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Andrzej Budaj, Steen Husted, Salim Yusuf, Gregory Y. H. Lip and Robert G.

Hart
Greg C. Flaker, John W. Eikelboom, Olga Shestakovska, Stuart J. Connolly, Scott Kaatz,
Antagonist Treatment (AVERROES) Trial
Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin k
Prevent Fibrillation Unsuitable for Warfarin: The Apixaban Versus Acetylsalicylic Acid to
Bleeding During Treatment With Aspirin Versus Apixaban in Patients With Atrial
Print ISSN: 0039-2499. Online ISSN: 1524-4628
Copyright 2012 American Heart Association, Inc. All rights reserved.
is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231 Stroke
doi: 10.1161/STROKEAHA.112.664144
2012;43:3291-3297; originally published online October 2, 2012; Stroke.
http://stroke.ahajournals.org/content/43/12/3291
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3291
T
he efficacy of warfarin for stroke prevention in
patients with atrial fibrillation (AF) is well estab-
lished by randomized clinical trials
13
but vitamin K antag-
onists (VKAs) remain underused in clinical practice.
46

Many patients who do not receive VKA receive aspirin for
stroke prevention.
Apixaban, a novel oral Factor Xa inhibitor, is superior
to aspirin for prevention of stroke in patients with AF who
were deemed unsuitable for warfarin anticoagulation in the
Apixaban versus Acetylsalicylic Acid to Prevent Stroke in
Atrial Fibrillation Patients Who Have Failed or Are Unsuitable
for Vitamin K Antagonist Treatment (AVERROES) trial.
7

Compared with aspirin, apixaban reduced the rate of stroke or
systemic embolism from 3.7%/year to 1.6%/year. The rate of
major bleeding was 1.4%/year with apixaban and 1.2%/year
with aspirin, not signicantly different.
Given the low rate of bleeding, apixaban appears to be
an attractive alternative to aspirin for stroke prevention
in patients with AF unsuitable for VKA. However, more
detailed information about bleeding risk would be useful to
guide clinicians concerning the relative merits of this new
anticoagulant when compared with aspirin. We analyze the
Background and PurposeApixaban reduces stroke with comparable bleeding risks when compared with aspirin in
patients with atrial brillation who are unsuitable for vitamin K antagonist therapy. This analysis explores patterns of
bleeding and denes bleeding risks based on stroke risk with apixaban and aspirin.
MethodsThe Apixaban versus Acetylsalicylic Acid to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or
Are Unsuitable for Vitamin K Antagonist Treatment (AVERROES) trial randomized 5599 patients with atrial brillation
and risk factors to receive either apixaban or aspirin. Bleeding events were dened as the rst occurrence of either major
bleeding or clinically relevant nonmajor bleeding.
ResultsThe rate of a bleeding event was 3.8%/year with aspirin and 4.5%/year with apixaban (hazard ratio with apixaban,
1.18; 95% CI, 0.921.51; P=0.19). The anatomic site of bleeding did not differ between therapies. Risk factors for
bleeding common to apixaban and aspirin were use of nonstudy aspirin >50% of the time and a history of daily/occasional
nosebleeds. The rates of both stroke and bleeding increased with higher CHADS
2
scores but apixaban compared with
aspirin was associated with a similar relative risk of bleeding (P interaction 0.21) and a reduced relative risk of stroke
(P interaction 0.37) irrespective of CHADS
2
category.
ConclusionsAnatomic sites and predictors of bleeding are similar for apixaban and aspirin in these patients. Higher
CHADS
2
scores are associated with increasing rates of bleeding and stroke, but the balance between risks and benets of
apixaban compared with aspirin is favorable irrespective of baseline stroke risk.
Clinical Trial Registration Informationwww.clinicaltrials.gov. Unique identier: NCT 00496769.
(Stroke. 2012;43:3291-3297.)
