patients with ACS is associated with an increased
risk for Holter monitor�detected recurrent ischemia and for
MACE, with greater anemia correlating with greater risk
(704–708). In 1 large analysis of multiple studies, the risk of
adverse outcome was higher in patients with NSTE-ACS with
hemoglobin levels <11 g/dL (704). The potentially detri-
mental effects of severe anemia include decreased myocar-
dial oxygen delivery and increased MVO
2
related to
maintenance of a higher cardiac output (704,709,710). Pa-
tients with anemia are less likely to be treated with aspirin,
and patients with ACS and anemia are likely to have more
bleeding complications with PCI (711). This has been corre-
lated with increased short-term risk of MACE outcomes,
including mortality; long-term risk remains controversial
(712–717). The ACUITY study suggests that the risk of mor-
tality associated with bleeding is at least as great as that
associated with procedure-related or spontaneous MI (718).
Major bleeding is a coprimary endpoint in many trials
and is a consideration when assessing the “net clinical
bene�t” of a new drug. A “universal de�nition of
bleeding” has been proposed to assist clinicians (547,719–
721). The incidence of major bleeding in patients with
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DECEMBER 23, 2014:e139– 228
ACS varies widely (0.4% to 10%) (715,722) owing to
differing de�nitions of major bleeding, patient pop-
ulations, anticoagulation regimens, and PCI or CABG.
Factors in patients with ACS related to an increased

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bleeding risk include older age, female sex, lower body
weight, history of prior bleeding and/or invasive
procedures, anemia, use of GP IIb/IIIa inhibitors or
thrombolytics, and CKD (522,711,713–715,722,723).Non–
weight-based dosing of anticoagulants and dosing of
antithrombin and antiplatelet medications that are not
adjustedforCKDareassociatedwithanincreasedriskof
bleeding (522,697,698). Bleeding is related to adverse
outcomes because it may be a marker of underlying
disease, such as occult malignancy; leads to cessation of
antithrombin and antiplatelet therapy; may prompt
transfusion, which itself may have adverse effects;
can cause hypotension; and, if intracranial, can be fatal
(724). Proton pump inhibitors decrease the risk of upper
GI bleeding, including in patients treated with DAPT.
Proton pump inhibitors are used in patients with a his-
tory of prior GI bleeding who require DAPT and are an
option in patients at increased risk of GI bleeding
(26,430).
Evaluation of the risk of bleeding includes a focused
history of bleeding symptoms, identi�cation of pre-
disposing comorbidities, evaluation of laboratory data,
and calculation of a bleeding risk score (688,716,725).
Approximately 15% of all patients with NSTE-ACS and 3%
to 12% of those not undergoing CABG receive blood
transfusion (702). Rates vary widely and are closer to the
lower �gure but increase in association with factors such
as coronary intervention, anticoagulant/antithrombotic
therapy, older age, female sex, anemia, renal insuf�-
ciency, and frailty. Tissue oxygenation does not change
ormayactuallydecreasewithtransfusion(722).Blood
transfusion in patients with ACS is associated with an
increased risk of adverse outcome, including death
(702–704). A restrictive transfusion strategy leads to an
outcome that is at least as good, if not better, than a
liberal transfusion strategy (699,700).Ananalysisofa
large ACS registry found no bene�t from blood trans-
fusion in patients with a nadir hematocrit >24% (702).In
a meta-analysis of 10 studies of patients with AMI,
transfusion versus no transfusion was associated with an
increase in all-cause mortality (18.2% versus 10.2%;
p<0.001) and subsequent MI rate (RR: 2.0; 95% CI: 1.06 to
3.93; p¼0.03) (726). A restrictive approach to transfusion
generally consists of no routine transfusion for a hemo-
globin level >7g/dLto8g/dL(699,700,727). A restrictive
approach to blood transfusion is advocated by the
American Association of Blood Banks (700) and the Eu-
ropean Society of Cardiology (727).Onthebasisofdata
available at the time of publication, a strategy of routine
liberal blood transfusion in hemodynamically stable
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
patients with NSTE-ACS and mild to moderate anemia is
not recommended.
See Online Data Supplement 31 for more information
on anemia, bleeding, and transfusion.
ded From: http://content.onlinejacc.org/ on 03/27/2015
and in-hospital mortality in patients with and without
ACS (728–731,735–739). The OR for development of these
endpoints with thrombocytopenia (compared to without
thrombocytopenia) is 2 to 8. Data from the CATCH
(Complications After Thrombocytopenia Caused by Hep-
arin) registry identi�ed a platelet count nadir of 125 �
109/L as a threshold, below which there is a linear
augmentation in probability of bleeding (740).Results
from CATCH highlighted that thrombocytopenia and
heparin-induced thrombocytopenia are often not diag-
nosed (728). Thrombocytopenia is generally a contrain-
dication for GP IIb/IIIa inhibitor therapy; direct thrombin
inhibitors are often considered in preference to UFH or
LMWH in patients with thrombocytopenia.
See Online Data Supplements 31 and 32 for additional
information on anemia, bleeding, and transfusion.
7.10. Cocaine and Methamphetamine Users: Recommendations
CLASS I
1. Patients with NSTE-ACS and a recent history of cocaine or
methamphetamine use should be treated in the same manner
as patients without cocaine- or methamphetamine-related
NSTE-ACS. The only exception is in patients with signs of
acute intoxication (e.g., euphoria, tachycardia, and/or
hypertension) and beta-blocker use, unless patients are
receiving coronary vasodilator therapy. (Level of Evidence: C)
CLASS IIa
1. Benzodiazepines alone or in combination with nitroglycerin
are reasonable for management of hypertension and tachy-
cardia in patients with NSTE-ACS and signs of acute cocaine
or methamphetamine intoxication (741–744).(Levelof
Evidence: C)
7.9. Thrombocytopenia
The incidence of thrombocytopenia in patients with ACS
varies from 1% to 13%. In 1 large prospective registry,
one third of patients treated with prolonged heparin
therapy developed some degree of thrombocytopenia
(728). Independent risk factors for the development of
thrombocytopenia include lower baseline platelet count,
older age, ACS, cardiac or vascular surgery, intravenous
UFH or both UFH and LMWH, duration of heparin therapy,
and low body mass index (728–730). The risk of throm-
bocytopenia is increased in patients treated with abcix-
imab and, to a lesser degree, with epti�batide or tiro�ban
(731–734).
Thrombocytopenia on presentation or related to
antithrombotic therapy is associated with signi�cantly
increased risk of thrombotic events, MI, major bleeding,
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
CLASS III: HARM
1. Beta blockers should not be administered to patients with
ACS with a recent history of cocaine or methamphetamine

7.11. Vasospastic (Prinzmetal) Angina: Recommendations
CLASS I
1. CCBs alone (753–757) or in combination with long-acting
Amsterdam et al.
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
e192
Downloaded From
use who demonstrate signs of acute intoxication due to the
risk of potentiating coronary spasm. (Level of Evidence: C)
Cocaine exerts multiple effects on the cardiovascular system,
which may precipitate ACS (48,744,745). Acute cocaine
exposure results in increased BP, heart rate, endothelial
dysfunction, and platelet aggregation, all of which may
precipitate ACS. Cocaine’s direct vasoconstrictor effect can
produce coronary vasospasm. Long-term use of cocaine re-
sults in progressive myocyte damage and accelerated
atherosclerosis (48,744,745).
ACS in patients with a history of cocaine use should be
treated in the same manner as patients without cocaine
use (744). The exception is in patients with ACS in the
presence of acute cocaine intoxication. Because cocaine
stimulates both alpha- and beta-adrenergic receptors,
administration of intravenous beta blockers may result in
unopposed alpha stimulation with worsening coronary
spasm (48,132,744–746).Evidencesuggestsitissafeto
administer intravenous beta blockers in patients with
chest pain and recent cocaine ingestion, although infor-
mation is lacking about the effects of beta-blocker
administration during the acute stages of cocaine intoxi-
cation (747,748). Intravenous beta blockers should be
avoidedinpatientswithNSTE-ACSwithsignsofacute
cocaine intoxication (euphoria, tachycardia, and/or hy-
pertension). In these patients, benzodiazepines alone or
in combination with nitroglycerin have been useful for
management of hypertension and tachycardia owing to
their effects on the central and peripheral manifestations
of acute cocaine intoxication (741–744).
