(ASPOT25) Drug-Drug Interactions Between Direct-Acting Oral Anticoagulants and Antiseizure Medications: A Target Trial Emulation

Background: Certain antiseizure medications (ASMs) can interact with direct-acting oral anticoagulants (DOACs; rivaroxaban, apixaban, dabigatran, edoxaban) by inducing the P-glycoprotein (P-gp) and CYP3A4 enzyme systems. This interaction leads to a reduction in the concentration of DOACs, thus increasing the risk of thromboembolism.

Objectives: To evaluate the association of drug-drug interactions involving DOACs and ASMs on the risk of thromboembolism.

Methods: We used Merative MarketScan data from 2011 and 2019 and conducted a retrospective target trial emulation study comparing adults who used DOACs and interacting ASMs versus DOACs and non-interacting ASMs. We included DOAC users age>=18 years who newly initiated an ASM (time zero) and were continuously enrolled in one years before time zero. Interacting ASMs included topiramate, levetiracetam, valproic acid, carbamazepine, oxcarbazepine, phenytoin, primidone, zonisamide, or phenobarbital, and non-interacting drugs included gabapentin, pregabalin, clonazepam, lamotrigine, or lacosamide. The primary outcome was time to first stroke or systemic embolism. We calculated stabilized inverse probability of treatment weights (IPTW) using logistic regression that included baseline age, sex, comorbidities, comedications and components of CHA₂DS₂-VASc score. We used an IPTW Cox proportional hazards regression model to determine an association of drug-drug interactions with stroke or systemic embolism.

Results: Among the 33,701 eligible participants, 5,611 (16.6%) initiated an interacting ASM and 28,090 (83.4%) initiated a non-interacting ASM. In the IPTW cohort, all covariates had standardized mean differences less than 0.03, suggesting covariate balance between the two exposure groups. The incidence of stroke or systemic embolism per 100 person-years was 5.70 in interacting drugs vs. 2.95 in non-interacting drugs. In the IPTW Cox model, individuals using DOACs and interacting ASMs had 41% higher risk of stroke or systemic embolism (hazard ratio, 1.41; 95% CI, 1.04-1.92) compared to those using non-interacting ASMs.

Conclusions: Among US adults, concomitant use of DOAC with interacting ASMs was associated with an increased risk of stroke or systemic embolism.