Key Words: apixaban atrial brillation clinical trial factor Xa inhibitor hemorrhage risk prediction
Bleeding During Treatment With Aspirin Versus Apixaban
in Patients With Atrial Fibrillation Unsuitable for Warfarin
The Apixaban Versus Acetylsalicylic Acid to Prevent Stroke in Atrial
Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K
Antagonist Treatment (AVERROES) Trial
Greg C. Flaker, MD; John W. Eikelboom, MBBS; Olga Shestakovska, MSc; Stuart J. Connolly, MD;
Scott Kaatz, DO, MSc; Andrzej Budaj, MD, PhD; Steen Husted, MD, DSc;
Salim Yusuf, MBBS, DPhil; Gregory Y. H. Lip, MD; Robert G. Hart, MD
Received May 22, 2012; nal revision received August 21, 2012; accepted August 28, 2012.
From the University of MissouriColumbia, Columbia, MO (G.C.F.); the Population Health Research Institute, McMaster University and Hamilton
Health Sciences, Hamilton, Ontario, Canada (J.W.E., O.S., S.J.C., S.Y., R.G.H.); Henry Ford Hospital, Detroit MI (S.K.); Postgraduate Medical School,
Warsaw, Poland (A.B.); Aarhus University Hospital, Skejby, Aarhus, Denmark (S.H.); and the University of Birmingham Centre for Cardiovascular
Sciences, City Hospital, Birmingham, UK (G.Y.H.L.).
The online- only Data Supplement is available with this article at http://stroke.ahajournals.org/lookup/suppl/doi:10.1161/STROKEAHA.112.
664144/-/DC1.
Correspondence to Greg C. Flaker, MD, Five Hospital Drive, CE306, Columbia, MO 65212. E- mail akerg@health.missouri.edu
2012 American Heart Association, Inc.
Stroke is available at http://stroke.ahajournals.org DOI: 10.1161/STROKEAHA.112.664144
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3292 Stroke December 2012
sites of bleeding and the clinical and laboratory predictors
of major and clinically relevant nonmajor bleeding during
apixaban and aspirin therapy in the AVERROES trial. We also
assess the risk of bleeding with apixaban versus aspirin in
patients determined to be at low, moderate, and high risk of
ischemic stroke.
Methods
The design, inclusion criteria, study execution, and main results of
the AVERROES trial have been published.
7,8
The AVERRROES
trial- included patients were not candidates for oral anticoagulation
with a VKA (eg, warfarin). Reasons for unsuitability for VKA are
listed in the main article.
8
Investigators were asked to indicate the rea-
son for unsuitability for warfarin, which included an inability to main-
tain an international normalized ratio within the therapeutic range,
international normalized ratio could not be assessed at requested
intervals, uncertainty about the patients ability to comply with in-
structions, anticipated difculty in contacting the patient about urgent
dosing changes, uncertainty regarding a favorable balance between
the benets and the risk of therapy for patients with CHADS
2
=1, or
patient refusal. In most patients, multiple reasons for unsuitability for
VKA therapy were provided. Salient exclusion criteria relevant to
bleeding were recent serious bleeding and active peptic ulcer disease.
Patients were randomized to receive apixaban (5 mg twice daily) or
aspirin (81324 mg daily) administered double- blind. A reduced dose
of apixaban (2.5 mg twice a day) was assigned to participants who met
at least 2 of the following criteria: (1) age 80 years; (2) body weight
60 kg; or (3) serum creatinine 1.5 mg/dL or 133 mol/L. For this
analysis, the estimated glomerular ltration rate was calculated using
the CKD- EPI (Chronic Kidney Disease Epidemiology Collaboration)
formula, considered to be more accurate than other equations and
appropriate for population studies.
9
Patients were strongly encour-
aged to stop open- label aspirin if they were taking aspirin at baseline.
Patients who developed a clear indication for antiplatelet therapy dur-
ing the study were advised to not exceed 100 mg daily of aspirin.
The bleeding outcome of interest for these analyses was the rst
occurrence of either major bleeding or clinically relevant nonmajor
bleeding, both dened in the online- only Data Supplement.
