Arrhythmia/Electrophysiology

Apixaban in Comparison With Warfarin in Patients

With Atrial Fibrillation and Valvular Heart Disease
Findings From the Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial
Alvaro Avezum, MD, PhD; Renato D. Lopes, MD, PhD, MHS; Phillip J. Schulte, PhD;
Fernando Lanas, MD; Bernard J. Gersh, MB, ChB, DPhil; Michael Hanna, MD; Prem Pais, MD;
Cetin Erol, MD; Rafael Diaz, MD; M. Cecilia Bahit, MD; Jozef Bartunek, MD, PhD;
Raffaele De Caterina, MD, PhD; Shinya Goto, MD, PhD; Witold Ruzyllo, MD, PhD;
Jun Zhu, MD; Christopher B. Granger, MD; John H. Alexander, MD, MHS
BackgroundApixaban is approved for the prevention of stroke and systemic embolism in patients with nonvalvular atrial
fibrillation. However, the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation
(ARISTOTLE) trial included a substantial number of patients with valvular heart disease and only excluded patients with
clinically significant mitral stenosis or mechanical prosthetic heart valves.
Methods and ResultsWe compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major
bleeding, and death in patients with and without moderate or severe valvular heart disease using Cox proportional hazards
modeling. Of the 18201 patients enrolled in ARISTOTLE, 4808 (26.4%) had a history of moderate or severe valvular heart
disease or previous valve surgery. Patients with valvular heart disease had higher rates of stroke or systemic embolism
and bleeding than patients without valvular heart disease. There was no evidence of a differential effect of apixaban over
warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism (hazard ratio [HR],
0.70; 95% confidence interval [CI], 0.510.97 and HR, 0.84; 95%, CI 0.671.04; interaction P=0.38), causing less major
bleeding (HR, 0.79; 95% CI, 0.611.04 and HR, 0.65; 95% CI, 0.550.77; interaction P=0.23), and reducing mortality
(HR, 1.01; 95% CI, 0.841.22 and HR, 0.84; 95% CI, 0.730.96; interaction P=0.10).
ConclusionsMore than a quarter of the patients in ARISTOTLE with nonvalvular atrial fibrillation had moderate or severe
valvular heart disease. There was no evidence of a differential effect of apixaban over warfarin in reducing stroke or
systemic embolism, causing less bleeding, and reducing death in patients with and without valvular heart disease.
Clinical Trial RegistrationURL: http://www.clinicaltrials.gov. Unique identifier: NCT00412984.
(Circulation. 2015;132:624-632. DOI: 10.1161/CIRCULATIONAHA.114.014807.)
Key Words:apixaban atrial fibrillation heart diseases hemorrhage oral anticoagulant stroke
valvular heart disease

alvular heart disease is common worldwide although the

etiology varies by region. In higher-income countries,
the most common cause of valvular heart disease is degenerative, whereas in developing regions, rheumatic heart disease is
the main cause.14 Valvular heart disease, independent of the
underlying cardiac rhythm, is associated with a higher risk of
thromboembolic events.5 Atrial fibrillation is associated with a
substantially higher risk of thromboembolism in patients with
rheumatic mitral stenosis.6 Oral anticoagulation with vitamin
K antagonists is indicated for the prevention of stroke and

systemic embolism in patients with cardiac valve replacement

and in patients with atrial fibrillation and mitral stenosis.7,8 The
term valvular atrial fibrillation arose at the time of the original
warfarin trials9 to describe patients with rheumatic mitral stenosis or prosthetic heart valves, who were deemed at such high
risk of stroke without warfarin that it would be unethical to
assign them to control10 (Jonathan L. Halperin, MD, personal
communication, June 2014). In the Apixaban for Reduction in

Clinical Perspective on p 632

Received July 28, 2014; accepted June 11, 2015.

