Antithrombotic Therapy for Atrial Fibrillation and Coronary Artery Disease in Patients With Prior Atherothrombotic Disease: A Post Hoc Analysis of the AFIRE Trial

Abstract

Background Among patients with atrial fibrillation and stable coronary artery disease, those with histories of atherothrombotic disease are at high-risk for future ischemic events. This study investigated the efficacy and safety of rivaroxaban monotherapy in patients with atrial fibrillation, coronary artery disease, and histories of atherothrombotic disease. Methods and Results This was a post hoc subanalysis of the AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial. Patients with non-valvular atrial fibrillation and coronary artery disease were recruited and randomized to receive the rivaroxaban monotherapy or combination therapy with rivaroxaban plus antiplatelet drug. For the purpose of this sub-study, participants were divided into 2 subgroups, including the atherothrombosis group (those with histories of myocardial infarction, stroke, and/or peripheral artery disease; n=1052, 47.5%) and non-atherothrombosis group (n=1163, 52.5%). The efficacy end point included cardiovascular events or all-cause death, while the safety end point was major bleeding. Net adverse events consisted of all-cause death, myocardial infarction, stroke, or major bleeding. In the atherothrombosis group, rivaroxaban monotherapy was significantly associated with a lower risk of net adverse events when compared with combination therapy (hazard ratio [HR], 0.50; 95% CI, 0.34-0.74; P<0.001), with a decrease in both efficacy (HR, 0.68; 95% CI, 0.47-0.99; P=0.044) and safety (HR, 0.37; 95% CI, 0.19-0.71; P=0.003) end points. By contrast, there were no differences between treatment outcomes for the non-atherothrombosis group. Conclusions Rivaroxaban monotherapy significantly reduced net adverse events as compared with combination therapy for patients with atrial fibrillation, coronary artery disease, and prior atherothrombotic disease. Registration URL: https://www.umin.ac.jp/ctr/; Unique identifier: UMIN000016612. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02642419.

Keywords: antiplatelet drug; antithrombotic therapy; atrial fibrillation; coronary artery disease; direct oral anticoagulant.

Conflict of interest statement

Dr Kimura reports grants from the Japan Cardiovascular Research Foundation; grants and personal fees from Bayer Yakuhin, Daiichi Sankyo, Sanofi, MSD, and AstraZeneca; personal fees from Bristol‐Myers Squibb and Nippon Boehringer Ingelheim. Dr Yasuda reports grants from Takeda Pharmaceutical, Abbott, and Boston Scientific; personal fees from Daiichi‐Sankyo and Bristol‐Meyers. Dr Kaikita reports grants from Grants‐in‐Aid for Scientific Research (20K08451) from the Ministry of Education, Culture, Sports, Science and Technology of Japan; grants and personal fees from Bayer Yakuhin and Daiichi Sankyo. Dr Akao reports grants from the Japan Agency for Medical Research and Development; personal fees from Bristol‐Myers Squibb and Nippon Boehringer Ingelheim; grants and personal fees from Bayer Yakuhin and Daiichi Sankyo. Dr Ako reports personal fees from Bayer Yakuhin and Sanofi; grants and personal fees from Daiichi Sankyo. Dr Matoba reports grants from Japan Cardiovascular Research Foundation; personal fees from Nippon Boehringer Ingelheim, Daiichi Sankyo, Astra Zeneca, and Bayer Yakuhin. Dr Nakmaura reports grants and personal fees from Bayer Yakuhin, Daiichi Sankyo, and Sanofi; personal fees from Bristol‐Myers Squibb and Nippon Boehringer Ingelheim. Dr Miyauchi reports personal fees from Amgen Astellas BioPharma, Astellas Pharma, MSD, Bayer Yakuhin, Sanofi, Takeda Pharmaceutical, Daiichi‐Sankyo, Nippon Boehringer Ingelheim, and Bristol‐Myers Squibb. Dr Hagiwara reports grants and personal fees from Bayer Yakuhin; grants from Nippon Boehringer Ingelheim; personal fees from Bristol‐Myers Squibb. Dr Hirayama reports grants and personal fees from Boston Scientific Japan, Otsuka Pharmaceutical, Sanofi, Astellas Pharma, Bristol‐Myers Squibb, Daiichi Sankyo, and Bayer Yakuhin; grants from Fukuda Denshi, Abbott Japan, Japan Lifeline, Takeda Pharmaceutical, Sumitomo Dainippon Pharma; personal fees from Toa Eiyo, Nippon Boehringer Ingelheim, Amgen Astellas BioPharma, and AstraZeneca. Dr Ogawa reports personal fees from Towa Pharmaceutical, Bristol‐Meyers Squibb, Pfizer, Toa Eiyo, Bayer Yakuhin, and Novartis Pharma. The remaining authors have no disclosures to report.

Figures

Figure 1. Participant flow.

Patients were randomized (1:1) to receive either rivaroxaban monotherapy or combination therapy with rivaroxaban plus antiplatelet drug. For the purpose of this study, AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) participants were divided into 2 subgroups, including the atherothrombosis group (patients with prior myocardial infarction, stroke, and/or peripheral artery disease) and the non‐atherothrombosis group.

Figure 2. Kaplan‐Meier curves between the non‐atherothrombosis and atherothrombosis groups.

The atherothrombosis group consisted of patients with prior myocardial infarction, stroke, or peripheral artery disease. A, The primary efficacy end point was a composite of cardiovascular events or all‐cause mortality, while (B) the primary safety end point was major bleeding as defined based on criteria established by the International Society on Thrombosis and Haemostasis. C, Net adverse clinical events consisted of death from any cause, myocardial infarction, stroke, and major bleeding. HR indicates hazard ratio.

Figure 3. Kaplan‒Meier curves for prior atherothrombotic disease and treatment group.

Kaplan–Meier curves for (A) the primary efficacy entpoint, (B) primary safety end point, and (C) net clinical adverse events (4 groups, based on the non‐atherothrombosis/atherothrombosis group and treatment type). Interaction P is for group (non‐atherothrombosis or atherothrombosis)×interventions (monotherapy or combination therapy). Combi indicates combination therapy; HR, hazard ratio; and Mono, monotherapy

Figure 4. Supposed relationship between antithrombotic therapy strength and risk of ischemic and bleeding events.

A, Non‐atherothrombosis group; (B) atherothrombosis group. Red lines indicate bleeding event risk, while blue lines indicate ischemic event risk. Bleeding risk was higher in the atherothrombosis group than in the non‐atherothrombosis group, as seen from the right edge of the figures (no antithrombotic therapy). The red line for bleeding risk in the atherothrombosis group rises more steeply than that of the non‐atherothrombosis group. Thus, the optimal “therapeutic window” (green area in the figures) may be narrower and of lesser range in the atherothrombosis group. DOAC indicates direct oral anticoagulant; and SAPT, single antiplatelet therapy.