Atrial fibrillation

Balanced information for better care
Atrial fibrillation
Anticoagulation: a key strategy
Slow(er), even if not steady, wins the race
Atrial fibrillation increases the risk of stroke
and other important clinical outcomes
FIGURE 1. Patients with AF have increased morbidity and mortality compared to patients
of the same age without AF.1,2
5x
Increased risk in AF Patients
3x
2x
DEATH
HEART FAILURE
STROKE
AF affects more than 5 million people in the US, particularly the elderly.3
FIGURE 2. The prevalence of AF increases sharply with age.4
12
Women
Men
Prevalence, %
10
8
6
4
2
0
< 55
55-59
60-64
65-69
70-74
Age
2
Atrial Fibrillation
75-79
80-84
> 85
Anticoagulation dramatically reduces
the risk of stroke in AF
Older patients with AF benefit more from anticoagulation.
FIGURE 3. Reduction in stroke risk with anticoagulation increases with age.5
< 65 years
65-74 years
75-84 years
> 85 years
8%
38%
55%
61%
Relative stroke reduction with anticoagulation
Balance the risks and benefits of anticoagulation therapy.
FIGURE 4. While anticoagulation decreases the risk of stroke, it increases the risk of
bleeding. These factors must be weighed when selecting anticoagulation therapy.
Bleeding risk
Stroke risk
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Estimate the need for treatment.
CHA 2DS2-VASc is a powerful predictor
of stroke in AF
TABLE 1. The CHA 2DS2 -VASc score is based on readily available clinical characteristics.6
Letter
Characteristic
Points (if yes)
C
congestive heart failure*
1
H
hypertension
1
A
age ≥ 75 years
2
D
diabetes
1
S
stroke, TIA, or thromboembolism
2
V
vascular disease**
1
A
age 65-74 years
1
S
sex: female
1
Maximum 9 points
* Congestive heart failure: left ventricle ejection fraction ≤ 40
**Vascular disease: myocardial infarction, peripheral vascular disease, or aortic plaque
FIGURE 5. Stroke risk with and without anticoagulation.7 Both the risk of stroke and the
Stroke rate, % per year
benefit of anticoagulation go up sharply with CHA 2DS2 -VASc score.
14
Anticoagulation
12
No anticoagulation
i 6.7%
7
8
i 4.0%
8
6
i 2.6%
i 1.8%
4
0
i 6.1%
i 5.3%
10
2
i 6.1%
i 1.2%
i 0.1%
i 0.3%
0
1
2
3
4
5
6
9
CHA2DS2 —VASc score
At every CHA2DS2-VASc score, anticoagulation reduces the risk of stroke by about half.
4
Atrial Fibrillation
Estimate the risk of treatment.
The HAS-BLED score helps predict the risk
of bleeding with anticoagulation
TABLE 2. HAS-BLED is based on common patient characteristics.8
Letter
Parameter
Points (if yes)
H
hypertension (>160 mmHg systolic)
A
abnormal renal and/or liver function (1 point each)*
S
stroke
1
B
bleeding history
1
L
labile INRs** (time in therapeutic range < 60%)
1
E
elderly (age ≥ 65 years)
1
D
drugs or alcohol (1 point each)+
1
1 or 2
1 or 2
Maximum 9 points
* Abnormal renal function: Cr >2.26 md/dL, dialysis, or renal transplant. Abnormal liver function:
cirrhosis or total bilirubin > 2x upper limit of normal, with ALT/AST/AP > 3x upper limit of normal
**This score was developed for patients on warfarin, but it generally applies to other anticoagulants as well.
+
Drugs: antiplatelet agents, nonsteroidal anti-inflammatories; Alcohol: ≥ 8 drinks per week
Risk of major bleed, % per year
FIGURE 6. Major bleeding risk increases sharply with increasing HAS-BLED score.8
14
13%
12
10
9%
8
6
4%
4
2
0
1%
1%
0
1
2%
2
3
4
5+
HAS-BLED score
Major bleeding is defined as bleeding requiring hospitalization, causing a decrease in hemoglobin
of > 2 g/L, and/or requiring blood transfusion that was not hemorrhagic stroke.
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Balance CHA 2DS2-VASc and HAS-BLED
scores to select anticoagulation therapy
FIGURE 7. Guidance to help choose best anticoagulation options.7,9,10
Annual bleeding
risk on anticoag.
