1. Efficacy of levetiracetam, fosphenytoin, and valproate for established status epilepticus by age group (ESETT): a double-blind, responsive-adaptive, randomised controlled trial
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James M Chamberlain, Jaideep Kapur, Shlomo Shinnar, Jordan Elm, Maija Holsti, Lynn Babcock, Alex Rogers, William Barsan, James Cloyd, Daniel Lowenstein, Thomas P Bleck, Robin Conwit, Caitlyn Meinzer, Hannah Cock, Nathan B Fountain, Ellen Underwood, Jason T Connor, Robert Silbergleit, Emily Gray, Sonya Gunter, Amy Fansler, Valerie Stevenson, Erin Bengelink, Deneil Harney, Mickie Speers, Joy Black, Natalie Fisher, Donna Harsh, Arthi Ramakrishnan, Lindsey Harris, Nia Bozeman, Aimee Spiteri, Yuko Palesch, Holly Tillman, Wenle Zhao, Qi Pauls, Chris Arnaud, Catherine R. Dillon, Jodie Riley, Teldon Alford, Cassidy Conner, Lisa Coles, Abhi Sathe, Scott Janis, Adam Hartman, Brandy Fureman, Eugen Trinka, David Treiman, David Wright, Jonathan Ratcliff, Alex Hall, Alaina Williams, Harold Simon, Nicholas Stanley, Roger Humphries, Theresa Mims, Joann Short, Elizabeth Jones, Misty Ottman, Nina Gentile, Derek Isenberg, Hannah Reimer, Vernon Sayoc Kalugdan, Claude Hemphill, Debbie Yi Madhok, Jeany Duncan, Dominica Randazzo, James Quinn, Anita Visweswaran, Rosen Mann, Opeolu Adeoye, Jason McMullan, Brandon Foreman, Sara Keegan, Michelle Biros, Brian Driver, Audrey Hendrickson, Jamie Stang, Christopher Lewandowski, Joseph Miller, Kaleem Chaudhry, Shannen Berry, Craig Warden, Rachel Blake, Jennifer NB Cook, Erin Sabolick, Antoine Selman, Katrina Kissman, Monica Moore, J. Stephen Huff, Lea Becker, Jan Claassen, Angela Velazquez, Cristina Falo, Zlatan Coralic, Jackie Grupp-Phelan, Jill Baren, Angela Ellison, Ashley Woodford, Ima Samba, Marlena Kittick, Ralph Riviello, John Massey, Lisa Bonacquisti, Steven Levine, Sergey Motov, Christian Fromm, Rukhsana Hossain, Antonios Likourezos, Illya Pushkar, Thomas Terndrup, Salman Khaliqdina, Michael Hill, Bjorn Peterson, Alexia Terwilliger, Joseph Holm, Kyra Wicklund, Sandi Wewerka, Robert Welch, Claire Pearson, Vijaya Arun Kumar, Farhan Ayaz, Saikat Bhuiyan, Valerie H. Mika, Lola Morgan, Floyd Jones, Lorraine Dishman, Thomas Henry, Ford Erickson, Abbey Staugaitis, Chloe Lawyer, Kathleen Miller, Clif Callaway, Alexandra Urban, Sara DiFiore, Peter Adams, Brian Baum, Jason Nomura, Barbara Davis, Tom Aufderheide, Amanda Emmrich, Melissa Mena, Jacob Labinski, Chinwe Ogedegbe, Diana McCarthy, Arelis Villot-Santiago, Joshua Goldstein, Eric S. Rosenthal, Abigail Cohen, Chen Mei Su, Greg Tirrell, Melissa Howell, Marissa Hendrickson, Dan Nerheim, Eric Jaton, Barbara Biney, Christopher Gibson, Erica Dahlmeier, Katherine (Lamond) Blackburn, Oluwarotimi (Tim) Vaughan-Ogunlusi, Shahriar Zehtabchi, Richard Sinert, Bryce Petty, Scott Youngquist, Margaret Carlson, Nadege Gilles, Sarah (Zelonis) Weingast, Barney Stern, Jennifer Hopp, Virginia Ganley, Joseph Ornato, Christopher Hogan, Alan Payne, Kate Shreve, Peter Dayan, Nathan Kuppermann, Kurt Denninghoff, Rachel Stanley, Richard Ruddy, E. Brooke Lerner, J. Michael Dean, Charles Casper, Lise Nigrovic, Walt Schalick, Doug Nelson, Bobbe Thomas, Pamela Okada, Amanda Lee, Natasha Truesdale, Steven Chan, Mhadhumithaa Naresh, Venita Robinson, Jieun Hwang, Kristi Carlston, Michael Dela Cruz, Toni Harbour, Reena Karki, Daniel M. Cohen, Amy Nowakowski, Cindy Lin, Erin Fisher Kenny, Dale Steele, Lisa H. Merck, Erin Ryan, Kristin Basso, Lesley (Wasilewski) D'Urso, Kathleen Brown, Gina Nauman, Matthew Ledda, Sean Gillen, Vanessa Grant, Cheryl Vance, Daniel K. Nishijima, Kyle Pimenta, Noelle Herzog, Jonathan Bennett, Christine Eisenhart, Danny Thomas, Duke Wagner, Robert W. Hickey, Rose Azrak, Daniel Rubalcava, Juan Mondragon, Victor Gonzalez, Maha Khalil, Kristina Hart, Sara Parker, Angela Lumba-Brown, Kim Quayle, Sri Chinta, Debra Robinson, Maria Kwok, Brooke Peery, Julie Ochs, and Leonor Suarez
