Clinical Question: Among patients with atrial fibrillation (AF) receiving apixaban or rivaroxaban, does concomitant use of diltiazem increase the risk of serious bleeding compared with metoprolol for rate control?
Background: Direct oral anticoagulants, including apixaban and rivaroxaban, are commonly prescribed for stroke prevention in AF. Both agents are metabolized through cytochrome P450 3A4 (CYP3A4) and P-glycoprotein (P-gp). Because diltiazem inhibits CYP3A4 and P-gp, concomitant use may increase direct oral anticoagulant plasma concentrations and potentially increase the risk of bleeding.
Study Design: Population-based, propensity score-matched retrospective cohort study
Setting: IBM MarketScan database
Synopsis: This study identified 23,104 diltiazem users and 84,967 metoprolol users with AF who were newly initiated on apixaban or rivaroxaban and had no prior anticoagulation use. Patients receiving diltiazem were propensity score matched 1 to 1 with those receiving metoprolol, yielding 23,000 patients per group. The primary outcome was hospitalization for serious bleeding. Secondary outcomes included stroke or systemic embolism. Compared with metoprolol, diltiazem use was associated with a higher risk of serious bleeding (467 versus 397 events; rate difference, 5.4 events per 1,000 person-years; 95% CI, 1.2 to 9.6). Bleeding risk was greatest among patients receiving diltiazem doses greater than 120 mg/day. Rates of ischemic stroke and systemic embolization were similar between groups. Limitations include the retrospective observational design, reliance on administrative claims data, and the potential for residual confounding from unmeasured variables despite propensity score matching.
Bottom Line: Among patients with AF treated with apixaban or rivaroxaban, concomitant use of diltiazem was associated with a small but statistically significant absolute increase in the risk for serious bleeding compared with metoprolol, without a meaningful difference in stroke or systemic embolism. Clinicians should consider this potential drug interaction, particularly when prescribing higher doses of diltiazem.
Citation: Dawwas GK, et al. The risk for bleeding in patients with atrial fibrillation from concomitant use of apixaban or rivaroxaban with diltiazem compared with metoprolol. Ann Intern Med. 2026;179(4):515-523. https://doi.org/10.7326/ANNALS-25-01408.
Dr. Renda
Dr. Renda is a PGY-2 internal medicine resident at the University of Tennessee Health Sciences College of Medicine and Erlanger Hospital, both in Chattanooga, Tenn.