Diltiazem inhibits cytochrome P450 3A4 and P-glycoprotein, potentially affecting metabolism of factor Xa inhibitors and increasing bleeding risk. This retrospective active-comparator cohort study published in the Annals of Internal Medicine assessed bleeding outcomes in patients with atrial fibrillation receiving apixaban or rivaroxaban in combination with diltiazem compared with metoprolol.

Using a U.S. administrative health care database, commercially insured patients with atrial fibrillation were identified. The primary outcome was a composite of serious bleeding events leading to hospitalization. Secondary outcomes included composites of stroke or systemic embolism. Diltiazem exposure was stratified as high dose (>120 mg/day) and low dose (≤120 mg/day). Propensity score matching was applied to adjust for differences between diltiazem and metoprolol users. 

The matched cohort included 23,000 diltiazem users and 23,000 metoprolol users. Diltiazem use was associated with a higher rate of serious bleeding (rate difference [RD] 5.4 per 1,000 person-years; 95% CI 1.2 to 9.6). Bleeding risk was greater with high-dose versus low-dose diltiazem (high dose RD 9.2; 95% CI 2.7 to 15.7; low dose RD 2.6; 95% CI 0.5 to 8.0). Estimated 12- and 6-month absolute risk differences were 0.48 and 0.31 percentage points, respectively.

Diltiazem use was associated with increased serious bleeding compared with metoprolol among commercially insured patients with atrial fibrillation receiving apixaban or rivaroxaban. Residual confounding remains a limitation.