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 AF patients were included between 2013 and 2019 using Belgian nationwide data. Concomitant use of P-gp/CYP3A4-results 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.