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Use of Antithrombotics in Non-Valvular Atrial Fibrillation - Adult - Inpatient/Ambulatory

Use of Antithrombotics in Non-Valvular Atrial Fibrillation - Adult - Inpatient/Ambulatory - Clinical Hub, UW Health Clinical Tool Search, UW Health Clinical Tool Search, Clinical Practice Guidelines, Cardiovascular


1
Use of Antithrombotics in Non-Valvular
Atrial Fibrillation – Adult –
Inpatient/Ambulatory
Clinical Practice Guideline
Note: Active Table of Contents – Click to follow link
EXECUTIVE SUMMARY ........................................................................................ 3
SCOPE ................................................................................................................. 3
METHODOLOGY .................................................................................................. 4
DEFINITIONS ....................................................................................................... 5
INTRODUCTION .................................................................................................. 5
RECOMMENDATIONS ....................................................................................... 11
UW HEALTH IMPLEMENTATION ........................................................................ 20
APPENDIX A. EVIDENCE GRADING SCHEME(S) ................................................... 21
REFERENCES ...................................................................................................... 22
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Contact for Content:
Name: Anne Rose, PharmD; Anticoagulation Stewardship - Pharmacy
Phone Number: (608) 263-9738
Email Address: arose@uwhealth.org
Contact for Changes:
Name: Philip Trapskin, PharmD, BCPS; Drug Policy Manager - Pharmacy
Phone Number: (608) 265-0341
Email Address: ptrapskin@uwhealth.org
Guideline Author(s):
Christopher Hulstein, PharmD ± Pharmacy
Anne Rose, PharmD ± Pharmacy
Coordinating Team Members:
$QQH�2¶&RQQRU��0'�± Cardiology
Review Individuals/Bodies:
Inpatient Anticoagulation Committee ± May 2016
Ambulatory Anticoagulation Committee ± May 2016
Committee Approvals/Dates:
Pharmacy & Therapeutics Committee (Last Periodic Review: 06/16/2016)
Release Date: June 2016 | Next Review Date: July 2018
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Executive Summary
Guideline Overview
This document is intended to be used by primary care providers, cardiologists, hospitalists,
pharmacists, and nursing to guide the use of antithrombotics in adult patients diagnosed with
non-valvular atrial fibrillation (NVAF) in the inpatient, ambulatory and emergency department
settings. Guidance for transitioning between different anticoagulant agents is also included.
This guideline will review antithrombotics used in non-valvular AF and will aim to provide clinical
support in selecting an anticoagulant agent that is best suited based on individual patient needs
and risk factors.
Key Revisions (2016 Periodic Review)
1. Edoxaban has been added to 2016 update as a first-line oral anticoagulant.
2. CHADS2 Score has been removed from 2014 version. It is now recommended to utilize the
CHA2DS2VASc Score to determine necessity of anticoagulation.
Key Practice Recommendations
1. Oral anticoagulation should be initiated in patients with non-valvular AF with prior stroke,
transient ischemic attack (TIA), or a CHA2DS2-VASc score of 2 or greater.
2. Apixaban, dabigatran, edoxaban, rivaroxaban, and warfarin are all considered first-line
therapies.
3. Selection of an oral anticoagulant should be based on patient-specific factors such as renal
function, age, drug-drug interactions, and cost of therapy.
Companion Documents
1. Atrial Fibrillation Management ± Adult ± Inpatient/Ambulatory - CPG
2. ED Atrial Fibrillation Management Algorithm
3. Ambulatory Guideline for Management of Warfarin ± Adult ± Ambulatory - CPG
4. Inpatient Guideline for Management of Warfarin ± Adult ± Inpatient - CPG
5. Procoagulant Guideline ± Adult ± Inpatient ± CPG
6. Periprocedural Anticoagulation (Bridging) ± Adult ± Inpatient/Ambulatory ± CPG
Scope
Disease/Condition(s):
Non-valvular atrial fibrillation (AF)
Clinical Specialty:
Primary Care, Cardiology, Pharmacy, Nursing
Intended Users:
Advanced Practice Providers, Pharmacists, Physicians, Registered Nurses
Objective(s):
To minimize stroke incidence associated with non-valvular AF and minimize bleeding rates
associated with oral anticoagulation.
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Target Population:
Adult patients diagnosed with non-valvular AF in the inpatient, ambulatory and emergency
department settings.
Interventions and Practices Considered:
ξ This guideline recommends when to initiate oral anticoagulation in adult patients with
non-valvular AF based on stroke and bleeding risks
ξ This guideline provides recommendations for appropriate oral anticoagulation selection
based on patient-specific factors
Major Outcomes Considered:
ξ Stroke incidence in adult patients with non-valvular AF
ξ Incidence of major and minor bleeding events in adult patients with non-valvular AF
receiving oral anticoagulation for stroke prevention
Methodology
Methods Used to Collect/Select the Evidence:
Electronic database searches (e.g., PUBMED) were conducted by the guideline author(s) and
workgroup members to collect evidence for review. Expert opinion and clinical experience were
also considered during discussions of the evidence.
Methods Used to Formulate the Recommendations:
The workgroup members agreed to adopt recommendations developed by external
organizations and/or arrived at a consensus through discussion of the literature and expert
experience. All recommendations endorsed or developed by the guideline workgroup were
reviewed and approved by other stakeholders or committees (as appropriate).