From Research Division, Dante Pazzanese Institute of Cardiology, So Paulo, Brazil (A.A.); Duke Clinical Research Institute, Duke Medicine, Durham,
NC (R.D.L., P.J.S., C.B.G., J.H.A.); Universidad de La Frontera, Temuco, Chile (F.L.); Mayo Clinic College of Medicine, Rochester, MN (B.J.G.);
Bristol-Myers Squibb, Princeton, NJ (M.H.); St. Johns Medical College & Research Institute, Bangalore, India (P.P.); Ankara University School of
Medicine, Turkey (C.E.); ECLA Estudios Cardiolgicos Latinoamrica, Rosario, Argentina (R.D.); INECO Neurociencias Oroo, Rosario, Santa Fe,
Argentina (M.C.B.); Cardiovascular Center Aalst, OLV Hospital, Aalst, Belgium (J.B.); G. dAnnunzio University, Chieti, Italy and Fondazione Toscana
G. Monasterio, Pisa, Italy (R.D.C.); Tokai University School of Medicine, Isehara, Japan (S.G.); National Institute of Cardiology, Warsaw, Poland (W.R.);
and Fu Wai Hospital, Beijing, China (J.Z.).
Correspondence to Alvaro Avezum, MD, PhD, Dante Pazzanese Institute of Cardiology, Av. Dante Pazzanese, 500 04012909 So Paulo, Brazil. E-mail
avezum@dantepazzanese.org.br
2015 American Heart Association, Inc.
Circulation is available at http://circ.ahajournals.org

DOI: 10.1161/CIRCULATIONAHA.114.014807

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624

Avezum et al Apixaban Versus Warfarin in Patients With AF and VHD 625

Stroke and Other Thromboembolic Events in Atrial Fibrillation
(ARISTOTLE) trial, apixaban, a direct oral factor Xa inhibitor,
was found to reduce stroke or systemic embolism, cause less
bleeding, and reduce mortality in comparison with warfarin
and has been approved for stroke prevention in nonvalvular
atrial fibrillation. The ARISTOTLE trial excluded patients with
moderate or severe mitral stenosis and mechanical prosthetic
heart valves, but included a substantial number of patients with
other valvular heart disease, thus offering an opportunity to
evaluate the effect of apixaban in comparison with warfarin
in patients with atrial fibrillation and valvular heart disease.11

Methods
Patient Population
The design and results of the ARISTOTLE trial have been published
(clinicaltrials.gov NCT00412984).12 In brief, ARISTOTLE was a
noninferiority trial to compare apixaban with warfarin in patients
with atrial fibrillation and at least 1 additional risk factor for stroke.
Exclusion criteria included clinically significant (moderate or severe)
mitral stenosis, indications for oral anticoagulation other than atrial
fibrillation (including mechanical prosthetic heart valves), and planned
use of concomitant high-dose aspirin (>165 mg/d) or dual-antiplatelet
therapy. Patients with valvular heart disease, including aortic stenosis,
aortic regurgitation, mild mitral stenosis, mitral regurgitation, tricuspid stenosis, tricuspid regurgitation, valve repair, or bioprosthetic valve
replacement were eligible for enrollment in ARISTOTLE. Patients
were considered to have valvular heart disease if they had (1) a history of at least moderate valvular heart disease, (2) baseline echocardiographic evidence of at least moderate valvular heart disease, or (3)
a history of previous valve surgery reported on the trial case report
form. All data regarding valvular heart disease were site reported based
on available medical history. There was no central echocardiography
laboratory confirming valvular heart disease or its severity. All patients
provided written informed consent, and approval by the appropriate
institutional review boards/ethics committees was obtained at all sites.
Patients were randomly assigned to apixaban 5.0 mg twice daily
and warfarin placebo or to dose-adjusted warfarin (target international normalized ratio of 2.03.0) and apixaban placebo. A 2.5-mg
dose of apixaban was used in patients randomly assigned to apixaban
with 2 of the following: age 80 years, body weight 60 kg, or
serum creatinine 133 mol/L (1.5 mg/dL).

Objectives
The objectives of this secondary analysis were to (1) describe
the frequency and characteristics of valvular heart disease in the
ARISTOTLE population; (2) compare the rates of stroke or systemic
embolism, major bleeding, and death in patients with atrial fibrillation with and without valvular heart disease; and (3) assess the efficacy and safety of apixaban in comparison with warfarin in patients
with atrial fibrillation with and without valvular heart disease.

Clinical Outcomes
The primary outcome was stroke or systemic embolism, and the main
safety outcome was major bleeding as defined by the International
Society on Thrombosis and Haemostasis.12,13 The key secondary efficacy outcome was death from any cause. All efficacy and safety outcome events were adjudicated by a blinded clinical events committee
with the use of prespecified criteria.

