Antiseizure Medications Display Mortality Differences in Poststroke Epilepsy

Johan Zelano, MD, PhD

A recently conducted cohort study using data from linked Swedish registries showed that mortality varies based on antiseizure medication (ASM) use for patients who develop poststroke epilepsy. Furthermore, those treated with lamotrigine (Lamictal) had significantly lower hazard of cardiovascular and all-cause death compared to those treated with carbamazepine (Tegretol), the reference study drug.¹

Stroke is the most commonly identified cause of new-onset epilepsy in adults.² To understand more about the theoretical concerns about the detrimental effects of ASM on survival, senior author Johan Zelano, MD, PhD, consultant neurologist, Sahlgrenska University Hospital, and colleagues conducted a population-based cohort study with 2577 poststroke patients using all-cause death as the primary outcome.

Patients included in the analysis had acute stroke from July 1, 2005, to December 31, 2010, with a subsequent onset of epilepsy before December 31, 2014. A Cox proportional hazards regression model was used to determine the primary outcome, while cardiovascular death was assessed using Fine-Gray competing risk regression models.

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Compared with carbamazepine, the adjusted HR of all-cause death was 0.72 (95% CI, 0.60-0.86) for lamotrigine, the lowest of any of the observed ASMs, followed by 0.96 (95% CI, 0.80-1.15) for levetiracetam (Keppra), 1.40 (95% CI, 1.23-1.59) for valproic acid, 1.16 (95% CI, 0.88-1.51) for phenytoin, and 1.16 (95% CI, 0.61-1.66) for oxcarbazepine (Trileptal; Novartis). Controlled variables such as age, sex, stroke type, living arrangements before and after stroke, activities of daily living dependence before stroke, status epilepticus, diabetes, statin use, and smoking were found to be significant in the multivariable model.¹

"Our findings raise the possibility that specific ASMs influence the risk of cardiovascular and all-cause death, although our study design does not allow causal inference,” the study authors wrote. "Altered vascular risk is suspected to be the main reason behind our findings. Treatment with enzyme-inducing ASMs (carbamazepine and phenytoin) enhances metabolism of drugs commonly used in secondary prevention after stroke, including anticoagulants, calcium channel blockers, and statins."

Patients who were prescribed valproic acid showed a higher risk of both cardiovascular and all-cause death than other ASMs. The adjusted HR of cardiovascular death—considered the underlying cause of 969 deaths (63%) in the overall study cohort—was 0.76 (95% CI, 0.61-0.95) for lamotrigine, 0.77 (95% CI, 0.60-0.99) for levetiracetam, 1.40 (95% CI, 1.19-1.64) for valproic acid, 1.02 (95% CI, 0.71-1.47) for phenytoin, and 0.71 (95% CI, 0.42-1.18) for oxcarbazepine.

Zelano et al also assessed differences in indicators of epilepsy severity between groups. In total, the median number of hospital admissions with a main diagnosis of epilepsy, seizures, or status epilepticus per year of follow up was 0 (interquartile range [IQR], 0-0) for carbamazepine, 0 (IQR, 0-0.234) for lamotrigine, 0 (IQR, 0-0) for levetiracetam, and 0 (IQR, 0-0.269) for valproic acid. Admissions were significantly more common among those taking lamotrigine and valproic acid than those taking carbamazepine.

An additional sensitivity analysis was conducted using just the Swedish Cause of Death Register (CDR) to compare epilepsy-related causes using ICD-10 code R568, G40, or G41. In total, 14% (100 of 715) of deaths in the carbamazepine group had a seizure-related diagnostic code listed as an associated cause, which was significantly lower than those on valproic acid (23%; 83 of 366), levetiracetam (21%; 31 of 145), and lamotrigine (22%; 34 of 153).

Lamotrigine, a drug commonly used to treat poststroke epilepsy, recently had concerns raised about its proarrhythmic effects in March 2021. At the time, the FDA issued a safety warning for the drug after a review of study findings showed a potential increased risk of heart rhythm problems. In multiple cases, abnormal electrocardiographic findings were observed, as well as reported problems of chest pain, loss of consciousness, and cardiac arrest.³ 

REFERENCES

1. Larsson D, Baftiu A, Landmark CJ, et al. Association between antiseizure drug monotherapy and mortality for patients with poststroke epilepsy. JAMA Neurol. Published online December 13, 2021. doi:10.1001/jamaneurol.2021.4584.

2. Graham NS, Crichton S, Koutroumanidis M, Wolfe CD, Rudd AG. Incidence and associations of poststroke epilepsy. Stroke. 2013;44:605-611. doi:10.1161/STROKEAHA.111.000220.

3. Studies show increased risk of heart rhythm problems with seizure and mental health medicine lamotrigine (Lamictal) in patients with heart disease. News release. FDA. March 31, 2021. Accessed January 3, 2022. https://www.fda.gov/drugs/drug-safety-and-availability/studies-show-increased-risk-heart-rhythm-problems-seizure-and-mental-health-medicine-lamotrigine