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Findings from long awaited epilepsy trial could improve patient safety

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The largest trial for more than twenty years into the epileptic seizure condition, status epilepticus, has shown that two unlicensed drugs (levetiracetam and valproate) are just as effective as the only current licensed drug for the condition (fosphenytoin/phenytoin).

The research, by scientists at leading institutions in the US and UK*, including St George’s, involved 384 patients who were treated for status epilepticus across 57 hospitals in the US. By randomly assigning patients to receive one of the three drugs, they found that each drug stopped the seizures in around half the patients, saving many from admission to intensive care and associated complications.

Status epilepticus is the name for any seizure that lasts a long time, or a series of seizures where the person doesn't regain consciousness in between, and can occur at any age. Only around half of status epilepticus cases are in people with a history of epilepsy, with other common causes including stroke, brain injury or infections. The condition can be life-threatening with around 15 in 100 cases resulting in death.

The initial treatment for patients is the sedative drug, benzodiazepine, which works for up to 7 out of 10 patients if given promptly in adequate doses. But for those that don’t respond, the only licensed drug is phenytoin, or its prodrug fosphenytoin. The researchers aimed to gather evidence on the effectiveness and safety of fosphenytoin, as well as newer alternative drugs levetiracetam and valproate, as a second line treatment. Both are established treatments for epilepsy, but not licensed for use in status epilepticus.

The study results showed the drugs were equivalent in terms of effectiveness in stopping seizures. Similarly, there were no clear differences in terms of drug safety when comparing across outcomes including life-threatening hypotension, heart problems, seizure recurrence and death.

According to Professor Hannah Cock, co-author of the study from St George’s, the broader picture shows that these two alternative drugs are preferable to phenytoin. “Phenytoin takes at least double the time (20 minutes or more) to administer,” she said. 

“It can exacerbate seizures in some types of epilepsy, with multiple potential drug interactions in an already critically ill population often needing multiple medications."

Reports over 5 years to the UK National Patient Safety Agency also show that phenytoin was the only drug where loading dose errors were associated with fatalities.

Professor Cock continued: “The sooner seizures can be ended, the better the outcome for patients. At St George’s we get convulsive status epilepticus patients at least once per week, and we want to treat them quickly with best practice care.

“Our results show that we now have two other options to give to patients who need urgent care, and should give doctors the confidence to use these other medicines.”

The next steps for the research team will be to assess treatment options for patients with refractory status epilepticus, where patients show no response to the initial benzodiazepine treatment or follow up drugs.

 * The institutions involved are: University of Virginia; Medical University of South Carolina; Children’s National Medical Center, Washington, DC; University of Michigan; University of Minnesota; University of California, San Francisco; Albert Einstein College of Medicine, Montefiore Medical Center; National Institutes of Health, Bethesda; St. George’s, University of London; St. George’s University Hospitals NHS Foundation Trust; ConfluenceStat, Orlando; University of Central Florida College of Medicine.

Source: Kapur et al. “Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus,” New England Journal of Medicine, November 28, 2019.

Published: 27 November 2019

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