CLINICAL QUESTION

Are adults with atrial fibrillation (AF) who take apixaban (Eliquis) or rivaroxaban (Xarelto) at increased risk of serious bleeding from taking diltiazem or metoprolol for rate control?

BOTTOM LINE

Adults with AF who take apixaban or rivaroxaban for stroke prevention are at a significantly increased risk of serious bleeding with the concurrent use of diltiazem compared with metoprolol for rate control. The risk is highest in patients taking diltiazem dosages higher than 120 mg per day, those with a HAS-BLED (hypertension, abnormal renal and liver function, stroke, bleeding risk, labile international normalized ratio, elderly [older than 65 years], drug and alcohol use) score of 4 or higher, and those taking rivaroxaban compared with apixaban. (Level of Evidence = 2b)

SYNOPSIS

The most commonly prescribed direct oral anticoagulants— apixaban and rivaroxaban—are metabolized and eliminated by hepatic cytochrome P450 enzymes. Diltiazem is commonly prescribed for adults with AF, and it is a strong inhibitor of cytochrome P450; therefore, concurrent use with apixaban or rivaroxaban may significantly increase the risk of serious bleeding events. The investigators analyzed data from multiple Medicare registries to identify adults with AF who were 65 years or older and filled a prescription for apixaban or rivaroxaban (N = 204,155). Eligible study participants included those who were concurrently filling a prescription for diltiazem (n = 53,275) or metoprolol (n = 150,880). Multiple adjustments occurred to control for potential confounders, including frailty status, cardiovascular disease, chronic kidney disease, cancer, and other medication use that could potentially inhibit the P450 system. Summary measures for the risk of stroke or hemorrhage were versions of the CHA₂DS₂-VASc (congestive heart failure, hypertension, age 75 years or older [doubled], diabetes mellitus, stroke/transient ischemic attack/thromboembolism [doubled], vascular disease, age 65 to 74 years, sex category [female]) score and the HAS-BLED score.

During 90,927 person-years of follow-up, serious bleeding events resulting in hospitalization or death occurred significantly more often in patients taking diltiazem vs. metoprolol (60.3 vs. 49.7 events per 1,000 person-years; relative difference of 10.6; 95% CI, 7.0 to 14.2). No significant differences occurred in the risk for ischemic or hemorrhagic stroke, systemic embolism, or death not related to bleeding. Risk was highest for patients treated with a diltiazem dosage of 120 mg or higher per day (number needed to harm = 15 additional cases for every 1,000 person-years). Risk was also increased in patients with a HAS-BLED score of 4 or higher and in those taking rivaroxaban.

Study design: Cohort (retrospective)

Funding source: Government

Setting: Population-based

Reference: Ray WA, Chung CP, Stein CM, et al. Serious bleeding in patients with atrial fibrillation using diltiazem with apixaban or rivaroxaban. JAMA. 2024;331(18):1565-1575.