medwireNews: Treating patients who have concurrent atrial fibrillation (AF) and epilepsy with direct-acting oral anticoagulants (DOACs) and enzyme-inducing antiseizure medications (EI ASMs) simultaneously is not associated with a greater risk for thromboembolic events, suggests a study published in JAMA Neurology.
“EI ASMs induce permeability glycoprotein efflux transporter protein (which is involved in intestinal absorption and renal elimination of DOACs) and/or cytochrome p450 3A4 (CYP3A4; which is involved in intestinal absorption and renal elimination of DOACs),” explain Emily Acton (University of Pennsylvania, Philadelphia, USA) and colleagues.
“Consequently, these inducers are hypothesized to lead to sub-therapeutic DOAC levels and, therefore, an elevated risk of thromboembolic events.”
To investigate whether this is the case, the investigators analyzed data from the US Clinformatics Data Mart Database between 2010 to 2021 to identify a cohort of adults with diagnostic claims for epilepsy and AF.
They compared the rate of thromboembolic events that occurred during 14,078 new treatment episodes of concurrent ASM and DOAC use. Of these episodes, 3619 involved co-administration of one or more EI ASMs for epilepsy, including carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone, or topiramate, with a DOAC – apixaban, dabigatran, or rivaroxaban – for AF (exposed group). The remaining 10,459 episodes involved one or more non-EI ASMs, such as gabapentin, lacosamide, lamotrigine, levetiracetam, or pregabalin, in addition to a DOAC (referent group).
The median age of the patients was 74 years, 52.4% were women, and the majority (70.5%) were White.
Over a median of 5166 person–years of observation, there were a total of 457 thromboembolic events, at an incidence rate of 88.5 per 1000 person–years.
The researchers note that there was no significant difference in the rate of events between the exposed and referent groups. The exposed group had 111 thromboembolic events over a median 1382 person–years of observation, while the referent group experienced 346 thromboembolic events over a median 3783 person–years of observation. This translated to crude incidence rates per 1000 person–years of 80.3 versus 91.5 and an incidence rate ratio of 0.88.
The results remained true when thromboembolic event rates were compared across 6420 treatment exposures that were propensity-score matched for age, gender, and multiple major comorbidities, with a nonsignificant incidence rate ratio of 1.11.
The team also used regression models with robust variance estimators to account for clustering within matched pairs, and in these the adjusted hazard ratio for thromboembolic events with the use of DOACs plus EI ASMs versus non-EI ASMs was a nonsignificant 1.10.
Acton and colleagues also looked at bleeding rates across 14,158 new concomitant treatment episodes, of which 3642 involved combined treatment with EI ASMs and DOACs and 10,516 combined treatment with non-EI ASMs and DOACs.
The team notes that there was a “moderate reduction in the risk of major bleeding events associated with DOAC use with EI ASMs compared with non-EI ASMs.”
Specifically, there were 62 major bleeding events over 1408 person–years of observation in the exposed group, at an incidence rate of 44.0 per 1000 person–years. This compared with 296 events over 3834 person–years of observation, at an incidence rate of 77.2 per 1000 person–years.
This translated to a significant 43% reduced incidence for major bleeding events with concomitant use of EI ASMs compared with non-EI ASMs. For 6492 treatment episodes that were propensity-score matched, the incidence rate was reduced a significant 36%.
This finding “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,” suggest the authors.
They conclude: “These data suggesting the safety of EI ASM use with DOACs have important implications for the care of the many adults with epilepsy who require anticoagulation especially across a larger global community where EI ASMs remain mainstays of epilepsy treatment.”
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