Apixaban in patients with atrial fibrillation.

Abstract

Vitamin K antagonists have been shown to prevent stroke in patients with atrial fibrillation. However, many patients are not suitable candidates for or are unwilling to receive vitamin K antagonist therapy, and these patients have a high risk of stroke. Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients.
In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who were at increased risk for stroke and for whom vitamin K antagonist therapy was unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg per day), to determine whether apixaban was superior. The mean follow up period was 1.1 years. The primary outcome was the occurrence of stroke or systemic embolism.
Before enrollment, 40% of the patients had used a vitamin K antagonist. The data and safety monitoring board recommended early termination of the study because of a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per year) among patients assigned to apixaban and 113 (3.7% per year) among those assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI], 0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and 4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P=0.07). There were 44 cases of major bleeding (1.4% per year) in the apixaban group and 39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI, 0.74 to 1.75; P=0.57); there were 11 cases of intracranial bleeding with apixaban and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year, P<0.001). The treatment effects were consistent among important subgroups.
In patients with atrial fibrillation for whom vitamin K antagonist therapy was unsuitable, apixaban reduced the risk of stroke or systemic embolism without significantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769.).

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original article
The new england journal of medicine
n engl j med 364;9 nejm.org march 3, 2011
806
Apixaban in Patients with Atrial Fibrillation
Stuart J. Connolly, M.D., John Eikelboom, M.B., B.S., Campbell Joyner, M.D.,
Hans-Christoph Diener, M.D., Ph.D., Robert Hart, M.D., Sergey Golitsyn, M.D., Ph.D.,
Greg Flaker, M.D., Alvaro Avezum, M.D., Ph.D., Stefan H. Hohnloser, M.D.,
Rafael Diaz, M.D., Mario Talajic, M.D., Jun Zhu, M.D., Prem Pais, M.B., B.S., M.D.,
Andrzej Budaj, M.D., Ph.D., Alexander Parkhomenko, M.D., Ph.D., Petr Jansky, M.D.,
Patrick Commerford, M.B., Ch.B., Ru San Tan, M.B., B.S., Kui-Hian Sim, M.B., B.S.,
Basil S. Lewis, M.D., Walter Van Mieghem, M.D., Gregory Y.H. Lip, M.D.,
Jae Hyung Kim, M.D., Ph.D., Fernando Lanas-Zanetti, M.D.,
Antonio Gonzalez-Hermosillo, M.D., Antonio L. Dans, M.D.,
Muhammad Munawar, M.D., Ph.D., Martin O’Donnell, M.B., Ph.D.,
John Lawrence, M.D., Gayle Lewis, Rizwan Afzal, M.Sc.,
and Salim Yusuf, M.B., B.S., D.Phil.,
for the AVERROES Steering Committee and Investigators*
The affiliations of the authors are listed
in the Appendix. Address reprint re-
quests to Dr. Connolly at Population
Health Research Institute, 237 Barton St.
E., Hamilton, ON L8L 2X2, Canada, or at
stuart.connolly@phri.ca.
* A complete list of the AVERROES (Apix-
aban Versus Acetylsalicylic Acid [ASA] to
Prevent Stroke in Atrial Fibrillation Pa-
tients Who Have Failed or Are Unsuit-
able for Vitamin K Antagonist Treatment)
Steering Committee members and site
investigators is available in the Supple-
mentary Appendix, available at NEJM.org.
This article (10.1056/NEJMoa1007432) was
published on February 10, 2011, at NEJM
.org.
N Engl J Med 2011;364:806-17.
Copyright © 2011 Massachusetts Medical Society.
Abstract
Background
Vitamin K antagonists have been shown to prevent stroke in patients with atrial
fibrillation. However, many patients are not suitable candidates for or are unwilling
to receive vitamin K antagonist therapy, and these patients have a high risk of stroke.
Apixaban, a novel factor Xa inhibitor, may be an alternative treatment for such patients.
Methods
In a double-blind study, we randomly assigned 5599 patients with atrial fibrillation who
were at increased risk for stroke and for whom vitamin K antagonist therapy was
unsuitable to receive apixaban (at a dose of 5 mg twice daily) or aspirin (81 to 324 mg
per day), to determine whether apixaban was superior. The mean follow up period was
1.1 years. The primary outcome was the occurrence of stroke or systemic embolism.
