Interactions of Enzyme-Inducing Antiseizure Medications with Direct-Acting Oral Anticoagulants: Risk of Thromboembolic and Major Bleeding Events
Abstract number :
2.273
Submission category :
7. Anti-seizure Medications / 7C. Cohort Studies
Year :
2023
Submission ID :
554
Source :
www.aesnet.org
Presentation date :
12/3/2023 12:00:00 AM
Published date :
Authors :
Presenting Author: Emily Acton, MSCE – University of Pennsylvania
Sean Hennessy, PharmD, PhD – University of Pennsylvania; Michael Gelfand, MD, PhD – University of Pennsylvania; Charles Leonard, PharmD, MSCE – University of Pennsylvania; Warren Bilker, PhD – University of Pennsylvania; Di Shu, PhD – University of Pennsylvania; Allison Willis, MD, MS – University of Pennsylvania; Scott Kasner, MD, MSCE – University of Pennsylvania
Rationale:
Co-prescription of antiseizure medications (ASMs) with direct-acting oral anticoagulants (DOACs) is common due to frequent concurrency and causal links between epilepsy and the indications for anticoagulation. However, enzyme-inducing-ASMs (EI-ASMs) may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk. Evidence for these interactions comes primarily from in vitro and animal studies, with research in humans lacking and complicated in interpretation by methodological limitations.
Methods:
We leveraged large-scale healthcare data to conduct a population-based, incident-user cohort study among a nationally representative population of adults with epilepsy co-prescribed DOACs with ASMs. Thromboembolic and major bleeding event rates were contrasted between episodes of exposure to DOACs with EI-ASMs versus active comparator episodes of exposure to DOACs with non-enzyme inducing ASMs. Outcomes were identified based on a series of validated, diagnosis-based coding algorithms. Data-adaptive high-dimensional propensity score matching was employed to produce estimates with rigorous control for observed confounders and proxies for unobserved confounders. Adjusted hazard ratios (aHRs) were estimated based on Cox proportional hazard models with robust variance estimators to account for clustering within matched pairs. We performed these analyses in three separate cohorts distinguished by indication for anticoagulation: 1) indication-agnostic, 2) atrial fibrillation, or 3) deep vein thrombus/pulmonary embolism.
Results:
Among epilepsy populations with incident ASM+DOAC use, we identified 20,660 and 20,855 episodes that met eligibility criteria for assessment of thromboembolic and major bleeding outcomes, respectively. Incidence per 1,000 person-years was 94.5 for thromboembolic events and 63.2 for major bleeding events. Compared with use of non-enzyme inducing ASMs, use of EI-ASMs with DOACs was not associated with a difference in thromboembolic events (aHR=1.11, 95% CI: 0.89-1.39), but was associated with a reduction in major bleeding events (aHR=0.74, 95% CI: 0.56-0.97). Indication-specific analyses are presented in the Table and Figure.
Conclusions:
These studies present large-scale, real-world evidence of EI-ASM use alongside DOACs without significantly elevated risk of thromboembolic events among a nationally representative epilepsy population. Additional research is needed on the reduction in risk of major bleeding events associated with EI-ASMs, as this may be suggestive of pharmacokinetic interaction occurring to a degree that lowers DOAC levels without necessarily negating therapeutic effects. These data elucidating the safety of EI-ASM use with DOACs have important implications for the care of the many adults with epilepsy that require anticoagulation, especially across a larger global community where EI-ASMs remain mainstays of epilepsy treatment.
Funding: National Institute of Neurological Disorders and Stroke, Grant/Award Number: 1F31NS130952-01.
Anti-seizure Medications