Lamotrigine linked to lowest danger of mortality in epilepsy after stroke

Among the anti-epileptic drugs (ASM) used as monotherapy for post-stroke epilepsy (PSE), lamotrigine is associated with the lowest risk of mortality and valproic acid with the highest risk, new research suggests.

Investigators looked at more than 2,500 patients, most of them in their late seventies, and used carbamazepine as a comparator.

The results showed that valproic acid, phenytoin, and oxcarbazepine had a significantly higher risk of all-cause death and cardiovascular death compared to carbamazepine, while lamotrigine had a significantly lower risk of both side effects. Although levetiracetam was associated with a lower risk of cardiovascular death, it showed no significant difference in all-cause mortality.

“We found differences in survival between patients [with PSE] are being treated with various anti-epileptic drugs, “lead author David Larsson, MD, Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden, told Medscape Medical News.

“The message for practicing clinicians is that those with post-stroke epilepsy are a vulnerable group who will benefit from tailored treatment, and the choice of anti-epileptic drugs depends on many factors,” said Larsson.

“However, at the group level, it seems sensible to avoid drugs that might interfere with other drugs used to prevent stroke and heart disease,” he added.

The results were published online in JAMA Neurology on December 13th.

Possible drug interaction?

“Observational studies have linked epilepsy to increased mortality,” noted Larsson.

“There have been concerns that enzyme-inducing anti-epileptic drugs like carbamazepine could interact with drugs used to prevent stroke, potentially increasing the risk of cardiovascular events,” he said.

The researchers therefore wanted to “investigate whether the mortality rate varies with different anti-epileptic drugs”.

The researchers drew on data from four large population registers that included all adults in Sweden with acute stroke from July 1, 2005 to December 31, 2010 and with a subsequent epilepsy outbreak before December 31, 2015 (n = 2577; 54% male; mean age 78 years).

The median time between the stroke and the first seizure-related diagnosis code was just under 1 year (347 days). The median follow-up time from the start of treatment to death or censorship at the end of the study was 2.2 years.

Covariates included demographics, stroke characteristics, lifestyle choices, activities of daily living, and smoking habits before the stroke. It also included comorbidities such as high blood pressure, diabetes, and atrial fibrillation, as well as medications such as statins and antidepressants.

Of the patients, 82% had suffered an acute ischemic stroke, most (70%) had hypertension, and most (82%) had lived without assistance before their stroke. After the stroke, only 44% were able to live without help.

The researchers chose carbamazepine as the reference drug because it is widely prescribed and has enzyme-inducing properties.

Improved metabolism

1550 deaths occurred during the study period. The highest 3-year survival rate was associated with lamotrigine and the lowest with valproic acid and phenytoin (Table 1).

Table 1. 3-year survival rate vs. carbamazepine

drug	Survival Rate (95% CI)
Lamotrigine	.62 (.56 – .67)
Levetiracetam	.55 (0.49 – .61)
Oxcarbazepine	.54 (.39 – .68)
Carbamazepine	.53 (.50 – .56)
Valproic acid	.34 (.30 – .39)
Phenytoin	.32 (.21 – .43)
KI = confidence interval

When the researchers analyzed the 5-year survival rate, the differences between lamotrigine, valproic acid, and carbamazepine remained statistically significant.

Lamotrigine also had the lowest mortality risk versus carbamazepine, followed by levetiracetam, while phenytoin, oxcarbazepine, and valproic acid had the highest risk (Table 2).

Table 2. Adjusted hazard ratio for all cause death compared to carbamazepine

drug	Adjusted HR (95% CI)
Lamotrigine	.72 (.60 – .86)
Levetiracetam	.96 (.80 – 1.15)
Phenytoin	1.16 (0.88-1.51
Oxcarbazepine	1.16 (0.81-1.66)
Valproic acid	1.40 (1.23-1.59)
HR = hazard ratio

The underlying cause of death was cardiovascular disease in more than half of the cases (63%). Lamotrigine and valproic acid were both associated with a significantly lower and higher risk of cardiovascular death, respectively, compared to carbamazepine (Table 3).

Table 3. Risk of cardiovascular death compared to carbamazepine

drug	Adjusted HR (95% CI)
Lamotrigine	.76 (.61 – .95)
Levetiracetam	.77 (.60 – .99)
Phenytoin	1.02 (0.71-1.47)
Oxcarbazepine	.71 (.42 – 1.18)
Valproic acid	1.40 (1.19-1.64)

A series of sensitivity analyzes “suggested that the differences were less likely to be explained by the severity of epilepsy or variations in prescribing patterns over time,” Larsson said.

“Our results raise the possibility that certain ASMs influence the risk of cardiovascular and total death, although our study design does not allow any causal inferences,” the researchers write.

However, they do suggest that an altered vascular risk may be responsible for the results. In particular, enzyme-inducing ASMs (carbamazepine and phenytoin) improve the metabolism of drugs commonly used in secondary prevention after stroke, including anticoagulants, calcium channel blockers, and statins.

The researchers add that the US Food and Drug Administration has issued a safety notice regarding the possible proarrhythmic effects of lamotrigine, and the International League Against Epilepsy has also issued recommendations on the cardiac risk of lamotrigine.

“However, our real world research does not suggest that lamotrigine

should pose a particular risk to patients with PSE at group level, “the researchers write.

“Think again”

In a comment for Medscape Medical News, RPW Rouhl, MD, PhD, neurologist at Maastricht University Medical Center, Academic Center for Epileptology Kempenhaeghe / MUMC, The Netherlands, described the study as “well done”.

However, it was “hard to determine why” the anti-epileptic drugs (AEDs) that posed the lowest risk of death were lamotrigine and levetiracetam, said Rouhl, who was not involved in the research.

He added that the study “has some slight weaknesses that stem from its design”. For example, combining multiple registers “does not result in a case-finding,” he noted.

In addition, study participants would “probably” have a PSE, “but only the combination of the registration in this stroke database and the diagnosis code for epilepsy after the stroke speaks for it,” said Rouhl.

In addition, only patients who received monotherapy were included, “while patients with poor response may need a change of AED or combination therapy with AEDs receiving the AED treatments,” he noted.

Nonetheless, Rouhl described the mortality data as “very compelling” and added: “Although it is uncertain whether the effect is specific to patients with post-stroke epilepsy, the effects on mortality for patients in these cohorts are of older age present .”

Because of this, “Neurologists should think twice before prescribing valproic acid to elderly patients and possibly other elderly AEDs,” concluded Rouhl.

The study was funded by grants from the Swedish State, the Swedish Society of Medicine, the Swedish Society for Medical Research, the Linnea and Josef Carlsson Foundation, the Gothenburg Medical Society, and the Magnus Bergvall Foundation. Larsson and Rouhl have not disclosed any relevant financial relationships. The information provided by the other authors is listed in the original work.

JAMA Neurol. Published online 13 December 2021. Executive summary

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