Results
Before enrollment, 40% of the patients had used a vitamin K antagonist. The data
and safety monitoring board recommended early termination of the study because of
a clear benefit in favor of apixaban. There were 51 primary outcome events (1.6% per
year) among patients assigned to apixaban and 113 (3.7% per year) among those
assigned to aspirin (hazard ratio with apixaban, 0.45; 95% confidence interval [CI],
0.32 to 0.62; P<0.001). The rates of death were 3.5% per year in the apixaban group and
4.4% per year in the aspirin group (hazard ratio, 0.79; 95% CI, 0.62 to 1.02; P = 0.07).
There were 44 cases of major bleeding (1.4% per year) in the apixaban group and
39 (1.2% per year) in the aspirin group (hazard ratio with apixaban, 1.13; 95% CI,
0.74 to 1.75; P = 0.57); there were 11 cases of intracranial bleeding with apixaban
and 13 with aspirin. The risk of a first hospitalization for cardiovascular causes was
reduced with apixaban as compared with aspirin (12.6% per year vs. 15.9% per year,
P<0.001). The treatment effects were consistent among important subgroups.
Conclusions
In patients with atrial fibrillation for whom vitamin K antagonist therapy was un-
suitable, apixaban reduced the risk of stroke or systemic embolism without signifi-
cantly increasing the risk of major bleeding or intracranial hemorrhage. (Funded by
Bristol-Myers Squibb and Pfizer; ClinicalTrials.gov number, NCT00496769.)
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Apixaban in Patients with Atrial Fibrillation
n engl j med 364;9 nejm.org march 3, 2011
807
A
fective than aspirin for the prevention of stroke
in patients with atrial fibrillation, but its use is
limited by a narrow window for a therapeutic
benefit and by the need for lifelong coagulation
monitoring owing to a marked variation in its
effect both from one patient to another and with-
in the individual patient.2 Maintaining the inter-
national normalized ratio (INR) in the therapeu-
tic range is challenging and for many patients is
achieved less than 60% of the time — a finding
that counteracts the potential benefit of vitamin K
antagonist therapy and increases its risks.3 Con-
sequently, at least a third of patients with atrial
fibrillation who are at risk for stroke are either
not started on vitamin K antagonist therapy or
discontinue the therapy once it is started.3-5
Aspirin reduces the risk of stroke in patients
with atrial fibrillation by about 20% and is used
in treating patients with atrial fibrillation for
whom vitamin K antagonist therapy is unsuit-
able.6 The addition of clopidogrel to aspirin in
patients for whom vitamin K antagonist therapy
is unsuitable further reduces the risk of stroke
by 28%, but the combination increases the risk
of major hemorrhage.7 There is a need for better
antithrombotic agents.
Apixaban is a direct and competitive inhibitor
of factor Xa.8 It has about 50% bioavailability,
and approximately 25% is excreted by the kidney.
Apixaban, at a dose of 2.5 mg twice daily, has
been shown to be effective and safe for the pre-
vention of venous thromboembolism after elective
orthopedic surgery.9,10 The AVERROES (Apixaban
Versus Acetylsalicylic Acid [ASA] to Prevent Stroke
in Atrial Fibrillation Patients Who Have Failed or
Are Unsuitable for Vitamin K Antagonist Treat-
ment) study was therefore designed to determine
the efficacy and safety of apixaban, at a dose of
5 mg twice daily, as compared with aspirin, at a
dose of 81 to 324 mg daily, for the treatment of
patients with atrial fibrillation for whom vita-
min K antagonist therapy was considered un-
suitable.
trial fibrillation is a common ar-
rhythmia that increases the risk of stroke.1
Vitamin K antagonist therapy is more ef-
Methods
Study Design and Oversight
We conducted the study at 522 centers in 36
countries. Enrollment began on September 10,
2007, and was completed on December 23, 2009.
The study was designed by the steering commit-
tee (see the Supplementary Appendix, available
with the full text of this article at NEJM.org), to-
gether with the sponsors, Bristol-Myers Squibb
and Pfizer. The data were collected, validated,
and analyzed at the Population Health Research
Institute at Hamilton Health Sciences and Mc-
Master University, Hamilton, Canada, with on-site
monitoring by the sponsors. All drafts of the
manuscript were written by the first author, with
the sponsors and all the other authors providing
comments. All the authors vouch for the find-
ings. There were no agreements between the au-
thors and the sponsors that limited the authors’
ability to publish the overall study results. The
protocol was approved by the ethics committee at
each participating site, and all patients provided
written informed consent before enrollment.
