Results from the Established Status Epilepticus Treatment Trial (ESETT) were recently published in New England Journal of Medicine (NEJM), providing medical directors with a research-centric resource to turn to when epileptic patients don’t respond to traditional benzodiazepines.
Specifically, ESETT was an NIH and FDA funded joint effort by the Neurological Emergencies Treatment Trials (NETT) Network and the Pediatric Emergency Care Applied Research Network (PECARN) in which adult and pediatric patients in an emergency department setting were randomized to either levetiracetam (i.e. Keppra), fosphenytoin (i.e. Cerebyx) or valproate (i.e. Depakene or Epival).
The study was performed across 57 hospital emergency departments by a mixture of pediatric, adult and combined facilities. Patients were eligible if they had received “adequate” doses of benzodiazepines by EMS or the ED and their convulsions had either never stopped or they had a recurrent seizure within 30 minutes of the last benzodiazepine.
The outcome of interest after receipt of one of the trial drugs was the absence of any clinically apparent seizure as well as improvement in responsiveness at the 60-minute mark. This had to be achieved without additional anticonvulsants or paralytics.
After 400 patients were enrolled, the data and safety monitoring board stopped enrollment as the trial had reached the predetermined futility marker, in which there was a 99% chance all three drugs were equal. Based on the intent-to-treat analysis, 47% of patients saw an absence of seizures after 60 minutes when given levetiracetam, compared to 45% and 46% for fosphenytoin and valproate respectively.
Given that over 50% of the patients did not see cessation of their seizures during the study period, it’s not surprising that 42% of patients had a serious adverse event. But due to the nature of this disease, not all of these events may have been preventable.
Memorable quotes on status epilepticus
Here are some memorable quotes from the ESETT Trial.
“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) and decreased mortality among children.”
“Enrollment was discontinued at the recommendation of the data and safety monitoring board after the trial met the predefined futility criterion in a planned interim analysis, since there was a 1% chance of showing a most effective or least effective treatment if the trial were to continue to the maximum sample size.”
“A total of 248 serious adverse events occurred in 42% of patients. The most frequent serious adverse events were convulsions after 60 minutes, a depressed level of consciousness, and respiratory distress.”
“In conclusion, fosphenytoin, valproate, and levetiracetam were effective in approximately half the patients with benzodiazepine-refractory status epilepticus, and they did not differ significantly with regard to effectiveness and safety.”
Key takeaways on status epilepticus treatment
Following are 5 top takeaways from the ESETT Trial.
1. Randomized control trials are the truest way to evaluate an intervention
EMS is fraught with protocols, policies and procedures that haven’t changed since the day they were written. At the opposite end of the spectrum, but equally problematic, some EMS agencies get behind the newest science and technology without appropriately vetting utility within the prehospital setting. Randomized control trials offer the industry a chance to ask questions in a way that protects us from our own biases, growing the dearth of evidenced-based care we have to choose from.
2. Stopping a trial for futility is a big deal
More often than not, randomized control trials are initiated because there is a suggestion in observational studies that one drug or intervention is better than another. So if upon randomization, the trial is stopped early, that’s a surprising outcome. In this case, it meant there there is only a 1% chance than any one of the drugs would be better (or worse) than the others.
This time point is determined by the investigators before the trial begins to ensure a limited bias, making the stoppage of said trial that much more damning.
3. PECARN research can inform prehospital care
For over two decades, PECARN has been a leader in pediatric emergency medicine research. The recent decision by the federal government to expand the network to include EMS agencies is great for prehospital emergency medicine as it means that infrastructure could potentially facilitate advances in the prehospital setting. But as with any research network, only time will tell if the expansion into EMS has paid off.
4. The sub-analyses will likely expand the story
The sub-analyses from this RCT won’t be available for year(s), however, they may further inform, and even contradict the parent study upon release. A great example of this recently is the ALPS study in which amiodarone, lidocaine and placebo were seen as equals for OHCA arrhythmias until data was analyzed based on the type of vascular access. When controlling for vascular access, it looks like lidocaine and amiodarone could have come out on top if the study had been powered differently.
5. These results mean operations can dictate drug usage
While the science should drive the drug provided to patients in the prehospital setting, this trial provides the unique opportunity for agencies to pick the drug that makes the best operational sense. Given how rarely these patients are seen, it means shelf life, cost and ease of use can take a front seat when deciding which drug to use.