Statistical Methods
Baseline characteristics, risk factors, and concomitant medications are
described by valvular heart disease status and randomized treatment.
Continuous variables are presented as the median with 25th and 75th
percentiles, and categorical variables are presented as the number and
percentage. These variables were compared by overall valvular heart

disease status using a Wilcoxon rank-sum test or Pearson 2 test for

continuous and categorical variables, respectively. KaplanMeier
event rate curves compare the primary efficacy and safety outcomes
by valvular heart disease status and randomized treatment. The treatment effect of apixaban in comparison with warfarin was assessed by
valvular heart disease status for all efficacy and safety outcomes using
Cox proportional hazards models. The results are presented as hazard
ratios (HRs) and 95% confidence intervals (CIs) for apixaban versus
warfarin among those with and without valvular heart disease; P values
for the interaction of effect of randomized treatment and valvular heart
disease status are provided. Proportional hazards assumptions were
assessed for valvular heart disease status and for randomized treatment
by plotting Schoenfeld residuals and assessing correlation over time;
no violations were suggested. Analyses for the primary outcome and
key secondary efficacy outcomes included all patients for whom valvular heart disease status was known and were analyzed by randomized
treatment group. The safety outcome analysis included all patients who
received at least 1 dose of study medication.
Among the subgroup of patients with valvular heart disease, we further evaluated treatment interactions with valve location (mitral, aortic,
and tricuspid) for the primary efficacy and safety outcomes. Finally, to
assess the sensitivity of the results to our definition of valvular heart
disease, each outcome was evaluated in the same manner by using a
definition that included any, including mild, valvular heart disease.

Role of the Funding Source

Bristol-Myers Squibb and Pfizer funded the ARISTOTLE trial and
supported this analysis through a grant to Duke University. All analyses were conducted at the Duke Clinical Research Institute, and the
authors had full access to all data through the Duke Clinical Research
Institute. The authors are fully responsible for the study design, data
collection, analysis and interpretation of the data, and writing of the
manuscript. The sponsor played no role in the decision to submit the
manuscript for publication.

Results
In ARISTOTLE, 18201 patients with atrial fibrillation and at
least 1 risk factor for stroke were randomly assigned and data on
valvular heart disease status were available for 18197 patients.
Of these patients, 4808 (26.4%) had a history of moderate or
severe valvular heart disease or previous valve surgery. Of these
4808 patients, 3237 (67.3%) had a medical history of at least
moderate valvular heart disease; 3723 (77.4%) had baseline
echocardiography data with at least moderate valvular heart disease; and 251 (5.2%) had previous valve surgery (Figure1). The
numbers of patients with specific valve lesions are described in
Table1. Importantly, the categories are not mutually exclusive.
The majority of patients with valvular heart disease had mitral
or tricuspid regurgitation; a smaller proportion had aortic stenosis, other valve lesions, or previous valve surgery. Patients
randomly assigned to apixaban and warfarin had similar type
and frequency of valvular heart disease (P>0.05 for all).

Baseline Characteristics
The baseline characteristics of patients with and without valvular heart disease are shown in Table2. Patients with valvular heart disease were older; had more previous myocardial
infarction, heart failure, prior bleeding, and renal impairment;
had more persistent or permanent atrial fibrillation; had a
higher mean CHADS2 score; and had less hypertension and
diabetes mellitus than patients without valvular heart disease.
Among patients with and without valvular heart disease, those
randomly assigned to apixaban or warfarin had similar baseline characteristics (data not shown, P>0.05 for all).

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626CirculationAugust 25, 2015

Figure 1. Flowchart illustrating patient

population. VHD indicates valvular heart
disease.

Outcomes According to Valvular Heart Disease

Status

of apixaban in comparison with warfarin in reducing stroke

or systemic embolism were consistent in patients with (HR,
0.70; 95% CI, 0.510.97) and without (HR, 0.84; 95% CI,
0.671.04) valvular heart disease (interaction P value=0.38).
Other efficacy outcomes, including stroke, ischemic stroke,
hemorrhagic stroke, death from any cause, and several composite outcomes were consistently and similarly reduced with
apixaban in comparison with warfarin (Figure4).
The benefits of apixaban in comparison with warfarin in
causing less major bleeding were also consistent in patients with
(HR, 0.79; 95% CI, 0.611.04) and without (HR, 0.65; 95% CI,
0.550.77) valvular heart disease (interaction P value=0.23).
Similarly, consistent results were seen for other bleeding outcomes including intracranial bleeding, major or clinically relevant nonmajor bleeding, and any bleeding (Figure5).

Patients with valvular heart disease had higher rates of stroke or

systemic embolism than patients without valvular heart disease
(3.2% versus 2.4%; HR, 1.34; 95% CI, 1.101.62; P=0.003) and
higher rates of death than patients without valvular heart disease
(9.1% versus 6.2%; HR, 1.48; 95% CI, 1.321.67; P<0.001).
Patients with valvular heart disease also tended to have higher
rates of major bleeding than those without valvular heart disease; however, this difference was not statistically significant
(4.6% versus 4.3%; HR, 1.11; 95% CI, 0.951.29; P=0.21).

