Authors: Husain, AM, Lee, JW, Kolls, BJ, et al. “Randomized trial of lacosamide versus fosphenytoin for nonconvulsive seizures.” Ann Neurol 2018; 83:1174-1185
Reviewed by: Sara Stern-Nezer, MD, MPH, Assistant Clinical Professor, University of California, Irvine
Read the article.*
*You will need to log in to US National Library of Medicine National Institutes of Health to read this article.
The Treatment of Recurrent Electrographic Non-convulsive Seizures (TRENdS) study is a prospective, noninferiority multicenter randomized control trial comparing IV fosphenytoin (fPHY) to lacosamide (LCM) for treatment of nonconvulsive seizures (NCSs). Enrolled patients were ³18 years of age, undergoing cEEG with at least one electrographic seizure lasting at least 10 seconds and <30 minutes (with or without clinical correlate) requiring initiation of additional medication who also had a seizure within 6 hours of randomization. Exclusion criteria included: 1) pre-existing treatment with fPHT/LCM; 2) known contraindication to either drug; 3) therapeutic hypothermia; 4) generalized convulsive seizures or status epilepticus on EEG; and 5) anoxic injury. Patients were randomized 1:1 to receive either 20mg/kg phenytoin equivalent or 400mg LCM bolus. Patients were observed for six hours; if they had a breakthrough seizure, they received study drug rebolus, and if they went on to have additional seizure within 26 hours, they entered crossover arm of study to receive alternate study medication. If they didn’t have a breakthrough seizure, they were observed for another 18 hours for breakthrough seizures.
NCSs were defined as either 1) repetitive generalized or focal spikes, sharps or spike-wave complexes ³3Hz; or 2) sequential, rhythmic periodic or quasi-periodic waves ³1Hz with unequivocal evolution in frequency, morphology or location. NCSE was defined if these patterns persisted ³30 minutes. Interpretation of cEEG was done by blinded, trained encephalographers and then confirmed by two blinded central electroencephalographers who independently marked all seizures. Physicians caring for patients were not blinded to intervention. Primary outcome was lack of electrographic seizure for 24 hours after study drug or rebolus administration completed. Secondary outcome was percentage of patients requiring rebolus. Analysis was done for intention to treat (ITT) population including 1) all patients; 2) modified ITT including those with at least 16 hours of cEEG available during 24-hour follow-up; and 3) safety, which included all patients.
A total of 74 patients were enrolled in the trial with 37 in each arm. The mITT group included 30 in the CLM and 32 in fPHT arms. The study target was to enroll 200 patients, but funding was withdrawn. There were no significant differences in demographic factors, medical history, epilepsy history, other seizure medications used or seizure burden between the two groups. Seizure frequency decreased by 98 percent in the LCM arm and 76 percent in the fPHT arms after initial treatment (p=0.129). In patients who crossed over to receive the other drug, median seizure burden decreased by 99 percent in LCM group and 100 percent in fPHY compared to baseline. Serious adverse effects occurred equally in both groups, including hypotension, cardiac arrhythmias, respiratory failure and multi-organ hypersensitivity reactions (11.4 percent in LCM, 13.5 percent in fPHT).
This prospective, multisite, blinded randomized control trial found that LCM was non-inferior to fPHY for treatment of nonconvulsive seizures and that adverse effects were similar between the two groups. This latter point in of itself is interesting, given the common view that fPHY causes more adverse effects than LCM. The study was well designed and worked to limit bias and showed good efficacy in treatment with either medication; moreover, addition of the second drug in patients who had breakthrough seizures on the first agent alone succeeded in aborting seizures in almost all patients. This supports the efficacy of either medication and is reassuring to physicians limited based on side effect profile. The sample size was smaller than estimated based on power calculations because of withdrawal of funding in the midst of the study. Moving forward, it would be ideal to see if treatment of these seizure with one medication or another has any long-term effects on hospital days, discharge condition and long-term outcomes. Additionally, a larger study powered to determine if specific underlying etiologies for seizures are better treated with one medication or another would also be beneficial as we move forward into the era of precision medicine. #NEWSReview #LiteratureWatch #SaraStern-Nezer