All analyses were based on the intention- to- treat principle. The
rates of major and clinically relevant nonmajor bleeding were
Figure 1. Kaplan- Meier estimates of
the cumulative hazard function for major
bleeding (A) and the composite of major
and clinically relevant nonmajor bleeding
(B) in 2 treatment groups. Probability value
is from the likelihood ratio test, Cox pro-
portional hazards regression model.
Table 1. Site of Bleeding
Major Bleeding Major or Clinically Relevant Nonmajor Bleeding
No. of Events %/y No. of Events %/y
Aspirin (N=2791) Apixaban (N=2808) P Value Aspirin (N=2791) Apixaban* (N=2808) P Value
Intracranial 13 (0.41) 11 (0.35) 0.69 13 (0.41) 11 (0.35) 0.69
Gastrointestinal 14 (0.45) 11 (0.35) 0.56 39 (1.25) 42 (1.35) 0.73
Respiratory tract 0 1 (0.03) . . . 8 (0.25) 6 (0.19) 0.59
Supercial/hematoma/puncture site 3 (0.10) 3 (0.10) . . . 22 (0.70) 13 (0.41) 0.13
Genitourinary 1 (0.03) 0 . . . 17 (0.54) 23 (0.74) 0.34
Ear, nose, and throat** 2 (0.06) 0 . . . 15 (0.48) 25 (0.80) 0.11
Surgical bleeding/trauma 5 (0.16) 6 (0.19) 0.75 8 (0.25) 9 (0.29) 0.80
Other 3 (0.10) 13 (0.41) . . . 6 (0.19) 14 (0.45) 0.07
*One patient in the apixaban group with intracranial site of bleeding was excluded from the analysis of the composite of major and clinically relevant nonmajor
bleeding.
P value is from the likelihood ratio test (Cox proportional hazards regression model). The rates were not compared if no. of events was <5 in either of the treatment
groups.
An event is the rst occurrence of major bleeding (left) and either major or clinically relevant nonmajor bleeding (right) at the specic site. The time to event is the
time between the randomization date and the event rst occurrence.
Percent per year is the rate per 100 patient- years of follow- up.
Supercial/hematoma/puncture site includes bruising/ecchymosis, conjunctival, and subcutaneous.
Genitourinary includes hematuria, urinary tract, and vaginal.
**Ear, nose, and throat includes epistaxis and gingival.
Surgical bleeding/trauma includes trauma/laceration.
Other includes intraocular, intra- articular, intramuscular, pericardial, retroperitoneal, and no source identied.
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Flaker et al Bleeding With Aspirin and Apixaban 3293
calculated based on the specic location of the bleeding in
patients treated with aspirin or apixaban. Rates were calculated as
the number of rst events per number of patient- years of follow- up.
Patients were censored at death, loss of follow- up, or end of study,
whichever occurred rst. The occurrence of site- specic bleeding
with aspirin and apixaban was compared using Cox proportional
hazards regression models. For the composite outcome of major
and clinically relevant nonmajor bleeding, a number of baseline
clinical and laboratory characteristics were considered as potential
risk factors for bleeding with aspirin and apixaban. Univariate Cox
proportional hazards regression models were used to assess the as-
sociations between the characteristics and the rates of a bleeding
event unadjusted for other risk factors in the 2 treatment groups.
Multivariable Cox models included characteristics that were either
signicantly associated with the outcome in the univariate analysis
or were known important risk factors. These characteristics were
tted regardless of the characteristics apparent level of signicance
in the univariate analysis. Signicance was established at the 5%
level.
Cox proportional hazards regression models were used to
assess the effect of apixaban compared with aspirin on the rate of
bleeding events as well as stroke in subgroups by ischemic stroke
risk categories as evaluated by the CHADS
2
score: 0 to 1 (low), 2
(intermediate), and 3 to 6 (high). The signicance of interaction
between the ischemic stroke risk categories and the effect of apixa-
ban compared with aspirin on stroke and bleeding outcome was
also assessed.
