P-gp/CYP3A4 inhibitor use ups bleeding, mortality risks in NOAC-treated AF patients

Bleeding and mortality risks are elevated in atrial fibrillation (AF) patients treated with nonvitamin K antagonist oral anticoagulant (NOAC) who are also using P-glycoprotein (P-gp) and CYP3A4 inhibitors, reports a study, noting the need for close monitoring of these individuals.

This meta-analysis included randomized controlled trials and observational studies, retrieved from the databases of PubMed and Embase, that examined the impact of concomitantly used P-gp/CYP3A4-interacting drugs on the risk–benefit profile of NOACs in AF patients.

Fifteen studies met the inclusion criteria and included 21,711 and 306,421 NOAC-treated AF patients with and without P-gp/CYP3A4 inhibitor use, respectively. One study included P-gp/CYP3A4 inducers.

Concomitant use of P-gp/CYP3A4 inhibitors in NOAC-treated AF patients correlated with a significantly higher risk of major bleeding (relative risk [RR], 1.10, 95 percent confidence interval [CI], 1.01‒1.19) and all-cause mortality (RR, 1.14, 95 percent CI, 1.05‒1.23) compared with nonusers.

On the other hand, no significant difference was observed in the risk of stroke/systemic embolism (RR, 0.88, 95 percent CI, 0.77‒1.01), intracranial bleeding (RR, 0.89, 95 percent CI, 0.68‒1.15), and gastrointestinal bleeding (RR, 1.09, 95 percent CI, 0.91‒1.30).

Concomitant use of amiodarone with NOACs resulted in lower thromboembolic (RR, 0.75, 95 percent CI, 0.61‒0.92), similar major bleeding (RR, 0.92, 95 percent CI, 0.80‒1.07), but higher mortality risks (RR, 1.21, 95 percent CI, 1.05‒1.39).

Furthermore, coadministration of verapamil or diltiazem correlated with an increased risk of major bleeding (RR, 1.64, 95 percent CI, 1.31‒2.06) and similar thromboembolic (RR, 1.10, 95 percent CI, 0.75‒1.61) and mortality risks (RR, 1.01, 95 percent CI, 0.77‒1.33).

“P-gp and CYP3A4-interacting drugs influence plasma levels of NOACs,” the authors said.