CLINICAL RESEARCH
European Heart Journal (2014) 35, 224–232 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
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, irrespective of concomitant aspirin use.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Concomitant medications † Aspirin † Atrial fibrillation † Stroke † Systemic embolism † Major bleeding
Introduction Oral anticoagulation is recommended for the prevention of thromboembolic events in patients with atrial fibrillation (AF) at risk for stroke.1 – 3 Oral anticoagulants have been shown to be
more effective for stroke prevention than antiplatelet therapy with aspirin alone4,5 or aspirin plus clopidogrel.6 However, patients with AF frequently also have coronary artery disease or other indications for aspirin.7,8 Randomized trials and observational studies have demonstrated high rates of bleeding with the combination of
* Corresponding author. Tel: +919 668 8955, Fax: +919 668 7085, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]
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Received 30 October 2012; revised 23 September 2013; accepted 26 September 2013; online publish-ahead-of-print 20 October 2013
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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 reductions in ischaemic events.16,17 Therefore, recent consensus recommendations 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, apixaban 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 vascular disease, and (ii) evaluate the efficacy and safety of apixaban compared with warfarin in patients receiving and not receiving concomitant aspirin overall and in the subgroups of patients with and without arterial vascular disease.
Methods 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 additional risk factor for stroke or systemic embolism. Risk factors included age ≥75 years, hypertension, diabetes, heart failure, or reduced leftventricular 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 eligible 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. Outcomes in this analysis include stroke or systemic embolism, ischaemic stroke, myocardial infarction, all-cause mortality, major bleeding classified according to the International Society on Thrombosis and Haemostasis (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.
Baseline categorical variables are presented as percentages and continuous 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%, diabetes, 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 randomized 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 marginal 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 treatment (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 coronary 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 percutaneous 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.
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Patient population and study drug
Statistical analysis
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 Institute, and interpreted by the authors. All authors, including two (M.H., H.P.) employed by the sponsors, commented on the manuscript. The decision to publish the final manuscript was made by the first author (J.H.A.).
Results
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 hypertension, 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 revascularization 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 nonaspirin users (12.8%).
Effect of apixaban vs. warfarin among aspirin users and non-users Ischaemic events Outcomes among aspirin users and non-users randomized to apixaban vs. warfarin are shown in Figure 2. Compared with warfarin, apixaban 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: apixaban 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 infarction, and death both in the overall population and among the subgroups 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 warfarin 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, ischaemic stroke, myocardial infarction, and death and higher rates of
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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 concomitant 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, predominantly 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.
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Apixaban vs. warfarin with concomitant aspirin in patients with AF
227
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.
Discussion In the ARISTOTLE trial, apixaban reduced stroke or systemic embolism 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 embolism, 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 anticoagulation, 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 vascular 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
among patients without a history of arterial vascular disease, a substantial number were taking aspirin. Current consensus recommendations 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. warfarin on both ischaemic events and bleeding in patients with AF. Recognizing 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 bleeding 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 adjustment 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 confounding or mean that aspirin is not beneficial in patients with AF who are also taking an anticoagulant.29 The consistently and substantially higher rates of bleeding with concomitant use of aspirin and oral anticoagulation confirm prior findings9 – 15 and should lead to a
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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.
