Levetiracetam, Fosphenytoin, and Valproate for Status Epilepticus patients who do not respond to Benzodiazepines
The New England Journal of Medicine: Published on December, 2019
Evidence supports the use of
benzodiazepines as the initial treatment for status epilepticus; however,
seizures do not respond to benzodiazepines in up to a third of patients.
Of the three medications most
commonly used to treat benzodiazepine-refractory status epilepticus —
levetiracetam, fosphenytoin, and valproate.
Early termination of convulsive
status epilepticus decreases the risk of cardiac and respiratory complications
and is associated with a reduced risk of admission to an intensive care unit
(ICU).
Clinical guidelines emphasize the
need for rapid control of benzodiazepine-refractory status epilepticus but do
not provide guidance regarding the choice of medication on the basis of either
efficacy or safety.
TAKE-HOME MESSAGE
Authors performed a randomized
clinical trial to determine the superiority or inferiority of the three
commonly used anticonvulsant medications with regard to treatment success among
patients with status epilepticus in the emergency department.
In this trial, 384 patients with
status epilepticus that was unresponsive to benzodiazepine treatment were
randomized to receive levetiracetam, fosphenytoin, or valproate. Seizure
cessation and improved alertness at 60 minutes were observed in
· 47% of
patients treated with levetiracetam,
· 45% of
patients treated with fosphenytoin, and
· 46% of
patients treated with valproate.
No significant differences in
adverse events were reported among groups.
These results demonstrate seizure cessation and improved alertness at 60 minutes in approximately 50% of patients treated with levetiracetam, fosphenytoin, or valproate.
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.
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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%), 53 patients assigned
to fosphenytoin (45%), and 56 patients assigned to valproate (46%). 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.
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