Direct-Acting Oral Anticoagulants and Antiseizure Medications for Atrial Fibrillation and Epilepsy and Risk of Thromboembolic Events

Abstract

Importance: Direct-acting oral anticoagulants (DOACs) are commonly prescribed with antiseizure medications (ASMs) due to concurrency of and the association between atrial fibrillation (AF) and epilepsy. However, enzyme-inducing (EI) ASMs may reduce absorption and accelerate metabolism of DOACs, potentially lowering DOAC levels and elevating thromboembolism risk.

Objective: To assess the rates of thromboembolic and major bleeding events in adults with AF and epilepsy dispensed DOACs and EI ASMs vs DOACs with non-EI ASMs.

Design, setting, and participants: This active-comparator, new-user cohort study included US health care data from the Clinformatics Data Mart database from October 2010 to September 2021 for a nationally representative population of adults with AF and epilepsy.

Exposure: Evaluations included episodes of contiguous coadministration of DOACs for AF with EI ASMs (exposed) or non-EI ASMs (referent) for epilepsy.

Main outcomes and measures: Thromboembolic events (primary outcome) and major bleeding events (secondary outcome) were identified based on a series of validated, diagnosis-based coding algorithms. Data-adaptive, high-dimensional propensity score matching was used to control for observed confounders and proxies for unobserved confounders. Adjusted hazard ratios (AHRs) were estimated using Cox proportional hazards regression models with robust variance estimators to account for clustering within matched pairs.

Results: This study included 14 078 episodes (median age, 74 [IQR, 67-81]; 52.4% female) and 14 158 episodes (median age, 74 [IQR, 67-81]; 52.4% female) of incident DOAC and ASM use that met eligibility criteria for assessment of thromboembolic and major bleeding outcomes, respectively. Incidence was 88.5 per 1000 person-years for thromboembolic events and 68.3 per 1000 person-years for bleeding events. Compared with use of non-EI ASMs, 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) but was associated with a reduction in risk of major bleeding events (AHR, 0.63; 95% CI, 0.44-0.89).

Conclusions and relevance: In this cohort study, EI ASMs were not associated with alteration in DOAC efficacy. Further research is needed on the reduction in bleeding risk associated with EI ASMs, as this may suggest that pharmacokinetic interactions are associated with lowering DOAC levels without negating therapeutic effects.

Figure 1.. Active-Comparator, New-User Cohort Study Model Assessing Enzyme Inducing (EI) Antiseizure Medication (ASM) and Direct-Acting Oral Anticoagulant (DOAC) Interactions

Figure 2.. Kaplan-Meier Curves of Thromboembolic and Major Bleeding Event-Free Survival for Direct-Acting Oral Anticoagulant (DOAC) Use With Enzyme Inducing (EI) Antiseizure Medication (ASM) vs Non-EI ASM

Kaplan-Meier curves were truncated at 1.5 years of follow-up.

Figure 3.. Adjusted Hazard Ratios (AHRs) for Thromboembolic and Major Bleeding Outcomes for Direct-Acting Oral Anticoagulant (DOAC) Use With Enzyme Inducing (EI) Antiseizure Medication (ASM) vs Non-EI ASM

For the stratified events for major bleeding outcomes, AHRs were also calculated for other and unspecified major bleeding events, with findings of 0.67 (95% CI, 0.11-3.98) and 0.50 (95% CI, 0.04-5.64), respectively.