Key result
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.
Why the study?
P-glycoprotein and CYP3A4-interacting drugs influence NOAC plasma levels, but the clinical relevance of these pharmacokinetic interactions in AF patients remained questioned.
Does concomitant use of P-gp/CYP3A4-interacting drugs increase bleeding and mortality risks in NOAC-treated patients with atrial fibrillation?
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?
Relative Risk: 1.1 (95% CI 1.01–1.19)
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.
May warrant monitoring for bleeding in NOAC users on P-gp/CYP3A4 inhibitors; hypothesis-generating and leaves causality open.
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.
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Grymonprez et al. (2022) 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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