Impact of P‐glycoprotein and/or CYP3A4‐interacting drugs on effectiveness and safety of non‐vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: A meta‐analysis

摘要

Aims P‐glycoprotein (P‐gp) and CYP3A4‐interacting drugs influence plasma levels of non‐vitamin K antagonist oral anticoagulants (NOACs). However, the clinical relevance is questioned. Therefore, the impact of pharmacokinetically‐interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF) was investigated. Methods A meta‐analysis was performed based on randomized controlled trials and observational studies retrieved from Pubmed and Embase that investigated the impact of concomitantly used P‐gp/CYP3A4‐interacting drugs on the risk–benefit profile of NOACs in AF patients. Results Fifteen studies were included, investigating 21?711 and 306?421 NOAC‐treated AF patients with and without P‐gp/CYP3A4 inhibitor use respectively, while only 1 study included P‐gp/CYP3A4 inducers. In NOAC‐treated AF patients, concomitant use of P‐gp/CYP3A4 inhibitors was associated with significantly higher major bleeding (relative risk [RR] 1.10, 95% confidence interval [CI; 1.01–1.19]) and all‐cause mortality risks (RR 1.14, 95%CI [1.05–1.23]) compared to not using P‐gp/CYP3A4 inhibitors, while the risks of stroke/systemic embolism (RR 0.88, 95%CI [0.77–1.01]), intracranial bleeding (RR 0.89, 95%CI [0.68–1.15]) and gastrointestinal bleeding (RR 1.09, 95%CI [0.91–1.30]) were not significantly different. Concomitant use of amiodarone with NOACs was associated with lower thromboembolic (RR 0.75, 95%CI [0.61–0.92]), similar major bleeding (RR 0.92, 95%CI [0.80–1.07]) but higher mortality risks (RR 1.21, 95%CI [1.05–1.39]). Coadministration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI [1.31–2.06]), but comparable thromboembolic (RR 1.10, 95%CI [0.75–1.61]) and mortality risks (RR 1.01, 95%CI [0.77–1.33]). Conclusion Given the higher bleeding and mortality risks in NOAC‐treated AF patients concomitantly using P‐gp/CYP3A4 inhibitors, close monitoring is warranted.