The analyses were performed using SAS software, Version 9.2 of
the SAS System for SunOS (SAS Institute Inc, Cary, NC).
Results
Clinical characteristics of study participants have been reported
in detail
7
and are briey summarized here. Among the 5599
participants, the mean participant age was 70 years, 59% were
men, and 14% had a prior stroke or transient ischemic attack.
A total of 264 of the 2808 patients in the apixaban group (9%)
and 246 of the 2791 in the aspirin group (9%) took additional
nonstudy aspirin >50% of the time during follow- up.
After a mean follow- up of 1.1 years, there were 83 major
hemorrhages (44 on apixaban, 39 on aspirin, rst events) and
180 clinically relevant nonmajor hemorrhages (96 on apixaban,
84 on aspirin, rst events). Ten patients (3 on apixaban and 7
on aspirin) had both severities of bleeding. The annual rate of
major bleeding was 1.2% with aspirin and 1.4% with apixaban
(hazard ratio with apixaban, 1.13; 95% CI, 0.741.75; P=0.57),
and the annualized rate of clinically relevant nonmajor bleeding
was 2.7% with aspirin and 3.1% with apixaban (hazard ratio
with apixaban, 1.15; 95% CI, 0.861.54; P=0.35). One patient
in the apixaban group had an asymptomatic cerebral microbleed
Table 2. Multivariable Analysis of Predictors of the Composite of Major and Clinically Relevant Nonmajor
Bleeding in 2 Treatment Groups
Aspirin (N=2791) Apixaban* (N=2808)
Characteristic Hazard Ratio (95% CI) P Value Hazard Ratio (95% CI) P Value
Age 75 y 1.32 (0.881.98) 0.18 1.60 (1.102.32) 0.01
Female sex 0.82 (0.541.23) 0.33 0.96 (0.661.39) 0.82
Regular alcohol consumption (at least once/wk) 1.08 (0.681.66) 0.74 0.98 (0.641.49) 0.94
Prior stroke or transient ischemic attack 1.07 (0.611.75) 0.81 1.49 (0.952.25) 0.08
Hypertension, receiving treatment 0.78 (0.481.33) 0.35 1.49 (0.892.68) 0.13
Heart failure or LVEF 35% 0.90 (0.611.32) 0.59 0.85 (0.591.21) 0.37
Peripheral artery disease 2.30 (1.114.27) 0.03 1.89 (0.734.00) 0.17
Diabetes, receiving treatment 0.96 (0.591.49) 0.85 1.08 (0.691.62) 0.74
Classication of AF 0.43 0.19
Persistent versus paroxysmal 0.85 (0.471.50) 0.98 (0.611.55)
Permanent versus paroxysmal 1.18 (0.761.85) 0.72 (0.481.08)
History of cancer 0.96 (0.461.79) 0.91 1.30 (0.732.18) 0.36
Ever fainted 0.62 (0.321.09) 0.10 1.12 (0.701.72) 0.64
Daily/occasional nosebleeds 2.47 (1.264.42) 0.01 2.10 (1.113.65) 0.02
Hemorrhoids 1.38 (0.752.38) 0.29 1.29 (0.762.08) 0.33
Non- study aspirin >50% of the time 1.89 (1.133.02) 0.02 1.75 (1.092.70) 0.02
Hemoglobin g/L 0.621 (0.4190.922) 0.02 0.745 (0.5161.077) 0.12
Estimated GFR: 60 mL/min versus <60 mL/min 0.66 (0.440.98) 0.04 0.78 (0.541.13) 0.19
LVEF indicates left ventricular ejection fraction; AF, atrial brillation; GFR, glomerular ltration rate.
*One patient in the apixaban group with clinically relevant nonmajor bleeding and intracranial site of bleeding was excluded.
