The addition of interacting antiarrhythmics to direct oral anticoagulants in patients with non-valvular atrial fibrillation may not increase ischemic stroke risk compared to non-interacting antiarrhythmics

1. In non-valvular atrial fibrillation (NVAF) patients taking direct oral anticoagulants (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.

Click here to read this study in BMC Medicine

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