Methods Used to Assess the Quality of the Evidence/Strength of the Recommendations:
Recommendations developed by external organizations maintained the evidence grade
assigned within the original source document and were adopted for use at UW Health.
Internally developed recommendations, or those adopted from external sources without an
assigned evidence grade, were evaluated by the guideline workgroup using an algorithm
adapted from the Grading of Recommendations Assessment, Development and Evaluation
(GRADE) methodology (see Figure 1 in Appendix A).
Rating Scheme for the Strength of the Evidence/Recommendations:
See Appendix A for the rating scheme(s) used within this document.
Cost Analysis:
Table 1 – Outpatient Cost Analysis – (AWP)
Medication Price per day ($)
Apixaban 5 mg $$$
Aspirin 81 mg $
Dabigatran 150 mg $$$
Edoxaban 60 mg $$$$
Rivaroxaban 20 mg $$$$
Warfarin 5 mg $
Where $ = $0.01-$1.00, $$ = $1.01-$5.00, $$$ = 5.01-$10.00, and $$$$ = $10.01-$15.00
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Recognition of Potential Health Care Disparities:
While warfarin is the least expensive medication, the cost for monitoring the INR should be
considered. Additionally, the availability of INR monitoring and access, including transportation,
to clinic facilities should be considered. DOACs may have medication assistance programs for
patients who qualify.
Definitions
ξ Creatinine Clearance1
o )RU�SDWLHQWV�ZLWK�D�%0,�”���NJ�P2, creatinine clearance should be calculated
using the Cockcroft-Gault formula
 Cockcroft-Gault should be calculated using adjusted body weight (ABW)
ξ ABW= 0.4 (TBW ± ideal body weight) + ideal body weight
o For patients with a BMI >30 kg/m2, creatinine clearance can be calculated using
either the Salazar-Corcoran or Cockcroft-Gault formulas
 Salazar-Corcoran should be calculated using total body weight (TBW)
ξ DOAC ± Direct Oral Anticoagulant (includes apixaban, dabigatran, edoxaban, and
ULYDUR[DEDQ���DOVR�NQRZQ�DV�³12$&´��1RYHO�2UDO�$QWLFRDJXODQW��DQG�³762$&´��7DUJHW-
Specific Oral Anticoagulant)
Introduction
Atrial fibrillation (AF) is the most common cardiac arrhythmia, and is responsible for one-third of
hospitalizations due to arrhythmia. Currently, AF affects 2.5 million people in the United States;
however, this percentage is expected to increase to an estimated 16 million people by the year
2050, due to the aJLQJ�³Eaby-ERRPHU´�SRSXODWLRQ�2 One of the most concerning sequelae
associated with AF is ischemic stroke, with an incidence of about 5% per year in the absence of
appropriate prophylaxis.3 Traditionally, dose-adjusted vitamin K antagonists, such as warfarin,
have been used to prevent the occurrence of stroke in intermediate-to-high risk AF patients.
However, the development of novel, more directed anticoagulants have been shown to produce
more predictable anticoagulation, do not require monitoring anticoagulation status, and have
demonstrated improvement in patient outcomes. This group of newer oral agents, referred to as
direct oral anticoagulants (DOACs), includes apixaban, dabigatran, edoxaban, and rivaroxaban.
In 2014, the American Heart Association/American College of Cardiology/Heart Rhythm Society
published the Guideline for the Management of Patients with Atrial Fibrillation.4 This guideline
recommends use of warfarin, apixaban, dabigatran, or rivaroxaban for anticoagulation in
patients with non-valvular AF with prior stroke, transient ischemic attack (TIA), or a CHA2DS2-
VASc score of 2 or greater. This recommendation did not include edoxaban as it was approved
after the 2014 guideline was published. Currently there are no direct comparisons among
DOACs, and the American Heart Association has not made a stance on selection of one DOAC
over another. It is accepted that any of the DOACs could be considered as first line therapy.3
Selection of oral anticoagulation, therefore, should be based on patient-specific factors such as
renal function, age, drug-drug interactions, and cost of therapy.4
Other guidelines that provide recommendations for the management of AF have also included
DOACs as considerations when oral anticoagulant therapy is indicated but have not listed them
as preferred agents at this time. This was often due to agents not being FDA approved at the
time of guideline update.5,6
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Antithrombotics used in non-valvular atrial fibrillation include: (listed alphabetically)
1. Apixaban7 is a direct, competitive, reversible factor Xa inhibitor. This inhibition decreases
the activation of platelets and the conversion of fibrinogen to fibrin, leading to a decreased
ability to form fibrin clots. It was studied versus warfarin in a randomized, double-blind trial
for the prevention of ischemic or hemorrhagic stroke or systemic embolism.8 Apixaban 5 mg
BID demonstrated significantly lower rates of stroke and systemic embolism than warfarin.
Additionally, apixaban showed lower rates of intracranial hemorrhage and all major bleeding
as compared to warfarin. Results of the ARISTOLE trial are summarized in Table 2 and
general drug information is summarized in Table 3.