HAS-BLED
score
≥ 8%
≥4
4%
3
2%
2
1%
1
CHA2DS2-VASc
Absolute risk reduction
with anticoagulation
Recommended treatment
0
1
2
3
4
5
≥6
0.2%
0.5%
2%
3%
4%
6%
≥ 8%
No therapy
Novel oral anticoagulant (NOAC) or warfarin
See figure 8 below
Dose-reduced NOAC or warfarin with frequent INR monitoring
*Dose-reduced NOACs include rivaroxaban 15mg daily, apixaban 2.5mg BID, or edoxaban 30mg daily.
Dabigatran 75mg BID is FDA-approved but not tested in clinical trials.
**Patient factors such as creatinine clearance, weight and age, instead of HAS-BLED score,
may also warrant reduced-dose NOAC use.
FIGURE 8. Selecting anticoagulation in AF patients with a CHA 2DS2 -VASc score of 1
CHA2DS2-VASc score = 1
Does a patient have only one of the following:
•CHF
•hypertension
6
• age 65-74 years
•diabetes
YES
NO
Is patient agreeable to anticoagulation?
No anticoagulation therapy
for AF indicated
YES
NO
NOAC or warfarin
aspirin
Atrial Fibrillation
Stroke and bleeding risk with NOACs
FIGURE 9. Randomized trials have found NOACs to be at least as good or better than
warfarin in preventing strokes, with bleeding rates that are the same or lower.11-14
Relative risk compared to warfarin
dabigatran (Pradaxa)
Stroke
-34%**
Bleeding
-7%
-12%*
rivaroxaban (Xarelto)
4%
-21%**
apixaban (Eliquis)
-31%
†
* Non-inferior to warfarin
**Superior to warfarin
-13%*
edoxaban (Savaysa)
p < 0.001
†
-20%
†
-40
-30
-20
-10
0
NOAC better
10
20
warfarin better
FIGURE 10. In the NOAC trials, 38% of patients were ≥ 75 years of age. These patients
benefited more from NOACs compared to warfarin for preventing stroke and embolism,
with a similar risk of bleeding.10
Relative risk reduction from NOACs vs. warfarin
Age < 75 years
Age ≥ 75 years
7%*
Stroke/embolism
Major bleeding
15%
21%
22%
* 95% CI for relative risk crosses 1.0
In some trials, older patients with risk factors received reduced doses of NOACs.
• Overall, apixaban appears to have the best safety and benefit profile
of the NOACs compared to warfarin.
• Randomized clinical trials have found that compared to warfarin, all NOACs reduce
the risk of intracranial hemorrhage.
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Warfarin vs. the novel anticoagulants:
making the best choice
TABLE 3. Comparison of the NOACs and warfarin15
Mechanism
Dosing
frequency
Standard dose
Dose in renal
impairment+ Renal
contraindications
Other
considerations
dabigatran
rivaroxaban
apixaban
edoxaban
warfarin
Direct
thrombin
inhibitor
Direct factor
Xa inhibitor
Direct factor
Xa inhibitor
Direct factor
Xa inhibitor
Vitamin K
antagonist
Twice daily
Once daily
Twice daily
Once daily
Once daily
150 mg
20 mg
5 mg
60 mg
Based on INR
CrCl* 15-30:
75mg
CrCl 15-49:
15mg
Two of:
age ≥ 80,
weight ≤ 60 kg,
or SCr**
> 1.5: 2.5mg
CrCl 15-49:
30mg
No change
CrCl < 15
CrCl < 15
CrCl < 20 or
SCr > 2.5
CrCl < 15
or > 95
None
Can cause
dyspepsia—
consider PPI
Should be
taken with
evening meal
Do not use
in normal
renal function
Drug-diet
interactions;
Requires INR
monitoring
* CrCl: creatinine clearance; numbers are in mL/min
**SCr: serum creatinine; numbers are in mg/dL
+
Dosing reflects FDA labeling and may differ from inclusion criteria used in pivotal trials.
Patients may benefit from warfarin over NOACs if they:
• are taking warfarin with well-controlled INRs and are satisfied with the regimen
• have a contradiction to NOACs
• have severe or worsening renal impairment
• have mechanical heart valves
• are unable to afford NOAC copayments or deductibles
8
Atrial Fibrillation
Choosing rate control versus rhythm control
Lenient rate control may be the best approach for most patients,
but there are some for whom a different approach may be necessary.
