Pick Your Poison but Pick It Wisely: Choosing a Second-Line Medication for the Management of Status Epilepticus

Abstract

Efficacy of Levetiracetam, Fosphenytoin, and Valproate for Established Status Epilepticus by Age Group (ESETT): A Double-Blind, Responsive-Adaptive, Randomised Controlled Trial. Chamberlain JM, Kapur J, Shinnar S, Elm J, Holsti M, Babcock L, Rogers A, Barsan W, Cloyd J, Lowenstein D, Bleck TP, Conwit R, Meinzer C, Cock H, Fountain NB, Underwood E, Connor JT, and Silbergleit R, Neurological Emergencies Treatment Trials; Pediatric Emergency Care Applied Research Network investigators. Lancet. 2020;395(10231):1217-1224. doi:https://europepmc.org/article/med/32203691 Background: Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying etiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT), we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here, we describe our results after extending enrolment in children to compare outcomes in 3 age groups. Methods: In this multicenter, double-blind, response-adaptive, randomized controlled trial, we recruited patients from 58 hospital emergency departments across the United States. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalized convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 minutes after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods, and stratified by age-group (<18 years, 18-65 years, and >65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional anti-seizure medication at 1 hour from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analyzed by intention to treat. This study is registered in ClinicalTrials.gov, NCT01960075. Findings: Between November 3, 2015, and December 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged <18 years), 186 adults (18-65 years), and 51 older adults (>65 years). One hundred seventy-five (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenytoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41-62) of children, 44% (33-55) of adults, and 37% (19-59) of older adults; with fosphenytoin in 49% (38-61) of children, 46% (34-59) of adults, and 35% (17-59) of older adults; and with valproate in 52% (41-63) of children, 46% (34-58) of adults, and 47% (25-70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age-group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age-group. Interpretation: Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the 3 drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. : Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus 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. N Engl J Med. 2019;381(22):2103-2113. doi:10.1056/NEJMoa1905795 Background: The choice of drugs for patients with status epilepticus that is refractory to treatment with benzodiazepines has not been thoroughly studied. Methods: In a randomized, blinded, adaptive trial, we compared the efficacy and safety of 3 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. Results: 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, 39-55), 53 patients assigned to fosphenytoin (45%; 95% credible interval, 36-54), and 56 patients assigned to valproate (46%; 95% credible interval, 38-55). 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. Conclusions: 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 3 drugs were associated with similar incidences of adverse events (Funded by the National Institute of Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number, NCT01960075.).