Furthermore, due to missing values in some of the predictor variables, the total no. of patients used in the multivariable analysis was
5566 (2776 in the aspirin group and 2790 in the apixaban group), and the no. of events was 250 (115 in the aspirin group and 135 in
the apixaban group).
P value is from the likelihood ratio test of the overall signicance of a variable in the multivariable Cox proportional hazards
regression model. Hazard ratio 95% CI limits are prole likelihood limits.
Treated as a continuous variable. Hazard ratio and 95% CI limits are shown for the increase of 2 SDs. For hemoglobin,
SD=15.4 g/L.
Calculated using the CKD- EPI (Chronic Kidney Disease Epidemiology Collaboration) equation.
9
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3294 Stroke December 2012
detected by MRI as part of a prospective substudy. This patient
was reported as having a nonmajor intracranial hemorrhage
was excluded from this analysis. The rate of major or clini-
cally relevant nonmajor bleeding was 3.8%/year with aspirin
and 4.5%/year with apixaban (hazard ratio with apixaban, 1.18;
95% CI, 0.921.51; P=0.19). Kaplan- Meier cumulative haz-
ard rates show a steady accumulation of hemorrhages during
follow- up with no evidence of higher early rates of bleeding
(Figure 1AB).
Sites of Bleeding
The most frequent site of bleeding with both treatments was
gastrointestinal (1.35%/year with apixaban and 1.25%/year
with aspirin). The rates of site- specic major or clini-
cally relevant nonmajor bleeding were similar with the 2
antithrombotic treatments (Table 1). Of note the rates of
intracranial hemorrhage were 0.41%/year with aspirin and
0.35%/year with apixaban (P=0.96). Of all fatal intracranial
hemorrhages, 3 (0.1%/year) occurred in patients assigned to
apixaban and 4 (0.13%/year) occurred in those assigned to
aspirin.
Predictors of Bleeding
In multivariable analysis, the only statistically signicant
independent predictors of major and clinically relevant non-
major bleeding shared between those assigned to aspirin and
apixaban were the use of nonstudy aspirin >50% of the time
(P=0.02 for both treatments) and a history of daily/occasional
nosebleeds (P=0.01 and P=0.02, respectively). Additionally,
there were 4 independent predictors associated with the out-
come for one treatment but with a similar hazard ratio for the
other treatment, albeit not reaching statistical signicance: age
(75 years versus <75 years), estimated glomerular ltration
rate (60 mL/min versus <60 mL/min), hemoglobin, and
peripheral artery disease (Table 2).
Bleeding Risk in Selected Subgroups
The relative risks of major or clinically relevant nonmajor
bleeding were similar in patients assigned to apixaban com-
pared with aspirin in key subgroups based on baseline char-
acteristics (Figure 2). There were no signicant interactions
among age, sex, body mass index, study dose of aspirin or
aspirinplacebo, or estimated glomerular ltration rate and
randomized treatment for the outcome of major and clini-
cally relevant nonmajor bleeding. Using established models
to predict bleeding,
1013
the relative risks of major or clini-
cally relevant nonmajor bleeding were similar in patients
assigned to apixaban compared with aspirin (Figure 3)
with no signicant interactions between high- and low- risk
categories.
Balance Between Strokes Prevented and Bleeding
According to Ischemic Stroke Risk
Compared with aspirin, apixaban consistently reduced the
rate of ischemic stroke and systemic embolism irrespective of
CHADS
2
score (Table 3). The absolute risk of bleeding with
apixaban increased with increasing stroke risk. For low- risk
CHADS
2
(score 01), the stroke rates were only 0.7%/year,
whereas the bleeding event rate was 2.9%/year. For high- risk
CHADS
2
(score 36), the stroke rate was 1.8%/year, whereas
the bleeding rate was 6.1%/year. There was no heterogene-
ity of treatment effect of apixaban compared with aspirin for
bleeding according to CHADS
2
score risk categories. For
patients at higher risk for stroke (CHADS
2
36), the differ-
ence between ischemic strokes prevented and bleeding was
2.1%/year.
