European Heart Journal (2014) 35, 224–232 CLINICAL RESEARCH

doi:10.1093/eurheartj/eht445 Atrial fibrillation

Apixaban vs. warfarin with concomitant aspirin in

patients with atrial fibrillation: insights from the
ARISTOTLE trial
John H. Alexander 1*, Renato D. Lopes 1, Laine Thomas 1, Marco Alings 2, Dan Atar 3,
Philip Aylward 4, Shinya Goto 5, Michael Hanna 6, Kurt Huber 7, Steen Husted 8,
Basil S. Lewis 9, John J.V. McMurray10, Prem Pais 11, Hubert Pouleur 12,
Philippe Gabriel Steg 13, Freek W.A. Verheugt 14, Daniel M. Wojdyla 1,
Christopher B. Granger 1, and Lars Wallentin 15
1
Duke Clinical Research Institute, Duke Medicine, Duke University Medical Center, Box 3850, Durham, NC 27710, USA; 2Working Group on Cardiovascular Research the Netherlands,
Utrecht, The Netherlands; 3Oslo University Hospital, Oslo, Norway; 4Flinders Medical Center, Adelaide, Australia; 5Tokai University School of Medicine, Kanagawa, Japan; 6Bristol-Myers
Squibb, Princeton, NJ, USA; 7Department of Cardiology and Emergency Medicine, Wilhelminen Hospital, Vienna, Austria; 8Aarhus University, Aarhus, Denmark; 9Lady Davis Carmel
Medical Center, Haifa, Israel; 10BHF Cardiovascular Research, University of Glasgow, Glasgow, UK; 11St John’s Medical College, Bangalore, Karnataka, India; 12Pfizer, Inc., New York, NY,
USA; 13Hopital Bichat-Claude Bernard, Paris, France; 14Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands; and 15Uppsala Clinical Research Center, Uppsala
University, Uppsala, Sweden

Received 30 October 2012; revised 23 September 2013; accepted 26 September 2013; online publish-ahead-of-print 20 October 2013

Aims We assessed the effect of concomitant aspirin use on the efficacy and safety of apixaban compared with warfarin in
patients with atrial fibrillation (AF).
.....................................................................................................................................................................................
Methods In ARISTOTLE, 18 201 patients were randomized to apixaban 5 mg twice daily or warfarin. Concomitant aspirin use was
and results left to the discretion of the treating physician. In this predefined analysis, simple and marginal structured models were used
to adjust for baseline and time-dependent confounders associated with aspirin use. Outcome measures included stroke
or systemic embolism, ischaemic stroke, myocardial infarction, mortality, major bleeding, haemorrhagic stroke, major or
clinically relevant non-major bleeding, and any bleeding. On Day 1, 4434 (24%) patients were taking aspirin. Irrespective of
concomitant aspirin use, apixaban reduced stroke or systemic embolism [with aspirin: apixaban 1.12% vs. warfarin 1.91%,
hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.39–0.85 vs. without aspirin: apixaban 1.11% vs. warfarin 1.32%, HR
0.84, 95% CI 0.66– 1.07; P interaction ¼ 0.10] and caused less major bleeding than warfarin (with aspirin: apixaban 3.10%
vs. warfarin 3.92%, HR 0.77, 95% CI 0.60–0.99 vs. without aspirin: apixaban 1.82% vs. warfarin 2.78%, HR without aspirin
0.65, 95% CI 0.55–0.78; P interaction ¼ 0.29). Similar results were seen in the subgroups of patients with and without
arterial vascular disease.
.....................................................................................................................................................................................
Conclusion Apixaban had similar beneficial effects on stroke or systemic embolism and major bleeding compared with warfarin, ir-
respective of concomitant aspirin use.
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Keywords Concomitant medications † Aspirin † Atrial fibrillation † Stroke † Systemic embolism † Major bleeding

more effective for stroke prevention than antiplatelet therapy with

Introduction aspirin alone4,5 or aspirin plus clopidogrel.6 However, patients with
Oral anticoagulation is recommended for the prevention of AF frequently also have coronary artery disease or other indications
thromboembolic events in patients with atrial fibrillation (AF) at for aspirin.7,8 Randomized trials and observational studies have
risk for stroke.1 – 3 Oral anticoagulants have been shown to be demonstrated high rates of bleeding with the combination of

