Three antiepileptics equally effective in refractory status epilepticus: ESETT Trial

The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.

Three drugs, levetiracetam, fosphenytoin, and valproate, are equally safe and effective in treating patients with refractory status epilepticus in head to head comparison according to a study published in the New England Journal of Medicine.

"Doctors can be confident that the particular treatment they choose for their patients with status epilepticus is safe and effective and may help them avoid the need to intubate the patient as well as stays in the intensive care unit," said Robin Conwit, M.D., NINDS program director and an author of the study. "This was a truly collaborative, multidisciplinary study that involved paediatricians, emergency medicine doctors, neurologists, pharmacologists, and biostatisticians all contributing their expertise."

In the Established Status Epilepticus Treatment Trial (ESETT), led by Robert Silbergleit, M.D., professor at the University of Michigan, Ann Arbor; Jordan Elm, Ph.D., professor at Medical University of South Carolina; James Chamberlain, M.D., professor at George Washington University; and Jaideep Kapur, M.B., B.S., Ph.D., professor at the University of Virginia, more than 380 children and adults were randomized to receive levetiracetam, fosphenytoin, or valproate when they came to the emergency room experiencing a seizure. The researchers were trying to determine which of the anticonvulsant drugs was most effective in stopping seizures and improving a patient's level of responsiveness within 60 minutes of administering treatment.

The results showed that the three drugs stopped seizures and improved responsiveness in approximately half of the study participants. Specifically, these benefits were seen in 47% of subjects in the levetiracetam group, in 45% of participants in the fosphenytoin group and in 46% of subjects in the valproate group. These differences were not statistically significant.

There were no differences in serious side effects among the drugs.

"Our study suggests that clinical outcomes are driven by factors other than drugs. Differences in how doctors decide to treat status epilepticus, such as when they give more drugs or when to anaesthetize patients and put them on a mechanical ventilator, maybe more important than the specific treatments used to control seizures in patients," said Dr Silbergleit.

The study was stopped early when a planned interim analysis found that the drugs were equally safe and effective.

ESETT researchers utilized a clinical trial design known as response adaptive randomization to improve the study's efficiency and maximize the chances of identifying the best treatment. The study used an algorithm to determine which drugs patients would receive based on accumulating trial data.

"Using an innovative design for this clinical trial, we were able to answer this important question in a timely and cost-effective manner," said Dr Kapur. "In addition, this design lowered risk by reducing the chances that participants could have received what might have been determined to be the least effective treatment."

Status epilepticus is characterized by individual seizures or multiple seizures close together lasting more than five minutes, with a loss of consciousness. If not treated, it can lead to severe brain damage or death. Benzodiazepines are the first line of treatment for status epilepticus and are effective in two-thirds of patients. Refractory status epilepticus occurs in those patients in whom benzodiazepines do not stop their seizures.

Additional research is needed to prevent refractory status epilepticus and to find treatment options for the patients whose seizures do not respond to the three drugs investigated in this study.

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DOI: 10.1056/NEJMoa1905795

Journal : New England Journal of Medicine.