Efficacy and Safety of Apixaban and Warfarin in

Patient With and Without Valvular Heart Disease
Of the 13389 patients without valvular heart disease, 6681
were assigned to apixaban and 6708 were assigned to warfarin. Of the 4808 patients without valvular heart disease,
2438 were assigned to apixaban and 2370 were assigned to
warfarin. KaplanMeier curves for the primary efficacy and
safety outcomes by randomized treatment group and valvular
heart disease status are shown in Figures2 and 3. The benefits

Mitral and Aortic Valve Locations

Analysis by valve location is shown in Table3. Patients with
mitral valve disease had consistent benefits of apixaban over
warfarin for stroke or systemic embolism and major bleeding.
Similarly, patients with aortic valve disease had consistent

Table 1. Types of Valvular Heart Disease

Overall

Apixaban

Warfarin

n=4808

n=2438

n=2370

P Value

Any mitral valve disease

3578

74.4

1801

73.9

1777

75.0

0.38

Mitral regurgitation

3526

73.3

1778

72.9

1748

73.8

0.52

131

2.7

69

2.8

62

2.6

0.65

1150

23.9

604

24.8

546

23.0

0.16

887

18.4

462

19.0

425

17.9

0.36

Any VHD*

Mitral stenosis
Any aortic valve disease
Aortic regurgitation

384

8.0

208

8.5

176

7.4

0.16

Tricuspid regurgitation

Aortic stenosis

2124

44.2

1082

44.4

1042

44.0

0.77

Previous valve surgery

251

5.2

132

5.4

119

5.0

0.54

VHD indicates valvular heart disease.

*Patients may have more than one type of valvular heart disease.

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Avezum et al Apixaban Versus Warfarin in Patients With AF and VHD 627

Table 2. Baseline Characteristics by Valvular Heart Disease Status in Patients With Atrial Fibrillation
Characteristic

No VHD (N=13389)

Age, median (25th, 75th), y

Female sex, n/N (%)

69 (62, 76)

VHD (N=4808)
71 (64, 77)

P Value
<0.0001

4480/13389 (33.5)

1936/4808 (40.3)

North America

2876/13389 (21.5)

1598/4808 (33.2)

Latin America

2850/13389 (21.3)

617/4808 (12.8)

Europe

5439/13389 (40.6)

1902/4808 (39.6)

Asia Pacific

2224/13389 (16.6)

691/4808 (14.4)

Prior myocardial infarction

1748/13379 (13.1)

837/4807 (17.4)

2189/13387 (16.4)

595/4807 (12.4)

11198/13387 (83.6)

4212/4807 (87.6)

Age 75 y

3898/13389 (29.1)

1779/4808 (37.0)

Previous stroke, TIA, or SE

2632/13389 (19.7)

905/4808 (18.8)

0.21

HF or reduced LVEF

4113/13389 (30.7)

2337/4808 (48.6)

<0.0001

Diabetes mellitus

3460/13389 (25.8)

1086/4808 (22.6)

<0.0001

11811/13389 (88.2)

4102/4808 (85.3)

Region, n/N (%)

<0.0001
<0.0001

Type of AF, n/N (%)

<0.0001
<0.0001

Paroxysmal
Persistent or permanent
Qualifying risk factors, n/N (%)

Hypertension requiring treatment

CHADS2, mean (SD)

2.1 (1.1)

2.2 (1.1)

CHADS2 score

<0.0001

<0.0001
<0.0001
<0.0001

1

4802/13389 (35.9)

1379/4808 (28.7)

2

4692/13389 (35.0)

1823/4808 (37.9)

3

3895/13389 (29.1)

1606/4808 (33.4)

Warfarin/VKA experienced

7418/13389 (55.4)

2981/4808 (62.0)

Amiodarone

1529/13157 (11.6)

521/4748 (11.0)

0.23

-Blocker

8268/13157 (62.8)

3212/4748 (67.6)

<0.0001

Aspirin

4110/13389 (30.7)

1522/4808 (31.7)

0.22

Medications at time of randomization, n/N (%)

Clopidogrel

<0.0001

239/13389 (1.8)

99/4808 (2.1)

0.23

4004/13157 (30.4)

1823/4748 (38.4)

<0.0001

Normal (80 mL/min)

5909/13328 (44.3)

1608/4792 (33.6)

Mild impairment (>5080 mL/min)

5486/13328 (41.2)

