BACKGROUND: Diltiazem and verapamil are combined p-glycoprotein and moderate CYP3A4 inhibitors which significantly increase the concentrations of direct oral anticoagulants (DOACs) and may increase the risks of bleeding. Multiple real-world studies compared the concomitant therapy of diltiazem/verapamil and DOACs versus the DOAC monotherapy groups, but their main findings were contradictory.

OBJECTIVE: To evaluate the risks of bleeding and stroke between the concomitant therapy of diltiazem/verapamil and DOACs and DOAC monotherapy.

METHODS: A meta-analysis was performed to compare the concomitant therapy of diltiazem/verapamil and DOACs versus DOACs. Database searches through November 16, 2024 were performed using MEDLINE and Google Scholar. The primary outcome was major bleeding. The secondary outcomes included stroke or systemic embolism and gastrointestinal bleeding.

RESULTS: A total of 6 studies were included in this meta-analysis. It showed that the concomitant therapy of DOAC and diltiazem/verapamil was significantly associated with increased risks of major bleeding (odds ratio [OR] = 1.38; 95% CI = 1.24, 1.54; P < 0.01; I² = 0%) and gastrointestinal bleeding (OR = 1.19; 95% CI = 1.03, 1.37; P = 0.01; I² = 0%) compared with the DOAC monotherapy group. The concomitant therapy group was also significantly associated with the lower risk of stroke or systemic embolism compared with the DOAC monotherapy group (OR = 0.83; 95% CI = 0.73, 0.93; I² = 0%).

CONCLUSION AND RELEVANCE: This meta-analysis found that the concomitant therapy of DOACs with diltiazem/verapamil increases the risks of bleeding outcomes compared with the DOAC monotherapy group.