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 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.
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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.
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 = 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.
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 non-aspirin 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 = 0.10). There was also no evidence of a differential effect of apixaban compared with warfarin on ischaemic stroke (P interaction = 0.19), myocardial infarction (P interaction = 0.19), or death (P interaction = 0.23) among aspirin users and non-users.
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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.
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 = 0.29). Consistent benefits were seen with apixaban compared with warfarin among both aspirin users and non-users for haemorrhagic stroke (P interaction = 0.52), major or clinically relevant non-major bleeding (P interaction = 0.15), and any bleeding (P interaction = 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 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.