2101/4792 (43.8)

Moderate impairment
(>3050 mL/min)

1766/13328 (13.3)

980/4792 (20.5)

167/13328 (1.3)

103/4792 (2.1)

Digoxin
Renal function, n/N (%)

<0.0001

Severe impairment (30 mL/min)

ACE indicates angiotensin converting enzyme; AF, atrial fibrillation; ARB, angiotensin receptor blocker; CHADS2, congestive heart failure,
hypertension, age >75), diabetes mellitus, and stroke/TIA (2 points); HF, heart failure; LVEF, left ventricular ejection fraction; MI, myocardial
infarction; NSAID, nonsteroidal anti-inflammatory drug; SBP, systolic blood pressure; SD, standard deviation; SE, systemic embolism; TIA,
transient ischemic attack; and VHD, valvular heart disease.

benefits of apixaban over warfarin for stroke or systemic

embolism and for major bleeding. Similar benefits of apixaban in comparison with warfarin were also seen in patients
with tricuspid valve disease and in patients with previous
valve surgery (data not shown).

Sensitivity Analyses
When we included mild valvular heart disease by baseline
echocardiography, 10809 patients (59.4%) had valvular heart
disease at baseline (Table4). Consistent effects of apixaban in comparison with warfarin were seen in patients with
and without at least mild valvular heart disease for stroke or

systemic embolism, hemorrhagic stroke, death, and bleeding

outcomes. Analysis exploring interactions by treatment and
valvular heart disease severity were performed, and the results
across the gradient of valve disease severity were similar to
the main analysis for both the primary efficacy (interaction P
value=0.90) and safety (interaction P value=0.67) outcomes.

Discussion
In this analysis from the ARISTOTLE trial, we found that
more than a quarter of patients with nonvalvular atrial fibrillation and an indication for oral anticoagulation have moderate
or severe valvular heart disease. In this context, nonvalvular is

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628CirculationAugust 25, 2015

Stroke or Systemic Embolism

5
NoVHD, Apixaban
NoVHD, Warfarin
VHD, Apixaban
VHD, Warfarin

Event Rate, %

Figure 2. KaplanMeier estimates. Stroke or

systemic embolism in patients with and without
valvular heart disease by treatment assignment.
VHD indicates valvular heart disease.

0
0

12

18

24

30

2676
2628
919
915

1370
1375
467
478

Time, months

No. at Risk:
NoVHD, Apixaban
NoVHD, Warfarin
VHD, Apixaban
VHD, Warfarin

6681
6708
2438
2370

6430
6398
2305
2228

6253
6207
2222
2138

4534
4494
1573
1547

a misnomer and may be misleading. Patients with atrial fibrillation and valvular heart disease are at higher risk for stroke
and systemic embolism and bleeding than patients without
valvular heart disease and may derive particular benefit from
oral anticoagulation.
Valvular heart disease is common in both developed and
developing countries and imposes a huge burden on limited
healthcare resources. In comparison with other cardiovascular
diseases, there are few randomized clinical trials evaluating
the effects of medical intervention in patients with valvular
heart disease.14 Structural changes from the pressure and volume overload alter the electrophysiological properties of the

left atrium, and the rheumatic process itself may lead to atrial
fibrosis which may partially explain the occurrence of atrial
fibrillation in patients with valvular heart disease.15 Adjusting
for other relevant conditions, valvular heart disease is associated with a 1.8- to 3.4-fold higher risk of atrial fibrillation
in men and women, respectively.16 Although many patients
develop atrial fibrillation as the result of valvular heart disease, there are concomitant factors that may contribute to the
occurrence of atrial fibrillation, such as older age, heart failure,
hypertension, coronary artery disease, and diabetes mellitus.17
In the current analysis, we found that patients with valvular heart disease were older; had more previous myocardial

ISTH Major Bleeding

8
NoVHD, Apixaban
NoVHD, Warfarin
VHD, Apixaban
VHD, Warfarin

Event Rate, %

Figure 3. KaplanMeier estimates. Major

bleeding in patients with and without valvular
heart disease by treatment assignment. ISTH
indicates International Society on Thrombosis and
Haemostasis; and VHD, valvular heart disease.

