The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: The clear stroke trial

Arthur M. Pancioli, Joseph Broderick, Thomas G Brott, Thomas Tomsick, Jane Khoury, Judy Bean, Gregory Del Zoppo, Dawn Kleindorfer, Daniel Woo, Pooja Khatri, John Castaldo, James Frey, James Gebel, Scott Kasner, Chelsea Kidwell, Thomas Kwiatkowski, Richard Libman, Richard MacKenzie, Phillip Scott, Sidney StarkmanR. Jason Thurman

Research output: Contribution to journalArticle

103 Citations (Scopus)

Abstract

Background and Purpose: 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 μg/kg bolus followed by 0.75 μg/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.

Original languageEnglish (US)
Pages (from-to)3268-3276
Number of pages9
JournalStroke
Volume39
Issue number12
DOIs
StatePublished - Dec 1 2008

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Tissue Plasminogen Activator
Stroke
National Institutes of Health (U.S.)
Safety
Therapeutics
Clinical Trials Data Monitoring Committees
National Institute of Neurological Disorders and Stroke
Platelet Glycoprotein GPIIb-IIIa Complex
Fibrinolytic Agents
Intracranial Hemorrhages
Cerebral Hemorrhage
Fibrinolysis
Random Allocation
eptifibatide
Myocardial Infarction
Outcome Assessment (Health Care)
Incidence

Keywords

  • Acute stroke
  • Thrombolysis

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Clinical Neurology
  • Advanced and Specialized Nursing
  • Medicine(all)

Cite this

The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke : The clear stroke trial. / Pancioli, Arthur M.; Broderick, Joseph; Brott, Thomas G; Tomsick, Thomas; Khoury, Jane; Bean, Judy; Del Zoppo, Gregory; Kleindorfer, Dawn; Woo, Daniel; Khatri, Pooja; Castaldo, John; Frey, James; Gebel, James; Kasner, Scott; Kidwell, Chelsea; Kwiatkowski, Thomas; Libman, Richard; MacKenzie, Richard; Scott, Phillip; Starkman, Sidney; Thurman, R. Jason.

In: Stroke, Vol. 39, No. 12, 01.12.2008, p. 3268-3276.

Research output: Contribution to journalArticle

Pancioli, AM, Broderick, J, Brott, TG, Tomsick, T, Khoury, J, Bean, J, Del Zoppo, G, Kleindorfer, D, Woo, D, Khatri, P, Castaldo, J, Frey, J, Gebel, J, Kasner, S, Kidwell, C, Kwiatkowski, T, Libman, R, MacKenzie, R, Scott, P, Starkman, S & Thurman, RJ 2008, 'The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke: The clear stroke trial', Stroke, vol. 39, no. 12, pp. 3268-3276. https://doi.org/10.1161/STROKEAHA.108.517656
Pancioli, Arthur M. ; Broderick, Joseph ; Brott, Thomas G ; Tomsick, Thomas ; Khoury, Jane ; Bean, Judy ; Del Zoppo, Gregory ; Kleindorfer, Dawn ; Woo, Daniel ; Khatri, Pooja ; Castaldo, John ; Frey, James ; Gebel, James ; Kasner, Scott ; Kidwell, Chelsea ; Kwiatkowski, Thomas ; Libman, Richard ; MacKenzie, Richard ; Scott, Phillip ; Starkman, Sidney ; Thurman, R. Jason. / The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke : The clear stroke trial. In: Stroke. 2008 ; Vol. 39, No. 12. pp. 3268-3276.
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TY - JOUR

T1 - The combined approach to lysis utilizing eptifibatide and rt-PA in acute ischemic stroke

T2 - The clear stroke trial

AU - Pancioli, Arthur M.

AU - Broderick, Joseph

AU - Brott, Thomas G

AU - Tomsick, Thomas

AU - Khoury, Jane

AU - Bean, Judy

AU - Del Zoppo, Gregory

AU - Kleindorfer, Dawn

AU - Woo, Daniel

AU - Khatri, Pooja

AU - Castaldo, John

AU - Frey, James

AU - Gebel, James

AU - Kasner, Scott

AU - Kidwell, Chelsea

AU - Kwiatkowski, Thomas

AU - Libman, Richard

AU - MacKenzie, Richard

AU - Scott, Phillip

AU - Starkman, Sidney

AU - Thurman, R. Jason

PY - 2008/12/1

Y1 - 2008/12/1

N2 - Background and Purpose: 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 μg/kg bolus followed by 0.75 μg/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.

AB - Background and Purpose: 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 μg/kg bolus followed by 0.75 μg/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.

KW - Acute stroke

KW - Thrombolysis

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