Fear of the Dark: Concomitant Use of Direct Oral Anticoagulants and Antiseizure Medications

Abstract

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

Acton EK, Hennessy S, Gelfand MA, Leonard CE, Bilker WB, Shu D, Willis AW, Kasner SE. JAMA Neurol. 2024 Jul 8:e242057. doi: 10.1001/jamaneurol.2024.2057. Epub ahead of print. PMID: 38976246; PMCID: PMC11231911.

Importance: Direct-acting oral anticoagulants (DOACs) are commonly prescribed with antiseizure medications (ASMs) due to the concurrency of and the association between atrial fibrillation (AF) and epilepsy. However, enzyme-inducing (EI) ASMs may reduce absorption and accelerate the 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 versus DOACs with non-EI ASMs. Design, setting, and participantsDesign, setting, and participants. This active-comparator, new-user cohort study included US healthcare 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 the use of non-EI ASMs, the 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.

Commentary

Direct oral anticoagulants (DOACs) have been introduced to the market in 2010. These are either direct thrombin inhibitors (dabigatran) or FXa inhibitors (rivaroxaban, apixaban, edoxaban, betrixaban). Compared to heparin and vitamin K antagonists, DOACs have demonstrated (at least) equal efficacy, favorable safety profile, and ease of use due to their rapid onset of action, acceptable pharmacokinetic and pharmacodynamic properties, fixed dosing, no monitoring requirement, and fewer drug/disease/dietary interactions.^1,2 Hence, they have largely replaced such traditional therapeutic options for nonvalvular atrial fibrillation (AF) and venous thromboembolism. That is particularly relevant to persons with epilepsy (PWE), since arterial and venous strokes are frequent culprits of seizures, and the risk of venous thromboembolism is higher in PWE compared to the general population. ³ Such patients are also at higher risk of falls, which could result in detrimental hemorrhages, particularly in the case of supratherapeutic anticoagulant plasma concentrations (PCs).

Since most PWE require antiseizure medications (ASMs), could DOACs be safely co-administered? The same question is posed for a host of patients without epilepsy, who are nevertheless prescribed ASMs for other indications (eg, migraines, mood stabilization, peripheral neuropathy, etc). All DOACs are substrates of P-glycoprotein; an efflux pump that, when inhibited, would increase absorption, bioavailability, and the risk of bleeding. ¹ Additionally, the FXa inhibitors (aside for Betrixaban that undergoes hydrolysis) are metabolized through the cytochrome P450 (CYP) pathway, mostly via CYP3A4; when this pathway is induced, the clotting risk increases. ¹ Several ASMs (eg, phenytoin, phenobarbital, primidone, carbamazepine) potently induce both P-glycoprotein and CYP, while some (eg, oxcarbazepine, escirbazepine, topiramate) exert minor induction in the CYP pathway only. ² The data on other ASMs (eg, valproic acid and levetiracetam) are more controversial, and for the remainder of ASMs, they are not well established. ² Several studies have reported a reduction in the PCs of DOACs from enzyme-inducing ASMs (EI-ASMs). ⁴ The clinical repercussions of recurrent thromboembolism or heightened bleeding risk from these drug-drug interactions (DDIs) between DOACs and ASMs are not conclusively delineated.^4-11 In this nebulous milieu, the European Heart Rhythm Association recommended against concurrent use of EI-ASMs (in addition to valproic acid and levetiracetam) with DOACs. ¹²

The current study ¹³ attempts to elucidate this issue. By using a US population-based, healthcare database of adult PWE on ASMs and AF on co-dispensed DOACs, the authors evaluated whether the frequency of thromboembolic and major bleeding events differed between patients on EI-ASMs versus non EI-ASMs. With >14 000 exposure episodes within 11 years, the estimated incidence for thromboembolic events was 88.5 per 1000-person years and the estimated incidence for major bleeding events was 68.3 per 1000-person years. While there was no statistically significant difference in the incidence of thromboembolic events in patients on EI-ASMs versus non EI-ASMs, the authors identified a reduced risk of bleeding events in patients on EI-ASMs (AHR 0.63; 95% CI 0.44-0.89).

