Aatif M Husain1,2,3, Jong W Lee4, Bradley J Kolls1,3, Lawrence J Hirsch5, Jonathan J Halford6, Puneet K Gupta7, Yafa Minazad8, Jennifer M Jones9, Suzette M LaRoche9,10, Susan T Herman11, Christa B Swisher1, Saurabh R Sinha1,2, Adriana Palade12, Keith E Dombrowski1,2, William B Gallentine13, Cecil D Hahn14, Elizabeth E Gerard15, Manjushri Bhapkar3, Yuliya Lokhnygina3,16, M Brandon Westover17. 1. Department of Neurology, Duke University Medical Center, Durham, NC. 2. Neurodiagnostic Center, Veterans Affairs Medical Center, Durham, NC. 3. Duke Clinical Research Institute, Durham, NC. 4. Department of Neurology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA. 5. Department of Neurology, Yale University School of Medicine, New Haven, CT. 6. Department of Neurology, Medical University of South Carolina, Charleston, SC. 7. Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX. 8. Neurosciences Center, Huntington Memorial Hospital, Pasadena, CA. 9. Department of Neurology, Mission Health, Asheville, NC. 10. Department of Neurology, Emory University, Atlanta, GA. 11. Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. 12. Department of Neurology, University of Louisville, Louisville, KY. 13. Department of Pediatrics (Neurology), Duke University Medical Center, Durham, NC. 14. Division of Neurology, Hospital for Sick Children and Department of Paediatrics, University of Toronto, Toronto, Ontario, Canada. 15. Department of Neurology, Feinberg School of Medicine, Northwestern University, Chicago, IL. 16. Department of Biostatistics and Bioinformatics, Duke University, Durham, NC. 17. Department of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
Abstract
OBJECTIVE: The optimal treatment of nonconvulsive seizures in critically ill patients is uncertain. We evaluated the comparative effectiveness of the antiseizure drugs lacosamide (LCM) and fosphenytoin (fPHT) in this population. METHODS: The TRENdS (Treatment of Recurrent Electrographic Nonconvulsive Seizures) study was a noninferiority, prospective, multicenter, randomized treatment trial of patients diagnosed with nonconvulsive seizures (NCSs) by continuous electroencephalography (cEEG). Treatment was randomized to intravenous (IV) LCM 400mg or IV fPHT 20mg phenytoin equivalents/kg. The primary endpoint was absence of electrographic seizures for 24 hours as determined by 1 blinded EEG reviewer. The frequency with which NCS control was achieved in each arm was compared, and the 90% confidence interval (CI) was determined. Noninferiority of LCM to fPHT was to be concluded if the lower bound of the CI for relative risk was >0.8. RESULTS:Seventy-four subjects were enrolled (37 LCM, 37 fPHT) between August 21, 2012 and December 20, 2013. The mean age was 63.6 years; 38 were women. Seizures were controlled in 19 of 30 (63.3%) subjects in the LCM arm and 16 of 32 (50%) subjects in the fPHT arm. LCM was noninferior to fPHT (p = 0.02), with a risk ratio of 1.27 (90% CI = 0.88-1.83). Treatment emergent adverse events (TEAEs) were similar in both arms, occurring in 9 of 35 (25.7%) LCM and 9 of 37 (24.3%) fPHT subjects (p = 1.0). INTERPRETATION:LCM was noninferior to fPHT in controlling NCS, and TEAEs were comparable. LCM can be considered an alternative to fPHT in the treatment of NCSs detected on cEEG. Ann Neurol 2018;83:1174-1185.
RCT Entities:
OBJECTIVE: The optimal treatment of nonconvulsive seizures in critically illpatients is uncertain. We evaluated the comparative effectiveness of the antiseizure drugs lacosamide (LCM) and fosphenytoin (fPHT) in this population. METHODS: The TRENdS (Treatment of Recurrent Electrographic Nonconvulsive Seizures) study was a noninferiority, prospective, multicenter, randomized treatment trial of patients diagnosed with nonconvulsive seizures (NCSs) by continuous electroencephalography (cEEG). Treatment was randomized to intravenous (IV) LCM 400mg or IV fPHT 20mg phenytoin equivalents/kg. The primary endpoint was absence of electrographic seizures for 24 hours as determined by 1 blinded EEG reviewer. The frequency with which NCS control was achieved in each arm was compared, and the 90% confidence interval (CI) was determined. Noninferiority of LCM to fPHT was to be concluded if the lower bound of the CI for relative risk was >0.8. RESULTS: Seventy-four subjects were enrolled (37 LCM, 37 fPHT) between August 21, 2012 and December 20, 2013. The mean age was 63.6 years; 38 were women. Seizures were controlled in 19 of 30 (63.3%) subjects in the LCM arm and 16 of 32 (50%) subjects in the fPHT arm. LCM was noninferior to fPHT (p = 0.02), with a risk ratio of 1.27 (90% CI = 0.88-1.83). Treatment emergent adverse events (TEAEs) were similar in both arms, occurring in 9 of 35 (25.7%) LCM and 9 of 37 (24.3%) fPHT subjects (p = 1.0). INTERPRETATION:LCM was noninferior to fPHT in controlling NCS, and TEAEs were comparable. LCM can be considered an alternative to fPHT in the treatment of NCSs detected on cEEG. Ann Neurol 2018;83:1174-1185.
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