Impact of P-glycoprotein and/or CYP3A4-interacting drugs on the risk-benefit profile of NOACs in patients with atrial fibrillation: a meta-analysis

Abstract

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Research Foundation Flanders (FWO) Background 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. Purpose A critical appraisal of the impact of pharmacokinetically-interacting drugs on the effectiveness and safety of NOACs in patients with atrial fibrillation (AF). Methods After searching Pubmed and Embase, phase III randomized controlled trials (RCTs) and longitudinal observational cohort studies on the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk-benefit profile of NOACs in AF patients during a mean/median follow-up of ≥6 months were included. A fixed effects meta-analysis was performed with the Mantel-Haenszel method. Results Fifteen studies were included (10 post hoc analyses of RCTs, 5 observational studies), investigating 21,711 and 306,421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use respectively, while only one 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/SE (RR 0.88, 95%CI (0.77-1.01)), intracranial bleeding (RR 0.89, 95%CI (0.68-1.15)) and gastro-intestinal 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)), but higher mortality risks (RR 1.21, 95%CI (1.05-1.39)). Co-administration of verapamil or diltiazem was associated with higher major bleeding risks (RR 1.64, 95%CI (1.31-2.06)), but no significantly different thromboembolic or mortality risks. Conclusions Given the higher bleeding and mortality risks in NOAC-treated AF patients concomitantly using P-gp/CYP3A4 inhibitors compared to NOAC users not taking interacting drugs, close monitoring of these patients is warranted, including regular medication review and addressing modifiable bleeding risk factors. Regarding P-gp/CYP3A4 inducers, a considerable research gap was identified, necessitating more research on their impact.