Efficacy of Oral Anticoagulants in Epilepsy and Atrial Fibrillation Not Impacted by Antiseizure Medications

A nationally representative cohort study newly published in JAMA Neurology revealed that enzyme-inducing (EI) antiseizure medications (ASMs) were not associated with alteration of direct-acting oral anticoagulants (DOACs) efficacy compared with non-EI ASMs among patients with epilepsy and atrial fibrillation (AF). These data suggest important safety implications of EI ASM use with DOACs for patients with epilepsy who require anticoagulation, specifically across a bigger worldwide community where EI ASMs remain mainstays for epilepsy treatment.¹

In the study, the incidence was 88.5 per 1000 person-years for thromboembolic events (episodes of incident DOAC and ASM, n = 14,078; median age, 74 [IQR, 67-81]; women, 52.4%) and was 68.3 per 1000 person-years for bleeding events (episodes of incident DOAC and ASM, n = 14,158; median age, 74 [IQR, 67-81]; women, 52.4%) for those who used ASMs. Although use of EI ASMs with DOACs was not associated with a difference in risk of thromboembolic events (AHR, 1.10; 95% CI, 0.82-1.46) compared with use of non-EI ASMs, it was associated with a reduction in risk of major bleeding events (adjusted hazard ratios [AHRs], 0.63; 95% CI, 0.44-0.89).

“Prior investigations into the clinical consequences of EI ASM and DOAC interactions had inconsistent findings, including supporting an elevated risk of thromboembolic events, an elevated risk of major bleeding events, or no clinically relevant effects,” lead author Emily K. Acton, MSCE, an epidemiology PhD student at the University of Pennsylvania Perelman School of Medicine, and colleagues wrote.¹ “Therefore, the results from our investigation build on the existing literature to aid in providing further clarity on the safety of concurrent EI ASM and DOAC administration for the substantial population of adults with epilepsy and AF.”

Using an active-comparator, new-user approach^,2,3investigators analyzed United States health care data of adult patients with epilepsy and AF from the Clinformatics Data Mart database between October 2010 and September 2021. In the analysis, assessments included episodes of contiguous coadministration of DOACs for AF with EI ASMs or non-EI ASMs for epilepsy. The primary outcome was thromboembolic events, and the secondary outcome was major bleeding events. Investigators used data-adaptive, high-dimensional propensity score matching to control for observed confounders and proxies for unobserved confounders. Additionally, researchers had AHRs estimated utilizing Cox proportional hazards regression models with robust variance estimators to account for clustering in matched pairs.

Top Clinical Takeaways

Enzyme-inducing antiseizure medications did not compromise the efficacy of direct-acting oral anticoagulants in patients with epilepsy and atrial fibrillation.
The study found a reduced risk of major bleeding events when enzyme-inducing antiseizure medications were used with direct-acting oral anticoagulants.
The study's reliance on administrative claims data and the short follow-up duration are important limitations that may affect the precision and generalizability of the findings.

A total of 3619 patients were in the exposed group (EI ASMs) and 10,459 patients were in the referent group (non-EI ASMs). The majority of the participants in the exposed group were older (median age, 72 years; IQR, 65-79 years), women (n = 1910; 52.8%), and White (n = 2570; 71.0%). Prior to high-dimensional propensity scores matching, the patients in the referent group differed in terms of age distribution (median age, 74 years; 67-81 years) and had a greater prevalence of multiple major comorbidities such as complicated diabetes, history of ischemic stroke, and kidney failure based on claims in the 3 months before the start of the observation.

All told, the current study has several limitations. First, the reliance on administrative claims data restricted the evaluation of medication adherence, despite researchers’ efforts to address this with contiguous claims requirements. Second, the data did not specify prescription indications directly, leading investigators to focus on patients with diagnostic claims for epilepsy and AF, which might have impacted sensitivity and specificity. Third, authors noted that the short follow-up duration for some patients could have influenced the precision of the estimates. Furthermore, the study did not assess dose adjustments, and the inclusion of certain medications, like topiramate and oxcarbazepine, which may have also attenuated results. Lastly, investigators noted that although levetiracetam was included as a non-EI ASM, concerns about its interaction with DOACs were addressed through secondary analyses, which confirmed the main results.

“Our study also found a moderate reduction in the risk of major bleeding events associated with DOAC use with EI ASMs compared with non-EI ASMs. This may be suggestive of pharmacokinetic EI ASM interactions lowering DOAC levels to a degree that the risk of bleeding associated with DOACs is decreased without therapeutic effects necessarily being negated,” Acton et al noted.¹“Further research is needed to elucidate this association and the potential ensuing implications for DOAC dosing in select populations with epilepsy, particularly amid ongoing appraisals of the safety and effectiveness of dose-reduced DOACs in select populations with AF.”