(Circulation. 1995;91:2151-2157.)
© 1995 American Heart Association, Inc.
Articles |
Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial of the Platelet Integrin Glycoprotein IIb/IIIa Blocker Integrelin in Elective Coronary Intervention
Presented in part at the 66th Scientific Sessions of the American Heart Association, Atlanta, Georgia, November 8-11, 1993.
From the Department of Medicine, Duke University Medical Center (J.E.T., R.A.H., J.A.M., D.M.J., K.N.S., R.M.C.), Durham, NC; the Cleveland Clinic Foundation (K.K.-M., S.G.E., E.J.T.), Cleveland, Ohio; Baylor College of Medicine (N.S.K.), Houston, Tex; Christ Hospital (D.J.K.), Cincinnati, Ohio; Methodist Hospital (M.J.M.), Indianapolis, Ind; Mother Francis Hospital (F.I.N.), Tyler, Tex; Saint Vincent Hospital (J.E.S.), Erie, Pa; Lancaster General Hospital (S.J.W.), Lancaster, Pa; and COR Therapeutics, Inc (M.M.K., C.P.d.M.), South San Francisco, Calif.
Correspondence to James E. Tcheng, MD, Box 3275, Duke University Medical Center, Durham, NC 27710.
Background Platelet aggregation and thrombosis have been implicated in the pathogenesis of coronary angioplasty complications. Integrelin, a synthetic cyclic heptapeptide with high affinity and marked specificity for platelet integrin glycoprotein IIb/IIIa, effectively blocks ADP-induced platelet aggregation.
Methods and Results In 150 patients undergoing elective percutaneous coronary intervention, random assignment was made to one of three treatment regimens: placebo; a 90-µg/kg bolus of Integrelin before angioplasty followed by a 1.0-µg · kg-1 · min-1 infusion of Integrelin for 4 hours; or a 90-µg/kg bolus followed by a 1.0-µg · kg-1 · min-1 infusion of Integrelin for 12 hours. Patients were followed to 30 days for the composite occurrence of myocardial infarction, stent implantation, repeat urgent or emergency percutaneous intervention or coronary bypass surgery, or death. Pharmacodynamic data were obtained in a subset of 31 patients. Administration of a 90-µg/kg bolus of Integrelin achieved an 86% inhibition of platelet aggregation, and this inhibition was maintained by a 1.0-µg · kg-1 · min-1 infusion. There was a trend toward reduction in end-point events from 12.2% (placebo) to 9.6% (4-hour infusion) to 4.1% (12-hour infusion), although these differences were not statistically significant (P=.13 for the 12-hour group compared with placebo). Major bleeding occurred in 8%, 8%, and 2% of patients, while minor bleeding was observed in 14%, 33%, and 47% of patients, respectively. There was no difference in bleeding index among groups (1.5, 1.7, and 1.3, respectively), defined as [(change in hematocrit/3)+red blood cell units transfused].
Conclusions This first clinical investigation of Integrelin during routine, elective, low- and high-risk coronary intervention supports the potential efficacy of Integrelin in routine coronary interventions. Pharmacodynamic analyses demonstrate that profound and sustained inhibition of platelet function is achieved, although a higher bolus dose may be required. Definitive assessment of efficacy and safety will need to await a large-scale study powered to achieve statistical significance.