This is a carefully conducted study on a large, nationally representative sample. ¹³ To avoid confounding by indication, it was restricted only to patients on ASMs for epilepsy and DOACs for AF. The impact of EI-ASMs was investigated with the use of an active comparator group of PWE on non-EI-ASMs, to mitigate selection and indication bias. To balance patient characteristics between those two groups, an extensive list of covariates that represent clinically relevant parameters were factored in through high-dimensional propensity scores, with good balance, as indicated by their absolute standardized mean differences. To guarantee use synchronization, the study focused on new concurrent users of those two classes of medications after a 3-month baseline period. Switching between the two groups was given consideration by treating exposures as time-varying. Several a priori specified and post hoc subanalyses were undertaken. ¹³

On the other hand, claims-based studies always carry some risk of missing or misclassifying exposures and outcomes. Despite the use of propensity score-based techniques, the possibility of unmeasured confounding cannot be entirely excluded. As the authors acknowledge, ¹³ dosing of both ASMs and DOACs was not evaluated. Renal/hepatic function and body mass index fluctuations during co-administration were not taken into account, and, beyond antidepressants, concomitant use of several other medications (eg, antibiotics, antiarrhythmics) with potential DDIs with the prescribed ASMs and DOACs was not explicitly considered. ⁵ Such parameters were nevertheless available to the providers of those patients and may have affected their care. The lack of information on drug levels could not safeguard adherence nor provide biological plausibility of the identified associations. Although the study period spanned more than a decade, the censoring period itself was rather short and it did not include all third-generation ASMs. ¹³

The issue of concurrent use of ASMs and DOACs remains controversial, and this is reflected in the great degree of inconsistencies in the inclusion and reported severity of interactions between those two medication classes in international drug compendia. ¹⁴ Prior studies have reported an elevated risk of recurrent thromboembolism with EI-ASMs,^4,6,7 increased odds of hemorrhage,^5,8 or no association.^9-11 This ambiguity may stem from the methodological heterogeneity of the aforementioned literature (often limited sample size, predominantly retrospective nature, frequent misclassification risk, inappropriate selection of reference group resulting in selection bias, inadequate adjustment for confounders and reverse causality). The current study ¹³ attempted to address many of these limitations and suggested a favorable profile of EI-ASMs with regard to the bleeding risk, without compromising the risk of recurrent thromboembolism. While the former appears biologically plausible, it somehow contradicts the latter. Perhaps, there is indeed a “sweet spot,” where a reduction in PCs of DOACs is sufficient to reduce the risk of bleeds, but insufficient to induce the risk of clots; yet, without drug levels information to back this up, this remains conjectural.

This controversy notwithstanding, one should not lose sight of the big picture. Despite their undisputed advantages over vitamin K antagonists, DOACs require stricter compliance given their shorter half-lives, lack in many cases readily available reversal agents, and due to the absence of standardized laboratory monitoring, they result in fewer patient-clinician interactions. ¹ PWE on DOACs are typically elderly and frail with a multitude of additional comorbidities (eg, vascular risk factors, cognitive and balance issues, etc) and medications on board. Thus, unless otherwise necessary, the use of EI-ASMs may not be ideal for them in the first place, from a metabolic, cardiac, and other DDI standpoint. These patients require personalized assessment of their thromboembolic (eg, CHA₂DS₂-VASC score)* and their bleeding (eg, HAS-BLED score)** risk,^1,10 their cognition, balance and body mass index, their adherence, DOACs and ASMs potential adverse effects and DDIs. ¹ They need more frequent laboratory monitoring of complete blood count, serum creatinine and liver function tests, and, at times, PCs (for both DOACs and ASMs).^1,2 A careful start-up and follow-up scheme of managing those two medication classes and dealing with potential challenges (eg, signs of inefficacy or toxicity, need for medical or surgical interventions, etc) is required through collaboration between the stroke expert and the epileptologist, who tend to be the same individual in many parts of the world.

To sum up, DOACs have catalyzed significant practice changes in the therapeutic landscape of thromboembolism. The delicate balance between clotting and bleeding is cast by a fear of the “dark” in PWE who require concomitant use of ASMs, particularly those with EI properties. Until carefully designed, prospective, controlled, multicenter studies are conducted and widely accepted guidelines become available, physicians need to rely on the available data from experimental and observational studies, on their clinical judgment and close, individualized patient monitoring to shed some light and alleviate that fear.

* The acronym CHA₂DS₂-VASc stands for congestive heart failure, hypertension, age ≥75 (doubled), diabetes, stroke (doubled), vascular disease, age 65 to 74 and sex category (female).

** The acronym HAS-BLED stands for Hypertension, Abnormal liver/renal function, Stroke history, Bleeding history or predisposition, Labile INR, Elderly, Drug/alcohol usage.