Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation?

OBJECTIVE: To review pharmacokinetic and pharmacodynamic drug-drug interactions (DDIs) involving new oral anticoagulants for atrial fibrillation.

DATA SOURCES: A literature search was conducted via PubMed and the Cochrane database to identify DDI studies using the terms drug interactions, dabigatran, rivaroxaban, and apixaban. Prescribing information and Food and Drug Administration briefing documents were used to supplement published data.

STUDY SELECTION AND DATA EXTRACTION: English publications identified on Medline from 2005 up to August 2013 and US prescribing information for approved oral anticoagulants.

DATA SYNTHESIS: Articles reviewed focused on drugs affecting the permeability glycoprotein (P-gp) efflux transporter protein and/or cytochrome P (CYP) 450 3A4 enzymes, and pharmacodynamic DDIs when drugs are administered concomitantly. Phase I DDI studies have reported pharmacokinetic DDIs mediated by P-gp alone (dabigatran etexilate) or in combination with CYP3A4 enzymes (rivaroxaban and apixaban). Dabigatran etexilate should not be administered with any P-gp inhibitor in patients with severe renal impairment. Briefing documents indicate that rivaroxaban and apixaban should not be used with drugs that are strong inhibitors of both P-gp and CYP3A4. DDI studies involving rifampicin suggest that rivaroxaban and apixaban should be avoided when strong inducers of P-gp and CYP3A4 are used concurrently. Concomitant use of apixaban and strong dual inhibitors of P-gp and CYP3A4 should be avoided or the dose reduced. Five randomized clinical trials report additive effects with rivaroxaban, dabigatran, and apixaban when used concomitantly with antiplatelet agents; bleeding rates have been found to be higher, especially with dual antiplatelet therapy.

CONCLUSIONS: Awareness of drugs that alter the function of the P-gp efflux transporter protein and CYP3A4 enzymes and provide additive effects should enable prescribers to anticipate and avoid potential DDIs involving the new oral anticoagulants. To this end, briefing documents and prescribing information have applied cautionary measures for individuals treated with these newer anticoagulants.