PATIENT CHARACTERISTICS
FIGURE 11. Patient factors that determine whether it is better to control rate or rhythm16-18
• minimal symptoms
and normal
ventricular function
• symptomatic with
lenient rate control
LENIENT rate control
STRICT rate control
• reduced ventricular
function
• symptomatic
despite rate control
• cannot achieve
rate control
• younger age
RHYTHM control
Beta blockers and non-dihydropyridine calcium channel blockers are similarly effective
in controlling heart rate. Digoxin is less effective when used alone, but can be useful with
other medications.19,20
FIGURE 12. Managing rate control in AF
Target a resting heart rate of < 110 bpm using a beta-blocker, verapamil, or diltiazem.
Has goal HR been reached?
NO
Consider combining agents or adding digoxin.
Has goal HR been reached?
NO
Consider amiodarone or specialist referral.
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Prices of these regimens vary widely
FIGURE 13. Cost of a 30-day drug supply
Anticoagulants
apixaban (Eliquis) 10mg
$359
dabigatran (Pradaxa) 300mg
$386
edoxaban (Savaysa) 60mg
$292
rivaroxaban (Xarelto) 20mg
$378
warfarin (generic) 7.5mg
$24
warfarin (Coumadin) 7.5mg
$110
aspirin 325mg
$1
clopidogrel (generic) 75mg
$62
clopidogrel (Plavix) 75mg
$226
atenolol (generic) 75mg
$5
atenolol (Tenormin) 75mg
$272
carvedilol (generic) 37.5mg
$6
carvedilol (Coreg) 37.5mg
$327
carvedilol (Coreg CR) 40mg
$212
metoprolol (generic) 150mg
$6
metoprolol (Lopressor) 150mg
$174
Rate
metoprolol ER (generic) 150mg
$44
metoprolol ER (Toprol XL) 150mg
$104
diltiazem IR (generic) 240mg
$11
diltiazem ER (generic) 240mg
$25
diltiazem LA (Cardizem LA) 240mg
$146
diltiazem LA (generic) 240mg
$55
verapamil IR (generic) 240mg
$10
verapamil IR (Calan) 240mg
$193
verapamil ER (generic) 240mg
$10
verapamil ER (Calan SR) 240mg
$169
digoxin (generic) 0.25mg
$10
digoxin (Lanoxin) 0.25mg
$82
amiodarone (generic) 200mg
$9
amiodarone (Cordarone) 200mg
$145
amiodarone (Pacerone) 200mg
$14
Rhythm
dofetilide (Tikosyn) 1mg
$372
dronedarone (Multaq) 800mg
$445
flecainide (generic) 200mg
$25
flecainide (Tambocor) 200mg
$226
propafenone IR (generic) 450mg
$23
propafenone IR (Rythmol) 450mg
$467
propafenone ER (generic) 450mg
$185
propafenone ER (Rythmol SR) 450mg
$523
sotalol (generic) 160mg
$10
sotalol (Betapace) 160mg
$523
0
100
200
300
400
500
Prices from goodrx.com in April 2015, based on World Health Organization defined daily dose (except propafenone).
Not listed: diltiazem 240mg (Cardizem CD), which has a monthly cost of $907.
10
Atrial Fibrillation
600
Key messages
• Atrial fibrillation is a common cause of stroke; this risk is sharply reduced
by anticoagulation.
• Older AF patients are at the greatest risk of stroke and most likely to benefit
from anticoagulation.
• Use the CHA2DS2-VASc score to predict risk of stroke and HAS-BLED
to predict bleeding risk.
• The novel oral anticoagulants (NOACs) are preferable to warfarin for
many patients. Apixaban (Eliquis) has the most favorable benefit-risk profile
and is a good first choice for most patients initiating a NOAC.
• Warfarin is still a good choice for patients with stable INR who may not
benefit from switching to a NOAC, and patients with marked renal impairment,
mechanical heart valves, or cost concerns.
• Rate control is preferred over rhythm control for most patients, targeting
a heart rate of < 110 bpm. Patients with continued symptoms may require
a target rate of < 80 bpm.
Visit alosafoundation.org/modules/afib
for links to risk calculators, other resources,
and a longer evidence document.
References:
(1) Go AS, Mozaffarian D, Roger VL, et al. Heart disease and stroke statistics--2014 update: a report from the American Heart Association. Circulation.
2014;129(3):e28-e292. (2) January CT, Wann LS, Alpert JS, et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report
of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol.
