Lamotrigine linked to lower risk of death in post-stroke epilepsy

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

Investigators evaluated more than 2,500 patients, most in their late sixties, using carbamazepine as a comparator.

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

“We found differences in survival between patients [with PSE] treated with different antiepileptic drugs, “said lead author David Larsson, MD, Department of Neurology, Sahlgrenska University Hospital, Gothenburg, Sweden. Medscape Medical News.

“The take-home message for practicing clinicians is that people with epilepsy after stroke are a vulnerable group who benefit from tailor-made treatment, and the choice of antiepileptic drugs depends on many factors,” said Larsson.

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

The results were published online Dec. 13 in JAMA Neurology.

Possible drug interaction?

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

“There have been concerns that enzyme-inducing antiepileptic drugs, such as carbamazepine, may interact with drugs used in stroke prevention, possibly leading to an increased risk of cardiovascular events,” he said.

The researchers therefore “aimed to determine whether mortality varied with different antiepileptic drugs.”

Investigators relied on data from four large population-based registries including all adults in Sweden who had an acute stroke from July 1, 2005 to December 31, 2010, and with subsequent onset of epilepsy before December 31, 2015 ( n = 2577; 54% male; mean age: 78).

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

Covariates included demographic characteristics, stroke characteristics, lifestyle, activities of daily living, and pre-stroke smoking habits. It also included comorbidities such as hypertension, diabetes, and atrial fibrillation and 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 prior to their stroke. After the stroke, only 44% were able to live without assistance.

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

Improved metabolism

During the study period, 1,550 deaths occurred. 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 compared to carbamazepine

Medication Survival rate (95% CI)
Lamotrigine .62 (.56 – .67)
Levetiracetam .55 (.49 – .61)
Oxcarbazepine .54 (0.39 – .68)
Carbamazepine .53 (.50 – .56)
Valproic acid 0.34 (0.30 – 0.39)
Phenytoin .32 (0.21 – .43)
CI = 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 risk of mortality compared to carbamazepine, followed by levetiracetam, while phenytoin, oxcarbazepine and valproic acid had the highest risk (Table 2).

Table 2. Adjusted risk ratio for all-cause mortality compared to carbamazepine

Medication Adjusted HR (95% CI)
Lamotrigine .72 (0.60 – .86)
Levetiracetam .96 (0.80 – 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 = risk ratio

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

Table 3. Risk of cardiovascular death compared to carbamazepine

Medication Adjusted HR (95% CI)
Lamotrigine .76 (0.61 – .95)
Levetiracetam 0.77 (0.60 – 0.99)
Phenytoin 1.02 (0.71 – 1.47)
Oxcarbazepine 0.71 (0.42 – 1.18)
Valproic acid 1.40 (1.19 – 1.64)

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

“Our results 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 investigators write.

Nevertheless, they note that the altered vascular risk may explain the results. In particular, enzyme-inducing ASMs (carbamazepine and phenytoin) improve the metabolism of drugs commonly used in secondary prevention after stroke, in particular anticoagulants, calcium channel blockers and statins.

The researchers add that the United States Food and Drug Administration has issued a safety communication regarding the potential proarrhythmic effects of lamotrigine, and the International League Against Epilepsy has also issued recommendations on cardiac risk with lamotrigine.

However, “our real-world investigation does not suggest that lamotrigine

is expected to present a particular risk to patients with PSE at the group level, ”the investigators write.

“Think twice”

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

However, it is “difficult to determine why” the anti-epileptic drugs (AEDs) that conferred 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, using the combination of multiple registers “does not lead to case determination,” he noted.

Also, the study participants “probably” had PSE, “but that’s just the combination of the record in this stroke database and the post-epilepsy diagnostic code. ‘stroke that suggests it, “Rouhl said.

In addition, only patients taking monotherapy were included, “while patients with poor response to treatment may require a change in AED or combination therapy with AED, so perhaps the design selected patients with treatable epilepsy that may be more susceptible to the side effects of AED treatments, ”he noted.

Nonetheless, Rouhl called the mortality data “quite convincing”, adding: “while it is not certain whether the effect is entirely specific to patients with post-stroke epilepsy, the effects on mortality are there. for patients in these older patient cohorts. . “

For this reason, “neurologists should think twice before prescribing valproic acid, and possibly other older AEDs, to elderly patients,” Rouhl concluded.

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 did not disclose any relevant financial relationship. Disclosures by other authors are listed in the original article.

JAMA Neurol. Published online December 13, 2021. Summary

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