* Corresponding author. Tel: +919 668 8955, Fax: +919 668 7085, Email: john.h.alexander@duke.edu
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: journals.permissions@oup.com
Apixaban vs. warfarin with concomitant aspirin in patients with AF
aspirin therapy and vitamin K antagonists (VKAs).9 – 15 Clinical trials
comparing new oral anticoagulants with placebo in patients with
recent acute coronary syndromes already on antiplatelet therapy
also showed substantial increases in bleeding and inconsistent reduc-
tions in ischaemic events.16,17 Therefore, recent consensus recom-
mendations for patients with AF and a coronary stent recommend
combining antiplatelet and anticoagulant therapy for up to 12
months and then discontinuing antiplatelet therapy and continuing
only anticoagulation in the majority of patients.18 – 20
In the ARISTOTLE trial, in patients with AF at risk for stroke, apix-
aban was superior to warfarin for stroke prevention and resulted in
less major bleeding.21 The details of the efficacy and safety of apixaban
compared with warfarin in patients with AF receiving concomitant
aspirin have not been described. The objectives of this prespecified
analysis from the ARISTOTLE trial were to (i) describe the use
over time and dose of concomitant aspirin in patients with AF
overall and in the subgroups of patients with and without arterial vas-
cular disease, and (ii) evaluate the efficacy and safety of apixaban com-
pared with warfarin in patients receiving and not receiving
concomitant aspirin overall and in the subgroups of patients with
and without arterial vascular disease.
Methods
Patient population and study drug
The design and main results of the ARISTOTLE trial have been published
previously.21,22 Briefly, ARISTOTLE was a double-blind, double-dummy,
randomized clinical trial of 18 201 patients with AF and at least one add-
itional risk factor for stroke or systemic embolism. Risk factors included
age ≥75 years, hypertension, diabetes, heart failure, or reduced left-
ventricular systolic function, and prior stroke or systemic embolism.
Patients were randomized to warfarin and apixaban placebo (n ¼ 9081)
orapixaban 5 mg twice daily and warfarin placebo (n ¼ 9120). Patients with
two or three of the following characteristics—age ≥80 years, weight
≤60 kg, creatinine ≥1.5 mg/dL—at baseline were assigned to apixaban
2.5 mg twice daily or matching placebo. Warfarin was adjusted to a
target international normalized ratio (INR) of 2.0–3.0 using a blinded
encrypted bedside device.
Aspirin
Patients on aspirin ≥165 mg per day and those who required treatment
with both aspirin and a P2Y12 receptor antagonist at baseline were not eli-
gible to be enrolled in ARISTOTLE. The use and dosing of aspirin and of
P2Y12 receptor antagonists during the trial was left to the discretion of
the treating physician. For patients who required aspirin, a ‘low-dose’
(≤165 mg daily) was recommended. Patients who required antiplatelet
therapy during the trial and were considered to be at high risk for bleeding
could, but were not required to, temporarily discontinue study drug.
Outcomes
The median duration of follow-up in ARISTOTLE was 1.8 years. Out-
comes in this analysis include stroke or systemic embolism, ischaemic
stroke, myocardial infarction, all-cause mortality, major bleeding classi-
fied according to the International Society on Thrombosis and Haemo-
stasis (ISTH) scale, haemorrhagic stroke, major or clinically relevant
non-major bleeding, and any bleeding. All endpoints, with the exception
of any bleeding, were adjudicated by a clinical events committee blinded
to treatment assignment using prespecified criteria.
225
Statistical analysis
Baseline categorical variables are presented as percentages and continu-
ous variables as medians and 25th, 75th percentiles. Because a significant
proportion of patients taking aspirin at baseline stopped it on Day 1, we
defined aspirin users as those using aspirin on Day 1. We determined the
frequency of aspirin use during the trial overall and among patients with
and without a history of arterial vascular disease, which included a history
of coronary artery disease, stroke, or peripheral arterial disease. Because
we were interested in concomitant aspirin and anticoagulation use,
patients were censored when they permanently discontinued study
drug. Baseline characteristics were compared using the Wilcoxon rank
sum test for continuous variables and the x2 test for categorical variables.
All analyses were performed at the Duke Clinical Research Institute
(Durham, NC, USA) using SAS version 9.2 (SAS Institute, Inc., Cary,
NC, USA).
Outcomes are presented as the number of events and event rates per
year. Hazard ratios (HRs) and 95% confidence intervals (CIs) comparing
aspirin users and non-users were derived from a Cox proportional
hazards model after adjustment for a prespecified list of baseline variables
associated with either the propensity to use aspirin or the outcomes of
interest. These variables included age, sex, prior warfarin use, body
mass index, prior stroke, left-ventricular ejection fraction ≤40%, dia-
betes, hypertension, type of AF, prior myocardial infarction, peripheral
arterial disease, congestive heart failure, chronic kidney disease, prior
percutaneous coronary intervention, prior coronary artery bypass
surgery, and history of bleeding. Non-linearity in continuous covariates
was handled by fitting restricted cubic splines. Missing data were rare
for these covariates (,1.2%) and were handled by single imputation.
The interaction between randomized treatment and aspirin use was
tested in this Cox proportional hazards model. Hazard ratios for the ran-
domized treatment among aspirin users and non-users were derived
from this model with interaction. Analyses were conducted in the
overall population and in the subgroups of patients with and without
arterial vascular disease.
In addition to adjusting for baseline variables associated with either
the propensity to use aspirin or the outcomes of interest, we used mar-
ginal structural models to further adjust for potential time-dependent
confounders to estimate a HR for the effect of aspirin on outcome, and
