Concomitant use of P-gp/CYP3A4 inhibitors in NOAC-treated atrial fibrillation patients was associated with significantly higher risks of major bleeding (RR 1.10; 95% CI 1.01-1.19) and mortality.
Meta-Analysis (n=328,132)
Does concomitant use of P-gp/CYP3A4-interacting drugs increase bleeding and mortality risks in NOAC-treated patients with atrial fibrillation?
Concomitant use of P-gp/CYP3A4 inhibitors in NOAC-treated AF patients is associated with increased risks of major bleeding and all-cause mortality, warranting close clinical monitoring.
Relative Risk: 1.1 (95% CI 1.01–1.19)
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.
Grymonprez et al. (Tue,) conducted a meta-analysis in atrial fibrillation (n=328,132). P-gp/CYP3A4 inhibitors vs. not using P-gp/CYP3A4 inhibitors was evaluated on major bleeding (RR 1.10, 95% CI 1.01-1.19). Concomitant use of P-gp/CYP3A4 inhibitors in NOAC-treated atrial fibrillation patients was associated with significantly higher risks of major bleeding (RR 1.10; 95% CI 1.01-1.19) and mortality.
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