The study protocol, which is available at
NEJM.org, has been described in detail previous-
ly.11 Patients were eligible if they were 50 years
of age or older and had atrial fibrillation docu-
mented in the 6 months before enrollment or by
12-lead electrocardiography on the day of screen-
ing. Patients also had to have at least one of the
following risk factors for stroke: prior stroke or
transient ischemic attack, an age of 75 years or
older, arterial hypertension (receiving treatment),
diabetes mellitus (receiving treatment), heart fail-
ure (New York Heart Association class 2 or higher
at the time of enrollment), a left ventricular ejec-
tion fraction of 35% or less, or documented periph-
eral-artery disease. In addition, patients could
not be receiving vitamin K antagonist therapy,
either because it had already been demonstrat-
ed to be unsuitable for them or because it was
expected to be unsuitable. The reasons that vita-
min K antagonist therapy was unsuitable for the
patient had to be documented on the study case-
report forms.
The key exclusion criteria were the presence
of conditions other than atrial fibrillation for
which the patient required long-term anticoagu-
lation, valvular disease requiring surgery, a seri-
ous bleeding event in the previous 6 months or
a high risk of bleeding (e.g., active peptic ulcer
disease, a platelet count of <100,000 per cubic
millimeter or hemoglobin level of <10 g per deci-
liter, stroke within the previous 10 days, document-
ed hemorrhagic tendencies, or blood dyscrasias),
current alcohol or drug abuse or psychosocial
issues, life expectancy of less than 1 year, severe
renal insufficiency (a serum creatinine level of
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The new england journal of medicine
n engl j med 364;9 nejm.org march 3, 2011
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>2.5 mg per deciliter [221 μmol per liter] or a
calculated creatinine clearance of <25 ml per
minute), an alanine aminotransferase or aspar-
tate aminotransferase level greater than 2 times
the upper limit of the normal range or a total
bilirubin more than 1.5 times the upper limit of
the normal range, and allergy to aspirin.
Patients were randomly assigned to receive
apixaban at a dose of 5 mg twice daily or aspirin
at a dose of 81 to 324 mg per day. Randomiza-
tion was performed with the use of a 24-hour
central, computerized, automated voice-response
system. In keeping with the double-dummy de-
sign, patients who were assigned to receive apixa-
ban also received an aspirin placebo, and those
assigned to receive aspirin also received an apixa-
ban placebo. A reduced dose of apixaban (2.5 mg
twice daily) was used throughout the study for
patients who met two of the following criteria:
an age of 80 years or older, a body weight of 60 kg
or less, or a serum creatinine level of 1.5 mg per
deciliter (133 μmol per liter) or higher. The dose
of aspirin was one to four 81-mg tablets daily, with
the dose selected at the discretion of the local
investigator. Investigators were encouraged to
discontinue any nonstudy aspirin at the time of
randomization. Patients taking a thienopyridine
at baseline were not eligible for inclusion in the
study, although these drugs could be prescribed
during the study if an indication emerged.
Outcomes
The primary efficacy outcome was the occurrence
of stroke (ischemic or hemorrhagic) or systemic
embolism. Stroke was a clinical diagnosis that
was made on the basis of typical symptoms last-
ing at least 24 hours. Brain imaging, which was
available in the vast majority of patients, was not
required but was recommended for the general
diagnosis of stroke; however, it was required to
differentiate ischemic from hemorrhagic events.
The primary safety outcome was the occurrence
of major bleeding, defined as clinically overt
bleeding accompanied by one or more of the fol-
lowing: a decrease in the hemoglobin level of 2 g
per deciliter or more over a 24-hour period, trans-
fusion of 2 or more units of packed red cells,
bleeding at a critical site (intracranial, intraspi-
nal, intraocular, pericardial, intraarticular, intra-
muscular with compartment syndrome, or retro-
peritoneal), or fatal bleeding. Other outcomes of
interest included the rates of myocardial infarc-
tion, death from vascular causes, and death from
any cause, as well as of composites of major vas-
cular events. All outcomes were adjudicated by a
committee whose members were unaware of the
treatment assignments. Cases of stroke and intra-
cranial hemorrhage were adjudicated by neurolo-
gists.
