Charlottesville, VA—While clinical guidelines stress the importance of rapid control of benzodiazepine-refractory status epilepticus—to reduce the risk of cardiac and respiratory complications, among other adverse effects—they don’t specify which medication is superior, based on either efficacy or safety.

A report in the New England Journal of Medicine points out that benzodiazepines are preferred as the initial treatment for status epilepticus but adds that up to a third of patients don’t respond to the drugs.

For those patients, emergency departments (EDs) usually turn to levetiracetam, fosphenytoin, and valproate; only fosphenytoin is labeled by the FDA for this indication in adults and no indication has been approved for children, according to the Established Status Epilepticus Treatment Trial (ESETT) researchers.

The study group performed a randomized clinical trial to determine the superiority or inferiority of the three commonly used anticonvulsant medications, focusing on treatment success in epilepsy patients presenting to the ED.

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

“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 anesthetize patients and put them on a mechanical ventilator, may be more important than the specific treatments used to control seizures in patients,” said the University of Michigan’s Robert Silbergleit, MD, one of the leaders of the ESETT group.

Noting that which drug to choose for status epilepticus patients who don’t respond to benzodiazepine therapy has not been thoroughly studied, researchers conducted a randomized, blinded, adaptive trial. In it, they compared the efficacy and safety of three IV anticonvulsive agents—levetiracetam, fosphenytoin, and valproate—in children and adults with convulsive status epilepticus that was unresponsive to treatment with benzodiazepines.

The primary outcome was defined as absence of clinically evident seizures and improvement in the level of consciousness within 1 hour after the start of drug infusion, without the addition of anticonvulsant medication. The study team was also tracking safety outcomes, including life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.

For the study, 145 patients were randomly assigned to receive levetiracetam, 118 fosphenytoin, and 121 valproate.

“In accordance with a prespecified stopping rule for futility of finding one drug to be superior or inferior, a planned interim analysis led to the trial being stopped,” the authors write. “Of the enrolled patients, 10% were determined to have had psychogenic seizures. The primary outcome of cessation of status epilepticus and improvement in the level of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%; 95% credible interval, 39 to 55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned to valproate (46%; 95% credible interval, 38 to 55).”

Researchers explained that the posterior probability that each drug was the most effective was 0.41 for levetiracetam, 0.24 fosphenytoin, and 0.35 for valproate. The study reveals that, numerically, more episodes of hypotension and intubation occurred in the fosphenytoin group and more deaths occurred in the levetiracetam group than in the other groups, but those differences did not reach statistical significance.

“Using an innovative design for this clinical trial, we were able to answer this important question in a timely and cost-effective manner,” said lead author Jaideep Kapur, MB, PhD, of the University of Virginia. “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.”

 « Click here to return to Weekly News Update.