Impact of P-glycoprotein and CYP3A4-interacting drugs on clinical outcomes in patients with atrial fibrillation using non-vitamin K antagonist oral anticoagulants: a nationwide cohort study.

AIMS: The clinical relevance of common pharmacokinetic interactions with non-vitamin K antagonist oral anticoagulants (NOACs) often remains unclear. Therefore, the impact of P-glycoprotein (P-gp) and CYP3A4 inhibitors and inducers on clinical outcomes in NOAC-treated patients with atrial fibrillation (AF) was investigated.

METHODS AND RESULTS: AF patients were included between 2013-2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-interacting drugs at the time of NOAC initiation was identified. Among 193 072 NOAC-treated AF patients, 46 194 (23.9%) and 2903 (1.5%) subjects concomitantly used a P-gp/CYP3A4 inhibitor or inducer, respectively. After multivariable adjustment, concomitant use of P-gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (adjusted hazard ratio (aHR) 1.24, 95% confidence interval (CI) (1.18-1.30)) and all-cause mortality risks (aHR 1.07, 95%CI (1.02-1.11)), but not with thromboembolism in NOAC-treated AF patients. A significantly increased risk of major bleeding was observed with amiodarone (aHR 1.27, 95%CI (1.21-1.34)), diltiazem (aHR 1.28, 95%CI (1.13-1.46)), verapamil (aHR 1.36, 95%CI (1.03-1.80)), ticagrelor (aHR 1.50, 95%CI (1.20-1.87)), and clarithromycin (aHR 1.55, 95%CI (1.14-2.11)); and in edoxaban (aHR 1.24, 95%CI (1.06-1.45)), rivaroxaban (aHR 1.25, 95%CI (1.16-1.34)) and apixaban users (aHR 1.27, 95%CI (1.16-1.39)), but not in dabigatran users (aHR 1.07, 95%CI (0.94-1.23)). Concomitant use of P-gp/CYP3A4 inducers (e.g. antiepileptic drugs like levetiracetam) was associated with a significantly higher stroke risk (aHR 1.31, 95%CI (1.03-1.68)), but not with bleeding or all-cause mortality.

CONCLUSION: Concomitant use of P-gp/CYP3A4 inhibitors was associated with higher bleeding and all-cause mortality risks in NOAC users, whereas the use of P-gp/CYP3A4 inducers was associated with higher stroke risks.