Combined Approach to Lysis Utilizing Eptifibatide and Recombinant Tissue Plasminogen Activator in Acute Ischemic Stroke–Enhanced Regimen Stroke Trial
Authors: Pancioli Arthur M. , Adeoye Opeolu , Schmit Pamela A. , Khoury Jane , Levine Steven R. , Tomsick Thomas A. , Sucharew Heidi , Brooks Claudette E. , Crocco Todd J. , Gutmann Laurie , Hemmen Thomas M. , Kasner Scott E. , Kleindorfer Dawn , Knight William A. , Martini Sharyl , McKinney James S. , Meurer William J. , Meyer Brett C. , Schneider Alexander , Scott Phillip A. , Starkman Sidney , Warach Steven , Broderick Joseph P. , Pancioli Arthur M. , Adeoye Opeolu , Broderick Joseph , Schmit Pamela A. , Khoury Jane , Sucharew Heidi , Janis Scott , Tomsick Thomas , Brooks Claudette E. , Crocco Todd , Hemmen Thomas , Kasner Scott E. , McKinney James S. , Meurer William J. , Schneider Alex , Starkman Sidney , Warach Steven , Levine Steven , Moy Claudia , Welch K. Michael , Tietjen Gretchen , Clarke William R. , Bonomo Jordan , McDonough Erin , Ferioli Simona , De la Rosa Felipe de los Rios , Martini Sharyl , Woo Daniel , Garvin Rachel , Kleindorfer Dawn , Khatri Pooja , Gensic Anna , Flaherty Matthew , Kanter Daniel , Kissela Brett , Stettler Brian , Mackey Jason , Cadena Rhonda , Kohake Shannon , Heitsch Laura , Belagaje Samir , Vagal Achala , Hallenbeck John , Benson Richard , Hsia Amie , Jaitly Rakesh , Latour Lawrence , Lynch John , Merino Jose , Menon Ravi , Freeman Jason , Magadan Alejandro , Magaraja Nandakumar , Jothen Jennifer , Famakin Bonanle , Song Shlee , Katcheves Alex , Nadareishvili Zurab , Ritter Carsen , Barsan William , Brown Devin , Morgenstern Lewis , Silbergleit Robert , Rajajee Venkatakrishna , Rusche-Skolarus Lesli , Burke Jim , Fletcher Jeffrey , Adelman Eric , Wang Michael , Zahuranec Darin , Cucchiara Brett , Messe Steven , Wilson Christina , Ishida Koto , Mullen Michael , Raser Jonathan , Pawar Swaroop , Rose David , Shafi Neelofer , Rybinnik Igor , McGavery Michael , Beslow Lauren , Sansing Lauren , Ali Latisha , Abcede Hermelinda , Adamczyk Peter , Buxton William , Froehler Michael , Kim Doojin , Liebeskind David , Ovbiagele Bruce , Porter Verna , Rajajee Venkatakrishna , Rao Neal , Raychev Radoslav , Song Sarah , Saver Jeffrey , Tenser Matthew , Velani Shamsha , Yallapragada Anil , Meyer Brett , Guzik Any , Loc Kiet , Meyer Dawn , Tafreshi Gilda , Choe Jessica , Sodhi Ajeet , Delaney Patrick , Evans Sean , Ghausi Omar A. , Bruce Nhu , Neil Will , Huisa Brank , Stemer Andrew , Taylor Reid , Larson Jeanette , Larson Seth , Leacock Rodney , Dash Subasisni , Eisenstein Robert , Kapitanyan Raffi , Paolucci Ugo , Shah Chirag , Toe Win , Brick John , Lander Owen , Larrabee Hollynn , Gutmann Laurie , Minardi Joseph , Tadros Allison , Tillotson Roger , Whiteman Charles , Paulson Debra , Sikora Rosanna , Cummings Christopher , Foster John , Carrozzella Janice , Doellman Traci , Ewing Irene , Frasure Jamey , Goodall Emily , Kimmel Pamela , Spilker Judith , Tamer Robert , Waymeyer Peggy , Zeigler Joyce , Davis Lisa , Farsad Saman , Morella Teresa , Kade Allison , Frederiksen Shirley , Liz Mary , Luciano Jean , Guzy Judy , Grunberg Ileana , Rzesiewicz Teresa , Rapp Karen , Nanney Tracy , Shell Leslie , Perkins Margaret , Benton Cindy , Jones Robin , Hampton Lynne , Cuento Claudine , Alosky Rachel , Shepard Stephanie , Moccio Michelle , Albrecht Catherine , Rosario Yaritza , Caputo Deborah , Davis Stephen , Altemus Patricia , Power Martha , VanGilder Reyna , Sherman Jay , Barr Taura 
Published: July 2013

Background and Purpose—
In a previous study, 0.3 and 0.45 mg/kg of intravenous recombinant tissue plasminogen activator (rt-PA) were safe when combined with eptifibatide 75 mcg/kg bolus and a 2-hour infusion (0.75 mcg/kg per minute). The Combined Approach to Lysis Utilizing Eptifibatide and rt-PA in Acute Ischemic Stroke–Enhanced Regimen (CLEAR-ER) trial sought to determine the safety of a higher-dose regimen and to establish evidence for a phase III trial.

Methods—
CLEAR-ER was a multicenter, double-blind, randomized safety study. Ischemic stroke patients were randomized to 0.6 mg/kg rt-PA plus eptifibatide (135 mcg/kg bolus and a 2-hour infusion at 0.75 mcg/kg per minute) versus standard rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracranial hemorrhage within 36 hours. The primary efficacy outcome measure was the modified Rankin Scale (mRS) score ≤1 or return to baseline mRS at 90 days. Analysis of the safety and efficacy outcomes was done with multiple logistic regression.

Results—

Of 126 subjects, 101 received combination therapy, and 25 received standard rt-PA. Two (2%) patients in the combination group and 3 (12%) in the standard group had symptomatic intracranial hemorrhage (odds ratio, 0.15; 95% confidence interval, 0.01–1.40;
P
=0.053). At 90 days, 49.5% of the combination group had mRS ≤1 or return to baseline mRS versus 36.0% in the standard group (odds ratio, 1.74; 95% confidence interval, 0.70–4.31;
P
=0.23). After adjusting for age, baseline National Institutes of Health Stroke Scale, time to intravenous rt-PA, and baseline mRS, the odds ratio was 1.38 (95% confidence interval, 0.51–3.76;
P
=0.52).

Conclusions—
The combined regimen of intravenous rt-PA and eptifibatide studied in this trial was safe and provides evidence that a phase III trial is warranted to determine efficacy of the regimen.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00894803.