title: The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: the CLEAR stroke trial.
abstract: OBJECTIVE
  Multiple approaches are being studied to enhance the rate of thrombolysis for acute ischemic stroke. Treatment of myocardial infarction with a combination of a reduced-dose fibrinolytic agent and a glycoprotein (GP) IIb/IIIa receptor antagonist has been shown to improve the rate of recanalization versus fibrinolysis alone. The combined approach to lysis utilizing eptifibatide and recombinant tissue-type plasminogen activator (rt-PA) (CLEAR) stroke trial assessed the safety of treating acute ischemic stroke patients within 3 hours of symptom onset with this combination.
  
  
  METHODS
  The CLEAR trial was a National Institutes of Health/National Institute of Neurological Disorders and Stroke-funded multicenter, double-blind, randomized, dose-escalation and safety study. Patients were randomized 3:1 to either low-dose rt-PA (tier 1=0.3 mg/kg, tier 2=0.45 mg/kg) plus eptifibatide (75 microg/kg bolus followed by 0.75 microg/kg per min infusion for 2 hours) or standard-dose rt-PA (0.9 mg/kg). The primary safety end point was the incidence of symptomatic intracerebral hemorrhage within 36 hours. Secondary analyses were performed regarding clinical efficacy.
  
  
  RESULTS
  Ninety-four patients (40 in tier 1 and 54 in tier 2) were enrolled. The combination group of the 2 dose tiers (n=69) had a median age of 71 years and a median baseline National Institutes of Health Stroke Scale (NIHSS) score of 14, and the standard-dose rt-PA group (n=25) had a median age of 61 years and a median baseline NIHSS score of 10 (P=0.01 for NIHSS score). Fifty-two (75%) of the combination treatment group and 24 (96%) of the standard treatment group had a baseline modified Rankin scale score of 0 (P=0.04). There was 1 (1.4%; 95% CI, 0% to 4.3%) symptomatic intracranial hemorrhage in the combination group and 2 (8.0%; 95% CI, 0% to 19.2%) in the rt-PA-only arm (P=0.17). During randomization in tier 2, a review by the independent data safety monitoring board demonstrated that the safety profile of combination therapy at the tier 2 doses was such that further enrollment was statistically unlikely to indicate inadequate safety for the combination treatment group, the ultimate outcome of the study. Thus, the study was halted. There was a trend toward increased clinical efficacy of standard-dose rt-PA compared with the combination treatment group.
  
  
  CONCLUSIONS
  The safety of the combination of reduced-dose rt-PA plus eptifibatide justifies further dose-ranging trials in acute ischemic stroke.
authors.affiliation: Department of Emergency Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267-0769, USA. Arthur.pancioli@uc.edu
authors.forename: Arthur M
authors.initials: AM
authors.lastname: Pancioli
authors.forename: Joseph
authors.initials: J
authors.lastname: Broderick
authors.forename: Thomas
authors.initials: T
authors.lastname: Brott
authors.forename: Thomas
authors.initials: T
authors.lastname: Tomsick
authors.forename: Jane
authors.initials: J
authors.lastname: Khoury
authors.forename: Judy
authors.initials: J
authors.lastname: Bean
authors.forename: Gregory
authors.initials: G
authors.lastname: del Zoppo
authors.forename: Dawn
authors.initials: D
authors.lastname: Kleindorfer
authors.forename: Daniel
authors.initials: D
authors.lastname: Woo
authors.forename: Pooja
authors.initials: P
authors.lastname: Khatri
authors.forename: John
authors.initials: J
authors.lastname: Castaldo
authors.forename: James
authors.initials: J
authors.lastname: Frey
authors.forename: James
authors.initials: J
authors.lastname: Gebel
authors.forename: Scott
authors.initials: S
authors.lastname: Kasner
authors.forename: Chelsea
authors.initials: C
authors.lastname: Kidwell
authors.forename: Thomas
authors.initials: T
authors.lastname: Kwiatkowski
authors.forename: Richard
authors.initials: R
authors.lastname: Libman
authors.forename: Richard
authors.initials: R
authors.lastname: Mackenzie
authors.forename: Phillip
authors.initials: P
authors.lastname: Scott
authors.forename: Sidney
authors.initials: S
authors.lastname: Starkman
authors.forename: R Jason
authors.initials: RJ
authors.lastname: Thurman
mesh_terms: D000208:Acute Disease; D000368:Aged; D000369:Aged, 80 and over; D002545:Brain Ischemia / Q000188:drug therapy*; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D000077542:Eptifibatide; D005260:Female; D005343:Fibrinolytic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D006470:Hemorrhage / Q000139:chemically induced / Q000453:epidemiology; D006801:Humans; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D012720:Severity of Illness Index; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*
chemical_list: D005343:Fibrinolytic Agents; D010455:Peptides; D010975:Platelet Aggregation Inhibitors; D011994:Recombinant Proteins; D010959:Tissue Plasminogen Activator; D000077542:Eptifibatide
references.citation: AJNR Am J Neuroradiol. 1993 Jan-Feb;14(1):3-13
references.pmid: 8427107
references.citation: JAMA. 2001 May 16;285(19):2468-73
references.pmid: 11368699
references.citation: J Cereb Blood Flow Metab. 2005 Jan;25(1):87-97
references.pmid: 15678115
references.citation: Am J Cardiol. 2005 Mar 1;95(5):611-4
references.pmid: 15721101
references.citation: Stroke. 2004 Oct;35(10):2418-24
references.pmid: 15345796
references.citation: Neurology. 2002 Sep 24;59(6):862-7
references.pmid: 12297567
references.citation: J Clin Invest. 1998 Oct 1;102(7):1301-10
references.pmid: 9769322
references.citation: Stroke. 1986 Nov-Dec;17(6):1254-65
references.pmid: 3810730
references.citation: N Engl J Med. 1995 Dec 14;333(24):1581-7
references.pmid: 7477192
references.citation: Stroke. 2008 Jan;39(1):87-99
references.pmid: 18032739
references.citation: Am J Pathol. 1994 Jan;144(1):188-99
references.pmid: 8291608
references.citation: Circulation. 1999 May 11;99(18):2371-7
references.pmid: 10318656
references.citation: CNS Drugs. 2004;18(14):981-8
references.pmid: 15584768
references.citation: N Engl J Med. 1998 Aug 13;339(7):436-43
references.pmid: 9705684
references.citation: Brain Res. 2001 Sep 7;912(2):181-94
references.pmid: 11532435
references.citation: Lancet. 2001 Jun 16;357(9272):1905-14
references.pmid: 11425410
references.citation: Stroke. 2000 Jun;31(6):1402-09; discussion 1409-10
references.pmid: 10835463
references.citation: Circulation. 1995 Apr 15;91(8):2151-7
references.pmid: 7697843
references.citation: Lancet. 1997 May 17;349(9063):1422-8
references.pmid: 9164315
references.citation: Stroke. 2007 Feb;38(2):431-40
references.pmid: 17234988