Amongst antiseizure medications (ASMs) aged as monotherapy in poststroke epilepsy (PSE), lamotrigine is expounded with the lowest possibility for mortality and valproic acid is expounded with the most sensible probably possibility, new be taught suggests.
Investigators assessed more than 2500 sufferers, most of their gradual seventies, using carbamazepine as a comparator.
Results showed that valproic acid, phenytoin, and oxcarbazepine had an awfully a lot elevated possibility for all-trigger and cardiovascular loss of life when put next with carbamazepine, whereas lamotrigine had a considerably decrease possibility for both detrimental outcomes. Though levetiracetam used to be related with a decrease possibility for cardiovascular loss of life, it showed no well-known distinction in overall mortality.
“We learned differences in survival between sufferers [with PSE] treated with rather about a antiseizure medications,” lead author David Larsson, MD, Division of Neurology, Sahlgrenska University Sanatorium, Gothenburg, Sweden, told Medscape Medical News.
“The gather-home messages for practicing clinicians is that participants with epilepsy after a stroke recount a susceptible community that benefits from tailored treatment, and the gathering of antiseizure medications depends on many components,” Larsson acknowledged.
On the opposite hand, “on a community level, it appears to be like sensible to preserve faraway from medication that could per chance per chance additionally merely intervene with rather about a medication aged to waste stroke and heart disease,” he added.
The findings were published online December 13 in JAMA Neurology.
Imaginable Drug Interaction?
“Observational reviews accept as true with related epilepsy with elevated mortality,” Larsson well-known.
“There were concerns that enzyme-inducing antiseizure medications, equivalent to carbamazepine, could per chance accept as true with interplay with medication aged in stroke prevention, presumably ensuing in an elevated possibility of cardiovascular occasions,” he acknowledged.
The researchers because of this truth “aimed to evaluate if mortality varied with rather about a antiseizure medications.”
The investigators drew on knowledge from four colossal population-based fully registers consisting of all adults in Sweden with acute stroke from July 1, 2005, to December 31, 2010, and with subsequent onset of epilepsy sooner than December 31, 2015 (n = 2577; 54% male; indicate age, 78 years).
The median time between stroke and first seizure-related diagnostic code used to be a minute bit beneath 1 365 days (347 days). The median practice-up time from open up of treatment to loss of life or censoring at demand waste used to be 2.2 years.
Covariates included demographic traits, stroke traits, living intention, activities of each day living, and smoking habits sooner than the stroke. It additionally included comorbidities equivalent to hypertension, diabetes, and atrial fibrillation and medications equivalent to statins and antidepressants.
Amongst the sufferers, 82% had experienced an acute ischemic stroke, most (70%) had hypertension, and most (82%) had lived unassisted sooner than their stroke. After the stroke, handiest 44% were ready to dwell unassisted.
The researchers chose carbamazepine because the reference medication on narrative of it is some distance on the total prescribed and has enzyme-inducing properties.
Enhanced Metabolism
At some level of the demand period, 1550 deaths took place. The most sensible probably 3-365 days survival price used to be related with lamotrigine and the lowest with valproic acid and phenytoin (Desk 1).
Desk 1. 3-365 days Survival Price vs Carbamazepine
| Treatment | Survival Price (95% CI) | |||
|---|---|---|---|---|
| Lamotrigine | .62 (.56 – .67) | |||
| Levetiracetam | .55 (.49 – .61) | |||
| Oxcarbazepine | .54 (.39 – .68) | |||
| Carbamazepine | .53 (.50 – .56) | |||
| Valproic acid | .34 (.30 – .39) | |||
| Phenytoin | .32 (.21 – .43) | |||
| CI = confidence interval | ||||
When the researchers analyzed the 5-365 days survival price, the variations between lamotrigine, valproic acid, and carbamazepine remained statistically well-known.
Lamotrigine additionally had the lowest mortality possibility vs carbamazepine, followed by levetiracetam, whereas phenytoin, oxcarbazepine, and valproic acid had the most sensible probably possibility (Desk 2).
