Association between hemorrhage and direct oral anticoagulants in combination with verapamil: Analysis of Japanese Adverse Drug Event Report database andelectronic medical record data.

Abstract

The aim of this study was to investigate the risk of hemorrhage in concomitant therapy with direct oral anticoagulants (DOACs) and class IV antiarrhythmic drugs. First, disproportionality analysis (DPA) was performed using the Japanese Adverse Drug Event Report (JADER) database to investigate the risk of hemorrhage with DOACs. Second, a cohort study was performed using electronic medical record data to confirm the results of the JADER analysis. In the JADER analysis, hemorrhage was significantly associated with treatment with edoxaban and verapamil (reporting odds ratio = 1.66; 95% confidence interval (CI) = 1.04-2.67). The cohort study revealed that hemorrhage incidence significantly differed between the verapamil-treated group and the bepridil-treated group, with a higher risk for hemorrhage in the verapamil group (log-rank test: p <0.001). The multivariate Cox proportional hazards model also showed that the verapamil and DOAC combination was significantly associated with hemorrhage events compared with the bepridil and DOAC combination (hazard ratio (HR): 2.87, 95% CI: 1.17-7.07, p = 0.022). Furthermore, creatinine clearance (Ccr) ≥50 mL/min was significantly associated with hemorrhage events (HR: 2.72, 95% CI: 1.03-7.18, p = 0.043), and verapamil was significantly associated with hemorrhage in patients with Ccr ≥50 mL/min (HR: 3.58, 95% CI: 1.36-9.39, p = 0.010) but not in patients with Ccr <50 mL/min. Verapamil increases the risk of hemorrhage in patients on DOACs. Dose adjustment of DOACs based on renal function may prevent hemorrhage when verapamil is concomitantly administered.