Trial comparing three drugs for status epilepticus

Clinical Trials & Research

Status epilepticus is a condition that is characterized by repeated seizures and is a medical emergency. Treatment is usually with a Benzodiazepine such as Diazepam or Lorazepam etc. There have been not any studies that look at the comparative benefit of drugs that could be prescribed for those who do not respond to the benzodiazepines. The study titled, “Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus,” was published in the latest issue of the journal New England Journal of Medicine.

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Authors of the study wrote that initial treatment of status epilepticus should be with benzodiazepines, however, “seizures do not respond to benzodiazepines in up to a third of patients.” they added that three drugs are used in these cases – levetiracetam, fosphenytoin, and valproate, but of these three, only fosphenytoin is approved by the Food and Drug Administration (FDA) to be used in these cases in adults and no drugs have been approved for children with refractory status epilepticus. Need for termination of the seizures include decrease in “risk of cardiac and respiratory complications”, “risk of admission to an intensive care unit (ICU)” and “mortality among children”. They added that studies reveal that status epilepticus if not controlled could lead to neuronal loss and brain injury as has been seen in both animal studies and in humans. Thus it is of paramount importance to rapidly control the seizures in benzodiazepine-refractory status epilepticus. All said, no drug has been outlined in the guidelines for these cases wrote the researchers.

Authors Jaideep Kapur, professor at the University of Virginia, first author other investigators from the NETT and PECARN study explained that this was a randomized trial where they compared the effectiveness of three drugs used in patients of status epilepticus who do not respond to benzodiazepines. These include levetiracetam, fosphenytoin, and valproate use in children and adults. They checked if the patients given either of these three drugs regained consciousness within 60 minutes after starting the infusion of the drug without the need for other medications to control the seizures. They also looked at the safety of the medications to see if the drugs and the therapy led to complications such as life threatening hypotension, cardiac rhythm abnormalities, seizure recurrence, need for endotracheal intubation or death.

For the study the team included 384 patients who were randomly classified into three groups. A total of 145 received levetiracetam, 118 received fosphenytoin, and 121 received valproate therapy. A second episode necessitated randomization again for 16 patients, wrote the researchers. They wrote that 10 percent of all the patients had psychogenic seizures. The trial was stopped if the patients did not respond and the patient was provided adequate care to revive them.

Final results showed that among the 145 receiving levetiracetam, 68 or 47 percent regained consciousness within 60 minutes of administration of the medication. The time for regaining consciousness ranged between 39 to 55 minutes. Among the 118 patients on fosphenytoin, 53 (45 percent) and among the 121 receiving valproate 56 (46 percent) regained consciousness within 60 minutes respectively. The authors wrote that the probability that each drug was most effective was “0.41, 0.24, and 0.35, respectively”.

Speaking on safety of the drugs, they wrote that hypotension and need for intubation was seen most with fosphenytoin. Deaths were seen highest in numbers with levetiracetam. Statistically however these numbers were not significant.

The team wrote, “Status epilepticus stopped in approximately 50% of patients in each treatment group.” They said that there has been a meta analysis looking at 22 different studies with one of the three anti-epileptics that they compared. These studies showed that seizure control was achieved in 68.5 percent patients on levetiracetam, 75.7 percent patients with valproate and 50.2 patients with phenytoin. The numbers with levetiracetam and valporate were higher than the present study they wrote.

The researchers concluded that each of the three drugs in context of benzodiazepine-refractory convulsive status epilepticus “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.”

Some of the limitations of the studies included the need for adding a second drug in some patients who did not respond to the first drug adequately. This was done due to ethical reasons. Also 10 percent of the patients had psychogenic nonepileptic seizures. These patients had to be excluded from the initial study population. To confirm that they were not having an epileptic seizure, electroencephalogram or EEG had to be used. Further in 52 patients there was residual sleepiness or drowsiness 60 minutes after the drug administration. The dose of the drugs was determined from published research and the authors wrote that other higher doses could have raised the efficacy of the drugs.

The study was funded by the National Institute of Neurological Disorders and Stroke (NINDS) which is part of the National Institutes of Health (NIH). Robin Conwit, NINDS programme director and one of the authors said in a statement, “Doctors can be confident that the particular treatment they choose for their patients with status epilepticus is safe and effective, and may help them avoid the need to intubate the patient as well as stays in the intensive care unit. This was a truly collaborative, multidisciplinary study that involved paediatricians, emergency medicine doctors, neurologists, pharmacologists, and biostatisticians all contributing their expertise.”

“Our study suggests that clinical outcomes are driven by factors other than drugs. Differences in how doctors decide to treat status epilepticus, such as when they give more drugs or when to anesthetise patients and put them on a mechanical ventilator, may be more important than the specific treatments used to control seizures in patients,” added Dr. Robert Silbergleit, professor at the University of Michigan, who led the study.

NIH study finds anti-seizure drugs equally effective – https://www.healtheuropa.eu/nih-study-anti-seizure-drugs-for-epilepsy/95318/

Journal reference:

Randomized Trial of Three Anticonvulsant Medications for Status Epilepticus, Jaideep Kapur, M.B., B.S., Ph.D., Jordan Elm, Ph.D., James M. Chamberlain, M.D., William Barsan, M.D., James Cloyd, Pharm.D., Daniel Lowenstein, M.D., Shlomo Shinnar, M.D., Ph.D., Robin Conwit, M.D., Caitlyn Meinzer, Ph.D., Hannah Cock, M.D., Nathan Fountain, M.D., Jason T. Connor, Ph.D., et al., for the NETT and PECARN Investigators, N Engl J Med 2019; 381:2103-2113, DOI: 10.1056/NEJMoa1905795, https://www.nejm.org/doi/full/10.1056/NEJMoa1905795

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