Figure 2. Risk of major or clinically rel-
evant nonmajor bleeding with apixaban
versus aspirin in key subgroups according
to baseline characteristics. The squares
and horizontal lines indicate hazard ratios
and the 95% CIs. The dashed vertical line
represents the point estimate of the over-
all hazard ratio.
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Flaker et al Bleeding With Aspirin and Apixaban 3295
Discussion
The main results of this study are (1) the site- specic bleeding
rates for patients with AF judged unsuitable for VKA treatment
are not substantially different between apixaban and aspirin;
(2) independent predictors of bleeding are similar with aspirin
and apixaban; and (3) the balance between strokes prevented
and bleeding risk for apixaban compared with aspirin is favor-
able at all levels of stroke risk. Thus, apixaban is an attractive
choice for antithrombotic prophylaxis across the spectrum of
ischemic stroke risk in patients with AF unsuitable for warfa-
rin therapy.
A major reason for not using anticoagulants for stroke pre-
vention in AF is fear of bleeding. The rate of major bleed-
ing with warfarin in recently completed clinical trials varied
between 1.4% and 3.57%/year.
1418
The rate of major bleed-
ing with dabigatran, a direct thrombin inhibitor, has been
reported to be between 2.71% and 3.11%/year depending on
the dose.
18
Data from anticoagulation clinics have reported
the rate of major bleeding to be extremely variable in
elderly patients, ranging from 1.87%/year to 7.2%/year.
19,20

Although differences in patient populations and bleeding
denitions limit cross trial comparisons, the types of patients
(age, CHADS
2
score) included in AVERROES are similar to
those included in other contemporary antithrombotic trials in
AF. The low rate of major bleeding in this study with apixa-
ban should help allay fear about bleeding. The risk of major
bleeding with apixaban in patients eligible for warfarin is
the ARISTOTLE trial was also low, ranging from 0.52% to
2.13%/year depending on the criteria used for major bleed-
ing.
21
Another Factor Xa inhibitor, rivaroxaban, has a rate of
major and clinically relevant nonmajor bleeding comparable
with warfarin.
22
The site of major and clinically relevant nonmajor bleeding
during treatment with highly efcacious dosages of apixaban
in elderly patients with AF were all similar to that seen with
aspirin. By contrast, warfarin compared with aspirin
16
or dabi-
gatran
18
causes more central nervous system bleeding, possibly
explained by inhibition of the tissue Factor VIIA complex that is
present in high concentration in the brain and critically important
in normal hemostasis.
23,24
On the other hand, dabigatran etexi-
late, a drug with low bioavailability, causes more gastrointestinal
bleeding than warfarin, possibly due to elevated concentrations
Table 3. Rates of Ischemic Stroke and Bleeding Events According to Risk Categories of CHADS
2
Score in 2 Treatment Groups
Ischemic Stroke, Stroke of Uncertain Classication
or Systemic Embolism
Major or Clinically Relevant
Nonmajor Bleeding
No. of Events/Patient, %/y No. of Events/Patient, %/y
Aspirin
(N=2791)
Apixaban*
(N=2808)
Rate
Difference, %/y P Value
P Value for
Interaction
Aspirin
(N=2791)
Apixaban*
(N=2808)
Rate
Difference, %/y P Value
P Value for
Interaction
Overall 106/2788 (3.4) 45/2806 (1.4) 2.0 <0.001 116/2788 (3.8) 136/2806 (4.5) 0.7 0.19
CHADS
2
score 0.37 0.21
01 (low risk) 18/1022 (1.6) 8/1004 (0.7) 0.9 0.05 39/1022 (3.5) 32/1004 (2.9) 0.6 0.44
2 (intermediate risk) 37/954 (3.4) 22/1044 (1.9) 1.6 0.02 40/954 (3.7) 55/1044 (4.8) 1.1 0.23
36 (high risk) 51/812 (5.8) 15/758 (1.8) 4.0 <0.001 37/812 (4.2) 49/758 (6.1) 1.9 0.08
*One patient in the apixaban group with clinically relevant nonmajor bleeding and intracranial site of bleeding was excluded. Only patients who had CHADS
2
scores
nonmissing were included in the analysis shown. Four patients had CHADS
2
score missing (3 in the aspirin group and one in the apixaban group). The total no. of patients
used in the analysis of CHADS
2
score was 5594 (2788 in the aspirin group and 2806 in the apixaban group).
