ESETT

In Review

Kapur J, et al. "Randomized trial of three anticonvulsant medications for status epilepticus". The New England Journal of Medicine. 2019. 381(22):2103-2113.
PubMed • Full text • PDF • ClinicalTrials.gov

Clinical Question

In patients with benzodiazepine-refractory convulsive status epilepticus, is the second-line anti-convulsants levetiracetam, fosphenytoin, or valproate, more likely to lead to an absence of seizure activity and improved responsiveness at 60 minutes?

Bottom Line

In comparing levetiracetam, fosphenytoin, and valproate, they are all equally efficacious with a seizure cessation rate of approximately fifty percent and statistically similar rates of adverse events.

Major Points

Benzodiazepine are the first line agent for stopping seizure activity. Benzodiazepine are insufficient to control in up to a third of patients. If seizure activity is persistent or recurs, the question of which agent is the agent of choice is what this trial attempted to address.

The Established Status Epilepticus Treatment Trial (ESETT) randomized 384 patients to receive either levetiracetam 60mg/kg (max 4500mg) [n=145] or fosphenytoin 20mgPE/kg (max 1500mgPE) [n=118] or valproate 40mg/kg (max 3000mg) [n=121]. This trial was stopped after reach the predetermined review by the safety committee due to futility - in brief there is no difference between these three agents.

Overall, the trial found that the three agents are both equally effective and safe. For the primary outcome of abortion of status epilepticus and improvement of level of consciousness by 60 minutes, a little less than half of the patients in all three groups succeeded. When analyzed for the per-protocol population this finding was robust. Approximately two thirds of all three groups ended up in the ICU but for a median of one day and 20% required endotracheal intubation.

There are several strengths in this trial, asking a clinically important question, using weigh based dosing, and using an intended response-adaptive design. There are also several criticisms including patients were randomized regardless of the home maintenance therapy, the trial was stopped early due to futility but this may have missed a potential difference, and finally the trial enrolled a heterogenous population including pediatrics through adults to elders--they have a mixture of causes of seizure and thus may have washed out the treatment effect.

Guidelines

Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society, adapted If seizure continues after benzodiazepine therapy, choose one of the following as a single dose:

• fosphenytoin IV 20mgPE/kg, max 1500mgPE
• valproic acid IV 40 mg/kg, max 3000mg
• levetriacetam 60 mg/kg, max 4500mg

if none of the above is available, then

• phenobarbital 15 mg/kg

Design

• Multicentre, blinded, parallel-group, response-adaptive comparative-effectiveness randomized-controlled trial
• N=384
  • levetiracetam (n=145)
  • fosphenytoin (n=118)
  • valproate (n=121)
• Setting: 57 hospital emergency departments across the United States
• Enrollment: 3 Nov 2015 to 31 Oct 2017
• Analysis: Intention-to-treat
• Primary outcome: Abortion of status epilepticus and improvement of level of consciousness by 60 minutes

Population

Inclusion Criteria

• ≥ 2 years old
• generalized convulsive seizures lasting > 5 minutes
• continued or recurrent seizure despite receiving minimal adequate cumulative doses of benzodiazepines
  • children ≥ 32kg and adults
    • diazepam 10mg (IV or rectal)
    • lorazepam 4mg (IV)
    • midzolam 10mf (IV or intramuscular)
  • children < 32kg
    • diazepam 0.3mg/kg (IV or rectal)
    • lorazepam 0.1mg/kg (IM)
    • midazolam 0.3mg/kg (IM) or 0.2mg/kg (IV)
• No more than 30 minutes had passed after last dose of benzodiazepine

Exclusion Criteria

• acute precipitant of seizure was major trauma, hypoglycemia, hyperglycemia, cardiac arrest, or postanoxia
• pregnant
• incarcerated
• patient preemptively opted out of this trial
• already treated the current status epilepticus with anticonvulsant agents other than benzodiazepines
• intubated
• Known allergy or contraindications to any of the trial drugs, including known inborn metabolic disorder, liver disease, or severe renal impairment

Baseline Characteristics

Levetiracetam group shown

• mean age 33 years, 47% female, 67% history of epilepsy, mean seizure duration 62 min
• final diagnosis: 88% status epilepticus, 9% nonepileptic spell, 2.8% unable to adjudicate
• mean lorazepam equivalents: 4.7mg (≥ 32 kg) and 0.2mg/kg (< 32kg)
• 61% received benzodiazepine prior to arrival

Interventions

• levetiracetam 60mg/kg (max 4500mg) over 10 minutes
• fosphenytoin 20mgPE/kg (max 1500mgPE) over 10 minutes
• valproate 40mg/kg (max 3000mg) over 10 minutes

Outcomes

Comparisons are levetiracetam vs. fosphenytoin vs. valproate.

Primary Outcomes

cessation of seizures and improvement in consciousness at 60 min without other anticonvulsant medications

47% vs. 45% vs. 46%

Secondary Outcomes

admission to ICU

60% v. 59.3% vs. 58.7%

ICU length of stay, median

1 day bs. 1 day vs. 1 day

Hospital length of stay, median

3 days vs. 3 days vs. 3 days

Time to seizure termination from start of study drug, median

10.5 min vs. 11.7 min vs. 7 min

Subgroup Analysis

cessation of seizures and improvement in consciousness at 60 min without other anticonvulsant medications, per-protocol population

47% vs. 47% vs. 47%

cessation of seizures and improvement in consciousness at 60 min without other anticonvulsant medications, adjucticated-outcomes population

46% vs. 48% vs. 50%

Adverse Events

Life threatening hypotension

0.7% vs. 3.2% vs. 1.6%

Endotracheal intubation within 60min of start study drug

20% vs. 26% vs. 17%

Seizure recurrence within 1-12h after start of study drug

11% vs. 11% vs. 11%

Acute respiratory depression

8% vs. 13% vs. 8%

Death

4.7% vs. 2.4% vs. 1.6%

Criticisms

• patients were randomized to treatment arm regardless of the anticonvulsants they were receiving for long term seizure control
• 27% of included patients did not meet eligibility criteria
• unblinding of investigators/treating clinicians occurred in half of patients
• trial was stopped early due to futility but if it ran to the full 720 may have found a different outcome
• hetergenous enrollment (pediatric, adult, elders) may have washed out treatment effect
• responsiveness is a subjective outcomes and may not be reproducible
• fosphenytoin dose may have been suboptimal for all patients.

Funding

• National Institutes of Health
• Federal Drug Administration (America)