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

Br J Clin Pharmacol. 2022 Jul;88(7):3039-3051. doi: 10.1111/bcp.15265. Epub 2022 Feb 21.

Abstract

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.

Keywords: CYP3A4; NOAC; P-glycoprotein; amiodarone; atrial fibrillation; calcium channel blocker; drug interaction; meta-analysis.

Publication types

  • Meta-Analysis
  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Administration, Oral
  • Anticoagulants / adverse effects
  • Atrial Fibrillation* / chemically induced
  • Atrial Fibrillation* / complications
  • Atrial Fibrillation* / drug therapy
  • Cytochrome P-450 CYP3A
  • Cytochrome P-450 CYP3A Inhibitors / adverse effects
  • Gastrointestinal Hemorrhage / chemically induced
  • Humans
  • Stroke* / etiology
  • Thromboembolism* / chemically induced

Substances

  • ATP Binding Cassette Transporter, Subfamily B, Member 1
  • Anticoagulants
  • Cytochrome P-450 CYP3A Inhibitors
  • Cytochrome P-450 CYP3A
  • CYP3A4 protein, human