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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 (%) Weight, median (25th, 75th), kg
1405 (31.7) 83 (70, 97)
4990 (36.4) 82 (70, 95)
,0.0001 0.0015
BMI, median (25th, 75th), kg/m2
28.7 (25.4, 33.1)
Diabetes, n (%) Hypertension, n (%)
1282 (28.9) 3940 (88.9)
28.4 (25.2, 32.4) 3249 (23.7) 11 914 (87.0)
0.0022 ,0.0001 0.0010
History of CAD,a n (%)
2264 (51.1)
4354 (31.8)
,0.0001
History of MI, n (%) History of PCI, n (%)
1046 (23.6) 744 (16.8)
1529 (11.2) 903 (6.6)
,0.0001 ,0.0001
,3 months 3– 12 months
52 (7.0) 71 (9.6)
81 (9.0) 112 (12.5)
.12 months
618 (83.4)
706 (78.5)
518 (70.7) 184 (35.5)
562 (63.4) 203 (36.1)
334 (64.5)
359 (63.9)
582 (13.1) 501 (11.3)
620 (4.5) 1624 (11.9)
,0.0001 0.3172
291 (6.6)
589 (4.4)
,0.0001
1282 (28.9) 752 (17.0)
3791 (27.7) 1858 (13.6)
0.1098 ,0.0001
Time from most recent PCI
Proportion stent, n (%) Proportion DES Proportion BMS History of CABG, n (%) History of stroke, n (%) History of PAD, n (%)
Chronic kidney disease, n (%)
331 (7.5)
1174 (8.6)
1970 (44.4)
8398 (61.3)
1
1391 (31.4)
4763 (34.8)
2 3
1616 (36.4) 1427 (32.2)
4882 (35.6) 4054 (29.6)
707 (15.9) 3727 (84.1)
2066 (15.1) 11 630 (84.9)
,6 months 6 –24 months
1501 (33.9) 903 (20.4)
3543 (26.0) 2645 (19.4)
.24 months
2021 (45.7)
7459 (54.7)
1430 (32.2)
3007 (21.9)
Prior VKA use, n (%) CHADS2 score, n (%)
AF type, n (%) Paroxysmal Persistent or permanent
Latin America Europe Asia Pacific
,0.0001
,0.0001 916 (20.7)
2542 (18.6)
1360 (30.7) 728 (16.4)
5971 (43.6) 2179 (15.9)
2233 (50.4) 2201 (49.6)
6852 (50.0) 6847 (50.0)
Randomized group Apixaban Warfarin
0.0208 ,0.0001 ,0.0001
0.1666
Time from first onset of AF, n (%)
Region of enrolment North America
0.0019 0.8373
0.6917
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 who are receiving oral anticoagulation. This analysis addresses only aspirin, predominantly ‘low-dose’ aspirin, and not other antiplatelet regimens. There are substantial
proportions of patients with AF who have either acute coronary syndromes or who undergo percutaneous coronary intervention. Clopidogrel use was an exclusion criterion at randomization and only started in a small proportion of patients included in the ARISTOTLE
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Heart failure, n (%) LVEF ,40%, n (%)
0.0452
Apixaban vs. warfarin with concomitant aspirin in patients with AF
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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, 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. Numbers are event counts and event rates per year. CI, confidence interval; CRNM, clinically relevant non-major; HR, hazard ratio.
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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 Apixaban vs. Warfarin HR (95% CI)
Non-users Apixaban vs. Warfarin HR (95% CI)
Interaction P-value
............................................................................................................................................................................... Stroke or systemic embolism
0.85 (0.67–1.08)
0.1114
0.58 (0.37–0.92)
0.96 (0.71–1.30)
0.0772
Without arterial vascular disease Ischaemic stroke
0.60 (0.28–1.28) 0.72 (0.45–1.88)
0.72 (0.49–1.05) 0.99 (0.74–1.32)
0.6817 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) 1.15 (0.70–1.88)
0.83 (0.51–1.36) 0.77 (0.51–1.14)
0.8515 0.2144
With arterial vascular disease
1.08 (0.62–1.88)
0.73 (0.45–1.19)
0.3045
Without arterial vascular disease Death
1.38 (0.45–4.25) 1.03 (0.72–1.46)
0.84 (0.41–1.72) 0.85 (0.70–1.03)
0.4644 0.3727
With arterial vascular disease
0.93 (0.59–1.46)
1.00 (0.77–1.29)
0.7937
Without arterial vascular disease Major bleeding
1.17 (0.66–2.08) 0.74 (0.57–0.95)
0.71 (0.53–0.95) 0.68 (0.57–0.81)
0.1277 0.6312
With arterial vascular disease
0.77 (0.57–1.06)
0.74 (0.58–0.94)
0.8198
Without arterial vascular disease Haemorrhagic stroke