Table 2 – Summarized results of apixaban versus warfarin in NVAF
Outcome (rate per year) Apixaban 5 mg BID Warfarin INR 2-3 P value
Stroke or embolism 1.27 1.6 0.01
Hemorrhagic stroke 0.24 0.47 <0.001
Major bleeding 4.07 6.01 <0.001
Intracranial hemorrhage 0.33 0.8 <0.001
GI bleeding 0.76 0.86 0.37
Mortality 3.5 3.9 0.047
Table 3 – Apixaban medication information
Usual Dose 5 mg BID (for dose adjustments see Table 14)
Onset 3-4 hours; Bioavailability is ~50%, and is not affected by food
Half Life 15 hours
Metabolism Hepatic
Predominantly via CYP3A4/5, with alternative pathways through CYP 1A2,
2C8, 2C9, 2C19, and 2J2 to inactive metabolites. Excreted through the urine
(~27% as parent drug), and feces (~25% as metabolites)
Adverse Drug
Reactions
Bleeding
Nausea
Anemia
Increased transaminases
Drug Interactions Strong CYP3A4 inhibitors (e.g. azole antifungals, nicardipine, ritonavir)
may increase the serum concentrations
Strong CYP3A4 inducers (e.g. carbamazepine, nafcillin, phenobarbital,
phenytoin, rifampin) may decrease serum concentrations
P-gp inhibitors (e.g. amiodarone, cyclosporine, ketoconazole, quinidine,
verapamil) may increase the serum concentration
P-gp inducers (e.g. carbamazepine, dexamethasone, phenytoin, prazosin,
rifampin) may decrease the serum concentration
Black Boxed Warning Increased risk of ischemic events when stopped without adequate
anticoagulation with an alternative agent
Epidural or spinal hematomas may occur in those who are receiving neuraxial
anesthesia or are undergoing spinal puncture.
Contraindication Active bleeding, Hypersensitivity to apixaban
Major regional or lumbar block analgesia
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7
2. Aspirin non-selectively and irreversibly inhibits cyclooxygenase, reducing prostaglandin and
thromboxane A2 synthesis. This produces analgesic, anti-inflammatory, and anti-pyretic
effects, and reduces platelet aggregation.
2.1 Usual dose of aspirin is between 81 and 325 mg per day to prevent stroke in low risk
patients with AF
2.2 Time to peak serum concentration is ~1-2 hours
2.3 Metabolism is via hydrolysis to salicylate (active form) by esterases in the GI mucosa,
red blood cells, synovial fluid; metabolism occurs by hepatic conjugation
2.4 Adverse drug reactions include dyspepsia, nausea, and bleeding events
2.5 Contraindicated in patients with hypersensitivity to salicylates, rhinitis, nasal polyps,
inherited or acquired bleeding disorders, or in patients <16 years of age for viral
infections
3. Dabigatran etexilate9 is an oral prodrug that is rapidly converted by serum esterases to
dabigatran, direct, competitive inhibitor of both free and fibrin-bound thrombin (factor II). It
was studied versus warfarin in a randomized, blinded treatment arm trial for prevention of
stroke or systemic embolism in NVAF.10 Dabigatran 150 mg BID demonstrated lower rates
of stroke and embolism with a similar major bleeding rate to warfarin. Additionally,
dabigatran has significantly lower rates of intracranial hemorrhage but higher rate of GI
bleeding as compared to warfarin. Results of the RE-LY trial are summarized in Table 4 and
general drug information is summarized in Table 5.
Table 4 – Summarized results of dabigatran versus warfarin in NVAF
Outcome (rate per year) Dabigatran 150 mg BID Warfarin INR 2-3 P value
Stroke or embolism 1.11 1.69 <0.001
Hemorrhagic stroke 0.10 0.38 <0.001
Major bleeding 3.11 3.36 0.31
Intracranial hemorrhage 0.3 0.7 <0.001
GI bleeding 1.51 1.02 <0.001
Mortality 3.64 4.13 0.13
Table 5 – Dabigatran medication information
Usual Dose 150 mg BID (for dose adjustments see Table 14)
Onset 1 hour; May be delayed 2 hours by food
Half Life Half-life is generally 12-17 hours; increased in elderly (14-17 hours), mild-to-
moderate renal impairment (15-18 hours), and severe renal impairment (28
hours).
Metabolism Hepatic glucuronidation to active acylglucoronide isomers, and is excreted
through the urine (80%)
Adverse Drug Reaction Bleeding
Dyspepsia
Anemia
Increased ALT
Drug Interactions P-gp inhibitors (e.g. amiodarone, cyclosporine, ketoconazole, quinidine,
verapamil) may increase serum concentrations
P-gp inducers (e.g. carbamazepine, dexamethasone, phenytoin, prazosin,
rifampin) may decrease the serum concentration
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Black Boxed Warning Increased risk of ischemic events when stopped without adequate
anticoagulation with an alternative agent
Epidural or spinal hematomas may occur in those who are receiving neuraxial
anesthesia or are undergoing spinal puncture.
Contraindication Active bleeding
Hypersensitivity to dabigatran
Major regional or lumbar block analgesia
Mechanical prosthetic heart valves.
