LandmarkRCT

ESETT

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus

New England Journal of Medicine, 2019 · Multicenter, double-blind, response-adaptive randomized controlled trial (Established Status Epilepticus Treatment Trial), stopped early for futility in detecting a difference between arms after a planned interim analysis.

Clinical question

In benzodiazepine-refractory status epilepticus, is any one of levetiracetam, fosphenytoin, or valproate more effective as second-line therapy than the others?

Population: 384 children and adults with benzodiazepine-refractory convulsive status epilepticus.
Intervention: Levetiracetam (60 mg/kg, max 4500 mg).
Comparator: Fosphenytoin (20 mg PE/kg, max 1500 mg PE) or valproate (40 mg/kg, max 3000 mg).
Primary outcome: Absence of clinically evident seizures and improvement in responsiveness by 60 minutes after the start of the infusion, without need for additional anticonvulsant medication.
Secondary outcomes: Adverse events, including hypotension and need for intubation.
Outcomes by age subgroup (children, adults, older adults).
Result: The primary outcome was met in roughly half of patients in each arm, with no significant difference detected between levetiracetam, fosphenytoin, or valproate; the trial was stopped early for futility on the pre-specified comparison. (Primary outcome met in approximately 44-52% (children), 44-46% (adults), and 35-47% (older adults) across the three drugs, with overlapping confidence intervals and no statistically significant pairwise difference.)

What the trial found

None of the three second-line agents was superior to the other two for terminating benzodiazepine-refractory status epilepticus, and adverse event rates (including hypotension and need for intubation) were similar across arms.

Current guideline position

ESETT is generally read as supporting the 2016 AES guideline's position that no single second-line agent has established superiority, now with direct comparative-effectiveness data rather than indirect comparison across separate trials.

Clinical interpretation

ESETT did not identify a preferred second-line agent on efficacy or safety grounds — choice among levetiracetam, fosphenytoin, and valproate can reasonably be guided by other factors (infusion time, side-effect profile in a specific patient, drug availability, renal/hepatic considerations) rather than by an expected difference in seizure termination.

Limitations

The trial was powered to detect a difference between agents, not to establish equivalence — a 'no significant difference' result with a stopped-early, futility-driven design is not the same as proof that the drugs are truly interchangeable in every clinical situation.
Refractory status epilepticus (seizures continuing despite an adequate second-line agent) was not addressed by this trial.

High certainty

Clinical Context & Relevant Topics (1)

Disease Reference

Status Epilepticus

Recognition and time-sensitive escalation of care for prolonged or repeated seizures.

View Topic Context →

ESETT

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus