Concomitant use of direct oral anticoagulants and interacting antiarrhythmic drugs and the risk of stroke and bleeding among patients with non-valvular atrial fibrillation: a multinational cohort study

1. In non-valvular atrial fibrillation (NVAF) patients taking DOACs, adding amiodarone, diltiazem, dronedarone, or verapamil does not increase ischemic stroke risk compared with non-interacting antiarrhythmics.

2. These interacting antiarrhythmics do increase major bleeding by about 30%, especially in younger patients and when co-initiated, so closer monitoring or alternative agents should be considered.

Evidence Rating Level: 2 (Good) 

Direct oral anticoagulants (DOACs) and certain antiarrhythmic drugs share CYP3A4 and P-glycoprotein pathways, raising concern that coadministration could increase DOAC exposure and alter clinical outcomes in non-valvular atrial fibrillation (NVAF). This multinational cohort study used UK CPRD and Quebec RAMQ data to identify 54,078 adults with NVAF who were taking a DOAC and then initiated an antiarrhythmic; patients receiving interacting agents (amiodarone, diltiazem, dronedarone, verapamil) were compared with those receiving non-interacting agents (flecainide, propafenone, sotalol). Inverse-probability-of-treatment-weighted Cox models and random-effects pooling estimated hazard ratios for ischemic stroke or systemic embolism and for major bleeding. Use of interacting antiarrhythmics was not associated with a higher risk of ischemic stroke or TIA/systemic embolism versus non-interacting drugs (pooled HR 1.04, 95% CI 0.88–1.21). By contrast, concomitant interacting therapy increased major bleeding (pooled HR 1.30, 95% CI 1.19–1.41), largely from gastrointestinal and other extracranial sites, with a stronger association in patients younger than 70 years and in those co-initiated on both drugs. The authors conclude that while the effectiveness of DOACs is preserved, clinicians should preferentially select non-interacting rhythm or rate control agents, or intensify bleeding surveillance and gastroprotection, when interacting agents are necessary. These findings were consistent across databases and multiple sensitivity analyses and subgroups.

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