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Herz

, Volume 40, Supplement 2, pp 140–145 | Cite as

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

  • C. StöllbergerEmail author
  • J. Finsterer
Review article

Abstract

Background

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.

Objective

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.

Methods

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.

Results

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.

Conclusion

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 comedications 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.

Keywords

Atrial fibrillation Anticoagulation Proton pump inhibitors Drug–drug interaction Blood–brain barrier 

Relevanz von P-Glykoprotein in der Schlaganfallprävention mit Dabigatran, Rivaroxaban und Apixaban

Zusammenfassung

Hintergrund

Die neuen oralen Antikoagulanzien (NOAC) Dabigatranetexilat, Rivaroxaban und Apixaban haben eine ähnliche Wirksamkeit zur Schlaganfallprävention bei Vorhofflimmern (AF) wie der Vitamin-K-Antagonist Warfarin. Die NOAC-Absorption ist abhängig vom P-gp (P-Glykoprotein)-System im Darm, das durch eine Vielzahl von Medikamenten und Nahrungsmittelkomponenten moduliert wird.

Ziel

Ziel der Übersichtsarbeit ist es, einen Überblick über die P-gp-assoziierten Arznei- und Nahrungsmittelwechselwirkungen mit NOAC bei AF-Patienten zu geben.

Methoden

Eine Literaturrecherche erfolgte durch systematisches Screenen in MEDLINE nach Veröffentlichungen zwischen 1998 und 2013 mit den Stichworten Dabigatran, Rivaroxaban, Apixaban, P-Glykoprotein und Vorhofflimmern. Randomisierte klinische Studien, Längsschnittstudien, Fallserien und Kasuistiken wurden eingeschlossen.

Ergebnisse

Die Bioverfügbarkeit von Dabigatran wird durch eine Begleitmedikation mit Protonenpumpenhemmern, Amiodaron, Clarithromycin und Verapamil erhöht, und durch Rifampicin verringert. Die gleichzeitige Gabe von Erythromycin, Clarithromycin, Fluconazol, Ketoconazol und Ritonavir erhöht die Plasmakonzentration von Rivaroxaban. Es wurden weder Daten zu Apixaban und P-gp-modulierenden Medikamenten noch zum Einfluss von P-gp-Modulation durch Nahrungsmittel auf die Bioverfügbarkeit von NOAC gefunden. Die klinische Relevanz der Wechselwirkungen zwischen NOAC und P-gp-modulierenden Medikamenten oder Nahrungsmitteln ist weitgehend unbekannt, da Blutungskomplikationen unter NOAC und einer Komedikation mit P-gp-hemmenden Medikamenten hauptsächlich bei niereninsuffizienten Patienten beschrieben wurden.

Schlussfolgerungen

Die Rolle von P-gp-modulierenden Substanzen als potenzielle Mediatoren von Arzneimittel- und Nahrungsmittelwechselwirkungen zu untersuchen, ist dringend notwendig. Eine gründliche Analyse der in den 3 großen NOAC-Studien gesammelten Daten über die Rolle von P-gp-modulierenden Medikamenten in Hinblick auf Blutungen und ischämische Ereignisse ist wünschenswert. Pharmakologische Studien sollten den Einfluss P-gp-modulierender Substanzen auf die Plasmakonzentration von NOAC und die Gerinnungsparameter untersuchen. Bei der Verordnung von NOAC sollten Patienten auf potenzielle Interaktionen mit Medikamenten und Kräutern aufmerksam gemacht werden. Patienten, die unter NOAC Blutungen oder embolische Ereignisse erleiden, sollten nicht nur über ihre Komedikation, sondern auch nach der Einnahme nichtverschreibungspflichtiger Substanzen sowie nach ihren Ernährungsgewohnheiten befragt werden. Post-Marketing-Analysen von NOAC sollten Assoziationen zwischen Medikamenten- bzw. Nahrungsmittelaufnahme und Komplikationen, wie Blutungen oder Embolien, registrieren und untersuchen.

Schlüsselwörter

Vorhofflimmern Antikoagulation Protonenpumpeninhibitoren Arzneimittelinteraktionen Blut-Hirn-Schranke 

Notes

Compliance with ethical guidelines

Conflict of interest. C. Stöllberger and J. Finsterer state that they have no conflicts of interest. The accompanying manuscript does not include studies on humans or animals.

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Copyright information

© Urban & Vogel 2015

Authors and Affiliations

  1. 1.2. Medizinische AbteilungKrankenanstalt RudolfstiftungViennaAustria
  2. 2.Krankenanstalt RudolfstiftungViennaAustria

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