Methamphetamine abuse is becoming increasingly
common in the United States owing to the ease of
manufacturing and the lower cost of methamphetamines
compared with cocaine (131,749,750). Methamphetamines
may be ingested orally, inhaled, or used intravenously.
Methamphetamine affects the central nervous system by
simultaneously stimulating the release and blocking the
reuptake of dopamine and norepinephrine (751).Like
cocaine, methamphetamine exertsmultipleeffectsonthe
cardiovascular system, all of which may precipitate ACS
(131,750–752). The acute effects of methamphetamine are
euphoria, tachycardia, hypertension, and arrhythmias. MI
may result from coronary spasm or plaque rupture in the
presence of enhanced platelet aggregation. Long-term use
of methamphetamine has been associated with myocar-
ditis, necrotizing vasculitis, pulmonary hypertension, and
cardiomyopathy (750–752). Because methamphetamine
and cocaine have similar pathophysiological effects,
treatment of patients with ACS associated with metham-
2014 AHA/ACC NSTE-ACS Guideline
phetamine and cocaine use should theoretically be
similar.
See Online Data Supplement 33 for additional infor-
mation about cocaine and methamphetamine users.
: http://content.onlinejacc.org/ on 03/27/2015
nitrates (755,758) are useful to treat and reduce the fre-
quency of vasospastic angina. (Level of Evidence: B)
2. Treatment with HMG-CoA reductase inhibitor (759,760),
cessation of tobacco use (761,762), and additional athero-
sclerosis risk factor modi�cation (762,763) are useful in
patients with vasospastic angina. (Level of Evidence: B)
3. Coronary angiography (invasive or noninvasive) is recom-
mended in patients with episodic chest pain accompanied by
transient ST-elevation to rule out severe obstructive CAD.
(Level of Evidence: C)
CLASS IIb
1. Provocative testing during invasive coronary angiographyyy
may be considered in patients with suspected vasospastic
angina when clinical criteria and noninvasive testing fail to
establish the diagnosis (764–767). (Level of Evidence: B)
Vasospastic (Prinzmetal) angina chest pain typically occurs
without provocation, is associated with ST-elevation, and
usually resolves spontaneously or with rapid-acting nitro-
glycerin. Vasospastic angina may also be precipitated by
emotional stress, hyperventilation, exercise, or the cold. It
results from coronary vasomotor dysfunction leading to focal
spasm (768), which may occasionally be multifocal within a
single vessel and rarely involves >1 vessel. Vasospastic
angina occurs with normal coronary arteries, nonobstructive
CAD, and obstructive CAD, but prognosis is least favorable
with the latter. ST-elevation indicates transmural ischemia
and corresponds to the distribution of the involved artery
(769). A circadian variation is often present; most attacks
occur in the early morning (770,771). The most prominent
coronary risk factor is smoking. Most episodes resolve
without complications, but arrhythmias, syncope, MI, and
sudden death can occur (772).
Nonpharmacological provocative tests, such as cold
pressor and hyperventilation, have been used diagnosti-
cally; potent vasoconstrictors (e.g., acetylcholine) may
be useful when noninvasive assessment is uninforma-
tive (764–767). Smoking, which exacerbates coronary
vasospasm, should be proscribed, and CCBs are �rst-line
therapies (642); long-acting nitrates are also effective
when combined with CCBs (755,758). Statins improve
yyProvocative testing during invasive coronary angiography (e.g., using ergo-
novine, acetylcholine, methylergonovine) is relatively safe, especially when
performed in a controlled manner by experienced operators. However, sus-
tained spasm, serious arrhythmias, and even death can also occur very infre-
quently. Therefore, provocative testing should be avoided in patients with
signi�cant left main disease, advanced 3-vessel disease, presence of high-grade
obstructive lesions, signi�cant valvular stenosis, signi�cant LV systolic
dysfunction, and advanced HF.

e193
Downloa
endothelium-dependent vasodilation and can be useful in
vasospastic angina (759,760). Magnesium supplementa-
tion and alpha-receptor blockers may be effective and can
be added (755,758).
7.12. ACS With Angiographically Normal Coronary Arteries:
Recommendation
CLASS IIb
1. If coronary angiography reveals normal coronary arteries and
endothelial dysfunction is suspected, invasive physiological
assessment such as coronary �ow reserve measurement may
be considered (629,773–776). (Level of Evidence: B)
ACS associated with angiographically normal or non-
obstructive (<50% stenosis) coronary arteries (also referred
to as syndrome X) may be related to coronary endothelial
dysfunction (777); plaque rupture that may be evident only
with intracoronary ultrasound (778); coronary vasospasm
(779); and coronary artery dissection (780). Myocarditis may
present with electrocardiographic and biomarker �ndings
similar to ACS and can be distinguished by magnetic reso-
nance imaging (781–783). Intracoronary ultrasound and/or
optical coherence tomography to assess the extent of
atherosclerosis and exclude obstructive lesions may be
considered in patients with possible ACS and angiograph-
ically normal coronary arteries (778). If ECGs during chest
pain are not available and coronary spasm cannot be ruled
out, coronary angiography and provocative testing with
acetylcholine, adenosine, or methacholine and 24-hour
ambulatory ECG may be undertaken after a period of sta-
bilization. Endothelial dysfunction is more common in
women than in men (679,777,784–786), and chest pain is
typical or atypical (785,786). In the absence of a culprit
coronary lesion, prognosis of coronary endothelial
dysfunction and/or occult plaque rupture is favorable
(765,787).
Risk factor reduction and medical therapy with ni-
trates, beta blockers, and CCBs alone or in combination
are considered for endothelial dysfunction (788–790).
High doses of arginine have also been given (791). Imip-
ramine or aminophylline have been used in patients with
endothelial dysfunction for continued pain despite
optimal medical therapy. In postmenopausal women, es-
trogen reverses acetylcholine-induced coronary arterial
vasoconstriction, presumably by improving endothelium-
dependent coronary vasomotion, and reduces frequency
of chest pain (792). However, estrogen is not recom-
mended because of its demonstrated increase in cardio-
vascular and other risks (793).
Spontaneous coronary artery dissection affects a young,
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
predominantly female population. Treatment of sponta-
neous coronary artery dissection with CABG or stenting is
described to improve outcome (794),buthighratesof
stenting complications are reported (780).
ded From: http://content.onlinejacc.org/ on 03/27/2015
7.13. Stress (Takotsubo) Cardiomyopathy: Recommendations
CLASS I
1. Stress (Takotsubo) cardiomyopathy should be considered in
patients who present with apparent ACS and nonobstructive
CAD at angiography. (Level of Evidence: C)
2. Imaging with ventriculography, echocardiography, or
magnetic resonance imaging should be performed to con�rm
or exclude the diagnosis of stress (Takotsubo) cardiomyop-
athy (795–798). (Level of Evidence: B)
3. Patients should be treated with conventional agents (ACE
inhibitors, beta blockers, aspirin, and diuretics) as otherwise
indicated if hemodynamically stable. (Level of Evidence: C)
4. Anticoagulation should be administered in patients who
develop LV thrombi. (Level of Evidence: C)
CLASS IIa
1. It is reasonable to use catecholamines for patients with
symptomatic hypotension if out�ow tract obstruction is not
present. (Level of Evidence: C)
2. The use of IABP is reasonable for patients with refractory
shock. (Level of Evidence: C)
3. It is reasonable to use beta blockers and alpha-adrenergic agents
in patients with out�ow tract obstruction. (Level of Evidence: C)
CLASS IIb
1. Prophylactic anticoagulation may be considered to inhibit
the development of LV thrombi. (Level of Evidence: C)
Stress (Takotsubo) cardiomyopathy (also referred to as
transient LV apical ballooning or Takotsubo cardiomyopathy)
mimics NSTE or STEMI (799–803). There is no obstructive
CAD, and the distribution of electrocardiographic changes
and LV wall motion abnormalities usually includes >1 coro-
nary artery territory (801). Cardiac troponin elevations are
usually modest (798). The majority of cases occur in post-
menopausal women, and presentation is typically precipi-
tated by emotional or physical stress. Imaging by
echocardiography, ventriculography (696), or magnetic
resonance imaging (699) demonstrates characteristic hypo-
kinesis or dyskinesis of the LV apex with basilar increased
contractility. Variants include hypokinesis of the mid or base
of the left ventricle (795), and right ventricular involvement
is common (804). In the vast majority of patients, electro-
cardiographic and LV wall motion abnormalities normalize
within 1 to 4 weeks, and recurrences are uncommon (805).