4. Edoxaban11 is a direct, competitive, reversible factor Xa inhibitor. This inhibition decreases
the activation of platelets and the conversion of fibrinogen to fibrin, leading to a decreased
ability to form fibrin clots. It was studied versus warfarin in a randomized, double-blind,
double-dummy trial for the prevention of stroke or systemic embolism in NVAF.12 Edoxaban
60 mg daily was non-inferior to warfarin in regards to prevention of stroke and systemic
embolism. Edoxaban showed significantly less major bleeding and intracranial
hemorrhages, however, had higher incidence of GI bleeding when compared to warfarin.
Results of the ENGAGE-AF trial are summarized in Table 6 and general drug information is
summarized in Table 7.
Table 6 – Summarized results of edoxaban versus warfarin in NVAF
Outcome (rate per year) Edoxaban 60 mg daily Warfarin INR 2-3 P value
Stroke 1.49 1.69 0.11
Hemorrhagic Stroke 0.26 0.47 <0.001
Systemic Embolism 0.08 0.12 0.19
Major bleeding 2.75 3.43 <0.001
Intracranial hemorrhage 0.39 0.85 <0.001
GI bleeding 1.51 1.23 0.03
Table 7 – Edoxaban medication information
Usual Dose 60 mg daily (for dose adjustments see Table 14)
Onset 1 -2 hours
Half Life 10 ± 14 hours
Metabolism Approximately 50% of the drug is renally eliminated.
Adverse Drug Reaction Bleeding events
Anemia
Abnormal hepatic function tests
Drug Interactions Strong CYP3A4 inhibitors (e.g. azole antifungals, nicardipine, ritonavir) may
increase serum concentrations
Strong CYP3A4 inducers (e.g. carbamazepine, nafcillin, phenobarbital,
phenytoin, rifampin) may decrease serum concentrations. Use of edoxaban
with rifampin should be avoided
P-gp inhibitors (e.g. amiodarone, cyclosporine, ketoconazole, quinidine,
verapamil) may increase serum concentrations, but dose adjustment is not
recommended
P-gp inducers (e.g. carbamazepine, dexamethasone, phenytoin, prazosin,
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9
rifampin) may decrease serum concentrations. Use of edoxaban with rifampin
should be avoided
Black Boxed Warning CrCl > 95 mL/min: reduced efficacy in NVAF
Increased risk of ischemic events when stopped without adequate
anticoagulation with an alternative agent
Epidural or spinal hematomas may occur in those who are receiving neuraxial
anesthesia or are undergoing spinal puncture.
Contraindication Active pathological bleeding
5. Rivaroxaban13 is a direct, competitive, reversible Factor Xa inhibitor. This inhibition
decreases the activation of platelets and the conversion of fibrinogen to fibrin, leading to a
decreased ability to form fibrin clots. It was studied versus warfarin in a randomized, double
blind, double dummy clinical trial for the prevention of stroke and embolism in NVAF.14
Rivaroxaban 20 mg daily demonstrated non-inferiority to warfarin in the prevention of stroke
and embolism with a similar major bleeding rate to warfarin. Additionally, rivaroxaban
showed significantly lower rates of intracranial hemorrhage but higher rate of GI bleeding as
compared to warfarin. Results of the ROCKET-AF trial are summarized in Table 8 and
general drug information is summarized in Table 9.
Table 8 – Summarized results of rivaroxaban versus warfarin in NVAF
Outcome (rate per year) Rivaroxaban 20 mg daily Warfarin INR 2-3 P value
Stroke or embolism 1.7 2.2 <0.001
Hemorrhagic stroke 0.10 0.38 <0.001
Major bleeding 14.9 14.5 0.44
Intracranial hemorrhage 0.5 0.7 0.02
GI bleeding 3.2 2.2 <0.001
Table 9 – Rivaroxaban medication information
Usual Dose 20 mg daily with evening meal (for dose adjustments see Table 14)
Onset 2-4 hours
Half Life 5-12 hours; increased in elderly (11-19 hours)
Metabolism Primarily hepatic, via CYP3A4/5 and CYP2J2, and is excreted through the
urine (66% via tubular secretion), feces (28%)
Adverse Drug Reaction bleeding events, peripheral edema, back pain, and rash
Drug Interactions Strong CYP3A4 inhibitors (e.g. azole antifungals, nicardipine, ritonavir) may
increase serum concentrations
Strong CYP3A4 inducers (e.g. carbamazepine, nafcillin, phenobarbital,
phenytoin, rifampin) may decrease serum concentrations
P-gp inhibitors (e.g. amiodarone, cyclosporine, ketoconazole, quinidine,
verapamil) may increase serum concentrations
P-gp inducers (e.g. carbamazepine, dexamethasone, phenytoin, prazosin,
rifampin) may decrease the serum concentrations
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Black Boxed Warning Increased risk of ischemic events when stopped without adequate
anticoagulation with an alternative agent
Epidural or spinal hematomas may occur in those who are receiving neuraxial
anesthesia or are undergoing spinal puncture.
Contraindication Active bleeding
Hypersensitivity to rivaroxaban
Major regional or lumbar block analgesia
6. Warfarin competitively inhibits vitamin K epoxide reductase complex 1, which is the enzyme
responsible for reactivating vitamin K in the human body. Vitamin K is required to produce
clotting factors II, VII, IX and X, which are major factors involved in clot formation. This
inhibition by warfarin depletes the amount of functional vitamin K, and in turn decreases the
levels of clotting factors in the body. Table 10 summarized general drug information on
warfarin.