P value is from the likelihood ratio test of signicance of the effect of apixaban versus aspirin in patients within a risk category (Cox proportional hazards regression
model t separately in each subgroup). P value for interaction is from the Cox model t to all patients and is 0.37 for ischemic stroke and 0.21 for bleeding events.
An event is the rst occurrence of ischemic stroke, stroke of uncertain classication or systemic embolism (left), and major or clinically relevant nonmajor bleeding
(right). The time to event is the time between the randomization date and the event rst occurrence.
Percent per year is the rate per 100 patient- years of follow- up.
Figure 3. Risk of major or clinically rel-
evant nonmajor bleeding with apixaban
versus aspirin in patients at high and
low risk of bleeding based on estab-
lished risk models. The squares and
horizontal lines indicate hazard ratios
and the 95% CIs. The dashed vertical
line represents the point estimate of the
overall hazard ratio.
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3296 Stroke December 2012
of the drug in the gut as a result of low bioavailability and con-
version of the prodrug to dabigatran by gut esterases. Potent
inducers of the p- glycoprotein system (like rifampin) may result
in increased local levels of dabigatran in the gut because dabi-
gatran etexilate is a substrate for p- glycoprotein.
25
The bleeding
prole of apixaban suggests that it is suitable across the spec-
trum of patients with AF who are at risk for stroke.
Limitations
Clinically relevant nonmajor bleeding was not adjudicated by
an independent, blinded events committee although mitigated
by blinding of investigators to treatment assignment. Like
with all randomized trial, patients enrolled in this study may
differ from patients in clinical practice who are thought to be
unsuitable for warfarin.
Conclusions
Patients who have bleeding and who are judged unsuitable
for warfarin have a relatively low risk of major bleeding
or clinically relevant nonmajor bleeding when treated with
aspirin or apixaban. The anatomic sites of bleeding and
independent predictors of bleeding are similar for apixa-
ban and aspirin and the favorable balance between benefits
and risks of treatment are evident at all levels of ischemic
stroke risk. The initial step in the decision to prescribe an
anticoagulant for stroke prevention in patients with AF
involves weighing the benefit of stroke prevention against
the risk of bleeding. These data reassure that apixaban
is an attractive option for stroke prevention for patients
with AF deemed unsuitable for warfarin at all levels of
stroke risk.
Sources of Funding
The AVERROES study (NCT 00496769) was funded by Bristol- Myers
Squibb and Pzer.
