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Levetiracetam and direct oral anticoagulants—a systematic review

Levetiracetam und direkte orale Antikoagulanzien – ein systematisches Review

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Abstract

In 2018 the European Heart Rhythm Association brought attention to a possible interaction between levetiracetam (LEV) and direct oral anticoagulants (DOACs) due to an effect on p‑glycoprotein. In this systematic review, we aimed to evaluate the available clinical data concerning this possible interaction. On 16 May 2024, we launched a PubMed search on levetiracetam in combination with each of the four DOACs (i.e., apixaban, dabigatran, edoxaban, rivaroxaban). After removing reviews, duplicates, and case reports that do not consider possible interactions, we retained three databank analyses, three observational studies with fewer than ten patients for each DOAC in combination with LEV, one observational study with 26 patients treated with apixaban and LEV, and two case reports. While all observational studies found no clinically relevant interaction, the databank analyses found an increased risk for stroke of at least 1.45-fold (95% confidence interval: 1.02–2.07) for patients treated with LEV in combination with a DOAC. There seems to be an at least slightly increased risk for stroke in patients with atrial fibrillation treated with a DOAC and LEV. This is evident when evaluating large groups of patients only. We suggest a multicenter observational study to further evaluate interactions between DOACs and the commonly prescribed antiseizure medication levetiracetam.

Zusammenfassung

Im Jahr 2018 lenkte die European Heart Rhythm Association die Aufmerksamkeit auf mögliche Wechselwirkungen zwischen Levetiracetam (LEV) und den direkten oralen Antikoagulanzien (DOAC) wegen möglicher Einflüsse des LEV auf den P‑Glykoprotein-Transporter. Im vorliegenden systematischen Review werden die aktuell verfügbaren klinischen Daten zu diesem Problem referiert und kommentiert. Am 16. Mai 2024 führten wir eine PubMed-Suche mit Levetiracetam und jedem der DOAC (d. h. Apixaban, Dabigatran, Edoxaban, Rivaroxaban) durch. Nach Ausschluss von Übersichtsarbeiten, doppelt vorhandenen Studien und Fallberichten, die sich nicht mit Wechselwirkungen beschäftigten, verblieben 3 Datenbankanalysen, 3 Beobachtungsstudien mit jeweils weniger als 10 Patienten in jeder der möglichen Kombinationen, eine Beobachtungsstudie mit 26 Patienten unter der Kombination von Apixaban und LEV sowie 2 Fallberichte. Während in allen Beobachtungsstudien keine klinisch relevanten Interaktionen beschrieben wurden, stellte sich in den Datenbankanalysen ein wenigstens 1,45-fach (95 %-Konfidenzintervall, 95 %-KI: 10,2–2,07) erhöhtes Risiko für einen Schlaganfall für Patienten unter der Kombination von LEV mit einem DOAK heraus. Es scheint ein zumindest leicht erhöhtes Risiko für einen Schlaganfall für Patienten mit Vorhofflimmern unter der Kombination von LEV mit einem DOAC zu geben, welches nur bei der Auswertung vieler Patientendaten nachgewiesen werden kann. Eine multizentrische Beobachtungsstudie diesbezüglich wäre also wünschenswert.

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Data Availability

The data used in this study can be checked by repeating the PubMed research and excluding papers that were published after 16 May 2024.

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Authors and Affiliations

  1. Neurologische Akutklinik, Hardtwaldklinik I, Bad Zwesten, Germany

    Johannes Rösche & Yogesh Shah

  2. Department of Neurology, Rostock University Medical Center, Gehlsheimer Straße 20, 18147, Rostock, Germany

    Johannes Rösche & Matthias Wittstock

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  1. Johannes Rösche
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Correspondence to Johannes Rösche.

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Conflict of interest

J. Rösche received a speakerʼs honorarium from EISAI. M. Wittstock reports personal fees from Astra Zeneca, which are outside the submitted work. Y. Shah received speaker’s fees from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Bristol-Myers Squibb and Pfizer concerning novel anticoagulants in the past 5 years and also reimbursement for travel expenses from Boehringer Ingelheim and Daiichi Sankyo.

For this article no studies with human participants or animals were performed by any of the authors. All studies mentioned were in accordance with the ethical standards indicated in each case.

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Rösche, J., Wittstock, M. & Shah, Y. Levetiracetam and direct oral anticoagulants—a systematic review. Clin Epileptol (2024). https://doi.org/10.1007/s10309-024-00708-2

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