The pathogenesis has been attributed to excess catechol-
amine release (803), coronary spasm, or small coronary
vessel hypoperfusion (806).
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
Care is predominantly supportive and includes beta
blockers, vasodilators, and catecholamines. The latter 2
interventions must be used cautiously, because they may
induce out�ow tract obstruction (800). If shock is present,

been reported to be safely modi�ed by elimination of
e194
Downloaded From
IABP can be used. Prophylactic anticoagulation should be
considered to prevent or treat LV thrombus (798).
7.14. Obesity
Obesity is associated with conditions such as dyslipide-
mia, diabetes mellitus, hypertension, arrhythmias, and
HF that adversely affect ACS outcomes. In the MADIT
(Multicenter Automatic De�brillator Implantation)-II
trial, there was an inverse relation between body mass
index and both all-cause mortality and sudden cardiac
death in patients with LV dysfunction after MI (807).In
the SYNERGY trial of 9,837 patients with NSTEMI, mor-
tality was lower in morbidly obese patients, consistent
with the “obesity paradox” (808).The“obesity paradox”
has not been clari�ed and is under continuing investiga-
tion. Standard approaches to weight reduction in obese
patients are usually unsuccessful in producing large de-
creases in weight. A weight reduction study of obese and
morbidly obese patients following AMI resulted in weight
loss of only 0.5% in obese patients and 3.5% in morbidly
obese patients after 1 year (809). Two drugs, controlled-
release phentermine/topiramate (810) and lorcaserin
(811), are available for weight reduction but have not been
studied in patients following NSTE-ACS. Bariatric surgery
has been successful in reducing cardiovascular risk fac-
tors, including diabetes mellitus, hypertension, and dys-
lipidemia but has not been evaluated in post–ACS patients
(812). The 2013 obesity CPG provides comprehensive
strategies for weight reduction (16).
7.15. Patients Taking Antineoplastic/Immunosuppressive
Therapy
Antineoplastic or immunosuppressive therapy may con-
tribute to the development of NSTE-ACS. For example,
antineoplastic agents such as gemcitabine, sorafenib
sunitinib, and 5-�uorouracil have been associated with
coronary artery spasm or stenosis (813,814).Trastuzumab
and possibly other anticancer drugs may alter biomarker
levels (815). Antineoplastic agents can induce changes in
the arterial wall (813), and modulators of in�ammation may
promote atherogenesis (816). In patients receiving these
agents, it is prudent to communicate with the prescribing
clinician about the necessity of their continuation during
NSTE-ACS and future resumption.
8. QUALITY OF CARE AND OUTCOMES FOR
ACS—USE OF PERFORMANCE MEASURES
AND REGISTRIES
8.1. Use of Performance Measures and Registries:
Amsterdam et al.
2014 AHA/ACC NSTE-ACS Guideline
Recommendation
CLASS IIa
1. Participation in a standardized quality-of-care data registry
designed to track and measure outcomes, complications, and
: http://content.onlinejacc.org/ on 03/27/2015
performance measures can be bene�cial in improving the
quality of NSTE-ACS care (817–825). (Level of Evidence: B)
The development of national systems for ACS is crucial
and includes the participation of key stakeholders to eval-
uate care using standardized performance and
quality-improvement measures for ACS (819,821). Standard-
ized quality-of-care data registries include the NCDR
Registry�Get With the Guidelines, the Get With the
Guidelines quality-improvement program, the Acute
Myocardial Infarction Core Measure Set, and performance
measures required by The Joint Commission and the Cen-
ters for Medicare and Medicaid Services (817,823–825).The
AHA has promoted its Mission: Lifeline initiative to
encourage cooperation among prehospital emergency
medical services personnel and cardiac care professionals
(817). The evaluation of ACS care delivery across traditional
boundaries can identify problems with systems and enable
application of modern quality-improvement methods
(818,820,822). On a local level, registries as part of the
Chronic Care Model were associated with improved out-
comes in chronic diseases, including cardiovascular disease
(826,827).
9. SUMMARY AND EVIDENCE GAPS
Despite landmark advances in the care of patients with
NSTE-ACS since the publication of the 2007 UA/NSTEMI
CPG (212), many emerging diagnostic and therapeutic
strategies have posed new challenges. There is general
acceptance of an early invasive strategy for patients with
NSTE-ACS in whom signi�cant coronary vascular
obstruction has been precisely quanti�ed. Low-risk
patients with NSTE-ACS are documented to bene�tsub-
stantially from GDMT, but this is often suboptimally used.
Advances in noninvasive testing have the potential to
identify patients with NSTE-ACS who are at intermediate
risk and are candidates for invasive versus medical
therapy.
Newer, more potent antiplatelet agents in addition to
anticoagulant therapy are indicated irrespective of initial
treatment strategy. Evidence-based decisions will require
comparative-effectiveness studies of available and novel
agents. The paradox of newer and more potent antith-
rombotic and anticoagulant drugs that reduce major
adverse cardiac outcomes but increase bleeding risk
occurs with greater frequency in patients with AF.
Patients with AF who develop NSTE-ACS and receive a
coronary stent are the population at risk from triple
anticoagulant/antiplatelet therapy. This regimen has
JACC VOL. 64, NO. 24, 2014
DECEMBER 23, 2014:e139– 228
aspirin, a �nding that requires con�rmation.
Among the most rapidly evolving areas in NSTE-ACS
diagnosis is the use of cardiac troponin, the preferred
biomarker of myocardial necrosis. Although a truly

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e195
Downloa
ischemia-guided strategy compared with an early inva-
sive management strategy. An appreciable number of
patients with NSTE-ACS have angiographically normal or
nonobstructive CAD, a group in which women predomi-
nate. Their prognosis is not benign, and the multiple
mechanisms of ACS postulated for these patients remain
largely speculative. Clinical advances are predicated on
clari�cation of the pathophysiology of this challenging
syndrome.
A fundamental aspect of all CPGs is that these carefully
developed, evidence-based documents cannot encompass
all clinical circumstances, nor can they replace the judg-
ment of individual physicians in management of each
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College of Cardiology/American Heart Association
Task Force on Performance Measures (Writing
Committee to Develop Performance Measures
for ST-Elevation and Non-ST-Elevation
Myocardial Infarction). Circulation 2008;118:
2596–648.
822. Le May MR, So DY, Dionne R, et al. A citywide
protocol for primary PCI in ST-segment elevation
myocardial infarction. N Engl J Med 2008;358:
231–40.
823. National Cardiovascular Data Registry. Action
Registry–GWTG. 2009. Available at: http://www.ncdr.
com/webncdr/ACTION/Default.aspx. Accessed June
10, 2009.
824. QualityNet.com. Measure Comparison (Inpatient
Hospital Quality Measures). 2009. Available at: http://
www.qualitynet.org/dcs/ContentServer?c¼Page&
pagename¼QnetPublic%2FPage%2FQnetTier3
&cid¼1138900297065. Accessed June 10, 2009.
825. The Joint Commission. Acute Myocardial Infarc-
tion Core Measure Set. 2009. Available at: http://
www.jointcommission.org/core_measure_sets.aspx.
Accessed August 28, 2014.
826. McAlister FA, Lawson FM, Teo KK, et al.
A systematic review of randomized trials of disease
management programs in heart failure. Am J Med
2001;110:378–84.
827. Coleman K, Austin BT, Brach C, et al. Evidence on
the chronic care model in the new millennium. Health
Aff (Millwood) 2009;28:75–85.
KEY WORDS ACC/AHA Clinical Practice
Guidelines, acute coronary syndrome, angina,
unstable, antiplatelet agents, coronary artery
bypass graft, electrocardiography, ischemia,
myocardial infarction, percutaneous coronary
intervention, troponin
JACC VOL. 64, NO. 24, 2014
Amsterdam et al.
DECEMBER 23, 2014:e139– 228
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APPENDIX 1. AUTHOR RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES (RELEVANT)—
2014 AHA/ACC GUIDELINE FOR THE MANAGEMENT OF PATIENTS WITH NON–ST-ELEVATION
ACUTE CORONARY SYNDROMES
Committee
Member Employment Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other
Financial Bene�t
Expert
Witness
Voting
Recusals
by Section*
Ezra A.
