Impact of cytochrome P-450 3A4 enzyme/P-glycoprotein inducing antiseizure medications on direct oral anticoagulant therapy

OBJECTIVES: Concomitant use of cytochrome P-450 and P-glycoprotein (CYP 3A4/P-gp) inducing antiseizure medications and direct oral anticoagulants (DOAC) may result in reduced DOAC effectiveness, but study results are inconsistent and of variable quality. The purpose of this study was to assess the safety of concomitant CYP 3A4/P-gp inducing antiseizure medications and DOAC use. METHODS: This was a retrospective cohort study of adult patients who were newly, concomitantly receiving a DOAC (apixaban, dabigatran, or rivaroxaban) and either a CYP 3A4/P-gp inducer (carbamazepine, phenytoin, phenobarbital, or primidone) or noninducer (gabapentin). The primary outcome was the occurrence of a thromboembolic complication, defined as the composite of ischemic stroke and systemic embolism (S/SE) and venous thromboembolism (VTE). Secondary outcomes included the components of the primary composite as well as all-cause mortality and clinically relevant bleeding. Adjusted multivariate proportional hazards modeling was used to compare outcomes for each DOAC individually in the inducer and noninducer groups. RESULTS: There were 1843 and 14 647 patients who received a DOAC plus a CYP3A4/P-gp inducer and noninducer, respectively. Overall, patients were primarily older, white, had atrial fibrillation, and were dispensed dabigatran. After adjustment, there were no statistically significant differences in the primary outcome between the groups ( P > 0.05); however, concomitant inducer and DOAC use was associated with an increased risk of all-cause mortality ( P < 0.05). CONCLUSIONS: No excess risk of thrombosis during concomitant use of DOACs with CYP3A4/P-gp inducing antiseizure medications compared to use with gabapentin was identified. Further research is needed to confirm an association with excess all-cause mortality.