0.66 (0.42–1.04) 0.43 (0.21–0.87)
0.63 (0.50–0.81) 0.53 (0.32–0.87)
0.8754 0.6332
With arterial vascular disease
0.44 (0.19–1.02)
0.50 (0.25–1.01)
0.8204
Without arterial vascular disease Major or CRNM bleeding
0.46 (0.12–1.81) 0.73 (0.60–0.89)
0.57 (0.28–1.15) 0.67 (0.59–0.76)
0.7929 0.4623
With arterial vascular disease
0.78 (0.61–0.99)
0.75 (0.63–0.89)
0.8207
Without arterial vascular disease Any bleeding
0.64 (0.45–0.90) 0.69 (0.62–0.77)
0.60 (0.50–0.71) 0.72 (0.68–0.77)
0.7580 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
MI
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 antiplatelet 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 antiplatelet regimens. Secondly, the use of aspirin was neither randomized nor blinded. Although we adjusted for potential measured confounders, 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 apixaban 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 apixaban, 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 Research 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
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0.59 (0.40–0.87)
With arterial vascular disease
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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 (n 5 4434)
Aspirin non-usersa (n 5 13 699)
Adjusted HR (95% CI)
MSM adjusted HR (95% CI)
............................................................................................................................................................................... Stroke or systemic embolism With arterial vascular disease Without arterial vascular disease Ischaemic stroke With arterial vascular disease Without arterial vascular disease MI With arterial vascular disease Without arterial vascular disease Death With arterial vascular disease Without arterial vascular disease Major bleeding With arterial vascular disease Without arterial vascular disease Haemorrhagic stroke With arterial vascular disease Without arterial vascular disease With arterial vascular disease Without arterial vascular disease Any bleeding With arterial vascular disease Without arterial vascular disease
276 (1.22)
1.18 (0.94–1.49)
1.46 (1.15–1.85)
78 (1.76) 30 (1.10)
168 (1.62) 108 (0.87)
1.05 (0.80–1.38) 1.21 (0.80–1.84)
1.48 (1.11–1.97) 1.40 (0.91–2.14)
69 (0.96)
189 (0.83)
1.08 (0.80–1.43)
1.40 (1.05–1.88)
51 (1.15) 18 (0.66)
125 (1.21) 64 (0.52)
0.93 (0.67–1.30) 1.23 (0.72–2.10)
1.35 (0.96–1.91) 1.48 (0.85–2.56)
59 (0.82)
104 (0.46)
1.28 (0.92–1.80)
1.72 (1.21–2.44)
47 (1.06) 12 (0.44)
72 (0.69) 32 (0.26)
1.47 (1.01–2.14) 1.61 (0.81–3.19)
1.56 (1.05–2.32) 2.09 (1.08–4.07)
135 (1.87)
411 (1.80)
0.89 (0.73–1.09)
1.00 (0.81–1.24)
82 (1.83) 53 (1.94)
226 (2.17) 185 (1.49)
0.77 (0.60–1.00) 1.17 (0.85–1.60)
0.87 (0.67–1.14) 1.27 (0.91–1.77)
252 (3.50)
528 (2.30)
1.41 (1.21–1.66)
1.65 (1.40–1.94)
168 (3.77) 84 (3.07)
266 (2.54) 262 (2.10)
1.46 (1.20–1.78) 1.42 (1.10–1.83)
1.75 (1.41–2.17) 1.52 (1.17–1.97)
84 (0.47)
72 (0.32)
1.47 (0.96–2.25)
2.08 (1.35–3.21)
24 (0.54) 10 (0.37)
38 (0.36) 34 (0.27)
1.36 (0.81–2.29) 1.23 (0.60–2.54)
2.47 (1.41–4.30) 1.50 (0.73–3.12)
445 (6.34)
1030 (4.57)
1.27 (1.13–1.43)
1.36 (1.21–1.54)
299 (6.91) 146 (5.43)
507 (4.93) 523 (4.27)
1.36 (1.18–1.57) 1.25 (1.03–1.51)
1.39 (1.19–1.63) 1.33 (1.09–1.62)
1541 (27.38)
3837 (20.02)
1.30 (1.22–1.39)
1.31 (1.24–1.41)
995 (28.8) 546 (25.2)
1788 (20.3) 2049 (19.8)
1.39 (1.29–1.51) 1.28 (1.16–1.41)
1.38 (1.27–1.51) 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, SanofiAventis, 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 educational 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 membership 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 Biotechnologies, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline; lecture fees from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Schering-Plough, and Merck.
