Ischemic and non-ischemic stroke reported in DOAC treated patients with atrial fibrillation and levetiracetam drug interaction: a real-world study

Abstract

Abstract Background To date, the combination of direct oral anti coagulants and some anticonvulsants remain controversial. Therefore, the European Heart Rhythm recommendations do not support using levetiracetam with DOACs. Objectives This study sought to investigate reports on ischemic and hemorrhagic stroke with DOACs and the effect of levetiracetam on the rate of reporting in atrial fibrillation patients. Methods In this retrospective, pharmacovigilance study, the authors used the Food and Drug Administration adverse event reporting system to identify adverse events associated with DOACs with and without concomitant use of levetiracetam. The authors evaluated disproportionate reporting by the reporting odds ratio adjusted to age and sex (adjROR) and the lower bound of the shrinkage 95% confidence interval (Ω025 > 0 is deemed significant). Results The authors identified 1723 (1.3%), 1841 (1.5%), and 3731 (5.3%) MedDRA preferred terms for ischemic stroke in AF patients treated with rivaroxaban, apixaban, and dabigatran, respectively. Whereas reports that described hemorrhagic stroke included, 3016 (2.2%), 1346 (1.1%), and 1256 (1.8%) for rivaroxaban, apixaban and dabigatran. Significant disproportionality signal was identified for ischemic stroke in dabigatran AF patients, (adjROR 3.10; 95%CI, 2.94-3.28). Rivaroxaban demonstrated the lowest adjROR for ischemic stroke when compared to apixaban and dabigatran, (adjROR 0.38; 95%CI, 0.36-0.41). A reciprocal image was noticed for hemorrhagic stroke with a higher reporting odds ratio for rivaroxaban (adjROR 1.46; 95%CI, 1.38-1.55) and a lower reporting odds ratio for dabigatran (adjROR 0.75; 95%CI 0.70-0.78). With regards to the DOAC-levetiracetam-ischemic stroke triplet; rivaroxaban, apixaban and dabigatran illustrated a significant signal in the regression and shrinkage analysis models. The exp(B) 95%CI for the interaction was highest with dabigatran, (exp(B) 3.92; 95%CI, 3.08-3.98). Conclusions In this large post-marketing study to date, the authors identified an interaction resulting in decreased effectiveness between levetiracetam and the DOACs. The greatest strength of association was found to be with dabigatran, supporting a P-glycoprotein induction mechanism. The interaction does not seem to influence the risk of hemorrhagic stroke. In line with current studies, ischemic stroke was lowest for rivaroxaban compared to dabigatran and apixaban on account of a higher risk for hemorrhagic stroke. Dabigatran demonstrated significantly lower reporting on hemorrhagic stroke but on account of a higher risk of ischemic stroke. We highly recommend pharmacodynamic monitoring, either anti-Xa for apixaban and rivaroxaban or plasma diluted thrombin time for dabigatran while concomitantly prescribing anticonvulsants with the DOACs.ResultsSensitivity Analysis