Associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in patients with non-valvular atrial fibrillation

Liping Zhang,Xiaoyu Yan,Jeffrey I Weitz,Keith A A Fox,Alexander Solms,Anne Hermanowski-Vosatka,Gary Peters,Stephan Schmidt,Partha Nandy,Manesh Patel,Scott D Berkowitz,Stefan Willmann

doi:10.1007/s11239-020-02077-9

Abstract

Rivaroxaban exposure and patient characteristics may affect the rivaroxaban benefit–risk balance. This study aimed to quantify associations between model-predicted rivaroxaban exposure and patient characteristics and efficacy and safety outcomes in patients with non-valvular atrial fibrillation (NVAF), using data from the phase 3 ROCKET AF trial (NCT00403767). In ROCKET AF, 14,264 patients with NVAF were randomized to rivaroxaban (20 mg once daily [OD], or 15 mg OD if creatinine clearance was 30–49 mL/min) or dose-adjusted warfarin (median follow-up: 707 days); rivaroxaban plasma concentration was measured in a subset of 161 patients. In this post hoc exposure–response analysis, a multivariate Cox model was used to correlate individual predicted rivaroxaban exposures and patient characteristics with time-to-event efficacy and safety outcomes in 7061 and 7111 patients, respectively. There was no significant association between model-predicted rivaroxaban trough plasma concentration (Ctrough) and efficacy outcomes. Creatinine clearance and history of stroke were significantly associated with efficacy outcomes. Ctrough was significantly associated with the composite of major or non-major clinically relevant (NMCR) bleeding (hazard ratio [95th percentile vs. median]: 1.26 [95% confidence interval 1.13–1.40]) but not with major bleeding alone. The exposure–response relationship for major or NMCR bleeding was shallow with no clear threshold for an acceleration in risk. History of gastrointestinal bleeding had a greater influence on safety outcomes than Ctrough. These results support fixed rivaroxaban 15 mg and 20 mg OD dosages in NVAF. Therapeutic drug monitoring is unlikely to offer clinical benefits in this indication beyond evaluation of patient characteristics.

Highlights

Rivaroxaban, an oral direct factor Xa inhibitor, is approved for the prevention of stroke and systemic embolism (SE) in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors [1], based on the phase 3, randomized, controlled trial ROCKET AF (NCT00403767) [2]
Advanced age and impaired renal function are associated with increased rivaroxaban exposure [1] and are independent risk factors for NVAF-related thromboembolism and for major bleeding events in anticoagulant-treated patients [3,4,5,6]
It has been proposed that therapeutic drug monitoring may help guide anticoagulant dosing for individual patients

Summary

Introduction

Rivaroxaban, an oral direct factor Xa inhibitor, is approved for the prevention of stroke and systemic embolism (SE) in adults with non-valvular atrial fibrillation (NVAF) with one or more risk factors (e.g., prior stroke) [1], based on the phase 3, randomized, controlled trial ROCKET AF (NCT00403767) [2]. Advanced age and impaired renal function are associated with increased rivaroxaban exposure [1] and are independent risk factors for NVAF-related thromboembolism and for major bleeding events in anticoagulant-treated patients [3,4,5,6]. It has been proposed that therapeutic drug monitoring (i.e., plasma concentration-based dose adjustment) may help guide anticoagulant dosing for individual patients. This post hoc exposure–response analysis aimed to explore this possibility and to quantify the associations between predicted rivaroxaban exposures, patient characteristics and clinical outcomes in patients with NVAF using data from ROCKET AF

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