Status epilepticus stopped in approximately 50% of patients whether treated with levetiracetam, fosphenytoin, or valproate, the prospective Established Status Epilepticus Treatment Trial (ESETT) randomized trial found.
Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but the differences were not significant.
Levetiracetam, fosphenytoin, and valproate were equally effective in treating benzodiazepine-refractory status epilepticus, the prospective ESETT (Established Status Epilepticus Treatment Trial) randomized trial reported.
All three drugs stopped ongoing seizures in about half of the patients treated, who continued having seizures in the emergency department despite treatment with a benzodiazepine.
"Hypotension and endotracheal intubation were more frequent with fosphenytoin than with the other two drugs, and deaths were more frequent with levetiracetam, but these differences were not significant," wrote Robert Silbergleit, MD, of the University of Michigan, and co-authors in the New England Journal of Medicine.
Status epilepticus is a period of prolonged seizure, whether one has ongoing ictus or a series without recovery between seizures. Beyond 5 minutes, ongoing seizures are associated with injury to the brain. First-line treatment is benzodiazepines, often given pre-hospital or in the emergency department, but up to a third of patients do not respond, and second line agents are used. Only fosphenytoin is approved for this role by the FDA, but levitiracetam and valproate are also used, though evidence backing their safety and efficacy in this role is scant.
To compare the three agents in status epilepticus, investigators conducted a multicenter randomized trial. Of 384 patients enrolled between November 2015 and October 2017, 145 were randomized to levetiracetam, 118 to fosphenytoin, and 121 to valproate. Of the total, 10% had psychogenic seizure.
Enrolled patients were 2 years of age or older, had been treated with benzodiazepines for seizures lasting more than 5 minutes, and continued to have evidence of ongoing seizure lasting at least 5 minutes but no more than 30 minutes after the last dose of benzodiazepine was given. Minimal cumulative doses of benzodiazepines were defined as 10 mg or diazepam, 4 mg of lorazepam, or 10 mg of midazolam for adults, with weight-based cumulative dosing cutoffs for children weighing less than 32 kg. Patients whose seizures resulted from trauma, glucose abnormality, cardiac arrest or anoxic injury were excluded, as were those who were pregnant, incarcerated, already intubated, or already treated with a non-benzodiazepine agent. The trial drug was administered on a weight-based dosing scale for all patients, with maximum doses of levitiracetam 4,500 mg, fosphenytoin 1,500 mg, and valproate 3,000 mg.
Enrollment was discontinued in November 2017 when planned interim analysis found a 1% chance of showing a most or least effective treatment if the trial continued.
The primary outcome was 60-minute improvement in the level of consciousness and seizure cessation without additional treatment. Ongoing seizures were determined by the treating physician, and included focal or generalized movements, rhythmic eye movements, and myoclonus, while increased responsiveness included purposeful responses to painful stimuli, following commands, or speaking.
Primary safety outcomes included life-threatening hypotension or arrhythmias requiring pacing, defibrillation, chest compressions, or use of an antiarrhythmic agent.
Trial participants were 55% male, 43% black, and 16% Hispanic, with 39% children up to 17 years of age, 48% adults 18 to 65 years old, and 13% adults older than 65.
Seizure cessation with improvement of consciousness at 60 minutes occurred in 68 patients assigned to levetiracetam (47%), 53 patients assigned to fosphenytoin (45%), and 56 patients assigned to valproate (46%). 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.
The primary outcome was not achieved in 207 patients; of these 70% received additional anticonvulsant medications.
In a subset of 39 patients with additional audio information allowing reviewers to specify seizure end precisely, the median time for infusion to seizure termination was 10.5 minutes (interquartile range, 5.7 to 15.5) in the levetiracetam group, 11.7 minutes (interquartile range, 7.5 to 20.9) in the fosphenytoin group, and 7.0 minutes (interquartile range, 4.6 to 14.9) in the valproate group.
Respective seizure recurrence rates triggering further anticonvulsant treatment 60 minutes to 12 hours after trial drug infusion was 10.7%, 11.2%, and 11.2%.
A total of 248 serious adverse events occurred in 42% of participants. The most frequent were convulsions after 60 minutes, a depressed level of consciousness, and respiratory distress. Neither these or hypotension, intubation, or deaths were significantly different for the three drugs.
Limitations included unblinding in some patients with ongoing seizures to choose a second anticonvulsant. Also, clinical rather than electroencephalographic criteria were used to determine seizure cessation, and postictal state or medication-related sedation may have been counted as treatment failure in 52 patients who had resolution of clinically evident seizure but were not improving in consciousness at 60 minutes. Different dosing protocols might also change efficacy.
In an accompanying editorial, Phil Smith, MD, of the University Hospital of Wales, Cardiff wrote, "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."
This research was supported by grants from the National Institute of Neurological Disorders and Stroke (NINDS).
Silbergleit reported no disclosures.
Smith reported being co-editor of the BMJ journal Practical Neurology, which has published reviews on status epilepticus, and being an (unpaid) member of the NICE guidelines committee for Epilepsy, which will publish its guidelines in 2021.