Analysis of bioMARKer Distribution and Individual Reproducibility Under Rivaroxaban Treatment in Japanese Patients with Non-Valvular Atrial Fibrillation (R-MARK Study, CVI ARO2)

The "on-therapy range" of direct oral anticoagulants is the 90% interval of drug concentration. Previously, we reported the on-therapy range of rivaroxaban in a single-center cohort. The present study aimed to confirm the range and intraindividual reproducibility in a multicenter cohort.Eligible patients with non-valvular atrial fibrillation under rivaroxaban treatment for prevention of ischemic stroke were enrolled from nine institutes in Tokyo, Japan, between June 2016 and May 2017 (n = 324). The first and second (three months later) blood samples both taken within 1-5 hours after rivaroxaban intake were analyzed (n = 219). Plasma concentration of rivaroxaban (PC-Riv) and prothrombin time (PT) with five reagents were measured.The 90% interval of PC-Riv was 47.3-532.9 ng/mL. The 90% interval of PT measured with RecombiPlasTin 2G was 11.8-22.3 seconds, the widest range among the five reagents examined. PC-Riv reproducibility within a 90% interval was evaluated bidirectionally (first-to-second and second-to-first), and 92.4% of samples were reproducible. The change rate (CR) of PC-Riv between two samplings ranged widely, and high CR (≥54.3%, cutoff for predicting non-reproducibility) was predicted by concomitant drugs (non-dihydropyridine calcium antagonist and thiazide) and mitral regurgitation.We reported the on-therapy range of rivaroxaban in a multicenter cohort. This range was consistent with that of a single-center cohort and was highly reproducible within three months in daily clinical practice. However, caution is necessary regarding several factors that may affect the intraindividual variation of PC-Riv.