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Levetiracetam ,Adolescent ,Status epilepticus ,030204 cardiovascular system & hematology ,Article ,law.invention ,Young Adult ,03 medical and health sciences ,Age Distribution ,0302 clinical medicine ,Status Epilepticus ,Randomized controlled trial ,Double-Blind Method ,Fosphenytoin ,law ,medicine ,Humans ,030212 general & internal medicine ,Young adult ,Child ,Stroke ,Aged ,Aged, 80 and over ,Intention-to-treat analysis ,Dose-Response Relationship, Drug ,business.industry ,Valproic Acid ,Age Factors ,Infant ,General Medicine ,Emergency department ,Middle Aged ,medicine.disease ,Child, Preschool ,Phenytoin ,Female ,Anticonvulsants ,medicine.symptom ,business ,medicine.drug - Abstract
Summary Background Benzodiazepine-refractory, or established, status epilepticus is thought to be of similar pathophysiology in children and adults, but differences in underlying aetiology and pharmacodynamics might differentially affect response to therapy. In the Established Status Epilepticus Treatment Trial (ESETT) we compared the efficacy and safety of levetiracetam, fosphenytoin, and valproate in established status epilepticus, and here we describe our results after extending enrolment in children to compare outcomes in three age groups. Methods In this multicentre, double-blind, response-adaptive, randomised controlled trial, we recruited patients from 58 hospital emergency departments across the USA. Patients were eligible for inclusion if they were aged 2 years or older, had been treated for a generalised convulsive seizure of longer than 5 min duration with adequate doses of benzodiazepines, and continued to have persistent or recurrent convulsions in the emergency department for at least 5 min and no more than 30 min after the last dose of benzodiazepine. Patients were randomly assigned in a response-adaptive manner, using Bayesian methods and stratified by age group ( 65 years), to levetiracetam, fosphenytoin, or valproate. All patients, investigators, study staff, and pharmacists were masked to treatment allocation. The primary outcome was absence of clinically apparent seizures with improved consciousness and without additional antiseizure medication at 1 h from start of drug infusion. The primary safety outcome was life-threatening hypotension or cardiac arrhythmia. The efficacy and safety outcomes were analysed by intention to treat. This study is registered in ClinicalTrials.gov , NCT01960075 . Findings Between Nov 3, 2015, and Dec 29, 2018, we enrolled 478 patients and 462 unique patients were included: 225 children (aged 65 years). 175 (38%) patients were randomly assigned to levetiracetam, 142 (31%) to fosphenyltoin, and 145 (31%) were to valproate. Baseline characteristics were balanced across treatments within age groups. The primary efficacy outcome was met in those treated with levetiracetam for 52% (95% credible interval 41–62) of children, 44% (33–55) of adults, and 37% (19–59) of older adults; with fosphenytoin in 49% (38–61) of children, 46% (34–59) of adults, and 35% (17–59) of older adults; and with valproate in 52% (41–63) of children, 46% (34–58) of adults, and 47% (25–70) of older adults. No differences were detected in efficacy or primary safety outcome by drug within each age group. With the exception of endotracheal intubation in children, secondary safety outcomes did not significantly differ by drug within each age group. Interpretation Children, adults, and older adults with established status epilepticus respond similarly to levetiracetam, fosphenytoin, and valproate, with treatment success in approximately half of patients. Any of the three drugs can be considered as a potential first-choice, second-line drug for benzodiazepine-refractory status epilepticus. Funding National Institute of Neurological Disorders and Stroke, National Institutes of Health.
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- 2020