Table 10 – Warfarin medication information
Usual Dose Dosing based on INR range (typically 2-3).
Usual starting dose 5 mg
May consider 2.5 mg for elderly, hepatic impairment, poor nutrition, heart
failure, high bleeding risk, CYP2C9 slow metabolizers.
Onset 5-7 days of consistent dosing for full therapeutic effect.
Half Life 7 days
Metabolism Primarily hepatic via CYP2C9, with some minor pathways through CYP 2C8,
2C18, 2C19, 1A2, and 3A4
Adverse Drug Reaction Bleeding events
Less commonly hepatitis, skin necrosis, and ³SXUSOH�WRH´�V\QGURPH
Drug Interactions Strong CYP3A4 inhibitors (e.g. azole antifungals, nicardipine, ritonavir) may
increase serum concentrations
Strong CYP3A4 inducers (e.g. carbamazepine, nafcillin, phenobarbital,
phenytoin, rifampin) may decrease serum concentrations
P-gp inhibitors (e.g. amiodarone, cyclosporine, ketoconazole, quinidine,
verapamil) may increase serum concentrations
P-gp inducers (e.g. carbamazepine, dexamethasone, phenytoin, prazosin,
rifampin) may decrease the serum concentrations
Increased bleed risk
Black Boxed Warning Can cause major or fatal bleeding.
Contraindication Pregnancy
Hypersensitivity to warfarin
Hemorrhagic tendencies or blood dyscrasias
Recent or contemplated surgery of the CNS
Traumatic surgery resulting in large open surfaces
Spinal puncture or other procedures with the potential for uncontrollable
bleeding
Major regional or lumbar block analgesia
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Recommendations
Recommendations for Determining if Anticoagulation is Necessary
1. (YDOXDWH�WKH�SDWLHQW¶V�VWURNH�ULVN�XVLQJ�ULVN�DVVHVVPHQt strategy provided in Table 11
and the estimated yearly risk of stroke in Table 12 (AHA Class I, Level B)3,15
1.1 The CHA2DS2VASc Score incorporates additional risk factors for stroke. While it
is not as well validated as the CHADS2 Score, it has been validated in AF
populations and has been shown to dependably identify low risk patients who do
not need anticoagulation. The CHA2DS2VASc Score is the preferred risk
assessment strategy.4
Table 11 – CHA2DS2VASc Score16
Factors Points
Congestive Heart Failure 1
Hypertension 1
AJH�•�� 2
Diabetes Mellitus 1
Stroke/TIA/Thromboembolism 2
Vascular Disease
(MI, PAD, aortic plaque) 1
Age 65-74 1
Sex Category ± Female 1
Score:
0 = No antithrombotic therapy preferred
1 = Oral anticoagulation may be considered*
> 2 = Oral anticoagulation preferred
*if score of 1 from gender alone then no antithrombotic therapy preferred
Table 12 – Adjusted Yearly Stroke Risk for CHA2DS2VASc Scores
Score CHA2DS2VASc (%/year)
0 0
1 1.3
2 2.2
3 3.2
4 4
5 6.7
6 9.8
7 9.6
8 6.7
9 15.2
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2. (YDOXDWH�WKH�SDWLHQW¶V�EOHHGLQJ�ULVN using the HAS-BLED risk assessment strategy
outlined in Table 13. (AHA Class I, Level C)17
2.1 The HAS-BLED score stratifies patients as low, moderate, or high bleeding risk
based on individual bleeding risk factors. It has been shown to more accurately
predict the risk of major bleeding in patients receiving no antithrombotic or
antiplatelet therapy than another bleeding risk score, HEMORR2HAGES.
2.2 This score should not automatically exclude patients from receiving anticoagulation if
it is clinically indicated, particularly since many of the risk factors that may
predispose patients to a bleeding event are also risk factors that increase their risk
for stroke.
2.3 The HAS-BLED score should be used to identify risk factors for bleeding, and
attempts should be made to correct modifiable risks, such as uncontrolled
hypertension.18
Table 13 – HAS-BLED Score17
Factors Scoring
Hypertension (SBP >160 mmHg)
Score = 0-1: Low risk
Score = 2: Moderate risk
Score ≥3: High risk
High bleed risk considerations:
- Optimize blood pressure
control
- Check INRs frequently
- Utilize anticoagulation clinic
- Focus on fall prevention
- Utilize DOACs
Abnormal lab values
- Creatinine >2.26 mg/dL
- Bilirubin >2x the upper limit of normal
(ULN) and AST/ALT/AP >3x ULN
Stroke history
Bleeding history or predisposition
Labile INRs: Time in Therapeutic Range <60%
Elderly: >65 years
Drugs
- EtOH abuse
- ASA or NSAID use
Recommendations for Appropriate Anticoagulation Selection
Prior to initiating anticoagulation therapy the benefits and risks of anticoagulation should be
discussed with the patient, being sure to incorporate their priorities in the decision making
process. When anticoagulation has been identified as the therapy of choice to prevent ischemic
stroke in AF, selection of the most appropriate agent should be individualized based on both
clinical evidence and patient specific risk factors. (AHA Class I, Level C)
3. Oral Anticoagulation
3.1 Warfarin (AHA Class I, Level A)or a DOAC (AHA Class I, Level B) may be
considered. Prior to selecting an oral anticoagulant see #4 to develop an
individualized patient therapy plan (AHA Class I, Level C)
