Prehospital combination therapy disappoints in status epilepticus

By Eleanor McDermid, Senior medwireNews Reporter

Adding levetiracetam to prehospital treatment with clonazepam does not improve control of generalised convulsive status epilepticus, shows a randomised phase III trial.

In the SAMUKeppra trial, which is published in The Lancet Neurology, 74% of 68 patients given combination treatment with intravenous clonazepam (1 mg) and levetiracetam (2.5 g) ceased convulsions within 15 minutes of injection, as did 84% of 68 patients given clonazepam plus placebo.

The lack of additional benefit with levetiracetam is contrary to open-label and non-randomised studies that reported a high success rate for the drug in patients with status epilepticus.

“Despite the disappointingly negative results, this is an important clinical trial primarily because of its innovative design”, writes Jan Claassen (Columbia University, New York, USA) in a linked commentary.

Besides the trial being the first to assess prehospital combination therapy, it also achieved a “surprising and thought-provoking” high success rate in patients in the control group. This, Claassen suggests, is because the study protocol allowed for administration of a second clonazepam dose if convulsions had not ceased within 5 minutes of the first dose.

This finding may “shift attention from timing alone to questioning the intensity of initial interventions”, he says. “More aggressive early interventions with benzodiazepine drugs might be as important as identification of the best second-line drug for status epilepticus.”

Lead researcher Vincent Navarro (Hôpital de la Pitié-Salpêtrière, Paris, France) and colleagues tried adding levetiracetam to clonazepam (the standard first-line treatment in much of Europe) because the two drugs act via different mechanisms. Although the lack of benefit with levetiracetam on seizure control extended to 35 minutes after initial administration, the team did find that patients given combination therapy had a lower rate of new neurological deficits at the point of hospital discharge, at 2% compared with 13% for patients given placebo.

They therefore suggest that levetiracetam could be studied further for a possible neuroprotective effect.

And, in his commentary, Claassen stresses that the idea of using prehospital combination therapy “is not automatically discredited” by the trial’s outcomes, because different drug combinations may prove more successful.

“This trial by Navarro and colleagues does not change the management of convulsive status epilepticus, but it could inform us on how to do relevant trials in the future”, he concludes.

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