2014;64(21):e1-76. (3) Colilla S, Crow A, Petkun W, Singer DE, Simon T, Liu X. Estimates of current and future incidence and prevalence of atrial fibrillation
in the U.S. adult population. Am J Cardiol. 2013;112(8):1142-1147. (4) Go AS, Hylek EM, Chang Y, et al. Anticoagulation therapy for stroke prevention in atrial
fibrillation: how well do randomized trials translate into clinical practice? JAMA. 2003;290(20):2685-2692. (5) Singer DE, Chang Y, Fang MC, et al. The net
clinical benefit of warfarin anticoagulation in atrial fibrillation. Ann Intern Med. 2009;151(5):297-305. (6) Lip GY, Tse HF, Lane DA. Atrial fibrillation. Lancet.
2012;379(9816):648-661. (7) Friberg L, Rosenqvist M, Lip GY. Evaluation of risk stratification schemes for ischaemic stroke and bleeding in 182 678 patients
with atrial fibrillation: the Swedish Atrial Fibrillation cohort study. Eur Heart J. 2012;33(12):1500-1510. (8) Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns
HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest.
2010;138(5):1093-1100. (9) Olesen JB, Lip GY, Lindhardsen J, et al. Risks of thromboembolism and bleeding with thromboprophylaxis in patients with atrial
fibrillation: A net clinical benefit analysis using a ‘real world’ nationwide cohort study. Thromb Haemost. 2011;106(4):739-749. (10) Ruff CT, Giugliano RP,
Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of
randomised trials. Lancet. 2014;383(9921):955-962. (11) Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in Patients with Atrial
Fibrillation. N Engl J Med. 2009;361(12):1139-1151. (12) Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
N Engl J Med. 2011;365(10):883-891. (13) Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation.
N Engl J Med. 2011;365(11):981-992. (14) Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med.
2013;369(22):2093-2104. (15) Camm AJ, Lip GY, De Caterina R, et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation:
an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm
Association. Eur Heart J. 2012;33(21):2719-2747. (16) Van Gelder IC, Groenveld HF, Crijns HJ, et al. Lenient versus strict rate control in patients with atrial
fibrillation. N Engl J Med. 2010;362(15):1363-1373. (17) Van Gelder IC, Wyse DG, Chandler ML, et al. Does intensity of rate-control influence outcome in
atrial fibrillation? An analysis of pooled data from the RACE and AFFIRM studies. Europace. 2006;8(11):935-942. (18) Roy D, Talajic M, Nattel S, et al.
Rhythm control versus rate control for atrial fibrillation and heart failure. N Engl J Med. 2008;358(25):2667-2677. (19) Segal JB, McNamara RL, Miller MR,
et al. The evidence regarding the drugs used for ventricular rate control. J Fam Pract. 2000;49(1):47-59. (20) Olshansky B, Rosenfeld LE, Warner AL, et al.
The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study: approaches to control rate in atrial fibrillation. J Am Coll Cardiol.
2004;43(7):1201-1208.
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About this publication
These are general recommendations only; specific clinical decisions should be made by the
treating physician based on an individual patient’s clinical condition. More detailed information
on this topic is provided in a longer evidence document at alosafoundation.org.
The Independent Drug Information Service (IDIS) is supported by
the PACE Program of the Department of Aging of the Commonwealth
of Pennsylvania.
This material is provided by the Alosa Foundation, a nonprofit
organization which is not affiliated with any pharmaceutical company.
IDIS is a program of the Alosa Foundation.
This material was produced by Jennifer Lewey, M.D., Research Fellow, Brigham and Women’s Hospital;
Niteesh K. Choudhry, M.D., Ph.D., Associate Professor of Medicine (principal editor); Jerry Avorn,
M.D., Professor of Medicine; Michael A. Fischer, M.D., M.S., Associate Professor of Medicine; and Dae Kim,
M.D., M.P.H., Sc.D., Instructor in Medicine, all at Harvard Medical School; Eimir Hurley, BSc (Pharm),
MBiostat, Program Director; and Ellen Dancel, PharmD, MPH, Director of Clinical Material Development,
both at the Alosa Foundation. Drs. Avorn, Choudhry, and Fischer are physicians at the Brigham
and Women’s Hospital, and Dr. Kim practices at the Beth Israel Hospital, both in Boston. Dr. Lewey
practices cardiology at the Columbia University Medical Center in New York. None of the authors
accepts any personal compensation from any drug company.
Medical writer: Stephen Braun.
Copyright 2015 by the Alosa Foundation. All rights reserved.