Tuesday, February 4, 2020

Levetiracetam, fosphenytoin, and valproate for status epilepticus refractory to benzodiazepines

Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J, Lowenstein D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor JT, Silbergleit R; NETT and PECARN Investigators. Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus. N Engl J Med. 2019 Nov 28;381(22):2103-2113.


The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied.

In a randomized, blinded, adaptive trial, we compared the efficacy and safety of three intravenous 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 absence of clinically evident seizures and improvement in the level of consciousness by 60 minutes after the start of drug infusion, without additional anticonvulsant medication. The posterior probabilities that each drug was the most or least effective were calculated. Safety outcomes included life-threatening hypotension or cardiac arrhythmia, endotracheal intubation, seizure recurrence, and death.

A total of 384 patients were enrolled and randomly assigned to receive levetiracetam (145 patients), fosphenytoin (118), or valproate (121). Reenrollment of patients with a second episode of status epilepticus accounted for 16 additional instances of randomization. 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. 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). The posterior probability that each drug was the most effective was 0.41, 0.24, and 0.35, respectively. 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.

In the context of benzodiazepine-refractory convulsive status epilepticus, the anticonvulsant drugs 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. (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).

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.”


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