3.2 Currently, there are no trials that directly compare one DOAC to another.
4. Additional considerations to evaluate:
4.1 Prosthetic Heart Valves or Severe Valvular Disease
4.1.1 Warfarin is recommended with mechanical heart valves. Target INR
intensity should be based on the type and location of prosthesis4 (AHA
Class I, Level B)
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13
4.1.2 Dabigatran is contraindicated and should not be used in patients with AF
and mechanical heart valves.3,5,9 (AHA Class III: Harm, Level B)
4.1.3 Due to the lack of data, factor Xa inhibitors (apixaban, edoxaban,
rivaroxaban) should not be used in patients with AF and mechanical heart
valves. (AHA Class III: No Benefit, Level C)
4.2 Renal Function (AHA Class I, Level B)
4.2.1 Recommendations for dose reductions for each agent in renal insufficiency
should be followed. See Table 14.
4.2.2 CrCl < 15 mL/min not on hemodialysis: warfarin is the preferred agent
4.2.3 End stage kidney disease on dialysis: warfarin is preferred, but apixaban
may be considered
4.2.4 CrCl > 95 mL/min: edoxaban is not recommended
4.3 Age (UW GRADE moderate quality of evidence, conditional recommendation)
4.3.1 Age > 75 years: There was a trend towards increased risk of bleeding with
dabigatran when compared to warfarin.19
4.3.2 This trend was not observed with other DOACs8,20,21
4.4 History of GI disease and/or GI bleeding in the past year (UW GRADE moderate
quality of evidence, conditional recommendation)
4.4.1 Dabigatran, edoxaban, and rivaroxaban have been associated with an
increased risk of GI bleeding events as compared to warfarin and the other
DOACs10,20,21
4.4.2 Apixaban was shown to have a lower risk of GI bleeding compared to
warfarin8
4.4.3 Dyspepsia is also strongly associated with dabigatran use
4.5 Combination Antiplatelet Therapy (UW GRADE low quality of evidence,
conditional recommendation)
4.1 The addition of an antiplatelet to anticoagulant therapy can significantly
increase bleeding risk. Bleeding risk compared to stroke risk must be
weighed when using concomitant therapy.
4.2 “Triple therapy” (Aspirin, P2Y12 agents, & anticoagulant) or higher dose
aspirin (> 100 mg) and anticoagulant should be avoided if possible or if
not possible to avoid then duration of therapy should minimized4
4.3 If triple therapy is warranted, it is strongly recommended to obtain a
cardiology consult.
4.6 Drug Interactions (UW GRADE moderate quality of evidence, conditional
recommendation)
4.6.1 Warfarin has many documented drug interactions to consider. Closely
following the INR can help to monitor the effects of the drug interactions.
4.6.2 There are less documented drug interactions with DOACs, however, it is
not possible to monitor for increased or decreased effectiveness in the
presence of an interacting agent.
4.7 Monitoring (UW GRADE moderate quality of evidence, conditional
recommendation)
4.7.1 DOACs do not require laboratory monitoring of anticoagulation status and
may be preferred in patients who dislike frequent lab draws.
4.7.2 DOACs should have laboratory monitoring of CBC, creatinine, and liver
function tests at baseline, after 3-6 months of therapy and then at least
once a year.
4.7.3 Warfarin requires laboratory monitoring of the INR. The INR should be
checked at least twice weekly during initiation and monthly when stable.
This agent may be less preferable in patients who do not have the means
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14
or access to commit to intensive laboratory monitoring (AHA Class I, Level
A)
4.8 Financial Considerations (UW GRADE very low quality of evidence, conditional
recommendation)
4.8.1 While warfarin is the least expensive medication, the cost for monitoring the
INR should also be considered.
4.8.2 DOACs may have medication assistance programs for patients who qualify.
4.9 Medication Compliance (UW GRADE moderate quality of evidence, conditional
recommendation)
4.9.1 DOACs may be less preferable in patients who occasionally miss doses, as
the duration of action is shorter than warfarin. One missed dose of these
agents may place a patient at risk for stroke.
4.9.2 Warfarin may be less preferable in patients who are consistently non-
compliant with doses if the target INR goal is rarely achieved. DOACs are
recommended if unable to maintain a therapeutic INR on warfarin4 (AHA
Class I, Level C)
4.9.3 If once daily regimens are preferred consider edoxaban, rivaroxaban, or
warfarin.
4.9.4 If pill boxes or medication organizers are used to improve compliance, then
dabigatran must be dispensed in sealed blister-packs. If stored in open air,
it can compromise the effectiveness of the medication.
