Chamberlain JM, Kapur J, Shinnar S, et al. Efficacy of
levetiracetam, fosphenytoin, and valproate for established status epilepticus
by age group (ESETT): a double-blind, responsive-adaptive, randomised
controlled trial. Lancet. 2020;395(10231):1217‐1224. doi:10.1016/S0140-6736(20)30611-5
Abstract
Background: Benzodiazepine-refractory, or established,
status epilepticus is thought to be of similar pathophysiology in children and
adults, but differences in underlying aetiology 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 three age groups.
Methods: In this multicentre, double-blind,
response-adaptive, randomised controlled trial, we recruited patients from 58
hospital emergency departments across the USA. Patients were eligible for
inclusion if they were aged 2 years or older, had been treated for a
generalised 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
min 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
antiseizure medication at 1 h from start of drug infusion. The primary safety
outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy
and safety outcomes were analysed by intention to treat. This study is
registered in ClinicalTrials.gov, NCT01960075.
Findings: Between Nov 3, 2015, and Dec 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). 175 (38%)
patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin,
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 three drugs can be considered as a potential first-choice,
second-line drug for benzodiazepine-refractory status epilepticus.
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