Commentary
PCI is performed in about 20% of patients with atrial fibrillation. These patients require dual antiplatelet therapy to prevent ischemic events, combined with long-term anticoagulation to prevent stroke due to atrial fibrillation. Because the combination of anticoagulation and antiplatelet therapy is associated with a higher risk of bleeding, balancing the risk and benefit of dual antiplatelet therapy and anticoagulation in this population is crucial.
Previous studies have assessed the risk and benefit associated with anticoagulation and antiplatelet therapy. When warfarin plus clopidogrel (double therapy) was compared with warfarin, aspirin, and clopidogrel (triple therapy) in patients with acute coronary syndromes and stable ischemic coronary disease undergoing PCI, use of clopidogrel without aspirin (double therapy) was associated with a significant reduction in bleeding complications (19.4% versus 44.4%, HR, 0.36; 95% CI, 0.26-0.20; P < 0.0001) without increasing thrombotic events.1 Recent studies have compared triple therapy with warfarin to double therapy using direct oral anticoagulants (DOAC). The PIONEER AF-PCI study, which compared low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor to vitamin K antagonist plus dual antiplatelet therapy, found that the rates of clinically significant bleeding were lower in the low-dose rivaroxaban group compared to the triple-therapy group with a vitamin K antagonist (16.8% versus 26.7%; HR, 0.59; 95% CI, 0.47-0.76; P < 0.001).2 Similarly, the RE-DUAL PCI studied dabigatran and showed that the dual therapy group with dabigatran had a lower incidence of major or clinically relevant nonmajor bleeding events during follow-up compared to triple therapy including a vitamin K antagonist (15.4% versus 26.9%; HR, 0.52; 95% CI, 0.42-0.63; P < 0.001).3
In this context, Lopes at al investigated the clinical question of dual therapy versus triple therapy by performing a well-designed randomized clinical trial. In this trial with a 2-by-2 factorial design, the authors studied the effect of apixaban compared to vitamin K antagonist and the effect of aspirin compared to placebo. Major or clinically relevant nonmajor bleeding occurred in 10.5% of patients receiving apixaban, as compared to 14.7% of those receiving a vitamin K antagonist (HR 0.69; 95% CI, 0.58-0.81; P < 0.001). The incidence of major or clinically relevant nonmajor bleeding was higher in patients receiving aspirin than in those receiving placebo (16.1% versus 9.0%; HR, 1.89; 95% CI, 1.59-2.24; P < 0.001). Patients in the apixaban group had a lower incidence of death or hospitalization than those in the vitamin K antagonist group (23.5% versus 27.4%; HR, 0.83; 95% CI, 0.74-0.93; P = 0.002). The incidence of ischemic events was similar between the apixaban group and vitamin K antagonist group and between the aspirin group and placebo group.
The strengths of this current study include the large number of patients it enrolled. Taking the results from the PIONEER-AF, RE-DUAL PCI, and AUGUSTUS trials, it is clear that DOAC reduces the risk of bleeding compared to vitamin K antagonist. In addition, the AUGUSTUS trial was the first that evaluated the effect of aspirin in patients treated with DOAC and antiplatelet therapy. Aspirin was associated with increased risk of bleeding, with a similar rate of ischemic events compared to placebo.
The AUGUSTUS trial has several limitations. Although the incidence of ischemic events was similar between the apixaban group and the vitamin K antagonist group, the study was not powered to evaluate for individual ischemic outcomes. However, there was no clear evidence of an increase in harm. Since more than 90% of P2Y12 inhibitors used were clopidogrel, the safety and efficacy of combining apixaban with ticagrelor or prasugrel will require further study.