Amsterdam
(Chair)
University of
California (Davis)
Medical Center,
Division of
Cardiology—
Professor
None None None None None None None
Nanette
K. Wenger
(Vice Chair)
Emory University,
School of
Medicine—
Professor of
Medicine
(Cardiology)
� Abbott
� Amgen
� AstraZeneca
� Gilead Sciences†
� Janssen
Pharmaceuticals
� Medtronic
� Merck
� P�zer
None None � Abbott†
� Eli Lilly†
� Gilead
Sciences†
� Merck
� P�zer†
None None All sections
except 3.1.1,
3.4, 5.2, 6.3.1,
6.3.2, 6.3.6, 7.5,
7.6, 7.8, and 8.
Ralph G.
Brindis
University of
California, San
Francisco
Department of
Medicine and the
Phillip R. Lee
Institute for
Health Policy
Studies—Clinical
Professor of
Medicine
None � Volcano None None None None None
Donald E.
Casey, Jr
Atlantic Health—
Vice President of
Health and Chief
Medical Of�cer
None None None None None None None
Theodore G.
Ganiats
University of
California, San
Diego School of
Medicine—
Executive
Director of Health
Services Research
Center
None None None None None None None
David R.
Holmes, Jr
Mayo Clinic—
Consultant,
Cardiovascular
Diseases
None None None None None None None
Allan S. Jaffe Mayo Clinic,
Cardiovascular
Division—
Professor of
Medicine
� Abbott
� Alere
� Amgen
� Beckman-
Coulter
� Critical
Diagnostics
� ET Healthcare
� Ortho Clinical
Diagnostic
� Radiometer†
� Roche‡
None None None None None All sections
except 3.1, 3.1.1,
3.3, 4.1.2.1-
4.1.2.3, 4.2,
4.3.1, 4.3.2,
4.5, 5.1, 5.2,
6.2.1, 6.3.1,
6.3.3, 6.3.6,
7.2.2, 7.5, 7.6,
and 8.
Amsterdam et al.
JACC VOL. 64, NO. 24, 2014
2014 AHA/ACC NSTE-ACS Guideline
DECEMBER 23, 2014:e139– 228
e216
Downloaded From
� Thermo-Fisher‡
� Trinity
Hani Jneid Baylor College of
Medicine—The
Michael E.
DeBakey VA
None None None None None None None
Medical Center—
Assistant
Professor of
Medicine
Continued on the next page
: http://content.onlinejacc.org/ on 03/27/2015

Committee
Member Employment Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other
Financial Bene�t
Expert
Witness
Voting
Recusals
by Section*
Rosemary F.
Kelly
University of
Minnesota—
Professor
of Surgery; VA
Medical Center—
Chief, Cardiothoracic
Surgery
None None None None None None None
Michael C.
Kontos
Virginia
Commonwealth
University, Pauley
Heart Center—
Medical Director,
Coronary
Intensive Care
Unit, and Associate
Professor,
Internal Medicine
� Astellas
� General Electric
� Ikaria
� Prevencio
� Sano�-aventis
� Wellpoint/
Anthem
� Astellas
� AstraZeneca
None None � Astellas
� Eli Lilly‡
� Merck‡
� Novartis‡
None All sections
Glenn N.
Levine
Baylor College of
Medicine—
Professor
of Medicine;
Director,
Cardiac Care Unit
None None None None None None None
Philip R.
Liebson
Rush University
Medical Center—
McMullan-Eybel
Chair of
Excellence in
Clinical Cardiology
and Professor of
Medicine and
Preventive Medicine
None None None None None None None
Debabrata
Mukherjee
Texas Tech
University
Health Sciences
Center—Chief,
Cardiovascular
Medicine
None None None None None None None
Eric D.
Peterson
Duke University
Medical Center—
Fred Cobb, MD,
Distinguished
Professor of
Medicine; Duke
Clinical Research
Institute—Director
� Boehringer
Ingelheim
� Genentech
� Janssen
Pharmaceuticals
� Johnson &
Johnson
� Merck
None None � Eli Lilly†
� Johnson &
Johnson†
� Janssen
Pharmaceuticals†
DCRI has numerous
grants and
contracts
sponsored by
industry that are
relevant to the
content of this
CPG. Dr. Peterson
participated in
discussions but
recused himself
from writing or
voting, in
accordance with
ACC/AHA policy.
See comprehensive
RWI table for a
complete list of
companies
pertaining to this
organization.
None All sections
Continued on the next page
APPENDIX 1. CONTINUED
JACC VOL. 64, NO. 24, 2014
Amsterdam et al.
DECEMBER 23, 2014:e139– 228
2014 AHA/ACC NSTE-ACS Guideline
e217
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Committee
Member Employment Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other
Financial Bene�t
Expert
Witness
Voting
Recusals
by Section*
Marc S.
Sabatine
Brigham and
Women’s
Hospital,
Chairman—TIMI
Study Group,
Division of
Cardiovascular
Medicine;
Harvard Medical
School—Professor
of Medicine
� Amgen
� AstraZeneca
� Bristol-Myers
Squibb
� Merck
� P�zer
� Sano�-aventis
None None � Abbott
Laboratories†
� Amgen†
� AstraZeneca†
� Bristol-Myers
Squibb†
� BRAHMS†
� Critical
Diagnostics†
� Daiichi-Sankyo†
� Genzyme†
� GlaxoSmithKline†
� Nanosphere†
� Roche Diagnostics†
� Sano�-aventis†
� Takeda†
� AstraZeneca†
� Daiichi-Sankyo†
� Gilead†
� Johnson &
Johnson†
� Merck†
� Proventys†
� Siemens†
� Singulex†
None All sections
except 3.1.1, 5.2,
6.3.1, 6.3.2, 7.5,
7.8, and 8.
Richard W.
Smalling
University of Texas,
Health Science
Center at
Houston—
Professor and
Director of
Interventional
Cardiovascular
Medicine; James D.
Woods
Distinguished
Chair in Cardiovascular
Medicine
� Gilead
� Maquet
None None � Cordis
� E-valve Abbott
Vascular
� Edwards
Lifesciences
� Gilead
� Maquet
Datascope
� Cordis†
� E-valve†
None All sections
except 3.1, 3.1.1,
3.3, 3.4, 3.5.1,
4.1.2.1-4.1.2.3,
4.2, 4.3.1, 4.3.2,
5.2, 6.2.1, 6.3.1,
6.3.2, 6.3.3,
6.3.6, 7.2.2,
7.5, 7.8, and 8.
Susan J.
Zieman
National Institute
on Aging/NIH,
Geriatrics Branch,
Division of
Geriatrics and Clinical
Gerontology—Medical
Of�cer
None None None None None None None
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 GWC during the document development process. The table does not necessarily re�ect re-
lationships with industry at the time of publication. A person is deemed to have a signi�cant 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 �nancial bene�t are also included for the purpose of transparency. Relationships in this table are modest
unless otherwise noted.
According to the ACC/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 �nancial, professional or other personal gain or loss as
a result of the issues/content addressed in the document.
*Writing members are required to recuse themselves from voting on sections to which their speci�c relationships with industry and other entities may apply.
†Signi�cant relationship.
‡No �nancial bene�t.
ACC indicates American College of Cardiology, AHA, American Heart Association, BMS, Bristol-Myers Squibb; CPG, clinical practice guideline; DCRI, Duke Clinical Research Institute;
NIH, National Institutes of Health; NYU, New York University; RWI, relationships with industry and other entities; TIMI, Thrombolysis In Myocardial Infarction; and VA, Veterans Affairs.
APPENDIX 1. CONTINUED
Amsterdam et al.
JACC VOL. 64, NO. 24, 2014
2014 AHA/ACC NSTE-ACS Guideline
DECEMBER 23, 2014:e139– 228
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Reviewer Representation Employment Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other
Financial Bene�t
Expert
Witness
Deepak L.
Bhatt
Of�cial Reviewer—AHA VA Boston Healthcare System—
Professor of Medicine,
Harvard Medical School;
Chief of Cardiology
� BMS/P�zer
� DCRI (BMS/P�zer)
� DCRI (Eli Lilly)
� Eli Lilly
None None � AstraZeneca*
� Bristol-Myers
Squibb*
� Ethicon*
� The Medicines
Company
� Medtronic*
� Sano�-aventis*
� Takeda†
� Medscape Cardiology
(Advisory Board)†
� WebMD (Steering
Committee)†
None
John E.
