By Mark Moran
January 9, 2020
Article In Brief
Levetiracetam, fosphenytoin, and valproate—which are commonly included in the standard of care at emergency centers for status epilepticus—were equally safe and effective and appear to have roughly equivalent side effect profiles.
Three anticonvulsant medications used for benzodiazepine-resistant status epilepticus (SE) in an emergency setting appear to be equally effective, according to a randomized control trial published in the November 29, 2019, issue of The New England Journal of Medicine.
Levetiracetam, fosphenytoin, and valproate—which are commonly included in the standard of care at emergency centers for SE—also appear to have roughly equivalent side effect profiles. Fosphenytoin was associated with more hypotension and intubation, but these differences were not statistically significant, according to the report.
The trial was halted in response to pre-determined criteria, which stipulated that the study would be stopped if results did not yield clearly superior or inferior effectiveness for one of the medications.
Co-author Robert Silbergleit, MD, professor of emergency medicine at the University of Michigan, said the findings should reassure clinicians that any of the three anticonvulsants are similarly safe and effective.
“The take-away [message] from a clinical standpoint is that physicians should feel comfortable using any of these drugs and can choose one based on various practical considerations other than how well they work,” Dr. Silbergleit told Neurology Today.
“It may be a matter of availability—sometimes one or the other drug is in short supply, convenience of administration, or cost. Clinicians should know that all three of them have similar safety and effectiveness.”
Dr. Sibergleit told Neurology Today the results of the trial are surprising—most clinicians have a favored medication, and it was expected the trial would yield one that was more effective. But until now there were no definitive data comparing the three anticonvulsants.
Study Design, Findings
As part of the Established Status Epilepticus Treatment Trial, a total of 384 patients at 57 US hospital emergency departments were randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Patients were eligible if they had been treated with a generally accepted adequate cumulative dose of benzodiazepine for generalized convulsive seizures lasting more than five minutes and continued to have persistent or recurrent convulsions in the emergency department at least five minutes after the last dose.
Trial medications were infused based on patient weight: levetiracetam at a dose of 60 mg/kg (maximum, 4500 mg/kg); fosphenytoin at a dose of 20 mg/kg (maximum, 1500 mg); or valproate at a dose of 40 mg/kg (maximum, 3000 mg/kg).
The primary outcome was an absence of clinically apparent seizures (defined as visually observed focal or generalized tonic–clonic movements, nystagmoid or rhythmic eye movements, or generalized or segmental myoclonus) and improving responsiveness (defined as purposeful responses to noxious stimuli, the ability to follow commands, or verbalization) at 60 minutes after the start of trial drug infusion.
Physicians determined that cessation of SE and improved responsiveness occurred in 68 patients assigned to levetiracetam (47 percent), 53 patients assigned to fosphenytoin (45 percent), and 56 patients assigned to valproate (46 percent). 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 these differences were not significant.
Status epilepticus is commonly seen in emergency departments. Dr. Silbergleit said failure to respond to benzodiazepines may be related to the etiology of the seizure being experienced by the patient or may be related to the length of time patients have been seizing before treatment with benzodiazepines. In this trial, 10 percent of patients were determined to have psychogenic seizures.
Experts who reviewed the paper for Neurology Today said it is methodologically strong with convincing results; the most significant weakness, they said, is the lack of a more objective measure of seizure cessation.
“The strength of the study is the size, the generalizability, the waiver of consent in a large number of communities to perform this emergency treatment trial, the rigorous methodology overall, and the very clear, definitive results,” said Lawrence J. Hirsch, MD, FAAN, co-director of the Yale Comprehensive Epilepsy Center. “The main weakness is the lack of EEG to confirm termination of SE. It might have been useful to look at allergies including rashes over the following weeks, and mood and behavioral scales, but those were beyond the scope of this emergency treatment trial.
“Another minor weakness, likely unavoidable and a good teaching point, is that 10 percent of patients turned out to have non-epileptic events rather than status epilepticus,” Dr. Hirsch told Neurology Today. “This is a significant number of patients and warrants additional study to try to identify them early in their emergency treatment.”
He suggested that levetiracetam has become the most popular inpatient antiseizure medication in many centers, and the current study now provides class I data to justify its use for convulsive SE as well as less urgent situations.
“Levetiracetam is favored due to its ease of use with minimal interactions, rare allergies, rare hepatic or bleeding issues, and rare hypotension or any other issues during rapid infusion,” he said. “Neither fosphenytoin nor valproate are quite that ‘clean.’ I do worry about leaving patients with agitation, depression, anxiety, or other psychiatric issues on levetiracetam for the longer term, but that can be addressed in the non-urgent setting. In general, I'd avoid valproate in those with active hepatic dysfunction or bleeding issues, and avoid fosphenytoin in those with cardiac issues, hypotension, polypharmacy, or multiple drug allergies.”
Jack J. Lin, MD, professor of neurology and the biomedical engineering director at the University of California, Irvine, Comprehensive Epilepsy Program, echoed remarks about the subjective nature of determining seizure cessation. But he said the study offers useful clinical data about an emergency situation in which more objective measures may be impractical.
Dr. Lin said the study results mirror what has been found with seizure treatment generally, a phenomenon he said is likely related to the way drugs for epilepsy are developed.
“If you consider what we do to an animal to induce seizures—giving them either chemicals or electrical shocks—we are modeling seizures rather than the underlying condition of epilepsy,” he said. “The consensus among epileptologists is that animal models can't fully capture the human condition. We don't have biomarkers to determine which medication is best for which patient, so all of them are likely to prove effective.”
To this point, Dr. Silbergleit added that a great many other factors in clinical treatment may determine any one patient's response to medications. “It's interesting to speculate on why the drugs are equally effective,” he said. “It may be that they all just happen to have the same efficacy, but another possibility is that clinical efficacy depends more on factors related to how we care for these patients. It is possible that any number of clinical decisions—such as the length of time before giving another dose or another medicine, or how we decide when it is necessary to endotracheally intubate a patient—may have more of an effect on important clinical outcomes than the choice of medications themselves.”
“The take-away [message] from a clinical standpoint is that physicians should feel comfortable using any of these drugs and can choose one based on various practical considerations other than how well they work.”
—DR. ROBERT SILBERGLEIT
Dr. Silbergleit reported no disclosures relevant to the study. Dr. Lin disclosed that he serves on the speaker's bureau of UCB Pharma and has received an honorarium.