3 anticonvulsants similarly effective in stopping fatal epilepsy seizures

Three anticonvulsant drugs — levetiracetam, fosphenytoin, and valproate — are equally effective in stopping life-threatening epilepsy seizures in patients who are unresponsive to benzodiazepines, thus providing affirmation for physicians that any of the three drugs can be used for treating status epilepticus, according to results from ESETT*.

Clinicians have long been urged to intervene early to stop seizures, particularly those that have persisted over 5 minutes, in order to limit potential neurologic damage and brain injury. However, there has been no clear indication on which drug is best or how much to give.

“Prior to this, people were using their best guess as to which drug to use and how much of it to use. And [the study] puts those things to rest and tells you exactly how much of which to use, and what to expect,” said lead investigator Dr Jaideep Kapur, of the University of Virginia’s School of Medicine in Charlottesville, Virginia, US.

The primary outcome of seizure cessation and improvement in consciousness level within 60 minutes of treatment occurred in 47 percent, 45 percent, and 46 percent of patients treated with levetiracetam, fosphenytoin, and valproate, respectively. [N Engl J Med 2019;381:2103-2113]

The corresponding posterior probability that the drug was more effective than the other two comparators was 0.41, 0.24, and 0.35, respectively.

“[The] big takeaway is that each of these drugs works about 45 percent of the time. And this is an important finding because it tells us patients can get better. They don’t have to be placed on a ventilator,” said Kapur.

“Having three equally effective second-line intravenous medications means that the clinician may choose a drug that takes into account individual situations that may be modified by [other] factors,” commented Dr Phil Smith of University Hospital of Wales in Cardiff, UK in a linked editorial. [N Engl J Med 2019;381:2171-2172]

He pointed out that the other factors that can affect drug choice include underlying cause of status epilepticus, currently prescribed antiepileptic treatment, coexisting conditions (such as allergy, hypotension, liver and renal disease, risk for cardiac arrhythmia, and dependence on drug and alcohol), and medication cost and availability.

The prospective, double-blind, adaptive trial randomized 384 patients (mean age 33 years; ~30 percent aged ≤10 years) with status epilepticus refractory to benzodiazepines to receive any one of the three intravenous anticonvulsive agents: levetiracetam (n=145), fosphenytoin (n=118), or valproate (n=121) according to weight-based dosing** in the emergency department.   

The results were so clear that the three drugs were similarly effective in a planned interim analysis that the trial was stopped earlier for meeting the prespecified criterion for futility.

In terms of safety, life-threatening hypotension occurred at a rate of 0.7 percent, 3.2 percent, and 1.6 percent in the levetiracetam, fosphenytoin, and valproate groups, respectively, with no significant difference among the three groups. The incidence of endotracheal intubation was 20.0 percent, 26.4 percent, and 16.8 percent, respectively; whereas arrhythmia was 0.7 percent with levetiracetam and none in the other two treatment groups — neither showed significant difference among groups.  

“It has been a commendable achievement to deliver a multicentre, randomized, double-blind trial of a potentially lifesaving intravenous medication to 384 patients within high-pressure emergency department settings,” wrote Smith.

“The ESETT trialists have provided a service to adults and children with status epilepticus and to the teams managing their conditions. Providing evidence underpinning such an important treatment decision has the potential to save lives and brain tissue,” he added.