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All-cause mortality was significantly lower in people with post-stroke epilepsy treated with continuous lamotrigine (Lamictal) monotherapy compared with people who received carbamazepine (Tegretol), registry data in Sweden showed.

The opposite applied to people prescribed valproic acid (Depakene), who had a higher risk of cardiovascular and all-cause death compared with those treated with carbamazepine or lamotrigine, reported David Larsson, MD, of Sahlgrenska University in Gothenburg, and co-authors in .

"Our findings raise the possibility that specific anti-seizure medications influence the risk of cardiovascular and all-cause death, although our study design does not allow causal inference," Larsson and colleagues wrote. "Altered vascular risk is suspected to be the main reason behind our findings."

"Currently, treatment recommendations for post-stroke epilepsy are based primarily on trials conducted in older adults with epilepsy of various causes," they added. "The evidence supporting the use of specific anti-seizure medications is limited, but experts have suggested lamotrigine and levetiracetam [Keppra] as valid treatment options. Nonetheless, carbamazepine and valproic acid are commonly used among elderly patients with new-onset epilepsy."

In October 2020, the FDA added a to lamotrigine's prescribing information and medication guides based on in vitro studies. In February 2021, an ad hoc task force of the International League Against Epilepsy and the American Epilepsy Society released an .

The Larsson study provides "another piece of evidence that drugs that interfere with hepatic enzyme induction may have significant negative cardiovascular consequences," said Jacqueline French, MD, of the NYU Comprehensive Epilepsy Center in New York City, who wasn't involved with the research. A recent cohort study of people in England also found an associated with enzyme-inducing anti-seizure medicines, she noted.

"In regards to the recent FDA warning regarding lamotrigine, these findings suggest that switching patients with cardiovascular disease off lamotrigine to other anti-seizure medications, depending on selection and circumstances, might actually worsen outcomes," French told 番茄社区app.

In their analysis, Larsson and colleagues looked at linked registry data on all adults in Sweden with acute stroke from July 2005 through December 2010, with subsequent epilepsy onset before Dec. 31, 2014. The primary outcome was all-cause death, using carbamazepine as the reference. Cardiovascular death was also assessed.

Overall, 2,577 patients receiving continuous anti-seizure drug monotherapy were eligible for the study. A total of 1,199 patients received carbamazepine, 477 received valproic acid, 354 received levetiracetam, 320 received lamotrigine, 73 received phenytoin (Dilantin), and 46 received oxcarbazepine (Trileptal).

Median age of patients was 78, and 54% were men. Most participants (84%) had acute ischemic stroke, while 16% had intracerebral hemorrhage. Median follow-up was 2.2 years, and event-free patients had a median observation time of 4.3 years.

Compared with carbamazepine, the adjusted HR for all-cause mortality was 0.72 (95% CI 0.60-0.86) for lamotrigine, 0.96 (95% CI 0.80-1.15) for levetiracetam, 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 0.81-1.66) for oxcarbazepine.

The adjusted HR of cardiovascular death compared with carbamazepine 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. Levetiracetam showed a reduced risk of cardiovascular death over carbamazepine, but no significant difference in overall mortality, Larsson and co-authors pointed out.

Lamotrigine had the highest 3-year survival rate (0.62), followed by levetiracetam (0.55), oxcarbazepine (0.54), carbamazepine (0.53), valproic acid (0.34), and phenytoin (0.32).

Enzyme-inducing epilepsy drugs like carbamazepine and phenytoin enhance the metabolism of many secondary stroke prevention drugs, including anticoagulants, calcium channel blockers, and statins, Larsson and colleagues observed. Anti-seizure medications also have been linked directly to markers of vascular disease.

"For instance, carbamazepine and phenytoin have been associated with lipid abnormalities and increased levels of C-reactive protein, whereas valproic acid has been linked to weight gain, metabolic syndrome, and related endocrine abnormalities," they wrote. "Carbamazepine, phenytoin, and valproic acid, but not lamotrigine, have also been associated with increased carotid intima-media thickness (a surrogate marker for stroke and myocardial infarction)."

Sensitivity analyses adjusted for the year of treatment start suggested differences were not explained by improved stroke care over time, the researchers noted.

The study has several limitations, Larsson and colleagues acknowledged. It did not include information about all factors influencing anti-seizure drug selection and some confounding likely occurred. The findings are based only on patients using a single anti-epilepsy agent and do not extend to patients requiring drug changes for seizure control.

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