Brush, Jr
Of�cial Reviewer—ACC
Board of Trustees
Eastern Virginia Medical
School—Professor of
Medicine, Chief of Cardiology
None None None None None None
E. Magnus
Ohman
Of�cial Reviewer—
ACC/AHA Task Force
on Practice Guidelines
Duke Medicine—Professor
of Medicine
� AstraZeneca
� Bristol-Myers
Squibb
� Gilead*
� Janssen
Pharmaceuticals*
� The Medicines
Company
� Merck
� Pozen
� Roche
� Sano�-aventis
� Gilead*
� Janssen
Pharmaceuticals
None � Daiichi-Sankyo*
� Eli Lilly*
� Gilead*
None None
John F. Robb Of�cial Reviewer—ACC
Board of Governors
Dartmouth-Hitchcock Medical
Center—Director, Interventional
Cardiology and Cardiac
Catheterization Laboratories
None None None None None � Defendant, adverse
drug reaction, 2012
Sarah A.
Spinler
Of�cial Reviewer—AHA Philadelphia College of Pharmacy,
University of the Sciences in
Philadelphia—Professor of
Clinical Pharmacy
� Bristol-Myers
Squibb
� Daiichi-Sankyo
� Janssen
Pharmaceuticals
� Merck
None None None None � Plaintiff,
clopidogrel, 2013
Gorav Ailawadi Organizational
Reviewer—STS
University of Virginia Health
System—Thoracic and
Cardiovascular Surgery
� Abbott
� Atricure
None None None None None
Srihari S.
Naidu
Organizational
Reviewer—SCAI
Winthrop University Hospital—
Director, Cardiac
Catheterization Laboratory
None None None None None None
Robert L.
Rich, Jr
Organizational
Reviewer—AAFP
Bladen Medical Associates—
Family Physician
None None None None None None
Continued on the next page
APPENDIX 2. REVIEWER RELATIONSHIPS WITH INDUSTRY AND OTHER ENTITIES (RELEVANT)—2014 AHA/ACC GUIDELINE FOR THE
MANAGEMENT OF PATIENTS WITH NON–ST-ELEVATION ACUTE CORONARY SYNDROMES
J
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C
C
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4
,
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O
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2
4
,
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1
4
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s
t
e
r
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a
m
e
t
a
l
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D
E
C
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M
B
E
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2
3
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4
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Reviewer Representation Employment Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other
Financial Bene�t
Expert
Witness
Mouaz H.
Al-Mallah
Content Reviewer—
ACC Prevention of
Cardiovascular
Disease Committee
King Abdul-Aziz Cardiac
Center—Associate Professor
of Medicine
None None None None None None
John A.
Ambrose
Content Reviewer University of California San Francisco
Fresno Department of Medicine—
Professor of Medicine; Chief of
Cardiology; Program Director,
Cardiology Fellowship
None None None None None None
Giuseppe
Ambrosio
Content Reviewer—
ACC Prevention of
Cardiovascular
Disease Committee
Hospital of University of Perugia
School of Medicine—Medical
Director, Division of Cardiology
� Bayer*
� The Medicines
Company
� Merck Schering-
Plough†
� Sano�-aventis
� Merck
Schering-Plough
� P�zer
None None None None
H. Vernon
Anderson
Content Reviewer University of Texas—Professor of
Medicine, Cardiology Division
None None None None � Eli Lilly None
Jeffrey L.
Anderson
Content Reviewer—
ACC/AHA Task Force
on Practice Guidelines
Intermountain Medical Center—
Associate Chief of Cardiology
� Sano�-aventis None None � GlaxoSmithKline
� Harvard (DSMB)–
TIMI -48, -51, and
-54 Studies
None None
Fred S. Apple Content Reviewer University of Minnesota School of
Medicine, Hennepin County
Medical Center—Professor,
Laboratory Medicine and
Pathology
� Abbott Diagnostics
� Alere
� Beckman Coulter
� T2 Biosystems
None None � Abbott*
� Alere/Biosite*
� Biomerieux*
� Ortho-Clinical
Diagnostics*
� Radiometer*
� Roche
Laboratories*
� Siemens*
� Abbott Diagnostics–PI†
� Alere–PI†
� Ortho-Clinical
Diagnostics–PI†
None
Emmanouil S.
Brilakis
Content Reviewer—ACC
Interventional Section
Leadership Council
UT Southwestern Medical School—
Director, Cardiac Catheterization
Laboratory, VA North Texas
Healthcare System
� Bridgepoint Medical/
Boston Scienti�c*
� Janssen
Pharmaceuticals
� Sano�-aventis
None None None � Abbott Vascular
� AstraZeneca
� Cordis*
� Daiichi-Sankyo*
� The Medicines Company
� Medtronic*
None
Matthew J.
Budoff
Content Reviewer—ACC
Cardiovascular
Imaging Section
Leadership Council
Los Angeles Biomedical Research
Institute—Program Director,
Division of Cardiology and
Professor of Medicine
None � AstraZeneca† None � General Electric* None � Plaintiff, cardiac
treatment, 2013
James A. Burke Content Reviewer—ACC
Interventional Section
Leadership Council
Lehigh Valley Health Network—
Interventional Cardiologist
None None None None None None
Continued on the next page
APPENDIX 2. CONTINUED
A
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4
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O
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4
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Reviewer Representation Employment Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other
Financial Bene�t
Expert
Witness
Robert H.
Christenson
Content Reviewer—AACC University of Maryland School
of Medicine—Professor of
Pathology; Professor of
Medical and Research
Technology; Director, Rapid
Response Laboratory
� BG Medicine
� Critical Diagnostics
� Siemens Medical
Diagnostics
None None � The Medicines
Company
� AACC (President)†
� Roche Diagnostics
(University of Maryland
School of Medicine)*
None
Joaquin E.
Cigarroa
Content Reviewer—ACC
Interventional Section
Leadership Council
Oregon Health and Science
University—Associate Professor
of Medicine
None None None None � Catheterization and
Cardiovascular
Intervention
(Editorial Board)†
None
Marco A. Costa Content Reviewer—ACC
Cardiovascular
Imaging Section
Leadership Council
University Hospital for
Cleveland—Cardiologist
� Abbott Vascular*
� Boston Scienti�c
� Medtronic
None None � Abbott Vascular*
� Boston Scienti�c*
� Cordis*
� IDEV Technology†
� The Medicines
Company
� Medtronic*
� Micell*
� OrbusNeich†
� Abbott
� Cordis
� Medtronic
None
Prakash C.
Deedwania
Content Reviewer—ACC
Prevention of
Cardiovascular
Disease Committee
University of California San
Francisco—Chief of Cardiology
� Amgen
� P�zer
� P�zer
� Takeda
Pharmaceuticals
None None None None
James A. de
Lemos
Content Reviewer UT Southwestern Medical School—
Associate Professor of Medicine;
Director, Coronary Care Unit and
Cardiology Fellowship
� Diadexus
� Janssen
Pharmaceuticals
� AstraZeneca None � Abbott
Diagnostics†
� Daiichi-Sankyo† None
Burl R. Don Content Reviewer University of California Davis—
Professor of Medicine; Director
of Clinical Nephrology
None None None None None None
Lee A. Fleisher Content Reviewer University of Pennsylvania
Department of Anesthesiology—
Professor of Anesthesiology
None None None None None None
Mary G. George Content Reviewer—HHS Centers for Disease Control and
Prevention—Senior Medical
Of�cer, Division for Heart
Disease and Stroke Prevention
None None None None None None
Linda D. Gillam Content Reviewer—ACC
Cardiovascular
Imaging Section
Leadership Council
Morristown Medical Center—
Professor of Cardiology; Vice
Chair, Cardiovascular Medicine
None None None None None None
Continued on the next page
APPENDIX 2. CONTINUED
J
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4
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l
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Reviewer Representation Employment Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other
Financial Bene�t
Expert
Witness
Robert A.
Guyton
Content Reviewer—
ACC/AHA Task Force
on Practice Guidelines
Emory Clinic—Professor and Chief,
Division of Cardiothoracic
Surgery
� Medtronic None None None None None
Joerg
Herrmann
Content Reviewer—ACC
Interventional Section
Leadership Council
Mayo Medical School—Internal
Medicine and Cardiovascular
Disease
None None None None None None
Judith S.
Hochman
Content Reviewer—
ACC/AHA Task Force
on Practice Guidelines
New York University School of
Medicine, Division of
Cardiology—Clinical Chief of
Cardiology
� GlaxoSmithKline
� Janssen
Pharmaceuticals
None None None None None
Yuling Hong Content Reviewer—HHS Centers for Disease Control and
Prevention—Associate Director
None None None None None None
Lloyd W. Klein Content Reviewer—ACC
Interventional Section
Leadership Council
Rush Medical College—Professor
of Medicine
None None None None None None
Frederick G.
