Kapur J, Elm J, Chamberlain JM, Barsan W, Cloyd J,
Lowenstein D, Shinnar S, Conwit R, Meinzer C, Cock H, Fountain N, Connor JT,
Silbergleit R; NETT and PECARN Investigators. Randomized Trial of Three Anticonvulsant
Medications for Status Epilepticus. N Engl J Med. 2019 Nov
28;381(22):2103-2113.
Abstract
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%; 95% credible interval, 39 to 55), 53 patients assigned to
fosphenytoin (45%; 95% credible interval, 36 to 54), and 56 patients assigned
to valproate (46%; 95% credible interval, 38 to 55). 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. (Funded by the National Institute of
Neurological Disorders and Stroke; ESETT ClinicalTrials.gov number,
NCT01960075.).
________________________________________________________________________
Experts who reviewed the paper for Neurology Today said it
is methodologically strong with convincing results; the most significant
weakness, they said, is the lack of a more objective measure of seizure
cessation.
“The strength of the study is the size, the
generalizability, the waiver of consent in a large number of communities to
perform this emergency treatment trial, the rigorous methodology overall, and
the very clear, definitive results,” said Lawrence J. Hirsch, MD, FAAN,
co-director of the Yale Comprehensive Epilepsy Center. “The main weakness is
the lack of EEG to confirm termination of SE. It might have been useful to look
at allergies including rashes over the following weeks, and mood and behavioral
scales, but those were beyond the scope of this emergency treatment trial.
“Another minor weakness, likely unavoidable and a good
teaching point, is that 10 percent of patients turned out to have non-epileptic
events rather than status epilepticus,” Dr. Hirsch told Neurology Today. “This
is a significant number of patients and warrants additional study to try to
identify them early in their emergency treatment.”
He suggested that levetiracetam has become the most popular
inpatient antiseizure medication in many centers, and the current study now
provides class I data to justify its use for convulsive SE as well as less
urgent situations.
“Levetiracetam is favored due to its ease of use with
minimal interactions, rare allergies, rare hepatic or bleeding issues, and rare
hypotension or any other issues during rapid infusion,” he said. “Neither
fosphenytoin nor valproate are quite that ‘clean.’ I do worry about leaving
patients with agitation, depression, anxiety, or other psychiatric issues on
levetiracetam for the longer term, but that can be addressed in the non-urgent
setting. In general, I'd avoid valproate in those with active hepatic
dysfunction or bleeding issues, and avoid fosphenytoin in those with cardiac
issues, hypotension, polypharmacy, or multiple drug allergies.”
Jack J. Lin, MD, professor of neurology and the biomedical
engineering director at the University of California, Irvine, Comprehensive
Epilepsy Program, echoed remarks about the subjective nature of determining
seizure cessation. But he said the study offers useful clinical data about an
emergency situation in which more objective measures may be impractical.
Dr. Lin said the study results mirror what has been found
with seizure treatment generally, a phenomenon he said is likely related to the
way drugs for epilepsy are developed.
“If you consider what we do to an animal to induce
seizures—giving them either chemicals or electrical shocks—we are modeling
seizures rather than the underlying condition of epilepsy,” he said. “The
consensus among epileptologists is that animal models can't fully capture the
human condition. We don't have biomarkers to determine which medication is best
for which patient, so all of them are likely to prove effective.”
To this point, Dr. Silbergleit added that a great many other
factors in clinical treatment may determine any one patient's response to
medications. “It's interesting to speculate on why the drugs are equally
effective,” he said. “It may be that they all just happen to have the same
efficacy, but another possibility is that clinical efficacy depends more on
factors related to how we care for these patients. It is possible that any
number of clinical decisions—such as the length of time before giving another
dose or another medicine, or how we decide when it is necessary to
endotracheally intubate a patient—may have more of an effect on important
clinical outcomes than the choice of medications themselves.”
https://journals.lww.com/neurotodayonline/Fulltext/2020/01090/Three_Anticonvulsants_Are_Equally_Effective_for.1.aspx
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