to test for interaction between aspirin use and the randomized treat-
ment (apixaban vs. warfarin).23 This approach involves a Cox model
where aspirin status is a time-dependent covariate (i.e. patients can
contribute information to either the aspirin or non-aspirin category
depending on whether or not they are taking aspirin at a particular
time) and weighting is used to adjust for time-varying confounders
(i.e. variables measured during follow-up that may affect both
outcome and the chance of receiving aspirin). Post-randomization,
time-dependent confounders included whether or not the patient
was taking study drug, myocardial infarction, angina, percutaneous cor-
onary intervention, coronary stenting, non-intracranial major bleeding,
non-major bleeding, and interactions of prior myocardial infarction by
major non-intracranial bleeding, on study drug by angina and by percu-
taneous coronary intervention, on aspirin in the previous week by
angina, myocardial infarction by major non-intracranial bleeding and
by non-major bleeding, and age by non-major bleeding. Patients were
considered to be taking aspirin in a particular week if they received
aspirin for at least 50% of the days of the week. Patient weights were
re-calculated at weekly intervals during follow-up in order to balance
the case-mix between patients receiving and not receiving aspirin.
These analyses were also conducted in the overall population and
replicated in the subgroups of patients with and without arterial
vascular disease.
226
The ARISTOTLE trial was funded by Bristol-Myers Squibb (Princeton,
NJ, USA) and Pfizer, Inc. (New York, NY, USA) and they participated in
the trial design and data collection. The analyses presented here were
designed by the authors, performed at the Duke Clinical Research Insti-
tute, and interpreted by the authors. All authors, including two (M.H.,
H.P.) employed by the sponsors, commented on the manuscript. The de-
cision to publish the final manuscript was made by the first author (J.H.A.).
Results
Of the 18 201 patients enrolled in ARISTOTLE, 5632 (31%) were
using aspirin at baseline. Of the patients using aspirin at baseline,
1198 (21%) stopped within 1 day of enrolment. Thus, 4434 patients
(24%) were using aspirin on Day 1. Figure 1 illustrates the use of con-
comitant aspirin over time in the overall population and among
patients with and without a history of arterial vascular disease. The
rate of aspirin use was almost twice as high among patients with a
history of arterial vascular disease as among patients without a
history of arterial vascular disease. Among patients using aspirin on
Day 1, the majority were taking 75 (15%), 81 (30%), or 100 mg
(44%) daily. Among patients using aspirin on Day 1, 1134 (25.7%)
stopped aspirin during follow-up a median (25th, 75th) of 92 (15,
350) days after randomization. Among patients not using aspirin on
Day 1, 731 (5.4%) started aspirin during follow-up a median (25th,
75th) of 264 (112, 485) days after randomization.
Study drug discontinuation was more frequent among aspirin users
than among non-aspirin users (29.7 and 24.6%, P , 0.0001). Among
patients randomized to warfarin, the median (25th, 75th) time in
therapeutic range (INR ¼ 2.0 –3.0) was similar among aspirin users
and non-aspirin users [65.1 (50.7, 76.0) and 66.3 (52.0, 76.7)].
Use of antiplatelet agents other than aspirin was rare. On Day 1,
272 (1.5%) patients were receiving a P2Y12 receptor antagonist, pre-
dominantly clopidogrel. During the trial, a total of 579 patients (3.2%)
received a P2Y12 receptor antagonist in combination with study drug
for at least 1 day. Of these, only 135 (0.7%) patients took ‘triple
therapy’ with aspirin, a P2Y12 receptor antagonist, and study drug
for at least 7 days.
Baseline characteristics
Due to randomization, baseline characteristics were well matched
between the apixaban and warfarin groups among aspirin users and
non-users at baseline (data not shown). Baseline characteristics of
patients using and not using aspirin on Day 1 are shown in Table 1.
Aspirin users were more likely to be male, have diabetes or hyperten-
sion, and were significantly more likely to have a history of myocardial
infarction, percutaneous coronary intervention, coronary artery
bypass surgery, and peripheral arterial disease than non-users.
Aspirin use was more frequent in North America and less frequent
in Europe. Most aspirin users with a history of coronary revasculari-
zation had their most recent procedures more than 12 months prior
to enrolment. Aspirin users were less likely to have previously used
VKAs, had higher CHADS2 scores, and were more likely to have
recent onset AF than non-users. Aspirin users were more likely to
be using concomitant proton pump inhibitors (17.4%) than non-
aspirin users (12.8%).
J.H. Alexander et al.
Effect of apixaban vs. warfarin among
aspirin users and non-users
Ischaemic events
Outcomes among aspirin users and non-users randomized to apixa-
ban vs. warfarin are shown in Figure 2. Compared with warfarin, apix-
aban resulted in similar reductions in stroke or systemic embolism
among aspirin users and non-users (with aspirin: apixaban 1.12% vs.
warfarin 1.91%, HR 0.58, 95% CI 0.39–0.85 vs. without aspirin: apix-
aban 1.11% vs. warfarin 1.32%, HR 0.84, 95% CI 0.66 –1.07;
P interaction ¼ 0.10). There was also no evidence of a differential
effect of apixaban compared with warfarin on ischaemic stroke
(P interaction ¼ 0.19), myocardial infarction (P interaction ¼ 0.19),
or death (P interaction ¼ 0.23) among aspirin users and non-users.
Similar beneficial effects of apixaban compared with warfarin were
seen in the cohorts of patients with and without a history of arterial
vascular disease (Figure 2B and C ).
Results from marginal structural model analyses accounting for
whether a patient was actually taking aspirin at the time of their
event resulted in similar findings (Table 2). Using these techniques,
apixaban had a consistent effect among aspirin users and non-users
on stroke or systemic embolism, ischaemic stroke, myocardial infarc-
tion, and death both in the overall population and among the sub-
groups of patients with and without a history of arterial vascular
disease (Table 2).
Bleeding