Kushner
Content Reviewer Tulane University School of
Medicine—Clinical Professor of
Medicine; Heart Clinic of
Louisiana—Medical Director
None None None None None None
Ehtisham
Mahmud
Content Reviewer—ACC
Interventional Section
Leadership Council
University of California, San
Diego—Professor of
Medicine/Cardiology,
Chief of Cardiovascular Medicine;
Director, Interventional
Cardiology and Cardiovascular
Catheterization Laboratory
� Abiomed
� Cordis†
� Eli Lilly*
� Gilead
� Johnson & Johnson
� Medtronic
� Eli Lilly*
� Medtronic
None � Abbott Vascular*
� Accumetrics*
� Merck Schering-
Plough
� Boston Scienti�c*
� Gilead*
� The Medicines
Company
� Sano�-aventis*
None None
Carlos Martínez-
Sánchez
Content Reviewer—AIG Cardiology Society of Mexico—
President
None None None � AstraZeneca†
� Eli Lilly†
� Sano�-aventis†
None None
L. Kristen
Newby
Content Reviewer Duke University Medical
Center—Associate Professor
of Clinical Medicine
� Johnson & Johnson
� Daiichi-Sankyo
None None � Amylin
� AstraZeneca
� Bristol-Myers
Squibb*
� Eli Lilly
� GlaxoSmithKline
� Merck*
None None
Patrick T.
O’Gara
Content Reviewer Brigham and Women’s Hospital—
Professor of Medicine,
Harvard Medical School;
Director, Clinical Cardiology
None None None None None None
Continued on the next page
APPENDIX 2. CONTINUED
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Reviewer Representation Employment Consultant
Speakers
Bureau
Ownership/
Partnership/
Principal
Personal
Research
Institutional,
Organizational,
or Other
Financial Bene�t
Expert
Witness
Narith Ou Content Reviewer Mayo Clinic—Pharmacotherapy
Coordinator, Pharmacy Services
None None None None None None
Gurusher S.
Panjrath
Content Reviewer—ACC
Heart Failure and
Transplant Section
Leadership Council
George Washington Medical
Faculty Associates—Assistant
Professor of Medicine;
Director of Heart Failure and
Mechanical Support Program
None None None None None None
Rajan Patel Content Reviewer—ACC
Cardiovascular
Imaging Section
Leadership Council
Ochsner Clinic Foundation—
Interventional Cardiologist
None None None None None None
Carl J. Pepine Content Reviewer Shands Hospital at University of
Florida—Professor and Chief,
Division of Cardiovascular
Medicine
� Lilly/Cleveland
Clinic (DSMB)
None None � AstraZeneca*
� Gilead Sciences*
� Park-Davis*
� P�zer*
� Sano�-aventis*
None None
Sunil V. Rao Content Reviewer—ACC
Interventional Section
Leadership Council
Duke University Medical
Center—Associate Professor
of Medicine
� AstraZeneca
� Daiichi-Sankyo
� Eli Lilly
� Terumo Medical
� The Medicines
Company
None None � Sano�-aventis � Abbott Vascular† None
Pasala S.
Ravichandran
Content Reviewer—ACC
Surgeons’ Scienti�c
Council
Oregon Health and Science
University—Associate
Professor
None None None None None None
Michael W. Rich Content Reviewer Washington University School
of Medicine—Professor of
Medicine
None None None None None None
Frank W. Sellke Content Reviewer—
ACC/AHA Task Force
on Practice Guidelines
Brown Medical School, Rhode
Island Hospital—Professor;
Chief of Cardiothoracic Surgery
None None None None None None
Alan Wu Content Reviewer—AACC San Francisco General Hospital
and Trauma Center—Chief,
Clinical Chemistry Laboratory
� Abbott
� Singulex
None None None None 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 re�ect relationships with industry at the time of
publication. A person is deemed to have a signi�cant 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 signi�cant under the preceding de�nition. Relationships that exist with no �nancial
bene�t 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 ACC/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 �nancial,
professional or other personal gain or loss as a result of the issues/content addressed in the document.
*Signi�cant relationship.
†No �nancial bene�t.
AAAHC indicates Accreditation Association for Ambulatory Health Care; AACC, American Association for Clinical Chemistry; AAFP, American Academy of Family Physicians; AHA, American Heart Association; AIG, Association of International Governors;
BMS, Bristol-Myers Squibb; DCRI, Duke Clinical Research Institute; DSMB, data safety monitoring board; HHS, Health and Human Services; NHLBI, National Heart, Lung, and Blood Institute; NIH, National Institutes of Health; SCAI, Society for Car-
diovascular Angiography and Interventions; STS, Society of Thoracic Surgeons; TIMI, Thrombolysis In Myocardial Infarction; and VA, Veterans Affairs.
APPENDIX 2. CONTINUED
J
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C
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B
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2
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APPENDIX 3. ABBREVIATIONS
ACE ¼ angiotensin-converting enzyme
ACS ¼ acute coronary syndrome
AF ¼ atrial �brillation
AMI ¼ acute myocardial infarction
BP ¼ blood pressure
CABG ¼ coronary artery bypass graft
CAD ¼ coronary artery disease
CKD ¼ chronic kidney disease
CK-MB ¼ creatine kinase myocardial isoenzyme
COX ¼ cyclooxygenase
CPG ¼ clinical practice guideline
CrCl ¼ creatinine clearance
CT ¼ computed tomography
DAPT ¼ dual antiplatelet therapy
DE
EC
ED
GD
GP
GF
GW
HF ¼ heart failure
IABP ¼ intra-aortic balloon pump
IV ¼ intravenous
LMWH ¼ low-molecular-weight heparin
LV ¼ left ventricular
LVEF ¼ left ventricular ejection fraction
MACE ¼ major adverse cardiac event
MI ¼ myocardial infarction
MVO
2
¼ myocardial oxygen consumption
NSAID ¼ nonsteroidal anti-in�ammatory drug
NSTE-ACS ¼ non–ST-elevation acute coronary syndromes
NSTEMI ¼ non–ST-elevation myocardial infarction
PCI ¼ percutaneous coronary intervention
RCT ¼ randomized controlled trial
SC ¼ subcutaneous
ST
UA
UF
VF
VT
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2014 AHA/ACC NSTE-ACS Guideline
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S ¼ drug-eluting stent
G ¼ electrocardiogram
¼ emergency department
MT ¼ guideline-directed medical therapy
¼ glycoprotein
R ¼ glomerular �ltration rate
C ¼ guideline writing committee
//content.onlinejacc.org/ on 03/27/2015
EMI ¼ ST-elevation myocardial infarction
¼ unstable angina
H ¼ unfractionated heparin
¼ ventricular �brillation
¼ ventricular tachycardia

APPENDIX 4. ADDITIONAL TABLES
TABLE A Universal Classi�cation of MI
Type 1: Spontaneous MI
Spontaneous MI related to atherosclerotic plaque rupture, ulceration, �ssuring, erosion, or dissection with resulting intraluminal thrombus in $1 of the coronary arteries
leading to decreased myocardial blood �ow or distal platelet emboli with ensuing myocyte necrosis. The patient may have underlying severe CAD, but on occasion
nonobstructive or no CAD.
Type 2: MI secondary to ischemic imbalance
In instances of myocardial injury with necrosis where a condition other than CAD contributes to an imbalance between MVO
2
, e.g., coronary endothelial dysfunction,
coronary artery spasm, coronary embolism, tachy-/bradyarrhythmias, anemia, respiratory failure, hypotension, and hypertension with or without LVH.
Type 3: MI resulting in death when biomarker values are unavailable
Cardiac death with symptoms suggestive of myocardial ischemia and presumed new ischemic electrocardiographic changes or new LBBB, but death occurred before
blood samples could be obtained, before cardiac biomarker could rise, or in rare cases where blood was not collected for cardiac biomarker testing.
Type 4a: MI related to PCI
MI associated with PCI is arbitrarily de�ned by elevation of cTn values >5 � 99th percentile URL in patients with normal baseline values (<99th percentile URL) or a rise
of cTn values >20% if baseline values are elevated and are stable or falling. In addition, either (i) symptoms suggestive of myocardial ischemia, (ii) new ischemic
electrocardiographic changes or new LBBB, (iii) angiographic loss of patency of a major coronary artery or a side branch or persistent slow or no �ow or embolization,
or (iv) imaging demonstration of new loss of viable myocardium or new regional wall motion abnormality is required.