0
0

12

NoVHD, Apixaban
NoVHD, Warfarin
VHD, Apixaban
VHD, Warfarin

18

24

30

2451
2354
816
793

1219
1200
409
392

Time, months

No. at Risk:
6659
6691
2428
2360

5989
5911
2131
2015

5610
5512
1974
1842

4130
3997
1391
1333

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Avezum et al Apixaban Versus Warfarin in Patients With AF and VHD 629

Figure 4. Efficacy outcomes. Stroke or systemic

embolism; stroke; ischemic or unknown type
of stroke; hemorrhagic stroke; death from any
cause; composite of stroke, systemic embolism,
and death; and composite of stroke, systemic
embolism, myocardial infarction, and death
in patients with and without valvular heart
disease treated with apixaban versus warfarin.
*P value for the randomized treatment by
valvular heart disease status interaction. CI
indicates confidence interval; HR, hazard ratio;
MI, myocardial infarction; and SE, systemic
embolism.

infarction, bleeding, heart failure, and renal impairment; and

higher CHADS2 score. These variables may also contribute
to the higher rate of thromboembolic and bleeding events in
patients with valvular heart disease. Patients with mitral valve
disease may have higher left atrium volume, contributing to
blood stasis and promoting thrombus formation and leading to
higher rates of thromboembolic events.18 Among patients with
valvular heart disease, age, atrial fibrillation, and aortic stenosis are independent predictors of cerebrovascular events.5
In the ARISTOTLE study, detailed echocardiographic
information on valvular heart disease severity was not collected, and classification of valvular lesion and severity relied
on clinical data collected in the case report forms. Patients
with clinically significant (moderate to severe) mitral stenosis and those with mechanical prosthetic heart valves were
excluded; however, patients with any other form of valvular
heart disease including mild mitral stenosis, mitral regurgitation, aortic stenosis or regurgitation, tricuspid valve disease,
and previous valve surgery were included. Despite the population being characterized as having nonvalvular atrial fibrillation, these data confirm that apixaban, in comparison with
warfarin, resulted in reductions in stroke or systemic embolism, caused less bleeding, and reduced mortality similarly in
patients with and without valvular heart disease.
Patients with clinically significant (moderate or severe)
mitral stenosis were excluded because ARISTOTLE was
designed as a noninferiority trial. The noninferiority margin for ARISTOTLE was based on the previous systematic

review of 6 clinical trials that compared warfarin and placebo in patients with nonvalvular atrial fibrillation.9 These
trials excluded patients with mitral stenosis because, when
they were conducted, warfarin was already established to be
effective for thromboembolism prophylaxis in these patients
who are at such high risk of stroke without treatment that
assignment to control was considered unethical.10 Based on
the constancy assumption that is fundamental to noninferiority analyses, the ARISTOTLE trial excluded patients with
clinically significant mitral stenosis. There is no reason to
think that apixaban would not be effective for stroke prevention in patients with clinically important mitral stenosis;
however, before its use can be recommended, additional randomized data in patients with rheumatic mitral stenosis are
needed.
Patients with other indications for warfarin therapy,
including mechanical prosthetic heart valves, were excluded
from the ARISTOTLE trial. Recently, the Randomized,
Phase II Study to Evaluate the Safety and Pharmacokinetics
of Oral Dabigatran Etexilate in Patients after Heart Valve
Replacement (RE-ALIGN)19 study comparing dabigatran
with dose-adjusted warfarin evaluated patients who had
undergone aortic or mitral valve replacement within the
past 7 days and those who had undergone such replacement
at least 4 months earlier. The trial was terminated prematurely because of an excess of thromboembolic and bleeding
events among patients in the dabigatran group. The mechanism of risk for patients with mechanical heart valves may

Figure 5. Safety outcomes. ISTH major bleeding,

intracranial bleeding, major or clinically relevant
nonmajor bleeding, and any bleeding in patients
with and without valvular heart disease treated
with apixaban versus warfarin. *P value for the
randomized treatment by valvular heart disease
status interaction. CI, confidence interval; HR,
hazard ratio; and ISTH indicates International
Society on Thrombosis and Haemostasis.

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630CirculationAugust 25, 2015

Table 3. Apixaban Versus Warfarin in Patients With Mitral
and Aortic Valvular Heart Disease
Rate %/y (No. of Events)
Apixaban

Warfarin

HR (95% CI)*

Mitral VHD

(n=1801)

(n=1777)

Stroke or SE

1.32 (43)

1.89 (61)

0.70 (0.471.04)

ISTH major bleeding

2.12 (63)

2.94 (84)

0.72 (0.521.00)

Aortic VHD

(n=604)

(n=546)

Stroke or SE

1.57 (17)

2.88 (27)

0.55 (0.301.01)

ISTH major bleeding

2.98 (29)

4.21 (34)

0.72 (0.441.18)

