Levetiracetam and direct oral anticoagulants—a systematic review

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.