Concomitant Use of Diltiazem With Direct Oral Anticoagulants and Bleeding Risk in Atrial Fibrillation

Background Diltiazem, a moderate cytochrome P450 3A4 isozyme/P‐glycoprotein inhibitor, may potentiate the bleeding risk of direct oral anticoagulants (DOACs) through pharmacokinetic interactions. We evaluated the association between concomitant use of diltiazem with DOACs and bleeding among patients with atrial fibrillation, across varying degrees of kidney function. Methods and Results We identified 4544 patients with atrial fibrillation who were initiated on rivaroxaban (n=1583), apixaban (n=2373), or dabigatran (n=588), between 2010 and 2019 in Geisinger Health, with a mean age of 72 years and an estimated glomerular filtration rate of 70 mL/min per 1.73 m2. At the time of DOAC initiation, 15% patients were taking diltiazem and an additional 5% were initiated on diltiazem during follow‐up. Among DOAC users, using diltiazem concurrently (versus DOAC alone) was associated with an increased risk of any bleeding‐related hospitalization (unadjusted risk difference, 2.4; 95% CI, 0.6–4.2 events per 100 person‐years; adjusted hazard ratio, 1.56, 95% CI, 1.15–2.12), as well as major bleeding (unadjusted risk difference, 1.4 [95% CI, 0.1–2.6 events per 100 person‐years]; adjusted hazard ratio, 1.84 [95% CI, 1.18–2.85]). Increased risk of any/major bleeding with diltiazem was observed in both patients with and without CKD (estimated glomerular filtration rate