Relevance of P-glycoprotein in stroke prevention with dabigatran, rivaroxaban, and apixaban.

Abstract

The new oral anticoagulants (NOAC) dabigatran etexilate, rivaroxaban, and apixaban show similar efficacy for stroke prevention in patients with atrial fibrillation (AF) as the vitamin K antagonist warfarin. Absorption of NOACs is dependent on the intestinal P-glycoprotein (P-gp) system and P-gp activity is modulated by a variety of drugs and food components. The aim of this review is to give an overview of P-gp-associated drug-drug and drug-food interactions with NOACs in AF patients. A literature search was carried out by screening MEDLINE for the terms dabigatran, rivaroxaban, apixaban, P-glycoprotein, and atrial fibrillation from 1998 to 2013. Randomized clinical trials, longitudinal studies, case series, and case reports were included. Concomitant medication with proton pump inhibitors, amiodarone, clarithromycin, and verapamil increased bioavailability whereas rifampicin decreased the bioavailability of dabigatran. Coadministration of erythromycin, clarithromycin, fluconazole, ketoconazole, and ritonavir increased rivaroxaban plasma concentrations. No data were found on apixaban and P-gp-modulating drugs or on NOACs and food components modulating P-gp. The clinical relevance of interactions between NOACs and P-gp-modulating drugs or food components is largely unknown as bleeding complications under NOACs and P-gp-inhibiting drugs are mainly reported from patients with concomitant renal failure. There is an urgent need to investigate the role of P-gp-modulating substances as potential sources of drug-drug and drug-food interactions. A thorough analysis of the data accumulated in the three large NOAC trials regarding the role of P-gp-modulating drugs in bleeding and embolic events is desirable. Pharmacological studies should investigate the influence of P-gp-modulating drugs and food on NOAC plasma concentrations and coagulation parameters. When prescribing NOACs, patients should be informed about the potential interactions with drugs and herbal drugs. Patients who develop bleeding or embolic events under treatment with NOACs should be investigated for co-medications as well as for over-the-counter drugs and dietary habits. In post-marketing surveillance of NOACs, the association with drug or food intake with complications, bleeding, and embolic events should be registered.