Compared with warfarin, apixaban resulted in consistent reductions
in bleeding among both aspirin users and non-users (Figure 2A). There
were similar and statistically significant reductions in major bleeding
(with aspirin: apixaban 3.10% vs. warfarin 3.92%, HR 0.77, 95% CI
0.60–0.99 vs. without aspirin: apixaban 1.82% vs. warfarin 2.78%,
HR without aspirin 0.65, 95% CI 0.55–0.78; P interaction ¼ 0.29).
Consistent benefits were seen with apixaban compared with war-
farin among both aspirin users and non-users for haemorrhagic
stroke (P interaction ¼ 0.52), major or clinically relevant non-major
bleeding (P interaction ¼ 0.15), and any bleeding (P interaction ¼
0.70).
Similar beneficial effects of apixaban compared with warfarin on
bleeding were seen in the subgroups of patients with and without a
history of arterial vascular disease (Figure 2B and C).
For bleeding, results from marginal structural model analyses that
accounted for whether a patient was actually taking aspirin at the time
of their bleeding event resulted in similar findings (Table 2). Apixaban
had a consistent effect among aspirin users and non-users on causing
less major bleeding, haemorrhagic stroke, major or clinically relevant
non-major bleeding, and any bleeding both in the overall population
and in the subgroups of patients with and without a history of arterial
vascular disease (Table 2).
Outcomes among aspirin users and
non-users
Outcomes among aspirin users and non-users are shown in Table 3.
After adjustment for the propensity to use aspirin and for differences
in prognostically important baseline variables associated with aspirin
use, aspirin users had similar rates of stroke or systemic embolism, is-
chaemic stroke, myocardial infarction, and death and higher rates of
Apixaban vs. warfarin with concomitant aspirin in patients with AF
Figure 1 Net concomitant aspirin use over time overall and among patients with and without arterial vascular disease. This includes patients who
start and who stop aspirin. Arterial vascular disease includes a history of coronary artery disease, stroke, or peripheral arterial disease. Includes data
from Day 1 post-randomization until each patient’s permanent discontinuation of study drug.
bleeding when compared with non-users. After adjusting for both
baseline confounders and post-randomization variables associated
with aspirin use, aspirin users tended to have higher rates of stroke
or systemic embolism, ischaemic stroke, and myocardial infarction,
similar rates of death, and higher rates of bleeding than non-aspirin
users. In general, similar results were seen in the subgroups of
patients with and without a history of arterial vascular disease
(Table 3); although in patients with arterial vascular disease, aspirin
users tended to have higher rates of myocardial infarction and
lower rates of death than non-aspirin users.
Discussion
In the ARISTOTLE trial, apixaban reduced stroke or systemic embol-
ism and caused less bleeding than warfarin in patients with AF and at
least one risk factor for stroke.21 In this analysis of the concomitant
use of aspirin and oral anticoagulation from ARISTOTLE, the benefits
of apixaban over warfarin in terms of reducing stroke or systemic em-
bolism, causing less bleeding, and reducing mortality were consistent
irrespective of concomitant aspirin use. We found similar results,
with important benefits of apixaban over warfarin, in the subgroups
of patients with and without arterial vascular disease. If there is a
strong indication for a combination of aspirin and oral anticoagula-
tion, apixaban seems to be a safer alternative than warfarin in patients
with AF irrespective of concomitant aspirin use.
In ARISTOTLE, aspirin was used in combination with long-term
anticoagulation in 20 –25% of patients. Use of concomitant aspirin
was twice as common among patients with a history of arterial vascu-
lar disease as in patients without arterial vascular disease. Among
patients with arterial vascular disease, most did not have a recent
acute coronary event or revascularization procedure and even
227
among patients without a history of arterial vascular disease, a sub-
stantial number were taking aspirin. Current consensus recommen-
dations advise against using concomitant aspirin therapy in patients
with AF receiving oral anticoagulation without vascular disease or
with a remote (.12 month) history of an acute coronary event or
coronary stent.18 – 20,24
The use of aspirin in ARISTOTLE was not randomized and was left
to the discretion of the treating physician. Still we were interested in
getting as close as possible to establishing causal relationships
between concomitant aspirin use and the effects of apixaban vs. war-
farin on both ischaemic events and bleeding in patients with AF. Recog-
nizing that patients started and discontinued aspirin and interrupted
study drug during the trial, we evaluated outcomes after adjusting for
both baseline and time-dependent covariates that were associated
with aspirin use where the patients contributed to either the aspirin
or non-aspirin category depending on aspirin use at a different time,
and weighting was used to adjust for time-varying confounders.
This is a non-randomized comparison of aspirin users and
non-users. Patients receiving aspirin were different and had a
higher risk for both ischaemic events and bleeding than patients
not receiving aspirin. The relationship between aspirin use and bleed-
ing is consistent with the known risks of aspirin and the results of prior
studies and meta-analyses of randomized trials.15,25 – 28 Even after ad-
justment for measured confounders, however, we observed a trend
towards a higher rate of myocardial infarction and ischaemic stroke in
patients receiving aspirin. Given the known beneficial effects of
aspirin on the prevention of myocardial infarction and ischaemic
stroke in other populations, this may either represent residual con-
founding or mean that aspirin is not beneficial in patients with AF
who are also taking an anticoagulant.29 The consistently and substan-
tially higher rates of bleeding with concomitant use of aspirin and oral
anticoagulation confirm prior findings9 – 15 and should lead to a
228 J.H. Alexander et al.