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Major or CRNM bleeding
108 (1.51)
232
References
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1. European Heart Rhythm Association; European Association for Cardio-Thoracic Surgery. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J 2010;31:2369 –2429. 2. American College of Cardiology Foundation/American Heart Association Task Force. 2011 ACCF/AHA/HRS focused updates incorporated into the ACC/AHA/ ESC 2006 guidelines for the management of patients with atrial fibrillation: a report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2011;123:e269–e367. 3. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med 1999;131: 492 –501. 4. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Intern Med 2007; 146:857–867. 5. Connolly SJ, Pogue J, Eikelboom J, Flaker G, Commerford P, Franzosi MG, Healey JS, Yusuf S. Benefit of oral anticoagulant over antiplatelet therapy in atrial fibrillation depends on the quality of international normalized ratio control achieved by centers and countries as measured by time in therapeutic range. Circulation 2008; 118:2029 –2037. 6. ACTIVE Writing Group of the ACTIVE Investigators. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet 2006;367:1903 – 1912. 7. American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. 2009 Focused Updates: ACC/AHA Guidelines for the Management of Patients With ST-Elevation Myocardial Infarction (updating the 2004 Guideline and 2007 Focused Update) and ACC/AHA/SCAI Guidelines on Percutaneous Coronary Intervention (updating the 2005 Guideline and 2007 Focused Update): a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines. Circulation 2009; 120:2271 –2306. 8. Jneid H, Anderson JL, Wright RS, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, Fesmire FM, Ganiats TG, Lincoff AM, Peterson ED, Philippides GJ, Theroux P, Wenger NK, Zidar JP. 2012 ACCF/AHA focused update on the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2012;60:645–681. 9. Rothberg MB, Celestin C, Fiore LD, Lawler E, Cook JR. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med 2005;143:241 – 250. 10. Andreotti F, Testa L, Biondi-Zoccai GG, Crea F. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J 2006;27:519 –526. 11. Karjalainen PP, Porela P, Ylitalo A, Vikman S, Nyman K, Vaittinen MA, Airaksinen TJ, Niemela¨ M, Vahlberg T, Airaksinen KE. Safety and efficacy of combined antiplateletwarfarin therapy after coronary stenting. Eur Heart J 2007;28:726–732. 12. Hansen ML, Sørensen R, Clausen MT, Fog-Petersen ML, Raunsø J, Gadsbøll N, Gislason GH, Folke F, Andersen SS, Schramm TK, Abildstrøm SZ, Poulsen HE, Køber L, Torp-Pedersen C. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med 2010;170:1433 –1441. 13. Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction. N Engl J Med 2002;347:969 –974. 14. van Es RF, Jonker JJ, Verheugt FW, Deckers JW, Grobbee DE. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomized controlled trial. Lancet 2002;360:109 – 113. 15. Dentali F, Douketis JD, Lim W, Crowther M. Combined aspirin-oral anticoagulant therapy compared with oral anticoagulant therapy alone among patients at risk for cardiovascular disease: a meta-analysis of randomized trials. Arch Intern Med 2007;167:117 –124.
J.H. Alexander et al.
