Jaideep Kapur, MB, BS, PhDJaideep Kapur, MB, BS, PhD
Results from the Established Status Epilepticus Treatment Trial (ESETT) show that levetiracetam, fosphenytoin, and valproate are equally effective for stopping seizures and improving responsiveness in patients with benzodiazepine-refractory status epilepticus (SE).1

Benzodiazepines are considered the first line of treatment for patients with SE; however up to a third of patients have seizures that do not respond to treatment. Notably, among the 3 drugs studied in the ESETT trial, only fosphenytoin is indicated by the FDA for treatment of SE in adults.

The multicenter, blinded study included 384 patients (55% men; 39% age 2-17) who were randomly assigned to treatment with either levetiracetam (n = 145), fosphenytoin (n = 118), or valproate (n = 121) after receiving and not responding to minimal adequate cumulative doses of benzodiazepines for persistent or recurrent convulsive seizures. Exclusion criteria for those ineligible to participate included patients who were pregnant, those who received treatment with a second-line anticonvulsant or treatment with sedatives with anticonvulsant properties other than benzodiazepines. Notably, 10% of patients were determined to have psychogenic seizures. A total of 16 additional instances of randomization were added for patients who experienced a second episode of status epilepticus, though these second enrollments were not included in the intention-to-treat analysis.

Cessation of SE and improved responsiveness within 60 minutes of administered treatment occurred in 47% of patients in the levetiracetam group (95% CI, 39-55), 45% in the fosphenytoin group (95% CI, 36-54) and 46% in the valproate group (95% CI, 38- 55). Neither drug produced significantly different results than the next, and there was no variation in serious adverse effects observed among the 3 drugs. The trial was stopped early after an interim analysis showed no significant differences between the 3 drugs.

Using response adaptive randomization, investigators were able to improve the study’s efficacy and maximize the chances of identifying the best treatment. “This design lowered risk by reducing the chances that participants could have received what might have been determined to be the least effective treatment,” Jaideep Kapur, MB, BS, PhD, professor at the University of Virginia and lead investigator, said in a statement.2

In terms of adverse events, the frequency of life-threatening hypotension, arrhythmia, endotracheal intubation, and other outcomes were similar between the 3 study drugs, with no significant difference in the frequency of life-threatening hypotension and cardiac arrhythmia, the composite safety outcome, across the treatment groups. Of the serious adverse events that occurred in 42% of patients, the most common were convulsions after 60 minutes, depressed level of consciousness, and respiratory distress.

Although the 3 drugs proved effective in just under half of the patients studied, investigators will continue to explore other treatments for the patients whose seizures did not respond to the studied drugs.
REFERENCES
1. Kapur J, Elm J, Chamberlain JM, et al. Randomized trial of three anticonvulsant medications for status epilepticus. N Engl J Med. 2019;381:2103-2113. doi: 10.1056/NEJMoa1905795.
2. Head to head comparison finds three anti-seizure drugs equally effective for sever form of epilepsy [news release]. NIH. November 27, 2019. nih.gov/news-events/news-releases/head-head-comparison-finds-three-anti-seizure-drugs-equally-effective-severe-form-epilepsy. Accessed December 2, 2019.