Table 1 Baseline characteristics of aspirin users and non-users

Aspirin users (n 5 4434) Non-users (n 513 699) P-value

...............................................................................................................................................................................
Age, median (25th, 75th), years 70 (64, 76) 70 (62, 76) 0.0058
Female sex, n (%) 1405 (31.7) 4990 (36.4) ,0.0001
Weight, median (25th, 75th), kg 83 (70, 97) 82 (70, 95) 0.0015
BMI, median (25th, 75th), kg/m2 28.7 (25.4, 33.1) 28.4 (25.2, 32.4) 0.0022
Diabetes, n (%) 1282 (28.9) 3249 (23.7) ,0.0001
Hypertension, n (%) 3940 (88.9) 11 914 (87.0) 0.0010
History of CAD,a n (%) 2264 (51.1) 4354 (31.8) ,0.0001
History of MI, n (%) 1046 (23.6) 1529 (11.2) ,0.0001
History of PCI, n (%) 744 (16.8) 903 (6.6) ,0.0001
Time from most recent PCI 0.0452
,3 months 52 (7.0) 81 (9.0)
3– 12 months 71 (9.6) 112 (12.5)
.12 months 618 (83.4) 706 (78.5)
Proportion stent, n (%) 518 (70.7) 562 (63.4) 0.0019
Proportion DES 184 (35.5) 203 (36.1) 0.8373
Proportion BMS 334 (64.5) 359 (63.9)
History of CABG, n (%) 582 (13.1) 620 (4.5) ,0.0001
History of stroke, n (%) 501 (11.3) 1624 (11.9) 0.3172
History of PAD, n (%) 291 (6.6) 589 (4.4) ,0.0001
Heart failure, n (%) 1282 (28.9) 3791 (27.7) 0.1098
LVEF ,40%, n (%) 752 (17.0) 1858 (13.6) ,0.0001
Chronic kidney disease, n (%) 331 (7.5) 1174 (8.6) 0.0208
Prior VKA use, n (%) 1970 (44.4) 8398 (61.3) ,0.0001
CHADS2 score, n (%) ,0.0001
1 1391 (31.4) 4763 (34.8)
2 1616 (36.4) 4882 (35.6)
3 1427 (32.2) 4054 (29.6)
AF type, n (%) 0.1666
Paroxysmal 707 (15.9) 2066 (15.1)
Persistent or permanent 3727 (84.1) 11 630 (84.9)
Time from first onset of AF, n (%) ,0.0001
,6 months 1501 (33.9) 3543 (26.0)
6 –24 months 903 (20.4) 2645 (19.4)
.24 months 2021 (45.7) 7459 (54.7)
Region of enrolment ,0.0001
North America 1430 (32.2) 3007 (21.9)
Latin America 916 (20.7) 2542 (18.6)
Europe 1360 (30.7) 5971 (43.6)
Asia Pacific 728 (16.4) 2179 (15.9)
Randomized group 0.6917
Apixaban 2233 (50.4) 6852 (50.0)
Warfarin 2201 (49.6) 6847 (50.0)