European Heart Journal (2014) 35, 224–232 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
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, irrespective of concomitant aspirin use.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Concomitant medications † Aspirin † Atrial fibrillation † Stroke † Systemic embolism † Major bleeding
Introduction Oral anticoagulation is recommended for the prevention of thromboembolic events in patients with atrial fibrillation (AF) at risk for stroke.1 – 3 Oral anticoagulants have been shown to be
more effective for stroke prevention than antiplatelet therapy with aspirin alone4,5 or aspirin plus clopidogrel.6 However, patients with AF frequently also have coronary artery disease or other indications for aspirin.7,8 Randomized trials and observational studies have demonstrated high rates of bleeding with the combination of
* Corresponding author. Tel: +919 668 8955, Fax: +919 668 7085, Email: [email protected] Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2013. For permissions please email: [email protected]
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Received 30 October 2012; revised 23 September 2013; accepted 26 September 2013; online publish-ahead-of-print 20 October 2013
225
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 reductions in ischaemic events.16,17 Therefore, recent consensus recommendations 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, apixaban 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 vascular disease, and (ii) evaluate the efficacy and safety of apixaban compared with warfarin in patients receiving and not receiving concomitant aspirin overall and in the subgroups of patients with and without arterial vascular disease.
Methods 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 additional risk factor for stroke or systemic embolism. Risk factors included age ≥75 years, hypertension, diabetes, heart failure, or reduced leftventricular 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 eligible 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. Outcomes in this analysis include stroke or systemic embolism, ischaemic stroke, myocardial infarction, all-cause mortality, major bleeding classified according to the International Society on Thrombosis and Haemostasis (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.
Baseline categorical variables are presented as percentages and continuous 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%, diabetes, 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 randomized 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 marginal 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 treatment (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 coronary 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 percutaneous 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.
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Patient population and study drug
Statistical analysis
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 Institute, and interpreted by the authors. All authors, including two (M.H., H.P.) employed by the sponsors, commented on the manuscript. The decision to publish the final manuscript was made by the first author (J.H.A.).
Results
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 hypertension, 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 revascularization 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 nonaspirin users (12.8%).
Effect of apixaban vs. warfarin among aspirin users and non-users Ischaemic events Outcomes among aspirin users and non-users randomized to apixaban vs. warfarin are shown in Figure 2. Compared with warfarin, apixaban 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: apixaban 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 infarction, and death both in the overall population and among the subgroups 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 warfarin 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, ischaemic stroke, myocardial infarction, and death and higher rates of
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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 concomitant 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, predominantly 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.
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227
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.
