Research in context
Evidence before this study
We did a systematic search on PubMed for studies published up to July 13, 2019, with no language restrictions. The following keywords were used in different combinations: “percutaneous coronary intervention”, “PCI”, “coronary stenting”, “acute coronary syndrome”, “ACS”, “atrial fibrillation”, “AF”, “apixaban”, “rivaroxaban”, “edoxaban”, “dabigatran”, “vitamin K antagonist”, “warfarin”, “phenprocoumon”, “oral anticoagulation”, “oral anticoagulants”, “dual antithrombotic therapy”, “dual therapy”, “triple therapy”, “triple antithrombotic therapy”, “dual antiplatelet therapy”, “clopidogrel”, “aspirin”, and “randomised trial”. References of previous systematic reviews and meta-analyses were also screened for relevant studies. For this meta-analysis, we included all randomised controlled trials in patients with atrial fibrillation who received percutaneous coronary intervention (PCI) in at least 50% of the sample and were allocated to dual antithrombotic therapy (DAT) consisting of any non-vitamin K antagonist oral anticoagulant (NOAC) in combination with a P2Y12 inhibitor or triple antithrombotic therapy (TAT) consisting of any vitamin K antagonist (VKA) in combination with dual antiplatelet therapy (DAPT). Three completed trials (PIONEER-AF PCI, RE-DUAL PCI, and AUGUSTUS) were identified. The PIONEER-AF PCI (N=2124) trial showed either low-dose rivaroxaban (15 mg once daily) plus a P2Y12 inhibitor for 12 months or very-low-dose rivaroxaban (2·5 mg twice daily) plus DAPT for 1, 6, or 12 months was associated with lower rate of clinically significant bleeding (a composite of major bleeding or minor bleeding according to TIMI criteria or bleeding requiring medical attention) compared with standard therapy with a VKA plus DAPT for 1, 6, or 12 months. In the RE-DUAL PCI (N=2725) trial the ISTH classification bleeding risk was lower among those who received dual therapy with dabigatran (110 or 150 mg twice daily) and a P2Y12 inhibitor than those who received TAT. The AUGUSTUS (N=4614) trial assessed the safety and efficacy of standard-dose apixaban (5 mg twice daily) compared with a VKA and of low-dose acetylsalicylic acid (aspirin) compared with placebo, on a background of concomitant P2Y12 inhibitor therapy for 6 months in patients with atrial fibrillation and recent acute coronary syndrome or PCI. DAT use was associated with a greater than 40% reduction of ISTH-defined major or clinically relevant non-major (CRNM) bleeding compared with TAT.
Added value of this study
This is the first trial testing an edoxaban-based DAT versus a VKA-based TAT in patients with atrial fibrillation who had PCI. This study showed that DAT consisting of edoxaban in combination with an oral P2Y12 inhibitor is non-inferior to TAT (VKA, oral P2Y12 inhibitor, and 1-month to 12-month aspirin) with respect to the occurrence of major or CRNM bleeding at 12 months. The composite of cardiovascular death, stroke, myocardial infarction, definite stent thrombosis, or systemic embolic events, as well as its individual components, did not differ between groups.
Implications of all the available evidence
We pooled the four trials using crude number of events retrieved from each study and a random-effects model (Mantel-Haenszel method). Given the objective of this meta-analysis, we only selected treatment groups with NOAC-based DAT or VKA-based TAT from the included trials. Treatment effect was reported as risk ratio and 95% CI. A DAT consisting of a NOAC and an oral P2Y12 inhibitor compared with TAT based on VKA and DAPT was associated with lower risks of major or CRNM bleeding events and similar risks of major adverse cardiovascular events, all-cause death, stroke, stent thrombosis, or myocardial infarction. Thus, NOAC-based DAT was safer and as effective as VKA-based TAT (appendix p 41).