'First-Line' Drug for Post-Stroke Epilepsy Tied to Increased Mortality

Pauline Anderson

December 18, 2019

BALTIMORE ― A first-line drug for patients who develop post-stroke epilepsy (PSE) appears to increase mortality risk in these patients, new research shows.

Compared with carbamazepine, the antiepileptic drug (AED) valproic acid was associated with increased mortality, whereas lamotrigine was linked to decreased mortality.

"Post-stroke epilepsy patients are still getting valproic acid as a first-choice medication, and now we see that these patients have a higher mortality rate," study investigator David Larsson, MD, who is also a PhD candidate at the Sahlgrenska Academy, University of Gothenburg, Sweden, told Medscape Medical News.

The findings were presented here at the American Epilepsy Society (AES) 73rd Annual Meeting 2019.

Stroke, Epilepsy, and Mortality

In general, the mortality rate is high for patients who experience a stroke, but the rate is even higher for those who develop epilepsy.

Larsson told meeting delegates that there are several theories as to why this is, including the fact that AEDs increase the risk for cardiovascular events.

The aim of the current study was to determine whether AED monotherapy was associated with all-cause mortality or cardiovascular death in PSE patients. Researchers defined PSE as seizures occurring more than 1 week after a stroke.

The investigators accessed national Swedish registries to collect information on stroke, comorbidities, drugs that were dispensed, and deaths.

The analysis included 2926 patients (46% women) who had a stroke between 2005 and 2010, who survived for more than 2 months, and who received continuous AED monotherapy.

"We excluded patients who switched between drugs or took several drugs at once. By 'continuous,' we mean two or more dispensations of a single antiepilepsy drug every year," Larsson said.

Of the total patient group, 1359 received carbamazepine; 569, valproic acid; 377, levetiracetam; and 349, lamotrigine. The remainder received either phenytoin or oxcarbazepine.

The primary outcome measure was all-cause mortality. The secondary outcome was cardiovascular mortality.

During the study period, there were 1801 deaths.

After adjusting for age, sex, stroke subtype, stroke severity, hypertension, atrial fibrillation, diabetes, smoking, and statin use, results showed that the death rate was significantly higher with valproic acid than with carbamazepine (hazard ratio [HR], 1.35; 95% confidence interval [CI], 1.18 – 1.56). In contrast, they found that all-cause mortality was significantly lower with lamotrigine than with carbamazepine (HR, 0.75; 95% CI, 0.62 – 0.91).

There were no significant differences in outcomes with respect to levetiracetam and carbamazepine.

Cardiovascular disease was considered the underlying cause for 1131 of the total deaths. Mortality outcomes related to the different monotherapies were similar to those for all-cause deaths.

The investigators attempted to adjust for the most important confounders, but because this was a registry-based study, some factors were unknown, including seizure frequency, Larsson said. "Further studies are needed to rule out residual confounding," he added.

Possible Explanations?

Commenting on the study for Medscape Medical News, Jorge G. Burneo, MD, professor of neurology and epidemiology and codirector of the Epilepsy Program, Western University, London, Canada, said the results are interesting but that he would like more information on the study's methodology.

Burneo, who was not involved with the current study, was lead author of a recent article on the risk for new-onset epilepsy and refractory epilepsy in older adult survivors of stroke.

The relatively high mortality rate linked to valproic acid in the study could be partly due to weight gain, he added.

"Weight gain is one of the most common side effects of valproic acid, and increased weight by itself is a risk factor for cardiovascular disease," he said.

He noted that lamotrigine was the only drug in the current study that is not an "enzyme-inducer" and so does not stimulate the synthesis of a broad range of monooxygenase and conjugating enzymes. This may explain, at least in part, the reason mortality risk was lower among the patients who received it, Burneo added.

Another possible reason lamotrigine yielded better results with respect to mortality is that it may enhance mood. "If you've just had a stroke, your mood is not the greatest, and we know what when your mood is better, your general health is better," said Burneo.

Lamotrigine has previously been linked to a rare but potentially life-threatening skin rash, although introducing the drug very slowly should mitigate this risk, he noted.

"It may take up to 8 weeks to get to a reasonable dose of lamotrigine," he said.

Although Burneo advises his patients to stop taking the medication and to call him if they develop a rash, he said that he hasn't seen a lamotrigine-related skin rash "in all my years of practice."

Also commenting on the study for Medscape Medical News, Page B. Pennell, MD, director of research, Division of Epilepsy, Brigham and Women's Hospital, and professor of neurology, Harvard Medical School, Boston, Massachusetts, said the results "remind us that we should always try to personalize antiseizure medication."

Such treatments should be chosen on the basis of a variety of factors, including underlying etiology, comorbidities, and concomitant medications, said Pennell, who is also the immediate past-president of the AES.

The study was funded by the Swedish Society for Medical Research, the Swedish Society of Medicine, the Gothenburg Society of Medicine, the Magnus Bergvall Foundation, the Felix Neuberg Foundation, and Region Västra Götaland. The study authors, Burneo, and Pennell have reported no relevant financial relationships.

American Epilepsy Society (AES) 73rd Annual Meeting 2019: Abstract 1.221, platform session E05. Presented December 9, 2019.

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