Discussion In the ARISTOTLE trial, apixaban reduced stroke or systemic embolism 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 embolism, 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 anticoagulation, 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 vascular 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
among patients without a history of arterial vascular disease, a substantial number were taking aspirin. Current consensus recommendations 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. warfarin on both ischaemic events and bleeding in patients with AF. Recognizing 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 bleeding 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 adjustment 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 confounding or mean that aspirin is not beneficial in patients with AF who are also taking an anticoagulant.29 The consistently and substantially higher rates of bleeding with concomitant use of aspirin and oral anticoagulation confirm prior findings9 – 15 and should lead to a
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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.
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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 (%) Weight, median (25th, 75th), kg
1405 (31.7) 83 (70, 97)
4990 (36.4) 82 (70, 95)
,0.0001 0.0015
BMI, median (25th, 75th), kg/m2
28.7 (25.4, 33.1)
Diabetes, n (%) Hypertension, n (%)
1282 (28.9) 3940 (88.9)
28.4 (25.2, 32.4) 3249 (23.7) 11 914 (87.0)
0.0022 ,0.0001 0.0010
History of CAD,a n (%)
2264 (51.1)
4354 (31.8)
,0.0001
History of MI, n (%) History of PCI, n (%)
1046 (23.6) 744 (16.8)
1529 (11.2) 903 (6.6)
,0.0001 ,0.0001
,3 months 3– 12 months
52 (7.0) 71 (9.6)
81 (9.0) 112 (12.5)
.12 months
618 (83.4)
706 (78.5)
518 (70.7) 184 (35.5)
562 (63.4) 203 (36.1)
334 (64.5)
359 (63.9)
582 (13.1) 501 (11.3)
620 (4.5) 1624 (11.9)
,0.0001 0.3172
291 (6.6)
589 (4.4)
,0.0001
1282 (28.9) 752 (17.0)
3791 (27.7) 1858 (13.6)
0.1098 ,0.0001
Time from most recent PCI
Proportion stent, n (%) Proportion DES Proportion BMS History of CABG, n (%) History of stroke, n (%) History of PAD, n (%)
Chronic kidney disease, n (%)
331 (7.5)
1174 (8.6)
1970 (44.4)
8398 (61.3)
1
1391 (31.4)
4763 (34.8)
2 3
1616 (36.4) 1427 (32.2)
4882 (35.6) 4054 (29.6)
707 (15.9) 3727 (84.1)
2066 (15.1) 11 630 (84.9)
,6 months 6 –24 months
1501 (33.9) 903 (20.4)
3543 (26.0) 2645 (19.4)
.24 months
2021 (45.7)
7459 (54.7)
1430 (32.2)
3007 (21.9)
Prior VKA use, n (%) CHADS2 score, n (%)
AF type, n (%) Paroxysmal Persistent or permanent
Latin America Europe Asia Pacific
,0.0001
,0.0001 916 (20.7)
2542 (18.6)
1360 (30.7) 728 (16.4)
5971 (43.6) 2179 (15.9)
2233 (50.4) 2201 (49.6)
6852 (50.0) 6847 (50.0)
Randomized group Apixaban Warfarin
0.0208 ,0.0001 ,0.0001
0.1666
Time from first onset of AF, n (%)
Region of enrolment North America
0.0019 0.8373
0.6917
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 who are receiving oral anticoagulation. This analysis addresses only aspirin, predominantly ‘low-dose’ aspirin, and not other antiplatelet regimens. There are substantial
proportions of patients with AF who have either acute coronary syndromes or who undergo percutaneous coronary intervention. Clopidogrel use was an exclusion criterion at randomization and only started in a small proportion of patients included in the ARISTOTLE
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Heart failure, n (%) LVEF ,40%, n (%)
0.0452
Apixaban vs. warfarin with concomitant aspirin in patients with AF
229
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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, 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. Numbers are event counts and event rates per year. CI, confidence interval; CRNM, clinically relevant non-major; HR, hazard ratio.
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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 Apixaban vs. Warfarin HR (95% CI)
Non-users Apixaban vs. Warfarin HR (95% CI)
Interaction P-value
............................................................................................................................................................................... Stroke or systemic embolism
0.85 (0.67–1.08)
0.1114
0.58 (0.37–0.92)
0.96 (0.71–1.30)
0.0772
Without arterial vascular disease Ischaemic stroke
0.60 (0.28–1.28) 0.72 (0.45–1.88)
0.72 (0.49–1.05) 0.99 (0.74–1.32)
0.6817 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) 1.15 (0.70–1.88)
0.83 (0.51–1.36) 0.77 (0.51–1.14)
0.8515 0.2144
With arterial vascular disease
1.08 (0.62–1.88)