Statistical Analysis
We estimated that with a total of 5600 patients
enrolled and 226 primary outcome events, the
study would have at least 90% power to detect a
35% relative reduction in events with apixaban as
compared with aspirin, at a one-side alpha level
of 0.025, assuming a rate of the primary outcome
of 3.3% per year (i.e., 3.3 events per 100 person-
years) among patients taking aspirin. An indepen-
dent data and safety monitoring board monitored
the study for safety. Formal interim analyses were
planned when 50% and 75% of the primary effi-
cacy events had accrued. Stopping rules were
based on an analysis of the primary outcome for
which modified Haybittle–Peto boundaries of 4 SD
(log hazard ratio) were used in the first half of
the study and 3 SD in the second half. If either
of these thresholds was crossed, a confirmatory
analysis was to be performed 3 months later, and
if that analysis also crossed the specified bound-
ary, the data and safety monitoring board could
recommend that the trial be terminated. The
CHADS2 scale was used to assess a patient’s risk
of stroke. The CHADS2 scale is a measure of the
risk of stroke in patients with atrial fibrillation.
Congestive heart failure, hypertension, an age of
75 years or older, and diabetes are each assigned
1 point, and previous stroke or transient ischem-
ic attack is assigned 2 points; the score is calcu-
lated by summing all the points for a given pa-
tient, with a higher score indicating a greater risk
of stroke. All primary efficacy and safety analy-
ses were based on the intention-to-treat principle.
Cox proportional-hazards modeling and log-rank
testing were used for efficacy and safety analy-
ses. Baseline data are reported as means ±SD for
quantitative data and as percentages for propor-
tions. Data on adverse events were compared
with the use of chi-square tests.
Results
Patients
The baseline clinical characteristics were well
balanced between the two study groups (Table 1).
A total of 37% of the patients were from North
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Apixaban in Patients with Atrial Fibrillation
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America or Western Europe. In the 30 days be-
fore screening, three quarters of the patients had
been taking aspirin and 15% had been taking a
vitamin K antagonist. Of the 5599 patients en-
rolled, 2216 (40%) had previously received but
discontinued vitamin K antagonist therapy; for
932 of these patients (42%), it was determined
that the INR could not be maintained in the thera-
peutic range (Table 2). In the case of 2387 of the
5599 patients enrolled in the study (43%), the
physician had determined that INR measure-
ments could not be obtained or were unlikely to
be obtained at the requested intervals. Vitamin K
antagonist therapy was considered to be unsuit-
able for 1195 patients (21%) because the risk of
stroke was only moderate, as assessed by a score
of 1 on the CHADS2 scale. There were 2092 pa-
tients (37%) who did not want to take vitamin K
antagonists; in the case of 815 patients (15%),
this was the only reason that vitamin K antago-
nist therapy was unsuitable.
Early Termination of Study
The data and safety monitoring committee re-
viewed the results of the first planned interim
analysis of efficacy on February 19, 2010, at which
time 104 events had occurred, and observed a
treatment benefit in favor of apixaban for the pri-
mary outcome that exceeded 4 SD. The results of
a confirmatory analysis were reviewed on May
28, 2010, at which time the P value was 0.000002
(z = 4.76), and study termination was recommend-
ed. Events that occurred through May 28, 2010,
were included in the primary analyses. The pa-
tients’ final study visits were scheduled to occur
between July 1 and August 15, 2010. The mean
duration of follow-up through May 28, 2010, was
1.1 years.
Study Treatment
Most patients received apixaban or an apixaban
placebo at a dose of 5 mg twice a day. A total of
6% of the patients in the apixaban group and 7%
in the aspirin group received 2.5 mg twice a day,
according to protocol. A daily dose of 81 mg of
aspirin or aspirin placebo was used in the case of
65% of the patients in the apixaban group and
64% in the aspirin group. A total of 264 of the
2808 patients in the apixaban group (9%) and
246 of the 2791 in the aspirin group (9%) took
nonstudy aspirin more than 50% of the time dur-
ing the study. Clopidogrel was used at least once
during the study in combination with aspirin or
aspirin placebo by 38 patients in the apixaban
group (1%) and 46 in the aspirin group (2%) and
was used more than 50% of the time by 13 pa-
tients and 18 patients in the two groups, respec-
tively.
Outcome Events
There were 51 primary outcome events (a rate of
1.6% per year) among patients assigned to apixa-
ban and 113 (3.7% per year) among patients as-
signed to aspirin (hazard ratio with apixaban,
0.45, 95% confidence interval [CI], 0.32 to 0.62;
P<0.001; z = 4.76) (Table 3 and Fig. 1). The corre-
sponding rates of ischemic stroke were 1.1% per
year and 3.0% per year (hazard ratio with apixa-
ban, 0.37; 95% CI, 0.25 to 0.55; P<0.001). There
were six cases of hemorrhagic stroke (intracere-
bral hemorrhage) among patients receiving apix-
aban and nine among those receiving aspirin.