Desk 2. Adjusted Hazard Ratio for All-Reason Demise vs Carbamazepine
| Treatment | Adjusted HR (95% CI) | |||
|---|---|---|---|---|
| Lamotrigine | .72 (.60 – .86) | |||
| Levetiracetam | .96 (.80 – 1.15) | |||
| Phenytoin | 1.16 (.88 – 1.51 | |||
| Oxcarbazepine | 1.16 (.81 – 1.66) | |||
| Valproic acid | 1.40 (1.23 – 1.59) | |||
| HR = hazard ratio | ||||
The underlying reason within the aid of loss of life in extra than half of the cases (63%) used to be heart problems. Compared with carbamazepine, lamotrigine and valproic acid both were related with an awfully a lot decrease and elevated possibility for cardiovascular loss of life, respectively (Desk 3).
Desk 3. Risk for Cardiovascular Demise vs Carbamazepine
| Treatment | Adjusted HR (95% CI) |
|---|---|
| Lamotrigine | .76 (.61 – .95) |
| Levetiracetam | .77 (.60 – .99) |
| Phenytoin | 1.02 (.71 – 1.47) |
| Oxcarbazepine | .71 (.42 – 1.18) |
| Valproic acid | 1.40 (1.19 – 1.64) |
An array of sensitivity analyses “urged that the variations were much less doubtless to be defined by epilepsy severity or variations in prescription patterns over time,” Larsson acknowledged.
“Our findings raise the likelihood that stammer ASMs influence the likelihood of cardiovascular and all-trigger loss of life, even supposing our demand draw does no longer allow causal inference,” the investigators write.
On the opposite hand, they divulge that altered vascular possibility could per chance per chance additionally merely narrative for the findings. In stammer, enzyme-inducing ASMs (carbamazepine and phenytoin) strengthen the metabolism of gear frequently aged in secondary prevention after stroke, collectively with anticoagulants, calcium channel blockers, and statins.
The researchers add that the US Food and Drug Administration issued a safety verbal change regarding probably proarrhythmic results of lamotrigine, and the International League Against Epilepsy likewise issued suggestions about cardiac possibility with lamotrigine.
On the opposite hand, “Our precise-world investigation does no longer recommend that lamotrigine
must pose a stammer possibility for sufferers with PSE on a community level,” the investigators write.
“Mediate Twice”
Commenting for Medscape Medical News, R.P.W. Rouhl, MD, PhD, neurologist at Maastricht University Medical Heart, Academic Heart for Epileptology Kempenhaeghe/MUMC, The Netherlands, called the demand “nicely-conducted.”
On the opposite hand, it is some distance “noteworthy to establish why” the antiepileptic medication (AEDs) that conferred the lowest possibility for mortality were lamotrigine and levetiracetam, acknowledged Rouhl, who used to be no longer full of life with the be taught.
He added that the demand has “some tiny weaknesses which practice from its draw.” To illustrate, using the mixture of several registries “does no longer lead to case ascertainment,” he well-known.
To boot, demand participants “most doubtless” had PSE, “nonetheless it completely is handiest the mixture of registration on this stroke database and the diagnosis code of epilepsy after the stroke which implies this,” Rouhl acknowledged.
Additionally, handiest sufferers taking monotherapy were included, “whereas sufferers with a spoiled remedy response could per chance per chance additionally merely require switching of AED or mixture remedy with AEDs, so per chance the draw chosen sufferers with easy-to-treat epilepsy who could per chance per chance additionally very nicely be more inclined to detrimental results of the AED treatments,” he well-known.
On the opposite hand, Rouhl called the mortality knowledge “rather compelling,” collectively with, “even supposing it is some distance unsure whether the attain is fully particular for sufferers with put up-stroke epilepsy, the outcomes on mortality are there for sufferers in these cohorts of sufferers with a elevated age.”
For this reason, “neurologists must judge twice sooner than prescribing valproic acid, and presumably rather about a older AEDs as nicely, to aged sufferers,” Rouhl concluded.
The demand used to be funded by grants from the Swedish suppose, the Swedish Society of Treatment, the Swedish Society of Medical Be taught, the Linnea and Josef Carlsson Foundation, the Göteborg Medical Society, and the Magnus Bergvall Foundation. Larsson and Rouhl accept as true with disclosed no relevant monetary relationships. The rather about a authors’ disclosures are listed within the distinctive paper.
JAMA Neurol. Published online December 13, 2021. Abstract
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