0.73 (0.45–1.19)
0.3045
Without arterial vascular disease Death
1.38 (0.45–4.25) 1.03 (0.72–1.46)
0.84 (0.41–1.72) 0.85 (0.70–1.03)
0.4644 0.3727
With arterial vascular disease
0.93 (0.59–1.46)
1.00 (0.77–1.29)
0.7937
Without arterial vascular disease Major bleeding
1.17 (0.66–2.08) 0.74 (0.57–0.95)
0.71 (0.53–0.95) 0.68 (0.57–0.81)
0.1277 0.6312
With arterial vascular disease
0.77 (0.57–1.06)
0.74 (0.58–0.94)
0.8198
Without arterial vascular disease Haemorrhagic stroke
0.66 (0.42–1.04) 0.43 (0.21–0.87)
0.63 (0.50–0.81) 0.53 (0.32–0.87)
0.8754 0.6332
With arterial vascular disease
0.44 (0.19–1.02)
0.50 (0.25–1.01)
0.8204
Without arterial vascular disease Major or CRNM bleeding
0.46 (0.12–1.81) 0.73 (0.60–0.89)
0.57 (0.28–1.15) 0.67 (0.59–0.76)
0.7929 0.4623
With arterial vascular disease
0.78 (0.61–0.99)
0.75 (0.63–0.89)
0.8207
Without arterial vascular disease Any bleeding
0.64 (0.45–0.90) 0.69 (0.62–0.77)
0.60 (0.50–0.71) 0.72 (0.68–0.77)
0.7580 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
MI
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 antiplatelet 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 antiplatelet regimens. Secondly, the use of aspirin was neither randomized nor blinded. Although we adjusted for potential measured confounders, 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 apixaban 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 apixaban, 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 Research 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
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0.59 (0.40–0.87)
With arterial vascular disease
231
Apixaban vs. warfarin with concomitant aspirin in patients with AF
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 (n 5 4434)
Aspirin non-usersa (n 5 13 699)
Adjusted HR (95% CI)
MSM adjusted HR (95% CI)
............................................................................................................................................................................... Stroke or systemic embolism With arterial vascular disease Without arterial vascular disease Ischaemic stroke With arterial vascular disease Without arterial vascular disease MI With arterial vascular disease Without arterial vascular disease Death With arterial vascular disease Without arterial vascular disease Major bleeding With arterial vascular disease Without arterial vascular disease Haemorrhagic stroke With arterial vascular disease Without arterial vascular disease With arterial vascular disease Without arterial vascular disease Any bleeding With arterial vascular disease Without arterial vascular disease
276 (1.22)
1.18 (0.94–1.49)
1.46 (1.15–1.85)
78 (1.76) 30 (1.10)
168 (1.62) 108 (0.87)
1.05 (0.80–1.38) 1.21 (0.80–1.84)
1.48 (1.11–1.97) 1.40 (0.91–2.14)
69 (0.96)
189 (0.83)
1.08 (0.80–1.43)
1.40 (1.05–1.88)
51 (1.15) 18 (0.66)
125 (1.21) 64 (0.52)
0.93 (0.67–1.30) 1.23 (0.72–2.10)
1.35 (0.96–1.91) 1.48 (0.85–2.56)
59 (0.82)
104 (0.46)
1.28 (0.92–1.80)
1.72 (1.21–2.44)
47 (1.06) 12 (0.44)
72 (0.69) 32 (0.26)
1.47 (1.01–2.14) 1.61 (0.81–3.19)
1.56 (1.05–2.32) 2.09 (1.08–4.07)
135 (1.87)
411 (1.80)
0.89 (0.73–1.09)
1.00 (0.81–1.24)
82 (1.83) 53 (1.94)
226 (2.17) 185 (1.49)
0.77 (0.60–1.00) 1.17 (0.85–1.60)
0.87 (0.67–1.14) 1.27 (0.91–1.77)
252 (3.50)
528 (2.30)
1.41 (1.21–1.66)
1.65 (1.40–1.94)
168 (3.77) 84 (3.07)
266 (2.54) 262 (2.10)
1.46 (1.20–1.78) 1.42 (1.10–1.83)
1.75 (1.41–2.17) 1.52 (1.17–1.97)
84 (0.47)
72 (0.32)
1.47 (0.96–2.25)
2.08 (1.35–3.21)
24 (0.54) 10 (0.37)
38 (0.36) 34 (0.27)
1.36 (0.81–2.29) 1.23 (0.60–2.54)
2.47 (1.41–4.30) 1.50 (0.73–3.12)
445 (6.34)
1030 (4.57)
1.27 (1.13–1.43)
1.36 (1.21–1.54)
299 (6.91) 146 (5.43)
507 (4.93) 523 (4.27)
1.36 (1.18–1.57) 1.25 (1.03–1.51)
1.39 (1.19–1.63) 1.33 (1.09–1.62)
1541 (27.38)
3837 (20.02)
1.30 (1.22–1.39)
1.31 (1.24–1.41)
995 (28.8) 546 (25.2)
1788 (20.3) 2049 (19.8)
1.39 (1.29–1.51) 1.28 (1.16–1.41)
1.38 (1.27–1.51) 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, SanofiAventis, 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 educational 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 membership 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 Biotechnologies, Boehringer Ingelheim, AstraZeneca, and GlaxoSmithKline; lecture fees from Bristol-Myers Squibb, Pfizer, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Schering-Plough, and Merck.
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Major or CRNM bleeding
108 (1.51)
232
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