The rate of death was 3.5% per year in the apixa-
ban group and 4.4% per year in the aspirin group
(hazard ratio with apixaban, 0.79; 95% CI, 0.62
to 1.02; P = 0.07). The rate of hospitalization for
cardiovascular causes was lower in the apixaban
group than in the aspirin group (12.6% per year
vs. 15.9% per year; hazard ratio with apixaban,
0.79; 95% CI 0.69 to 0.91; P<0.001). In an analysis
that included all events up to the final study vis-
its, there were 56 primary outcome events (a rate
of 1.6% per year) in the apixaban group and 126
(3.6% per year) in the aspirin group (hazard ratio
with apixaban, 0.44; 95% CI, 0.32 to 0.60; P<0.001;
z = 5.12).
Adverse Events
There were 44 major bleeding events (a rate of
1.4% per year) among patients taking apixaban
and 39 (1.2% per year) among those taking aspi-
rin (hazard ratio with apixaban,1.13; 95% CI, 0.74
to 1.75; P = 0.57) (Fig. 1B). There were 188 and
153 minor bleeding events in the apixaban and
aspirin groups, respectively (hazard ratio with
apixaban, 1.24; 95% CI, 1.00 to 1.53; P = 0.05). In
an on-treatment analysis, which included only
events that occurred in patients while they were
receiving the study treatment (i.e., ≤2 days after
permanent discontinuation of the study medica-
tion), there were 45 major bleeding events (1.4%
per year) among patients in the apixaban group,
as compared with 29 (0.9% per year) among pa-
tients in the aspirin group (hazard ratio, 1.54;
95% CI, 0.96 to 2.45; P = 0.07). The composite
rate of stroke, systemic embolism, myocardial
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The new england journal of medicine
n engl j med 364;9 nejm.org march 3, 2011
810
infarction, death from vascular causes, or major
bleeding was reduced with apixaban, as compared
with aspirin (intention-to-treat analysis, 5.3% per
year vs. 7.2% per year; hazard ratio 0.74; 95% CI,
0.60 to 0.90; P = 0.003; on-treatment analysis, 4.0%
per year vs. 6.3% per year; hazard ratio, 0.64;
95% CI, 0.51 to 0.80; P<0.001).
At 2 years, the rates of permanent discontinu-
ation of the study medication were 17.9% per year
in the apixaban group and 20.5% per year in the
aspirin group; the risk of permanent discontinu-
ation was 12% lower in the apixaban group than
in the aspirin group (hazard ratio with apixaban,
0.88; 95% CI, 0.78 to 0.99; P = 0.03). Significantly
fewer patients in the apixaban group than in the
aspirin group had a serious adverse event (22%
Table 1. Baseline Characteristics of the Patients and Doses of Study Medication.*
Variable
Apixaban
(N = 2808)
Aspirin
(N = 2791)
Age — yr 70±970±10
Heart rate — beats/min 74±14 74±14
Systolic blood pressure — mm Hg 132±16132±16
Body-mass index† 28±528±5
Male sex — no. (%) 1660 (59)1617 (58)
Baseline electrocardiographic findings — no. (%)
Atrial fibrillation 1923 (68)1894 (68)
Atrial flutter19 (1)20 (1)
Sinus rhythm707 (25)730 (26)
Paced or other rhythm147 (5)139 (5)
Left ventricular hypertrophy 490 (17)498 (18)
Risk factors for stroke — no. (%)
Prior stroke or transient ischemic attack390 (14) 374 (13)
Hypertension, receiving treatment2408 (86) 2429 (87)
Heart failure1118 (40) 1053 (38)
NYHA class 1 or 2 932 (33)878 (31)
NYHA class 3 or 4 186 (7)175 (6)
Left ventricular ejection fraction ≤35%144 (5)144 (5)
Peripheral-artery disease 66 (2) 87 (3)
Diabetes, receiving treatment537 (19)559 (20)
Mitral stenosis 64 (2)50 (2)
Classification of atrial fibrillation — no. (%)
Paroxysmal760 (27)752 (27)
Persistent587 (21)590 (21)
Permanent1460 (52)1448 (52)
CHADS2‡
Mean score2.0±1.1 2.1±1.1
Score — no. (%)
0 or 11004 (36)1022 (37)
2 1045 (37)954 (34)
≥3758 (27) 812 (29)
High-school education or more — no. (%)1635 (58) 1635 (59)
Use of vitamin K antagonist within 30 days before screening — no. (%)401 (14) 426 (15)
Use of aspirin within 30 days before screening — no. (%)2137 (76)2081 (75)
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