CI indicates confidence interval; HR, hazard ratio; ISTH, International Society

on Thrombosis and Haemostasis; SE, systemic embolism; and VHD, valvular
heart disease.
*HR (95% CI) for apixaban versus warfarin.

be substantially different from those with atrial fibrillation

and may require different antithrombotic strategies. A total
of 251 patients with previous valve surgery (bioprosthetic
heart valve or valve repair) were enrolled in ARISTOTLE
and are included in this analysis. Unfortunately, however,
details of their valve surgery were not collected. Whether or
not apixaban is safe and effective in patients with previous
bioprosthetic valve surgery will likely also require additional
randomized data.
One quarter of the ARISTOTLE population had moderate
or severe valvular abnormalities; therefore, the term nonvalvular atrial fibrillation is a misnomer. A more appropriate description should be pursued to reflect the clinical characteristics of
those patients included in trials of new oral anticoagulation
agents. With the exception of those patients with mitral stenosis and with mechanical prosthetic heart valves, patients with
valvular heart disease and atrial fibrillation are an important
cohort of patients that could benefit from increased use of the
new oral anticoagulants. The current labeling and description
of these new oral anticoagulants as being indicated for nonvalvular atrial fibrillation may be leading to undertreatment of

one of the groups of patients that could benefit most from the
advantages of these new anticoagulants.
Other contemporary trials comparing new oral anticoagulants with warfarin had variable exclusion criteria for patients
with valvular heart disease. These included the presence of
a severe heart valve disorder (Randomized Evaluation of
Long-Term Anticoagulation Therapy [RE-LY]); hemodynamically significant mitral stenosis or any valve prosthesis
(Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition
Compared with Vitamin K Antagonism for Prevention of
Stroke and Embolism Trial in Atrial Fibrillation [ROCKET
AF]); and moderate or severe mitral stenosis, unresected atrial
myxoma, mechanical prosthetic heart valve (patients with
bioprosthetic heart valves or valve repair could be included;
Effective Anticoagulation with Factor Xa Next Generation in
Atrial Fibrillation [ENGAGE AF]).2022
Recently, data from the RE-LY trial of dabigatran versus warfarin in patients with atrial fibrillation showed similar benefits of dabigatran in comparison with warfarin in the
22% of patients with and the 78% of patients without valvular heart disease.23 Despite differing criteria for excluding
patients with valvular heart disease, all of these trials, including ARISTOTLE, include significant numbers of patients with
valvular heart disease and can inform the use of new oral anticoagulants in patients with atrial fibrillation and valvular heart
disease.

Limitations
This subgroup analysis in patients with and without valvular heart disease was not prespecified. Although a substantial portion of the population had valve disease, there may
be a lack of statistical power to detect heterogeneity in the
effects of apixaban versus warfarin. Valvular heart disease
was defined clinically without standardized core laboratory
verification. This can be viewed as a weakness or a strength
because this is how valvular heart disease is assessed clinically. There was no information on the etiology of valvular
heart disease and, for those with previous valve surgery, the

Table 4. Effect of Apixaban Versus Warfarin by Valvular Heart Disease Status, Including Mild Valvular Heart Disease
No VHD
(N=7388)

VHD
(N=10809)

Rate %/y (No. of Events)

Rate %/y (No. of Events)

Apixaban

Warfarin

HR (95% CI)*

Apixaban

Warfarin

HR (95% CI)*

Interaction
P Value

Stroke or SE

1.20 (82)

1.41 (95)

0.85 (0.641.15)

1.31 (130)

1.73 (170)

0.76 (0.600.95)

0.53

Hemorrhagic stroke

0.23 (16)

0.41 (28)

0.56 (0.311.04)

0.24 (24)

0.50 (50)

0.48 (0.290.78)

0.68

Death from any cause

3.21 (224)

3.91 (270)

0.82 (0.690.98)

3.74 (379)

3.96 (399)

0.95 (0.821.09)

0.22

ISTH major bleeding

1.73 (109)

3.09 (189)

0.56 (0.440.71)

2.41 (218)

3.09 (273)

0.78 (0.650.93)

0.03

Intracranial bleeding

0.33 (21)

0.76 (47)

0.44 (0.260.73)

0.34 (31)

0.84 (75)

0.40 (0.270.61)

0.81

Major or CRNM bleeding

3.38 (209)

5.49 (329)

0.62 (0.520.74)

4.55 (404)

6.37 (548)

0.72 (0.630.81)

0.18

16.48 (887)

24.24 (1191)

0.70 (0.640.76)

19.21 (1469)

26.95 (1869)

0.73 (0.680.78)

0.46

Efficacy end points

Safety end points

Any bleeding

CI indicates confidence interval; HR, hazard ratio; ISTH, International Society on Thrombosis and Haemostasis; MI, myocardial infarction; CRNM, clinically relevant
nonmajor; SE, systemic embolism; and VHD, valvular heart disease.
*HR (95% CI) for apixaban vs warfarin.
P value for the randomized treatment by valvular heart disease status interaction.

