Perspective:

Use of DOACs, including apixaban and rivaroxaban, has been an important advance in the prevention of stroke for patients with AF. This includes both easier to use regimens and less severe bleeding (e.g., intracranial hemorrhage) as compared to vitamin K antagonist therapy. However, while these medications are easy to prescribe and utilize, important drug-drug interactions are often overlooked. This includes the use of medications that inhibit CYP3A4 hepatic metabolism, such as diltiazem, apixaban, and rivaroxaban. As such, concurrent use of these medications can lead to an increased overall anticoagulant effect from these fixed-dose regimens.

This large, observational study provides the strongest evidence to date that co-administration of a strong CYP3A4 inhibitor, such as diltiazem, can lead to clinically relevant adverse events with DOAC co-administration. This includes a dose-response association, where the risk of serious bleeding was highest for patients receiving >120 mg/day of diltiazem. Importantly, the study did not find an increased risk of thrombotic events. Also importantly, this study did not assess the role of DOAC dose-reduction with co-administration of diltiazem, and this strategy cannot be recommended without further evidence ensuing efficacy and safety. In the meantime, clinicians should be aware of this clinically relevant drug-drug interaction and engage patients in a shared decision-making discussion about the use of various rate-controlling agents when they are managing AF. Additionally, this is an important opportunity for anticoagulation stewardship systems (e.g., pharmacist use of population health dashboards, clinical decision support alerts) to identify these at-risk patients and ensure that the safest therapies have been discussed with patients.