4.10 Administration (UW GRADE moderate quality of evidence, strong
recommendation)
4.10.1 Dabigatran capsules must be swallowed whole.9
4.10.2 Apixaban, rivaroxaban, and warfarin may be crushed7,13
5.10.2.1 There is no data available on crushing edoxaban
4.10.3 Rivaroxaban cannot be administered via a feeding tube placed distal to the
stomach13
4.10.4 Rivaroxaban should be administered with evening meal13
5.10.4.1 Though package labeling indicates the evening meal specifically,
the largest meal of the day may be considered
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Algorithm to Assist in Selecting Anticoagulation
*Avoid use of edoxaban if creatinine clearance is greater than 95 mL/min
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Table 14 – Anticoagulant Dosing Table7,9,11,13
Drug Dosing Monitoring Drug Interactions
CrCl (mL/min) Dose
Apixaban
Factor Xa inhibitor
•�� 5 mg BID
2.5 mg BID with concomitant
use of strong CYP3A4 and P-
gp inhibitors
2.5 mg BID if 2 of the following:
- DJH�•���\HDUV
- ERG\�ZHLJKW�”���NJ
- 6&U�•����PJ�G/
No routine monitoring is needed to
determine anticoagulation status.
Recommend baseline and annual
creatinine, CBC, AST/ALT/AP
Strong CYP3A4 or P-gp
inhibitors may increase serum
concentrations
Strong CYP3A4 or P-gp
inducers may decrease serum
concentrations
<15 (on HD) 5 mg BID
2.5 mg BID if either:
- DJH�•���\HDUV
- ERG\�ZHLJKW�”���NJ
<15 (not on HD) Avoid use
Aspirin
COX-inhibitor
Any 81 mg once daily No routine monitoring is needed to
determine anticoagulation status
Use in combination with other
antithrombotic agents may
increase the risk of bleeding
Dabigatran
Direct thrombin inhibitor
>30 150 mg BID
75 mg BID with concomitant
use of
P-gp inhibitor
No routine monitoring is needed to
determine anticoagulation status.
Recommend baseline and periodic
creatinine, CBC, AST/ALT/AP
P-gp inhibitors may increase
serum concentrations
P-gp inducers may decrease
serum concentrations
15-30 75 mg BID
Avoid use if concomitant use of
P-gp inhibitor
<15 Avoid use
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Table 14 – Anticoagulant Dosing Table (continued)
Edoxaban
Factor Xa inhibitor
>95 Avoid use No routine monitoring is needed to
determine anticoagulation status
Recommend baseline and annual
creatinine, CBC, AST/ALT/AP
Strong CYP3A4 or P-gp
inhibitors may increase serum
concentrations.
Strong CYP3A4 or P-gp
inducers may decrease serum
concentrations.
50-95 60 mg once daily
15-50 30 mg once daily
<15 Avoid use
Rivaroxaban
Factor Xa inhibitor
>50 20 mg once daily No routine monitoring is needed to
determine anticoagulation status.
Recommend baseline and annual
creatinine, CBC, AST/ALT/AP
Strong CYP3A4 or P-gp
inhibitors may increase serum
concentrations
Strong CYP3A4 or P-gp
inducers may decrease serum
concentrations
15-50 15 mg once daily
<15 Avoid use
Warfarin
Vitamin K Antagonist
Any Dose varies based on patient-
specific factors
A baseline INR prior to initiation
CBC, ALT, total bilirubin, and
creatinine within the preceding
3 months, and periodically
thereafter
Refer to the inpatient or
ambulatory warfarin guidelines for
INR monitoring
Refer to Table 5 in the inpatient
warfarin guideline, or Tables 10
and 11 in the ambulatory
warfarin guidelines for drug
interaction information
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Table 15 – Anticoagulant Transitioning7,9,11,13
Switch Procedure
Warfarin  Dabigatran Stop warfarin, start dabigatran when INR <2.0
Warfarin  Rivaroxaban Stop warfarin, start rivaroxaban when INR <3.0
Warfarin  Apixaban Stop warfarin, start apixaban when INR <2.0
Warfarin  Edoxaban 6WRS�ZDUIDULQ��VWDUW�HGR[DEDQ�ZKHQ�,15�”���
Dabigatran  Warfarin Dabigatran affects the INR – measuring INRs during co-administration may not be useful for
determining an appropriate dose of warfarin
ξStart warfarin while patient is still taking dabigatran
ξStop dabigatran 1-3 days later, depending on INR and CrCl
ξIf CrCl >50 mL/min: initiate warfarin 3 days prior to discontinuation of dabigatran
ξIf CrCl 31-50 mL/min: initiate warfarin 2 days before discontinuation of dabigatran
ξIf CrCl 15-30 mL/min: initiate warfarin 1 day before discontinuation of dabigatran
Rivaroxaban  Warfarin Rivaroxaban affects the INR – measuring INRs during co-administration may not be useful for
determining an appropriate dose of warfarin
ξInitiate warfarin and a parenteral anticoagulant 24 hours after discontinuation of rivaroxaban*
Apixaban  Warfarin Apixaban affects the INR – measuring INRs during co-administration may not be useful for determining
an appropriate dose of warfarin
ξIf continuous anticoagulation is necessary, discontinue apixaban and begin both a parenteral
anticoagulant with warfarin when the next dose of apixaban is due; discontinue parenteral
anticoagulant when INR reaches an acceptable range*
Edoxaban  Warfarin Oral option:
ξ For patients receiving 60 mg of edoxaban, reduce dose to 30 mg and begin warfarin
concomitantly. For patients receiving 30 mg of edoxaban, reduce the dose to 15 mg and begin
warfarin concomitantly.