Disclosures
Dr Flaker serves as a consultant for Bristol- Myers Squibb and
Pzer, Sano- Aventis, and Boehringer- Ingelheim. Dr Eikelboom
receives consulting fees from Bristol- Myers Squibb, Sano- Aventis,
Eli Lilly, Astra Zeneca, and Novartis and lecture fees from
Bristol- Meyers Squibb, Sano- Aventis, Eli Lilly, and Astra
Zeneca. Dr Connolly received payment for serving on the boards of
Boehringer- Ingelheim, Sano- Aventis, Portola and Merck; consult-
ing fees from Boehringer- Ingelheim, Sano- Aventis, Portola, and
Merck; and grant support on behalf of his institution, McMaster
University, from Boehringer- Ingelheim, Sano- Aventis, Portola, and
Bristol- Myers Squibb and lecture fees from Boehringer- Ingelheim,
Sano- Aventis, and Portola. Dr Kaatz received grant sup-
port from Boehringer- Ingelheim, Bristol- Myers Squibb, Bayer,
Jansen, Johnson and Johnson, Eisa, the National Institutes of
Health, Canadian Institute of Health Research, Blue Cross/Blue
Shield of Michigan; speaker honorarium from Jansen, Johnson
and Johnson, Glaxo Smith Kline, and Eisai; is a consultant for
Boehringer- Ingelheim, Bristol- Myer Squibb, Pzer, Jansen, Johnson
and Johnson, Daiichi Sankyo; and is on the membership board for
nonprot organizations AC Forum, National Certication Board
of Anticoagulation Providers and National Blood Clot Alliance
Medical, and Scientic Advisory Board. Dr Budaj received consult-
ing fees from Sano- Aventis, Eli Lilly, Novartis, and Astra Zeneca
and grant support both for himself and on behalf of his institution,
Grochowski Hospital, Sano- Aventis, Boehringer- Ingelheim, Glaxo
Smith Kline, Bristol- Myers Squibb, and Astra Zeneca and lecture
fees from Sano- Aventis, Boehringer- Ingelheim, Glaxo Smith Kline,
and Astra Zeneca and reimbursement for travel, accommodations, or
meeting expenses from Sano- Aventis, Boehringer- Ingelheim, Glaxo
Smith Kline, and Astra Zeneca. Dr Yusuf received consulting fees
from Boehringer- Ingelheim, Sano- Aventis, Novartis, Astra Zeneca,
Bristol- Myers Squibb, and Glaxo Smith Kline and grant support from
Boehringer- Ingelheim, Sano- Aventis, Novartis, Astra Zeneca, Glaxo
Smith Kline, and Bristol Myers Squibb. Dr Lip received consulting
fees from Astellas, Boehringer- Ingelheim, Bayer, Daiichi, Merck,
Portola, Biotronic, Sano- Aventis, and Astra Zeneca and grant sup-
port on behalf of his institution, City Hospital, from Bayer; lecture
fees from Boehringer- Ingelheim, Bayer, Merck, and Sano- Aventis;
and payment from Boehringer- Ingelheim for developing educational
presentations. Dr Hart was paid for services rendered as a member of
the Operations and Publications Committee of AVERROES.
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SUPPLEMENTAL MATERIAL

Appendix
Major bleeding, the primary safety outcome of AVERROES, was defined as clinically overt
bleeding accompanied by 1 or more of the following: decrease in hemoglobin of 2 g/dl over a
24-hour period, transfusion of 2 units of packed red blood cells, bleeding that occurs in a
critical site (intracranial, intra-spinal, intraocular, pericardial, intra-articular, intramuscular with
compartment syndrome, retroperitoneal), or bleeding that was fatal. Clinically relevant non-
major bleeding was defined as acute clinically overt bleeding that does not satisfy additional
criteria required for the bleeding event to be defined as a major bleeding event but results in
hospital admission, physician-guided medical or surgical treatment, or prompting a change in
antithrombotic therapy. Examples of clinically relevant non- major bleeding events include 1)
epistaxis (nose bleed) during which the subject seeks medical attention from a physician in an
emergency room, or requires an intervention, e.g., nasal pack, or experiences a single bleeding
episode persists for five minutes or more. 2) gastrointestinal bleeding, defined as vomitus
containing frank blood or coffee ground material which tests positive for blood, or
endoscopically confirmed bleeding, or frank blood per rectum or melena stools. 3) hematuria
which persists for 24 hours or more after instrumentation. 4) bruising/ecchymosis defined as any
bruise which is assessed as unusual (e.g., greater than expected following surgery). 5)
hematoma which is demonstrated radiographically, e.g. by ultrasound, CT, MRI, associated with
a drop in hemoglobin with no external evidence of bleeding. 6) hemoptysis, defined as the
expectoration of blood or blood-stained sputum. Major bleeding was centrally adjudicated by
those unaware of treatment assignment in order to apply uniformly these criteria.

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