Outcomes associated with under-dosing of rivaroxaban for management of non-valvular atrial fibrillation in real-world Japanese clinical settings

Abstract

The approved dose of oral anticoagulant rivaroxaban for patients with non-valvular atrial fibrillation (NVAF) in Japan is 15 mg once daily (od) in patients whose creatinine clearance is ≥ 50 mL/min, but recent real-world studies have demonstrated that these patients often received less than the recommended dose due to bleeding concerns. The effect of under-dosing on safety and effectiveness outcomes remains unclear. We used 1-year follow-up data from the XAPASS, a real-world Japanese prospective, single-arm, observational study. Of the 11,308 patients, 6521 patients who completed a 1-year follow-up and had a creatinine clearance ≥ 50 mL/min were included in this sub-analysis. Primary endpoints were any bleeding and a composite of stroke/non-central nervous system systemic embolism (non-CNS SE)/myocardial infarction (MI). Among the 6521 patients, 4185 (64.2%; mean CHADS2 score: 1.8) received the 15 mg od (recommended dose), whereas 2336 (35.8%; mean CHADS2 score: 2.3) received 10 mg od (under-dose). After adjusting for patient characteristics by propensity scoring and inverse probability of treatment weighting, incidence rates of major bleeding were comparable between under-dosed patients and patients who received the recommended dose (1.34 vs. 1.63 events/100 patient-years, p = 0.197), although the incidence rates of stroke/non-CNS SE/MI were higher in under-dosed patients than in those who received the recommended dose (2.15 vs. 1.48 events/100 patient-years, p = 0.009). In Japanese clinical practice, some NVAF patients receive rivaroxaban doses inconsistent with the recommendation. Considering the total clinical benefit, the recommended dose may be preferable in terms of balance of safety and effectiveness.Clinicaltrials.gov NCT01582737.Electronic supplementary materialThe online version of this article (10.1007/s11239-019-01934-6) contains supplementary material, which is available to authorized users.

Safety and effectiveness of non-vitamin K oral anticoagulants versus warfarin in real-world patients with non-valvular atrial fibrillation: a retrospective analysis of contemporary Japanese administrative claims data

“…Reduced dosing of NOACs is a pertinent clinical concern as it may impact the safety and/or effectiveness of treatment 18 31 32. In the current study, risks for bleeding and stroke/SE were generally consistent between the standard-dose and reduced-dose NOAC subgroups, and we observed a significantly lower risk of stroke/SE with reduced-dose apixaban versus warfarin.…”

“…Broadly, these real-world results provide supportive evidence for the existing RCTs that have demonstrated the clinical benefits of NOACs versus warfarin in patients with NVAF 6–10. Moreover, the current study builds on the emerging, real-world evidence base for the effectiveness and safety of NOACs in Japanese clinical practice 15–18 30…”

“…While RCTs are the gold standard for demonstrating the effectiveness of interventions, they are not fully representative of an unselected real-world population, thereby limiting the relevance of their findings to clinical practice. Consequently, a number of observational, real-world evidence studies have emerged to provide supportive evidence of the safety and/or effectiveness of NOACs in clinical practice 11–18. However, there remain several unmet knowledge gaps in the literature regarding the clinical outcomes of NOAC treatment in patients with NVAF, particularly in patient subgroups at high risk of adverse outcomes 19 20…”

Postmarketing surveillance on the clinical use of edoxaban in patients with nonvalvular atrial fibrillation (ETNA‐AF‐Japan): One‐year safety and effectiveness analyses

“…Under‐dosing of DOAC has been reported in many studies. Some studies reported higher thromboembolic events in nonrecommended lower‐dosed patients than in patients with the recommended dose, and others found no significant differences in clinical outcomes between the two patient groups 20,27‐30 . In this study, 11.4% of patients were receiving a nonrecommended lower‐dose, and physicians might have chosen the dose because of advanced age or renal dysfunction and were considered to be at a higher risk of bleeding.…”

Clinical Risk Factors of Thromboembolic and Major Bleeding Events for Patients with Atrial Fibrillation Treated with Rivaroxaban in Japan

“…Outcomes associated with the underdosing of rivaroxaban have been reported elsewhere. 17 Baseline characteristics of patients included in this subanalysis were similar to those of patients who completed 1-year follow-up. 15 Concomitant use of antiplatelets was predictive of both stroke/non-CNS SE/MI and major bleeding, whereas a history of ischemic stroke/ TIA and age greater than or equal to 75 years were predictors of stroke/non-CNS SE/MI only, and renal impairment (CrCl <50 mL/min) and diabetes were predictors of major bleeding only.…”