AF, atrial fibrillation; BMI, body mass index; BMS, bare-metal stent; CABG, coronary artery bypass graft surgery; CAD, coronary artery disease; DES, drug-eluting stent; LVEF,
left-ventricular ejection fraction; MI, myocardial infarction; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; VKA, vitamin K antagonist.
a
Defined as documented history of coronary artery disease or prior MI, PCI, or CABG.

careful assessment of the indications for aspirin in patients with AF proportions of patients with AF who have either acute coronary syn-
who are receiving oral anticoagulation. dromes or who undergo percutaneous coronary intervention. Clo-
This analysis addresses only aspirin, predominantly ‘low-dose’ pidogrel use was an exclusion criterion at randomization and only
aspirin, and not other antiplatelet regimens. There are substantial started in a small proportion of patients included in the ARISTOTLE
Apixaban vs. warfarin with concomitant aspirin in patients with AF 229

Figure 2 Event rates per year, adjusted hazard ratios, and 95% confidence intervals for the effect of apixaban vs. warfarin among patients using and
not using aspirin in the overall population (A), and in the subgroups of patients with (B) and without (C) arterial vascular disease. Adjusted for baseline
covariates including age, sex, prior warfarin or VKA use, body mass index, prior stroke, left-ventricular ejection fraction ≤40%, diabetes, hyperten-
sion, type of AF, prior myocardial infarction, peripheral arterial disease, congestive heart failure, chronic kidney disease, prior percutaneous coronary
intervention, prior coronary artery bypass surgery, and history of bleeding. Numbers are event counts and event rates per year. CI, confidence inter-
val; CRNM, clinically relevant non-major; HR, hazard ratio.
230 J.H. Alexander et al.

Table 2 Marginal structural model analyses assessing effect of apixaban vs. warfarin in aspirin users and non-users overall
and in subgroups of patients with and without a history of arterial vascular disease

Aspirin users Non-users Interaction P-value

Apixaban vs. Warfarin Apixaban vs. Warfarin
HR (95% CI) HR (95% CI)
...............................................................................................................................................................................
Stroke or systemic embolism 0.59 (0.40–0.87) 0.85 (0.67–1.08) 0.1114
With arterial vascular disease 0.58 (0.37–0.92) 0.96 (0.71–1.30) 0.0772
Without arterial vascular disease 0.60 (0.28–1.28) 0.72 (0.49–1.05) 0.6817
Ischaemic stroke 0.72 (0.45–1.88) 0.99 (0.74–1.32) 0.2685
With arterial vascular disease 0.71 (0.41–1.23) 1.09 (0.77–1.56) 0.2013
Without arterial vascular disease 0.75 (0.29–1.93) 0.83 (0.51–1.36) 0.8515
MI 1.15 (0.70–1.88) 0.77 (0.51–1.14) 0.2144
With arterial vascular disease 1.08 (0.62–1.88) 0.73 (0.45–1.19) 0.3045
Without arterial vascular disease 1.38 (0.45–4.25) 0.84 (0.41–1.72) 0.4644
Death 1.03 (0.72–1.46) 0.85 (0.70–1.03) 0.3727
With arterial vascular disease 0.93 (0.59–1.46) 1.00 (0.77–1.29) 0.7937
Without arterial vascular disease 1.17 (0.66–2.08) 0.71 (0.53–0.95) 0.1277
Major bleeding 0.74 (0.57–0.95) 0.68 (0.57–0.81) 0.6312
With arterial vascular disease 0.77 (0.57–1.06) 0.74 (0.58–0.94) 0.8198
Without arterial vascular disease 0.66 (0.42–1.04) 0.63 (0.50–0.81) 0.8754
Haemorrhagic stroke 0.43 (0.21–0.87) 0.53 (0.32–0.87) 0.6332
With arterial vascular disease 0.44 (0.19–1.02) 0.50 (0.25–1.01) 0.8204
Without arterial vascular disease 0.46 (0.12–1.81) 0.57 (0.28–1.15) 0.7929
Major or CRNM bleeding 0.73 (0.60–0.89) 0.67 (0.59–0.76) 0.4623
With arterial vascular disease 0.78 (0.61–0.99) 0.75 (0.63–0.89) 0.8207
Without arterial vascular disease 0.64 (0.45–0.90) 0.60 (0.50–0.71) 0.7580
Any bleeding 0.69 (0.62–0.77) 0.72 (0.68–0.77) 0.4857
With arterial vascular disease 0.71 (0.62–0.81) 0.72 (0.65–0.79) 0.9224
Without arterial vascular disease 0.65 (0.54–0.78) 0.73 (0.67–0.79) 0.2811

