Amiodarone, verapamil, or diltiazem use with direct oral anticoagulants and the risk of hemorrhage in older adults

Background— Routinely used cardiac medications, based on pharmacokinetics, are hypothesized to increase drug concentration levels of direct oral anticoagulants (DOACs) with the potential to increase the hemorrhage risk. We set out to compare the risk for hemorrhage following initiation of amiodarone, verapamil, or diltiazem (moderate CYP3A4 and/or P-glycoprotein activity) versus metoprolol or amlodipine (weak or no activity) among older adults prescribed DOACs.

Methods— We conducted a population-based, retrospective cohort study of all adults (≥66) on a DOAC (dabigatran, apixaban, rivaroxaban) (n= 295,038) who were newly prescribed amiodarone (n=4,872), verapamil (n=1,284) or diltiazem (n=14,638) compared with metoprolol or amlodipine from Ontario, Canada (2009-2016). The outcome was hospital admission or emergency room visit with a major hemorrhage (upper or lower gastrointestinal tract, intra-cranial) examined using weighted models.

Results— 1,737 hemorrhage events occurred [amiodarone 80 (1.6%) vs. metoprolol 503 (2.3%), verapamil 32 (2.5%) vs. amlodipine 406 (1.6%), diltiazem 312 (2.1%) vs. amlodipine 404 (1.5%)]. The weighted risk of major hemorrhage was not elevated with amiodarone, verapamil, or diltiazem initiation in DOAC users compared to metoprolol or amlodipine during the full follow-up period [Hazard ratio HR (95% confidence interval): Amiodarone HR 0.77 (0.61-0.97), Verapamil HR 1.32 (0.88-1.98), diltiazem HR 0.99 (0.85-1.15)]. This was consistent with a broader definition of bleeding, adjusting for kidney function, by DOAC type or dosage.

Conclusions— Hemorrhage risk with amiodarone, verapamil and diltiazem were similar to comparators among DOAC users > 66 years old.