Type 4b: MI related to stent thrombosis
MI associated with stent thrombosis is detected by coronary angiography or autopsy in the setting of myocardial ischemia and with a rise and/or fall of cardiac biomarker
values with $1 value above the 99th percentile URL.
Type 5: MI related to CABG
MI associated with CABG is arbitrarily de�ned by elevation of cardiac biomarker values >10 � 99th percentile URL in patients with normal baseline cTn values (<99th
percentile URL). In addition, either (i) new pathological Q waves or new LBBB, or (ii) angiographically documented new graft or new native coronary artery occlusion,
or (iii) imaging evidence of new loss of viable myocardium or new regional wall motion abnormality.
CABG indicates coronary artery bypass graft; CAD, coronary artery disease; cTn, cardiac troponin; LBBB, left bundle-branch block; LVH, left ventricular hypertrophy; MI, myocardial
infarction; MVO
2
, myocardial oxygen consumption; PCI, percutaneous coronary intervention; and URL, upper reference limit.
Modi�ed from Thygesen et al. (21).
TABLE B Pharmacological Therapy in Older Patients With NSTE-ACS
Age-Related
Pharmacological Change Clinical Effect
Dose-Adjustment
Recommendations Additional Precautions
General
principles
� YIn renal function (CrCl*):
drug clearance, water/
electrolyte balance
� SCr unreliable measure of
renalfunctioninolder
adults
� Change in body
composition
� [Fat, Ylean body mass/
total water
� YGI absorption
� [Levels renally cleared
drug
� Risk high/low electrolyte
levels
� [Levels hydrophilic agents
� YLevels lipophilic agents
� Longer time to reach
steady-state lipophilic
agents
� Calculate CrCl in all pts—renal-
dose accordingly
� Startatlowestrecommended
dose, titrate up slowly
� Avoid interacting drugs
� Consider Ydoses in women,
malnourished, hypovolemic
� Caution fall risk with YBP
agents and diuretics
� Monitor for ADR, especially
delirium
� Frequent monitoring of renal
function/electrolytes
� Minimize polypharmacy—watch
for drug-drug interactions
ASA Hydrophilic; levels [with Ytotal
body water; age-related
[plasma concentration for
similar dose
[Bleeding risk with [age,
dehydration, frailty, diuretics
� Maintenance¼81 mg/d (lowest
possible dose)
[Bleeding with NSAIDs, other AP,
AC, AT; [risk peptic ulcer with
NSAIDs
Nitrates [Sensitivity [Hypotensive response with
Ybaroreceptor response
Lowest dose possible, especially if
hypovolemic
[Risk OH, syncope, falls
ACE inhibitors YFirst-pass metabolism (some) May have Yeffect May need [dose [Risk AKI and [K
þ
and Yeffect with
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with Yeffect; enalapril
[effect
NSAIDs; avoid K-sparing diuretics
ARBs No signi�cant age-related No age-related clinical changes None [Risk AKI and [K
þ
and Yeffect with
changes NSAIDs; avoid K-sparing diuretics
Alpha blockers [Sensitivity; YBP with
Ybaroreceptor response
YBP; OH Avoid when possible [Risk OH, falls, syncope, especially
with loop diuretics
Continued on the next page
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TABLE B Continued
Age-Related
Pharmacological Change Clinical Effect
Dose-Adjustment
Recommendations Additional Precautions
Beta blockers YMyocardial sensitivity
(Ypostreceptor signaling),
[conduction system
sensitivity
Bradycardia/heart block; YBP
effect vs. younger pts
May need [dose with age Caution conduction system blocks
CCBs
� DHPs
(amlodipine;
nifedipine)
Lipophilic; Yhepatic and overall
clearance; [fat storage;
[sinus node sensitivity;
Ybaroreceptor response to
YBP
YBP more than non–DHP and
with [age; edema
hypotension, bradycardia
Initiate low dose, titrate cautiously Inhibits clopidogrel; [risk OH, falls,
syncope; most potent YBP �rst 3
mo, then less
� Non-DHP
(verapamil;
diltiazem)
YHepatic and overall clearance;
less PR prolongation than
DHP and with [age;
negative inotropy; [SA node
sensitivity and YHR than
DHP and with [age; YAV
conduction with [age;
Ybaroreceptor response to
YBP
YBP more with [age; edema;
[heart block; hypotension;
[bradycardia and
bradyarrhythmias with [age
Initiate low dose, titrate cautiously [Risk OH, falls, syncope; consider
rhythm monitoring
Diuretics YDiuretic/natriuretic response,
YEC space, [drug
concentration if YGFR;
Ybaroreceptor response to
volume shifts
[Sensitivity; [hypotension; risk
hypokalemia/
hypomagnesemia/
hyponatremia; Ydiuretic effect
with YGFR; risk
hypovolemia- Ythirst
May need [doses if YGFR; may need
[dose if cotreating with NSAIDs
� Monitor Na
þ
,K
þ
,Mg

levels;
[risk OH/falls;
� With NSAIDs: Ynatriuretic and
diuretic effect, [K
þ
, YMg

Heparins
� UFH Hydrophilic; [concentration,
especially if Ylean body
mass or Yplasma proteins;
[levels with [age
[Bleeding risk with age; more
potent anticoagulation per
dose with [age; weight-
based dosing but with
precautions for shift in body
composition
Weight-based 60 U/kg loading
dose þ 12 U/kg/h INF. Suggested
max loading dose: 400 U and
900 U/h INF or 5,000 U loading
dose/1,000 U/h if pt weight
>100 kg
[Bleeding with ASA; [bleeding risk
with other AP, AT, and GP IIb/
IIIa; vigilantly monitor aPTT
� LMWH Cleared renally; more
predictable dose response
than UFH; not dependent on
plasma protein levels;
[levels with Ylean body
mass; [effect with [age
[Bleeding risk with age and
weight and renally dosed
Enoxaparin: Weight-based 1 mg/kg
SC q 12 h; CrCl* <30 mL/min—
avoid or 1 mg/kg SC q 24 h; CrCl
30–60 mL/min: Y75%;
Dalteparin: Use caution in older pts
with low body weight or renal
insuf�ciency
� [Bleed with ASA
� Monitor anti-Xa; [bleeding
with GP IIb/IIIa with [age
Direct Thrombin Inhibitors
� Bivalirudin Cleared renally; more
predictable dose response;
not dependent on plasma
protein levels
Signi�cantly less bleeding in
older pts, even with renal
dysfunction vs. UFH þ GP
IIb/IIIa with similar ef�cacy
CrCl <30 mL/min: 1 mg/kg/h; CrCl:
30 to 60 mL/min—less bleeding
than UFH
Less bleeding than GP IIb/IIIa
inhibitor þ heparin
� Fondaparinux Cleared renally Renal/weight adjust; less
bleeding but similar ef�cacy
vs. enoxaparin in older pts
with NSTE-ACS, even with
mild to moderate renal
dysfunction
Renal adjustment: CrCl <30—
contraindicated; CrCl 30 to 60—
preferred over enoxaparin
YBleeding vs. enoxaparin; good
safety pro�le vs. UFH/LMWH
P2Y
12
Inhibitors
� Clopidogrel Lipophilic; [HPR; [metabolism;
[fat distribution; [to steady
state ([fat distribution/T
1
/
2
)
YAntiplatelet effect in some
older pts
Maintenance: 75 mg (no [response
to higher dose)
YEffect with proton pump inhibitors;
if HPR—may respond to prasugrel
or ticagrelor
� Prasugrel [19% Active metabolite >75 y
of age
[Bleeding risk Avoid in pts $75 y of age or if
weight #60 kg; 10 mg in very
high-risk pts
N/A
� Ticagrelor None known N/A None Reversible
GP IIb/IIIa Inhibitors
� Abciximab N/A � [Bleeding with [age
� [Bleeding risk without
clinical bene�t
Not recommended N/A
Continued on the next page
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2014 AHA/ACC NSTE-ACS Guideline
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TABLE B Continued
Age-Related
Pharmacological Change Clinical Effect
Dose-Adjustment
Recommendations Additional Precautions
� Epti�batide Weight/renally dosed [Bleeding risk Weight-based: 180 mcg/kg loading
dose þ 2 mcg/kg/min INF;
CrCl #50 mL/min: 1.0 mcg/kg/
min INF
Less bene�t/more bleeding with
[age
� Tiro�ban Weight/renally dosed [Bleeding risk Weight-based: 12 mcg/kg loading
dose þ 0.14 mcg/kg/min INF;
CrCl <30 mL/min: 6 mcg/kg
loading dose þ 0.05 mcg/kg/min
INF
In older pts with high bleeding risk,
low-dose INF effective with
Ybleeding
Warfarin [Sensitivity; Y20%–40%
clearance; protein binding;
[inhibition vitamin K-
dependent clotting factors
at same plasma levels with
[age
[Bleeding risk at lower INR;
higher INR/dose with [age;
[risk GI bleeding
� Loading: 4 mg/d � 4d
� Maintain mean dose Y0.4 mg/
w/y of age
Multiple drug interactions,
[frequency of monitoring; ASA
potentiates effect
New Oral AC† N/A N/A Contraindicated if CrCl <15 mL/min If pt taking when admitted, stop—
consider delaying angiogram/PCI
until effect wanes, switch to
UFH/dalteparin/bivalirudin/
fondaparinux; AP and DAPT
[bleeding 2� post-ACS—
consider BMS and radial access.