CI, confidence interval; CRNM, clinically relevant non-major; HR, hazard ratio; MI, myocardial infarction.

trial thus limiting our ability to assess the outcomes associated with
concomitant apixaban or warfarin and either clopidogrel or dual anti-
platelet therapy. Additional randomized clinical trials are needed to
determine the ideal antithrombotic regimens for patients with AF
and indications for antiplatelet therapy.
Limitations
This analysis has a number of limitations. First, we were only able to
assess concomitant ‘low-dose’ aspirin use and not other antiplate-
let regimens. Secondly, the use of aspirin was neither randomized
nor blinded. Although we adjusted for potential measured con-
founders, additional confounding almost certainly exists. Thirdly,
the fact that aspirin use was not blinded may have led to differential
post-randomization use of aspirin among patients assigned to apix-
aban and warfarin. Fourthly, as with all subgroup analyses, there
may be limited power to detect an interaction between apixaban
vs. warfarin and aspirin use. Fifthly, although we recorded when
patients started and stopped aspirin, we did not collect the
reasons for changes in aspirin therapy. Finally, these results from
a randomized clinical trial may not be generalizable to other
populations.
Conclusions
In ARISTOTLE, concomitant aspirin was used in 20 –25% of
patients with AF treated with an anticoagulant and was associated
with a higher risk of bleeding. We observed similar effects of apixa-
ban, compared with warfarin, on stroke or systemic embolism,
major bleeding, or mortality irrespective of concomitant aspirin
use. Adequately powered randomized clinical trials are needed to
better define the optimal antithrombotic regimen and its duration
in patients with both AF and atherosclerotic coronary artery
disease, and particularly in those with an acute coronary syndrome
or recent coronary stenting.
Acknowledgements
The authors acknowledge Elizabeth Cook from the Duke Clinical Re-
search Institute for her editorial support with this manuscript.
Funding
This work was supported by Bristol-Myers Squibb and Pfizer.
Conflict of interest: The ARISTOTLE trial was funded by Bristol-Myers
Squibb and Pfizer. J.H.A.: receives sponsored research support through
Apixaban vs. warfarin with concomitant aspirin in patients with AF 231

Table 3 Outcomes among aspirin users and non-users in all patients and in subgroups of patients with and without a
history of arterial vascular disease

Aspirin usersa Aspirin non-usersa Adjusted MSM adjusted

(n 5 4434) (n 5 13 699) HR (95% CI) HR (95% CI)
...............................................................................................................................................................................
Stroke or systemic embolism 108 (1.51) 276 (1.22) 1.18 (0.94–1.49) 1.46 (1.15–1.85)
With arterial vascular disease 78 (1.76) 168 (1.62) 1.05 (0.80–1.38) 1.48 (1.11–1.97)
Without arterial vascular disease 30 (1.10) 108 (0.87) 1.21 (0.80–1.84) 1.40 (0.91–2.14)
Ischaemic stroke 69 (0.96) 189 (0.83) 1.08 (0.80–1.43) 1.40 (1.05–1.88)
With arterial vascular disease 51 (1.15) 125 (1.21) 0.93 (0.67–1.30) 1.35 (0.96–1.91)
Without arterial vascular disease 18 (0.66) 64 (0.52) 1.23 (0.72–2.10) 1.48 (0.85–2.56)
MI 59 (0.82) 104 (0.46) 1.28 (0.92–1.80) 1.72 (1.21–2.44)
With arterial vascular disease 47 (1.06) 72 (0.69) 1.47 (1.01–2.14) 1.56 (1.05–2.32)
Without arterial vascular disease 12 (0.44) 32 (0.26) 1.61 (0.81–3.19) 2.09 (1.08–4.07)
Death 135 (1.87) 411 (1.80) 0.89 (0.73–1.09) 1.00 (0.81–1.24)
With arterial vascular disease 82 (1.83) 226 (2.17) 0.77 (0.60–1.00) 0.87 (0.67–1.14)
Without arterial vascular disease 53 (1.94) 185 (1.49) 1.17 (0.85–1.60) 1.27 (0.91–1.77)
Major bleeding 252 (3.50) 528 (2.30) 1.41 (1.21–1.66) 1.65 (1.40–1.94)
With arterial vascular disease 168 (3.77) 266 (2.54) 1.46 (1.20–1.78) 1.75 (1.41–2.17)
Without arterial vascular disease 84 (3.07) 262 (2.10) 1.42 (1.10–1.83) 1.52 (1.17–1.97)
Haemorrhagic stroke 84 (0.47) 72 (0.32) 1.47 (0.96–2.25) 2.08 (1.35–3.21)
With arterial vascular disease 24 (0.54) 38 (0.36) 1.36 (0.81–2.29) 2.47 (1.41–4.30)
Without arterial vascular disease 10 (0.37) 34 (0.27) 1.23 (0.60–2.54) 1.50 (0.73–3.12)
Major or CRNM bleeding 445 (6.34) 1030 (4.57) 1.27 (1.13–1.43) 1.36 (1.21–1.54)
With arterial vascular disease 299 (6.91) 507 (4.93) 1.36 (1.18–1.57) 1.39 (1.19–1.63)
Without arterial vascular disease 146 (5.43) 523 (4.27) 1.25 (1.03–1.51) 1.33 (1.09–1.62)
Any bleeding 1541 (27.38) 3837 (20.02) 1.30 (1.22–1.39) 1.31 (1.24–1.41)
With arterial vascular disease 995 (28.8) 1788 (20.3) 1.39 (1.29–1.51) 1.38 (1.27–1.51)
Without arterial vascular disease 546 (25.2) 2049 (19.8) 1.28 (1.16–1.41) 1.26 (1.14–1.40)