ξ INR must be measured at least weekly and just prior to the daily dose of edoxaban to minimize
the influence of edoxaban on INR measurements. Once a stable INR •��LV�DFKLHYHG��HGR[DEDQ
should be discontinued and the warfarin continued.
Parenteral option:
ξ Discontinue edoxaban and administer a parenteral anticoagulant (UFH or enoxaparin) and
warfarin at the time of the next scheduled edoxaban dose. Once a stable ,15�•��LV�DFKLHYHG�
edoxaban should be discontinued and warfarin continued.
UFH  DOAC ξ Start dabigatran, rivaroxaban, or apixaban at the time of heparin discontinuation
ξ Start edoxaban 4 hours after heparin discontinuation
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Table 15 – Anticoagulant Transitioning (continued)7,9,11,13
DOAC  IV UFH or
enoxaparin
Dabigatran:
ξIf CrCl >30 mL/min, start UFH or enoxaparin 12 hours after the last dose of dabigatran
ξIf CrCl <30 mL/min, consider starting UFH or enoxaparin 24 hours after the last dabigatran dose,
based on the clinical interpretation of the patients bleeding and thrombosis risk
Rivaroxaban:
ξStart UFH or enoxaparin 24 hours after the last rivaroxaban dose, based on the clinical
interpretation of the patients bleeding and thrombosis risk
Apixaban:
ξStart UFH or enoxaparin 12 hours after the last apixaban dose
Edoxaban:
ξStart UFH or enoxaparin at the time of the next dose of edoxaban
2YHUDOO�ULVN�VWUDWLILFDWLRQ�VKRXOG�IRFXV�RQ�WKH�SDWLHQW¶V�ULVN�RI�WKURPERHPEROLVP�VLQFH�WKH�FRQVHTXHQFHV�RI�D�WKURPERHPEROLF event
are more likely to have serious, lasting effects compared to consequences of major bleeding. It is recommended to provide
continuous therapeutic anticoagulation for patients with a recent stroke or TIA (within 3 months). Note that not all patients will require
bridging with a parenteral anticoagulant.
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UW Health Implementation
Potential Benefits:
ξ The benefit of this guideline is to identify appropriate use of DOACs and warfarin for
adult patients diagnosed with non-valvular atrial fibrillation, who are at an intermediate-
to-high risk of stroke.
Potential Harms:
ξ The risk of implementing this guideline and administering anticoagulant agents is
increased bleeding and can be related to underlying conditions, age, comorbidities, and
dose.
Qualifying Statements:
ξ The amount of data available is small and recent guidelines are based on few trials. The
recommendations included in this guideline are subject to change with the publication of
additional clinical trials.
Patient Resources
1. Health Facts For You #6252- Atrial Fibrillation
2. Health Facts For You #6900- Warfarin (Coumadin, Jantoven)
3. Health Facts For You #7826- Direct Oral Anticoagulants
4. Health Facts For You #6115- Stopping Anticoagulation and Antiplatelet Therapy for Patients
and Providers
5. Healthwise: Atrial Fibrillation
Guideline Metrics
1. Stroke Core Measure #3: Anticoagulation therapy for atrial fibrillation/flutter
2. Incidence of stroke in adult patients with non-valvular AF
3. Incidence of major and minor bleeding events in adult patients with non-valvular AF
receiving oral anticoagulation for stroke prevention
Implementation Plan/Clinical Tools.
1. Guideline will be posted on uConnect in a dedicated location for Clinical Practice Guidelines.
2. Release of the guideline will be advertised in the Physician/APP Briefing newsletter.
3. Content and hyperlinks within clinical tools, documents, or Health Link related to the
guideline recommendations (such as the following) will be reviewed for consistency and
modified as appropriate.
4. Education on this guideline will be distributed to ambulatory care providers, nurses and
pharmacists through publication of the Anticoagulation Newsletter. Recommendations will
be included in the development of an atrial fibrillation order set and imbedded into an
electronic clinical assessment tool for providers.
Disclaimer
Clinical practice guidelines assist clinicians by providing a framework for the evaluation and
treatment of patients. This guideline outlines the preferred approach for most patients. It is not
LQWHQGHG�WR�UHSODFH�D�FOLQLFLDQ¶V�MXGJPHQW�RU�WR�HVWDEOLVK�D�SURWRFRO�IRU�DOO�SDWLHQWV��,W�LV�
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.
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Appendix A. Evidence Grading Scheme(s)
Figure 1. GRADE Methodology adapted by UW Health
GRADE Ranking of Evidence
High We are confident that the effect in the study reflects the actual effect.
Moderate We are quite confident that the effect in the study is close to the true effect, but it is also
possible it is substantially different.
Low The true effect may differ significantly from the estimate.
Very Low The true effect is likely to be substantially different from the estimated effect.
GRADE Ratings for Recommendations For or Against Practice
Strong The net benefit of the treatment is clear, patient values and circumstances are
unlikely to affect the decision.
Weak/conditional Recommendation may be conditional upon patient values and preferences, the
resources available, or the setting in which the intervention will be implemented.
Figure 2. GRADE Methodology developed by the American Heart Association and
American College of Cardiology Foundation22
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