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Avezum et al Apixaban Versus Warfarin in Patients With AF and VHD 631

type of surgerybioprosthetic valve replacement versus
valve repairis unknown.

Conclusions
In a large contemporary clinical trial in patients with atrial
fibrillation and an indication for oral anticoagulation, over
a quarter of patients have a history of moderate or severe
valvular heart disease or previous valvular surgery. The
coexistence of atrial fibrillation and valvular heart disease is
associated with a higher risk of thromboembolic events and
bleeding. There was no evidence of a differential effect of
apixaban over warfarin in patients with and without valvular heart disease in reducing stroke and systemic embolism,
causing less major bleeding, and reducing mortality With the
exception of those with clinically significant mitral stenosis
or mechanical prosthetic heart valves, apixaban is an attractive alternative to warfarin in patients with atrial fibrillation
and valvular heart disease.

Acknowledgments
Elizabeth Cook of the Duke Clinical Research Institute provided editorial assistance.

Sources of Funding
The ARISTOTLE trial was supported by Bristol-Myers Squibb
and Pfizer.

Disclosures
Dr Avezum reports consulting and advisory board fees from
Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer. Dr Lopes
reports institutional research grants from Bristol-Myers Squibb,
Pfizer, and GlaxoSmithKline; and consulting/honoraria from Bayer,
Boehringer Ingelheim, Bristol-Myers Squibb, and Pfizer. Dr Hanna
is an employee of Bristol-Myers Squibb. Dr Pais reports a research
grant from AstraZeneca. Dr De Caterina reports research grants and
consulting fees/honoraria from Boehringer Ingelheim, Bayer, BristolMyers Squibb, Pfizer, and Daiichi-Sankyo. Dr Goto reports research
grants from Pfizer, and honoraria from Bristol-Myers Squibb. Dr
Zhu reports research grants from Bristol-Myers Squibb and Pfizer.
Granger reports research grants from AstraZeneca, Boehringer
Ingelheim, GlaxoSmithKline, the Medtronic Foundation, Merck,
Sanofi-Aventis, Astellas, and the Medicines Company; consulting
fees from AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline,
Hoffmann-La Roche, Novartis, Otsuka Pharmaceutical, SanofiAventis, and the Medicines Company. Dr Alexander reports institutional research grants from Bristol-Myers Squibb and Pfizer;
and consulting fees/honoraria from Bristol-Myers Squibb, Pfizer,
Boehringer Ingelheim, Bayer, and Ortho-McNeil-Janssen. The other
authors report no conflicts.

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Clinical Perspective
The coexistence of atrial fibrillation and valvular heart disease (VHD) is associated with a higher risk of thromboembolic
events and bleeding. There is a lack of available data evaluating new oral anticoagulants in patients with VHD and atrial
fibrillation. We compared the effect of apixaban and warfarin on rates of stroke or systemic embolism, major bleeding, and
death in 4808 patients with and without moderate or severe VHD, from the Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) study. Apixaban, in comparison with warfarin, had similar
relative and larger absolute benefits in reducing stroke or systemic embolism, causing less bleeding, and reducing mortality in patients with VHD in comparison with those without VHD. The current analysis provides a reliable evaluation of the
efficacy and safety of apixaban in patients with VHD, and the results will potentially improve the cardiovascular burden of
atrial fibrillation in VHD.

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Apixaban in Comparison With Warfarin in Patients With Atrial Fibrillation and Valvular
Heart Disease: Findings From the Apixaban for Reduction in Stroke and Other
Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) Trial
Alvaro Avezum, Renato D. Lopes, Phillip J. Schulte, Fernando Lanas, Bernard J. Gersh,
Michael Hanna, Prem Pais, Cetin Erol, Rafael Diaz, M. Cecilia Bahit, Jozef Bartunek, Raffaele
De Caterina, Shinya Goto, Witold Ruzyllo, Jun Zhu, Christopher B. Granger and John H.
Alexander
Circulation. 2015;132:624-632; originally published online June 23, 2015;
doi: 10.1161/CIRCULATIONAHA.114.014807
Circulation is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
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