Avoid GP IIb/IIIa inhibitor if
possible; [thrombotic risk
following discontinuation.
� Rivaroxaban 35% cleared renally; 65%
hepatic (CYP3A4); [levels in
hepatic and/or renal
dysfunction and [age
[Bleeding risk; not reversible CrCl 15–49 mL/min: 15 mg QD;
consider avoiding if CrCl 15–30
mL/min if [bleeding risk; CrCl
>50 mL/min: 20 mg QD
Some drug interactions
� Dabigatran 80% cleared renally; [plasma
level with [age,
especially $75 y
[Bleeding risk; not reversible CrCl 15–30 mL/min: 75 mg BID with
caution; CrCl 30–49 mL/min: 75
mg BID; CrCl >50 mL/min: 150
mg BID
Monitor pt and renal function
frequently; longest for effect to
wane with YCrCl; [risk
dyspepsia, GI bleeding
� Apixaban Hepatically cleared (minor
CYP3A4); dose adjust if
weight #60 kg; highly
protein bound
[Bleeding risk; not reversible CrCl 15–29 mL/min: 2.5 mg BID or
with 2 of the following: age $80
y/weight #60 kg/SCr $1.5 mg/
dL: SCr <1.5: 5 mg BID
[Risk abnormal liver function tests
*CrCl should be calculated for all older pts because SCr level does not accurately re�ect renal dysfunction: CrCl decreases with age 0.7 mL/min/y.
†These agents are not approved for NSTE-ACS but are included for management of pts with nonvalvular chronic atrial �brillation.
AC indicates anticoagulants; ACE, angiotensin-converting-enzyme; ACS, acute coronary syndromes; ADR, adverse drug reactions; AKI, acute kidney injury; AP, antiplatelets; aPTT,
activated partial thromboplastin time; ARB, angiotensin receptor blocker; ASA, aspirin; AT, antithrombins; AV, atrioventricular; BID, twice daily; BMS, bare-metal stent; BP, blood
pressure; CCBs, calcium channel blockers; CrCl, creatinine clearance; DAPT, dual antiplatelet therapy; DHP, dihydropyridine; EC, extracellular; GFR, glomerular �ltration rate; GI,
gastrointestinal; GP, glycoprotein; HPR, high platelet reactivity; HR, heart rate; INF, infusion; INR, international normalized ratio; K
þ
, potassium; LMWH, low-molecular-weight heparin;
max, maximum; Mg, magnesium; N/A, not available; NSAIDs, nonsteroidal anti-in�ammatory drugs; NSTE-ACS, non–ST-elevation acute coronary syndromes; OH, orthostatic hypo-
tension; PCI, percutaneous coronary intervention; pts, patients; QD; once daily; SA, sinoatrial; SC, subcutaneous; SCr, serum creatinine; T
1
/
2
, half-life; and UFH, unfractionated heparin.
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TABLE C Age-Related Physiological Changes: Clinical Impact in Older Patients With NSTE-ACS
Age-Related Change Clinical Alteration Clinical Impact in NSTE-ACS
[Central arterial stiffness [SBP/YDBP; [LVH; Ydiastolic function; Ycoronary perfusion
pressure; Yischemia/infarct threshold for tachycardia/
hypertension with and without coronary obstructive
disease; [PA pressure
[Risk end-organ damage (cerebrovascular accident, AKI);
[BP lability; [reinfarction/ischemia; orthostatic hypotension;
[HF; [pulmonary edema
LV diastolic function [LA size; Yearly passive LV �lling; [late LV �lling and
[LV EDP; [PA pressure
[Risk AF; ([pulmonary edema/YCO), [DOE; [pulmonary edema
with [HR/[BP
YResponse to beta-
adrenergic stimulation
YHR/Yinotropic responsiveness to stress; resting systolic LV
function unchanged with age
Hypotension, HF, YHR response
Conduction system changes YSinus node cells; YAV conduction; [LBBB; and [RBBB Dif�cult to interpret electrocardiographic MI/ischemia; [heart
block; SSS; [SVT, [sensitivity to conduction system drugs
YVolume regulating
hormones
YNa, K, and water regulation—BP lability Altered electrolytes, [sensitivity to �uid therapy/diuretics
Renal changes YGFR (0.8 mL/min/y), YNa/K clearance, normal serum
creatinine despite moderate to severe CKD, altered drug
clearance; Yurine concentrating ability
CrCl or eGFR must be calculated for drug dosing, [sensitivity
to contrast nephropathy, [risk AKI
Fat-muscle redistribution [Third spacing of �uid, may alter drug storage; YVO
2max
May alter �uid/drug dosing, decreased CO; DOE; early fatigability
YBaroreceptor sensitivity [BP lability Orthostatic hypotension, fall risk
Clotting factor/platelet
function/hemostasis
[Bleeding and clotting risk, [sensitivity to anticoagulants/
antithrombins
[Risk cerebrovascular accident/reinfarction/recurrent ischemia,
bleeding, thrombosis, PE, DVT; may alter drug dosing/
sensitivity;[stent thrombosis
AF indicates atrial �brillation; AKI, acute kidney injury; AV, atrioventricular; BP, blood pressure; CKD, chronic kidney disease; CO, cardiac output; CrCl, creatinine clearance; DBP,
diastolic blood pressure; DOE, dyspnea on exertion; DVT, deep vein thrombosis; EDP, end-diastolic pressure; eGFR, estimated glomerular �ltration rate; GFR, glomerular �ltration rate;
HF, heart failure; HR, heart rate; K, potassium; LA, left atrium; LBBB, left bundle-branch block; LV, left ventricular; LVH, left ventricular hypertrophy; MI, myocardial infarction; NA,
sodium; Na/K sodium and potassium clearance; NTSE-ACS, non–ST-elevation acute coronary syndrome; PA, pulmonary artery; PE, pulmonary embolism; RBBB, right bundle-branch
block, SBP, systolic blood pressure; SSS, sick sinus syndrome; SVT, supraventricular tachycardia; and VO
2max
, maximum oxygen consumption.
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TABLE D FREEDOM Trial: Key Outcomes at 2 Years and 5 Years After Randomization
Outcome
2y 5y
pValue*
PCI CABG PCI CABG
Number (%)
Primary composite† 121 (13.0) 108 (11.9) 200 (26.6) 146 (18.7) 0.005‡
Death from any cause 62 (6.7) 57 (6.3) 114 (16.3) 83 (10.9) 0.049
MI 62 (6.7) 42 (4.7) 98 (13.9) 48 (6.0) <0.001
Stroke 14 (1.5) 24 (2.7) 20 (2.4) 37 (5.2) 0.03§
Cardiovascular death 9 (0.9) 12 (1.3) 73 (10.9) 52 (6.8) 0.12
*P values were calculated with the log-rank test on the basis of all available follow-up data (i.e., >5 y).
†The primary composite outcome was rate of death from any cause, MI, or stroke.
‡p¼0.006 in the as-treated (non–intention-to-treat) analysis.
§p¼0.16 by the Wald test of the Cox regression estimate for study-group assignment in 1,712 patients after adjustment for average glucose level after procedure.
CABG indicates coronary artery bypass graft; FREEDOM, Future Revascularization Evaluation in Patients With Diabetes Mellitus: Optimal Management of Multivessel Disease; MI,
myocardial infarction; and PCI, percutaneous coronary intervention.
Modi�ed with permission from Farkouh et al. (616).
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