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 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. 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 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. 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 three drugs were associated with similar incidences of adverse events. (Funded by the National Institute of Neurological Disorders and Stroke.
Bibliographical noteFunding Information:
Supported by grants (U01NS088034, U01NS088023, U01NS056975, U01NS059041, and U01NS073476) from the National Institute of Neurological Disorders and Stroke (NINDS).
From the Department of Neurology, Uni versity of Virginia, Charlottesville (J.K., N.F.); the Data Coordination Unit, Department of Public Health Sciences, Medical University of South Carolina, Charleston (J.E., C.M.); the Division of Emergency Medicine, Children’s National Medical Center, Washington, DC (J.M.C.); the Department of Emergency Medicine, University of Michigan, Ann Arbor (W.B., R.S.); the College of Pharmacy, Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis (J.C.); the Department of Neurology, University of California, San Francisco, San Francisco (D.L.); the Departments of Neurology and Pediatrics, Albert Einstein College of Medicine, Montefiore Medical Center, New York (S.S.); the National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD (R.C.); St. George’s University of London and St. George’s University Hospitals NHS Foundation Trust, London (H.C.); and ConfluenceStat (J.T.C.) and the University of Central Florida College of Medicine (J.T.C.) — both in Orlando. Address reprint requests to Dr. Silbergleit at the University of Michigan Department of Emergency Medicine, 24 Frank Lloyd Wright Dr., Lobby H, Suite H3100, Ann Arbor, MI 48106, or at firstname.lastname@example.org.
The Established Status Epilepticus Treatment Trial (ESETT) was an investigator-initiated, multicenter, randomized, blinded, comparative-effectiveness trial of levetiracetam, fosphenytoin, and valproate for the treatment of patients with established status epilepticus in the emergency department. The trial was developed through a program funded by the National Institutes of Health and the FDA and was conducted by the Neurological Emergencies Treatment Trials (NETT) Network and the Pediatric Emergency Care Applied Research Network (PECARN).11 The investigators were responsible for the trial design, data collection, and data analysis. The authors wrote the manuscript and vouch for the accuracy and completeness of the data and reporting of ad- verse events and for the fidelity of the trial to the protocol, available with the full text of this article at NEJM.org. The trial was performed under an Investigational New Drug application with the FDA.
Supported by grants (U01NS088034, U01NS088023, U01NS056975, U01NS059041, and U01NS073476) from the National Institute of Neurological Disorders and Stroke (NINDS). Dr. Cloyd reports holding patent US9629797B2 on intravenous carbamazepine and holding intellectual property on intravenous topiramate, licensed to Ligand; Dr. Lowenstein, serving on an advisory board for Bloom Science; Dr. Shinnar, receiving fees for serving on data and safety monitoring boards from Eisai, INSYS Therapeutics, and UCB Biosciences; Dr. Cock, receiving consulting fees from BIAL Pharma UK and Sage Therapeutics; and Dr. Fountain, receiving grant support, paid to the University of Virginia Rectors and Visitors, from Cerebral Therapeutics, GW Pharmaceuticals, Medtronic, Neurelis, NeuroPace, SK Life Science, Takeda California, and UCB Biosciences. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.
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