CI, confidence interval; CRNM, clinically relevant non-major; HR, hazard ratio; MI, myocardial infarction; MSM, marginal structural model.
a
Numbers are event counts and event rates per year.

Duke University from Bristol-Myers Squibb and Pfizer; serves or has
served as a consultant to Bristol-Myers Squibb and Pfizer. R.D.L.:
grants from Bristol-Myers Squibb, AstraZeneca, Boehringer Ingelheim,
and Daiichi Sankyo; consulting fees from Bristol-Myers Squibb. L.T.:
none. M.A.: consulting fees from Bayer AG, Boehringer-Ingelheim,
MSD, and Sanofi-Aventis; travel support from Boston Scientific,
Bristol-Myers Squibb, and St Jude Medical. D.A.: consulting fees or
honoraria from Bristol-Myers Squibb. P.A.: research grants, honoraria,
and advisory boards for Bristol-Myers Squibb, Pfizer, Bayer, Johnson &
Johnson, Boehringer Ingelheim, Daiichi Sankyo, AstraZeneca, Sanofi-
Aventis, Merck, Eli Lilly, and The Medicines Company. S.G.: board
member of Bristol-Myers Squibb and Sanofi-Aventis; grants from
Boehringer Ingelheim, Otsuka, Eisai, Sanofi-Aventis, and Daiichi
Sankyo; consulting fees from Eisai; lecture fees from Eisai, Otsuka,
Daiichi Sankyo, Sanofi-Aventis, Bayer, Novartis, AstraZeneca, Asteras,
Pfizer, Medtronics-Japan, Tanabe-Mitsubishi, Takeda, Mochida, and
MSD; payments from Bayer and Sanofi-Aventis for developing educa-
tional presentations. M.H.: full-time employee of Bristol-Myers Squibb
and receives stock as part of his compensation. K.H.: lecture fees from
AstraZeneca, Bristol-Myers Squibb/Pfizer, Boehringer Ingelheim,
Bayer, Daiichi Sankyo, and Sanofi-Aventis. S.H.: advisory board mem-
bership for AstraZeneca, Bristol-Myers Squibb, Pfizer, and Bayer;
research support from GlaxoSmithKline, Pfizer, and Sanofi-Aventis.
B.S.L.: advisory board member for Bayer HealthCare. J.J.V.M.: none.
P.P.: none. H.P.: full-time Pfizer employee and owns stock in this
company. P.G.S.: travel support from Bristol-Myers Squibb; board
membership for Bayer, Bristol-Myers Squibb/Pfizer, AstraZeneca, and
Boehringer Ingelheim; consulting fees from Bristol-Myers Squibb, Eisai,
Ablynx, Amarin, Astellas, Eil Lilly, Medtronic, Novartis, Roche, Servier,
The Medicines Company, Sanofi, and AstraZeneca; grants from
Servier, Sanofi, and New York University School of Medicine; and
lecture fees from Pfizer, Amgen, Otsuka, and Aterovax. F.W.A.V.:
lecture fees from Bayer and AstraZeneca; consulting fees from Bayer
and Daiichi Sankyo. D.M.W.: none. C.B.G.: 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, Sanofi-Aventis,
and The Medicines Company; support from the Medtronic Foundation
and Merck for travel, accommodations, or meeting expenses. L.W.:
grants from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer
Ingelheim, GlaxoSmithKline, Schering-Plough, and Merck; consulting
fees from Regado Biosciences, Portola, CSL Behring, Athera Biotech-
nologies, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline;
lecture fees from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer
Ingelheim, GlaxoSmithKline, Schering-Plough, and Merck.
232
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