Abstract and Introduction
Abstract
Background Bleeding limits anticoagulant treatment in patients with acute coronary syndromes (ACS).
Objectives We investigated whether background concomitant antiplatelet therapy influences the effects of apixaban after ACS.
Methods This study examined high-risk ACS patients who were treated with aspirin or aspirin plus clopidogrel and who were randomized to apixaban 5 mg twice daily or placebo. In a post-hoc analysis, we assessed whether the effect of apixaban on efficacy and safety outcomes varied by the concomitant antiplatelet regimen by using simple Cox modeling and marginal structural models with propensity scores and antiplatelet therapy as a time-dependent covariate.
Results At baseline, of 7,364 patients, 16.3% (n = 1,202) were on aspirin alone, and 79.0% (n = 5,814) were on aspirin plus clopidogrel. A total of 19.2% (n = 1,415) switched antiplatelet therapy during follow-up. No differential effect of apixaban versus placebo was observed for the composite endpoint of cardiovascular death, myocardial infarction, and ischemic stroke in patients taking aspirin (12.21 per 100 patient-years vs. 13.21 per 100 patient-years; adjusted hazard ratio [HR]: 0.91; 95% confidence interval [CI]: 0.62 to 1.32) or aspirin plus clopidogrel (13.22 vs. 14.24; adjusted HR: 0.95; 95% CI: 0.78 to 1.14; pinteraction = 0.84). Compared with placebo, apixaban increased Thrombolysis In Myocardial Infarction major bleeding in patients taking aspirin (1.48 vs. 0.25; adjusted HR: 6.62; 95% CI: 0.75 to 51.73) and in patients taking aspirin plus clopidogrel (2.58 vs. 1.02; adjusted HR: 2.44; 95% CI: 1.34 to 4.45; pinteraction = 0.41). Similar results were obtained with marginal structural models and in patients treated with and without percutaneous coronary intervention.
Conclusions Post-ACS treatment with apixaban versus placebo showed no efficacy, but it increased bleeding regardless of concomitant therapy with aspirin alone or aspirin plus clopidogrel. (Apixaban for Prevention of Acute Ischemic Events 2 [APPRAISE-2]; NCT00831441)
Introduction
Despite the significant benefits of antiplatelet therapy for reducing ischemic and thrombotic events in patients with acute coronary syndromes (ACS), patients remain at high residual risk of repeat cardiovascular events after ACS, which is perhaps in part related to persistent thrombin generation. Consequently, there may be a role for long-term anticoagulants in addition to antiplatelet agents for the treatment of ACS. With respect to efficacy, studies of oral anticoagulation in the ACS population have provided mixed results; although warfarin and low-dose rivaroxaban were found to reduce recurrent ischemic and thrombotic events, apixaban and dabigatran did not provide any efficacy benefits compared with placebo. In contrast, studies have consistently demonstrated increased bleeding with the addition of anticoagulation to platelet inhibition in patients after an ACS.
Altering concomitant antiplatelet regimens, such as the use of mono rather than dual antiplatelet therapy, may mitigate some of the bleeding risks of novel oral anticoagulants in patients after an ACS, but these changes might also increase ischemic events. Although only rivaroxaban has an approved indication for secondary prevention after an ACS, exploration of this hypothesis in the ATLAS ACS 2-TIMI 51 (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction 51) trial was limited by the fact that only 7% of enrolled patients were on single antiplatelet therapy. Therefore, we studied apixaban, another factor Xa inhibitor, using data from the APPRAISE-2 (Apixaban for Prevention of Acute Ischemic Events 2) trial. In this post-hoc analysis, our goals were 1) to describe overall patterns of mono and dual antiplatelet therapy use over time, and 2) to examine the rates of ischemic and bleeding events in patients randomized to apixaban versus placebo in addition to aspirin alone or aspirin plus clopidogrel in the overall population and in the subgroups of patients who underwent and who did not undergo percutaneous coronary intervention (PCI).