Rivaroxaban Monotherapy in Atrial Fibrillation and Stable Coronary Artery Disease Across Body Mass Index Categories

Background The AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial showed both noninferiority for efficacy and superiority for safety endpoints of rivaroxaban monotherapy compared with those of rivaroxaban plus antiplatelet therapy (combination therapy) in patients with atrial fibrillation and stable coronary artery disease. Objectives This study sought to evaluate outcomes of rivaroxaban monotherapy in those patients across body mass index (BMI) categories. Methods Patients were categorized into 4 groups: underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5 to <25 kg/m2), overweight (BMI 25 to <30 kg/m2), and obesity (BMI ≥30 kg/m2). Efficacy (a composite of all-cause death, myocardial infarction, unstable angina requiring revascularization, stroke, or systemic embolism) and safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria) were compared between rivaroxaban monotherapy and combination therapy across BMI categories. Results This study analyzed 2,054 patients with a median age of 75.0 years and CHA2DS2-VASc score of 4. A significant interaction was not observed between BMI categories and effect of monotherapy for efficacy (P = 0.83) and safety (P = 0.07), although monotherapy was superior to combination therapy for efficacy in normal weight (HR: 0.64; 95% CI: 0.44-0.95) and safety in overweight (HR: 0.25; 95% CI: 0.10-0.62), whereas a significant difference in the endpoints was not observed in the other BMI categories. Conclusions Rivaroxaban monotherapy had a similar effect on prognosis across all BMI categories in patients with atrial fibrillation and stable coronary artery disease. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease [AFIRE]; UMIN000016612, NCT02642419)


T he AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With
Stable Coronary Artery Disease) trial demonstrated that rivaroxaban monotherapy was noninferior for cardiovascular events or death from any cause and was superior for major bleeding events to rivaroxaban plus antiplatelet therapy (combination therapy) in patients with atrial fibrillation (AF) and stable coronary artery disease (CAD) over 1 year after revascularization or those with angiographically confirmed CAD not requiring revascularization. 1 This result provides fundamental evidence of guidelinerecommended antithrombotic management with direct oral anticoagulant (DOAC) monotherapy for patients with AF and stable CAD. 2 In the AFIRE trial, the patients received fixed-dose rivaroxaban according to their creatinine clearance, irrespective of body weight or body mass index (BMI). 3 However, a previous pharmacokinetic study showed that about 20% of patients who are obese (over 120 kg) had a peak plasma concentration of DOACs below the therapeutic range of peak concentration, suggesting potential risk for underdosing of DOACs in patients who are extremely obese. 4 In current guidelines, avoiding use of DOACs has been recommended in patients with BMI >40 kg/m 2 or weight >120 kg. 5,6 In addition to the caution in extreme obesity, the European Heart Rhythm Association mentioned high bleeding risk with anticoagulation therapy in patients who are severely underweight. 6 The guidelines also proposed checking for accumulation of the drug when using DOACs for patients with extreme BMI. 5,6 Patients with AF and stable CAD have high risk of thrombotic cardiovascular and cerebrovascular events, as well as bleeding events, thus, the high risk of antithrombotic therapy-related bleeding complications remains a problem in those patients with extreme BMI. However, no accumulating evidence regarding efficacy and safety of these fixed-dose DOAC monotherapy or combination with antiplatelet drugs has been established in this population.
The aim of this post hoc analysis of the AFIRE trial was to evaluate outcomes of rivaroxaban monotherapy (vs combination therapy) in patients with AF and stable CAD across BMI categories.

STUDY DESIGN AND STUDY PARTICIPANTS.
This subanalysis of the AFIRE trial was a post hoc analysis. The detailed study design, protocol, and the primary results of the AFIRE trial have been published elsewhere. 1 Table 1. There was no statistical difference in allocation (rivaroxaban monotherapy or combination therapy), the mean CHA 2 DS 2 -VASc, and high score ($3) of  Table 2).
These tendencies were observed in the monotherapy, but not in the combination therapy.

DISCUSSION
The main findings of this subanalysis of the AFIRE trial were as follows: 1) patients with lower BMI were the older, had the lower creatinine clearance, and had the higher prevalence of reduced dose; 2) rivaroxaban monotherapy was superior to combination therapy for primary efficacy in normal BMI group, primary safety in overweight group, and NACE in normal BMI and overweight groups, whereas a significant difference in the endpoints was not observed in the other BMI categories although the underweight and obese   there is an obesity paradox. 20 In any case, the efficacy and safety of DOACs, compared with warfarin, in those patients who are obese with AF has been established. Based on these findings, we therefore speculated that rivaroxaban monotherapy with

FIGURE 6 Sensitivity Analysis of Study Endpoints
Sensitivity analysis using alternative cutoff of body mass index (quintile) was performed to compute crude HRs and 95% CIs for the study endpoints in the Cox proportional hazard regression model. Testing interaction between the treatment and the subgroup was performed.