Three anticonvulsant drugs used in benzodiazepine-refractory convulsive status epilepticus have been shown to have very similar levels of efficacy.
Use of levetiracetam, fosphenytoin, and valproate each led to seizure cessation and improved alertness by 60 minutes in approximately half the patients, and the three drugs were associated with similar incidences of adverse events in a new randomized controlled trial.
“Physicians can now be confident in using any of these three drugs for patients in status epilepticus for whom benzodiazepine therapy has not worked,” senior author, Robert Silbergleit, MD, University of Michigan Department of Emergency Medicine.
“As the three drugs all have similar levels of efficacy, a choice can be made based on availability, convenience, cost, and which one has worked well in the past,” he added.
The study, which was supported by the National Institute of Neurological Disorders and Stroke, was published in the November 28 issue of the New England Journal of Medicine.
Silbergleit noted that about 60% to 70% of patients in status epilepticus respond to benzodiazepines, “but that means 30% to 40% do not.”
He explained that there has been a gap in knowing how to treat patients who have not responded to benzodiazepines.
“Several different drugs are currently used if benzodiazepines fail,” he said. The three most common are levetiracetam, fosphenytoin, and valproate, which are used in the vast majority of patients, but it’s not clear if one is better than the others.
“There aren’t any comparative efficacy studies apart from some unreliable observational studies, and there is a real need to know how to treat these patients,” he said. Seizures are the most common neurological emergency seen in the emergency room (ER), he added, and seizures continuing for more than 5 minutes can be life-threatening.
For the current study, known as the Established Status Epilepticus Treatment Trial (ESETT), 384 children and adults with convulsive status epilepticus unresponsive to treatment with benzodiazepines were randomized to levetiracetam, fosphenytoin, or valproate.
The primary outcome of cessation of status epilepticus and improvement in level of consciousness at 60 minutes occurred in 47% of patients assigned to levetiracetam, 45% of those who received fosphenytoin, and 46% of those given valproate.
The posterior probability that levetiracetam was better than fosphenytoin and valproate was 0.41, the probability that fosphenytoin was better than levetiracetam and valproate was 0.24, and the probability that valproate was better than levetiracetam and fosphenytoin was 0.35.
There was a trend toward a shorter time to seizure termination favoring valproate, at 7.0 minutes, compared with 10.5 minutes for levetiracetam and 11.7 minutes for fosphenytoin — but these times could only be analyzed in the small subgroup of 39 patients (10%) for whom audio recordings had enabled accurate timing.
Safety outcomes were also similar between the three groups. The frequency of life-threatening hypotension was 0.7% in the levetiracetam group, 3.2% in the fosphenytoin group, and 1.6% in the valproate group.
Arrhythmia occurred in 0.7% in the levetiracetam group and there were no cases in the other two groups. Endotracheal intubation was necessary in 20.0% of the levetiracetam group, 26.4% of the fosphenytoin group, and 16.8% of the valproate group.
“We found that all three medications were pretty much exactly the same in both efficacy and safety, each one stopping seizures in about half of patients,” Silbergleit commented.
He pointed out that although it is possible that all three drugs do have similar efficacy despite different pharmacology and dosing, there may be other factors that could have influenced the results, such as how long physicians wait after the drug is given before moving to intubation and anesthesia.
“In this trial, the second-line drug was given between 5 and 30 minutes after the benzodiazepine,” he noted. “In most cases, if a patient is still convulsing 5 minutes after benzodiazepine administration then the second-line drug is given very soon, in the next minute or so, but we allowed an interval of up to 30 minutes to include patients who may have stopped convulsing with the benzodiazepine but then started again within half an hour.”
The second-line drug was given over a 10-minute infusion and physicians were advised to wait a further 10 minutes before moving on to intubation, “but not all physicians will have followed the protocol in exactly the same way,” Silbergleit explained.
He also noted that it can be difficult to know for sure who has responded. “It is not always easy to tell if a seizure has stopped without an EEG, which isn’t appropriate to do in the ER. Patients may have stopped convulsing but they may still be having seizures. We defined treatment success as stopping of convulsions and patients to have woken up and been responsive within 60 minutes, but it is variable how long some physicians want to wait before trying different approaches and some physicians may use different criteria for deciding when to intubate,” he said. “If the patient is not breathing well they may feel they have to intubate earlier.”
The researchers didn’t test these different clinical variables but they are planning to analyze their data to look at whether these different practice patterns may have had any effect on the results.
Silbergleit said the focus of research in status epilepticus could now shift to best practice for patients still having convulsions after the second-line drugs have been tried. “This is truly refractory status epilepticus.”
The availability of new more portable EEG machines will also lead to opportunities to better characterize patients and their needs in status epilepticus, he suggested.
“It is much easier to tell if a drug is working if we can see the EEG during treatment, but performing an EEG is currently quite a laborious process not suitable for quick use in the ER for patients in status epilepticus,” he said. “Newer smaller devices are now coming out with fewer electrodes. They may not give as much information but will be able to tell us if a patient is still in status epilepticus or not. This will help with decision-making in the emergency setting.”
“A Commendable Achievement”
In an accompanying editorial, Phil Smith, MD, University Hospital of Wales, Cardiff, UK, notes that status epilepticus is relatively common, with a reported annual incidence of between 10 and 41 cases per 100,000 population and a mortality of approximately 20%.
He points out that clinicians have long been urged instead to intervene early in the disorder, typically when seizures have persisted beyond 5 minutes, as delaying intervention can allow seizures to persist and become refractory, with risk of neurologic harm and death.
He says the current randomized trial is a “commendable achievement” and the results “may consolidate the drug management protocols for established [benzodiazepine-resistant] status epilepticus.”
“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 factors such as the presumed underlying cause of status epilepticus; coexisting conditions, including allergy, liver, and renal disease, hypotension, propensity to cardiac arrhythmia, and alcohol and drug dependence; the currently prescribed antiepileptic treatment; the cost of the medication; and governmental agency drug approval,” Smith states.
“Providing evidence underpinning such an important treatment decision has the potential to save lives and brain tissue. But the practical challenge for the management of status epilepticus remains the same as in the past: ensuring that clinicians are familiar with, and follow, a treatment protocol,” he concludes.
N Engl J Med. Published online November 28, 2019. Abstract, Editorial
