Effectiveness and safety of concomitant use of direct oral anticoagulants and antiarrhythmic drugs: a systematic review of observational studies.

Introduction: Concomitant use of antiarrhythmic drugs (AAs) may affect the effectiveness and safety of direct oral anticoagulants (DOACs) through pharmacokinetic interactions and other factors. Our systematic review aimed to provide an in-depth methodological assessment and synthesis of the available real-world evidence in the area.

Methods: We systematically searched MEDLINE/PubMed and EMBASE from January 2011 to October 2024 for observational studies assessing the effectiveness (risk of stroke) and safety (risk of major bleeding) associated with concomitant use of DOACs and AAs. We assessed the risk of bias using the Risk Of Bias In Non-randomized Studies of Interventions (ROBINS-I) tool.

Results: We identified 17 relevant studies including overall 2,613,693 patients. For stroke, all six studies showed no increased risk associated with concomitant use of DOACs and AAs. For major bleeding, seven studies showed an increased risk associated with concomitant use of DOACs and AAs (up to 187%), four studies showed heterogeneous results depending on the specific AA, and six studies showed no increased risk. When considering only higher-quality studies (n = 6), there was no association with the risk of stroke (n = 3). There were associations with an increased risk of major bleeding for concomitant use of DOACs and diltiazem (n = 2) or verapamil (n = 1), while findings for concomitant use of DOACs and amiodarone were inconsistent (n = 3).

Conclusions: Based on the synthesis of higher-quality real-world evidence, concomitant use of AAs does not seem to impact the effectiveness of DOACs. Findings on safety possibly depend on the specific AA, with diltiazem showing the highest risk.