ESETT: A Randomized Trial of 3 AEDs for Status Epilepticus

Kapur, J et al. Randomized Trial of Three Anticonvulsants Medications for Status Epilepticus. NEJM 2019;381;2103-13

This was a randomized, double-blinded, national multicenter pragmatic study to determine comparative effectiveness of traditional anti-epileptic medications in status epilepticus. The purpose of this study is to see if there is a difference between levetiracetem (Keppra), fosphenytoin (Cerebyx), and valproate (Depakote) in treatment of status epilepticus. By definition, these are second line treatments as first line treatment remains benzodiazepines (BZD). This is a well designed trial that was developed by the NIH and FDA then conducted by Neurological Emergencies Treatment Trials (NETT) and Pediatric Emergency Care Applied Research Network (PECARN). It utilized a response adaptive design to attempt to find the “best” AED (see below). Clear primary endpoint was established of seizure resolution and improving mental status one hour after starting trial medication. The protocol was guideline based as patients received cumulative BZD doses of 10 mg diazepam, 4 mg of lorazepam, or 10 mg of midazolam or weight based for children. Leaving the discussion of adequacy of those doses for another time, patients then went on to receive a weight based, unmarked vial of medication no more than 30 minutes after last dose of BZD. Dosing for these trial drugs were based off the Established Status Epilepticus Treatment Trial (ESETT) using 60 mg/kg of Levetiracetam (big doses of >4g !), 20mg/kg fosphenytoinand 40mg/kg of valproate. Protocol deviation was marked as unmasking trial drug in less than 60 minutes. 348 adults and children were enrolled into the study with interval analysis reaching a 1:1:1 trial drug administration. The primary endpoint was reached in less than half of all patients (46%) with absolutely no difference in efficacy. No difference in secondary end points such as ICU admission, median ICU stay, median ICU stay or median time to seizure termination after drug infusion. This study was not powered for to detect the rare adverse side effects but more patients that received fosphenytoin developed hypotension.

SAFETY OUTCOMES

Safety Outcome*	Levitiracetum	fosphenytoin	Valproic Acid
Hypotension	0.7%	3.2%	1.6%
Intubation	20%	26%	16.8%
Composite of Hypotension and arrhythmia	1.3%	3.2%	1.6%

Interestingly, pseudoseizure patients (~10%) were included which is clinically practical as there are times you simply do not know. 

JC Learning point: 

This trial did not have any statistical juijitsu as the primary endpoint was clear and there was no difference in efficacy. I speculate this will lead to use of levetiracetam as the go to second line agent as there is no difference to the other traditional agents which have their own respective drawbacks such as drug level monitoring, hypotension and arrhythmias as seen in rapid administration of fosphenytoin (which can easily happen in stressful situations like status epilepticus). The bigger take away for me here is 1 hour of status epilepticus is way too long for less than half the patients to improve from status epilepticus. The drawbacks of neurological damage, rhabdo and aspiration while waiting for these medications to take effect over an hour (which occurred in less than half of these patients) would be hard to stomach. As a newer emergency medicine physician, I have a tough time being patient for 15 minutes let alone 1 hour! Not to mention the longer these interventions take to have effect the more likely patients can develop super-refractory status which does not sound like fun. Bottom line, whichever second line anti-epileptic you go with, it likely does not make much of a difference in the short term as you continue to push BZD and move onto giving more BZD, intubation and propofol vs barbitutes.

Response Adaptive design

Adaptive designs allow for the review during the trial and then “adapting” the trial to allow to change the study for such changes as:

• Abandoning treatments or doses
• changing the allocation ratio of patients to trial arms
• identifying patients most likely to benefit and focusing recruitment efforts on them
• stopping the whole trial at an early stage for success or lack of efficacy.
• Refining the sample size

In the ESETT trial the adaptive part was that at interim analysis points the drugs were evaluated and probabilities to determine if one was better (via Bayesian methods) were reviewed. If one drug was found to be worse then that arm could be dropped and the two remaining ones would stay. Thus you would get a larger sample size for the better treatment arms. Surprisingly in all the interim analyses THIS DID NOT HAPPEN. The three drugs were all found to be equally probably by the end of the trial. 

By Sagar Dave and Jesse Shriki