Key Words: angioplasty • clinical trials • coronary disease • glycoproteins • peptides • platelet aggregation inhibitors
This article has been cited by other articles:
 |
|
 |
|
  C. Patrono, C. Baigent, J. Hirsh, and G. Roth Antiplatelet Drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) Chest, June 1, 2008; 133(6_suppl): 199S - 233S. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Patrono, B. Coller, G. A. FitzGerald, J. Hirsh, and G. Roth Platelet-Active Drugs: The Relationships Among Dose, Effectiveness, and Side Effects: The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy Chest, September 1, 2004; 126(3_suppl): 234S - 264S. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. Karvouni, D. G. Katritsis, and J. P. A. Ioannidis Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions J. Am. Coll. Cardiol., January 1, 2003; 41(1): 26 - 32. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kovesi and D. Royston Editorial I: Is there a bleeding problem with platelet-active drugs? Br. J. Anaesth., February 1, 2002; 88(2): 159 - 163. [Full Text] [PDF]
|
|
|
|
 |
|
 W. R. P. Agema, J. W. Jukema, S. N. Pimstone, and J. J. P. Kastelein Genetic aspects of restenosis after percutaneous coronary interventions;towards more tailored therapy Eur. Heart J., November 2, 2001; 22(22): 2058 - 2074. [PDF]
|
|
|
|
 |
|
 I. C. Gilchrist, J. C. O'Shea, T. Kosoglou, L. K. Jennings, T. J. Lorenz, M. M. Kitt, N. S. Kleiman, D. Talley, F. Aguirre, C. Davidson, et al. Pharmacodynamics and Pharmacokinetics of Higher-Dose, Double-Bolus Eptifibatide in Percutaneous Coronary Intervention Circulation, July 24, 2001; 104(4): 406 - 411. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 O. E. Olorundare, O. Peyruchaud, R. M. Albrecht, and D. F. Mosher Assembly of a fibronectin matrix by adherent platelets stimulated by lysophosphatidic acid and other agonists Blood, July 1, 2001; 98(1): 117 - 124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Mark Kharim Orcullo Santillan, J. Herring, D. A. Hoppensteadt, W. Jeske, J.-M. Herbert, and J. Fareed The Effect of a Novel Glycoprotein IIb/IIIa Antagonist, SR 121566A, on Platelet Aggregation and Activation in Rhesus Monkeys Clinical and Applied Thrombosis/Hemostasis, January 1, 2001; 7(1): 10 - 15. [Abstract] [PDF]
|
|
|
|
 |
|
 J. P. Abulencia, N. Tien, O. J. T. McCarty, D. Plymire, S. A. Mousa, and K. Konstantopoulos Comparative Antiplatelet Efficacy of a Novel, Nonpeptide GPIIb/IIIa Antagonist (XV454) and Abciximab (c7E3) in Flow Models of Thrombosis Arterioscler. Thromb. Vasc. Biol., January 1, 2001; 21(1): 149 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Patrono, B. Coller, J. E. Dalen, G. A. FitzGerald, V. Fuster, M. Gent, J. Hirsh, and G. Roth Platelet-Active Drugs : The Relationships Among Dose, Effectiveness, and Side Effects Chest, January 1, 2001; 119(1_suppl): 39S - 63S. [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Mousa, J. M. Bozarth, M. S. Forsythe, and A. Slee Differential antiplatelet efficacy for various GPIIb/IIIa antagonists: Role of plasma calcium levels Cardiovasc Res, September 1, 2000; 47(4): 819 - 826. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Weintraub, T. D. Thompson, S. Culler, S. J. Boccuzzi, E. R. Becker, A. S. Kosinski, and E. Mahoney Targeting Patients Undergoing Angioplasty for Thrombus Inhibition : A Cost-Effectiveness and Decision Support Model Circulation, July 25, 2000; 102(4): 392 - 398. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Cannon, C. H. McCabe, R. G. Wilcox, A. Langer, A. Caspi, P. Berink, J. Lopez-Sendon, J. Toman, A. Charlesworth, R. J. Anders, et al. Oral Glycoprotein IIb/IIIa Inhibition With Orbofiban in Patients With Unstable Coronary Syndromes (OPUS-TIMI 16) Trial Circulation, July 11, 2000; 102(2): 149 - 156. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. W. O'Neill, P. Serruys, M. Knudtson, G.-A. van Es, G. C. Timmis, C. van der Zwaan, J. Kleiman, J. Gong, E. B. Roecker, R. Dreiling, et al. Long-Term Treatment with a Platelet Glycoprotein-Receptor Antagonist after Percutaneous Coronary Revascularization N. Engl. J. Med., May 4, 2000; 342(18): 1316 - 1324. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Mousa, S. Khurana, and M. S. Forsythe Comparative In Vitro Efficacy of Different Platelet Glycoprotein IIb/IIIa Antagonists on Platelet-Mediated Clot Strength Induced by Tissue Factor With Use of Thromboelastography : Differentiation Among Glycoprotein IIb/IIIa Antagonists Arterioscler. Thromb. Vasc. Biol., April 1, 2000; 20(4): 1162 - 1167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Verstraete Synthetic Inhibitors of Platelet Glycoprotein IIb/IIIa in Clinical Development Circulation, February 15, 2000; 101 (6): e76 - e80. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Topol and J. S. Yadav Recognition of the Importance of Embolization in Atherosclerotic Vascular Disease Circulation, February 8, 2000; 101(5): 570 - 580. [Full Text] [PDF]
|
|
|
|
 |
|
 A. Brodison, R. Katira, R. S More, and A. Chauhan Current practice: Antiplatelet use in interventional cardiology Postgrad. Med. J., February 1, 2000; 76(892): 70 - 79. [Abstract] [Full Text]
|
|
|
|
|
|
D. J Schneider, D. J Taatjes, and B. E Sobel Paradoxical inhibition of fibrinogen binding and potentiation of {alpha}-granule release by specific types of inhibitors of glycoprotein IIb-IIIa Cardiovasc Res, January 14, 2000; 45(2): 437 - 446. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Faraday, J. J. Rade, D. C. Johns, G. Khetawat, S. J. Noga, J. F. DiPersio, Y. Jin, J. L. Nichol, J. S. Haug, and P. F. Bray Ex Vivo Cultured Megakaryocytes Express Functional Glycoprotein IIb-IIIa Receptors and Are Capable of Adenovirus-Mediated Transgene Expression Blood, December 15, 1999; 94(12): 4084 - 4092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. S. Weintraub, S. Culler, S. J. Boccuzzi, J. R. Cook, A. S. Kosinski, D. J. Cohen, J. Burnette, and for the RESTORE Trial Study Group Economic impact of GPIIB/IIIA blockade after high-risk angioplasty: Results from the restore trial J. Am. Coll. Cardiol., October 1, 1999; 34(4): 1061 - 1066. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. A. Mousa, R. Kapil, and D.-X. Mu Intravenous and Oral Antithrombotic Efficacy of the Novel Platelet GPIIb/IIIa Antagonist Roxifiban (DMP754) and Its Free Acid Form, XV459 Arterioscler. Thromb. Vasc. Biol., October 1, 1999; 19(10): 2535 - 2541. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Feng, K. Lindpaintner, M. G. Larson, V. S. Rao, C. J. O'Donnell, I. Lipinska, C. Schmitz, P. A. Sutherland, H. Silbershatz, R. B. D'Agostino, et al. Increased Platelet Aggregability Associated With Platelet GPIIIa PlA2 Polymorphism : The Framingham Offspring Study Arterioscler. Thromb. Vasc. Biol., April 1, 1999; 19(4): 1142 - 1147. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. F. Kong, R. M. Califf, D. P. Miller, D. J. Moliterno, H. D. White, R. A. Harrington, J. E. Tcheng, A. M. Lincoff, V. Hasselblad, and E. J. Topol Clinical Outcomes of Therapeutic Agents That Block the Platelet Glycoprotein IIb/IIIa Integrin in Ischemic Heart Disease Circulation, December 22, 1998; 98(25): 2829 - 2835. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R.F. Storey, R.G. Wilcox, and S. Heptinstall Differential Effects of Glycoprotein IIb/IIIa Antagonists on Platelet Microaggregate and Macroaggregate Formation and Effect of Anticoagulant on Antagonist Potency : Implications for Assay Methodology and Comparison of Different Antagonists Circulation, October 20, 1998; 98(16): 1616 - 1621. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Kereiakes, N. S. Kleiman, J. J. Ferguson, A. R. Z. Masud, T. M. Broderick, C. W. Abbottsmith, J. P. Runyon, L. C. Anderson, R. J. Anders, R. J. Dreiling, et al. Pharmacodynamic Efficacy, Clinical Safety, and Outcomes After Prolonged Platelet Glycoprotein IIb/IIIa Receptor Blockade With Oral Xemilofiban : Results of a Multicenter, Placebo-Controlled, Randomized Trial Circulation, September 29, 1998; 98(13): 1268 - 1278. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. A. Mousa, J. M. Bozarth, W. Lorelli, M. S. Forsythe, M. J. M. C. Thoolen, A. M. Slee, T. M. Reilly, and P. A. Friedman Antiplatelet Efficacy of XV459, A Novel Nonpeptide Platelet GPIIb/IIIa Antagonist: Comparative Platelet Binding Profiles with c7E3 J. Pharmacol. Exp. Ther., September 1, 1998; 286(3): 1277 - 1284. [Abstract] [Full Text]
|
|
|
|
|
|
The PURSUIT Trial Investigators Inhibition of Platelet Glycoprotein IIb/IIIa with Eptifibatide in Patients with Acute Coronary Syndromes N. Engl. J. Med., August 13, 1998; 339(7): 436 - 443. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Y. Suzuki, P. Hillyer, S. Miyamoto, S. Niewiarowski, L. Sun, A. K. Rao, S. Hollenbach, and L. H. Edmunds Jr Integrilin prevents prolonged bleeding times after cardiopulmonary bypass Ann. Thorac. Surg., August 1, 1998; 66(2): 373 - 381. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
The Platelet Receptor Inhibition in Ischemic Syndr A Comparison of Aspirin plus Tirofiban with Aspirin plus Heparin for Unstable Angina N. Engl. J. Med., May 21, 1998; 338(21): 1498 - 1505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. K. Breddin Antiplatelet Agents in Cardiovascular and Cerebrovascular Diseases Clinical and Applied Thrombosis/Hemostasis, April 1, 1998; 4(2): 87 - 95. [Abstract] [PDF]
|
|
|
|
|
|
C. P. Cannon, C. H. McCabe, S. Borzak, T. D. Henry, M. D. Tischler, H. S. Mueller, R. Feldman, S. T. Palmeri, K. Ault, S. A. Hamilton, et al. Randomized Trial of an Oral Platelet Glycoprotein IIb/IIIa Antagonist, Sibrafiban, in Patients After an Acute Coronary Syndrome : Results of the TIMI 12 Trial Circulation, February 3, 1998; 97(4): 340 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. J. Topol Toward a New Frontier in Myocardial Reperfusion Therapy : Emerging Platelet Preeminence Circulation, January 20, 1998; 97(2): 211 - 218. [Full Text] [PDF]
|
|
|
|
|
|
R. Altman Controversies in Antithrombotic Therapy in Cardiovascular Diseases Clinical and Applied Thrombosis/Hemostasis, January 1, 1998; 4(1): 11 - 24. [Abstract] [PDF]
|
|
|
|
|
|
M. A. Mascelli, S. Worley, N. J. Veriabo, E. T. Lance, S. Mack, T. Schaible, H. F. Weisman, and R. E. Jordan Rapid Assessment of Platelet Function With a Modified Whole-Blood Aggregometer in Percutaneous Transluminal Coronary Angioplasty Patients Receiving Anti-GP IIb/IIIa Therapy Circulation, December 2, 1997; 96(11): 3860 - 3866. [Abstract] [Full Text]
|
|
|
|
|
|
D. R. Phillips, W. Teng, A. Arfsten, L. Nannizzi-Alaimo, M. M. White, C. Longhurst, S. J. Shattil, A. Randolph, J. A. Jakubowski, L. K. Jennings, et al. Effect of Ca2+ on GP IIb-IIIa Interactions With Integrilin : Enhanced GP IIb-IIIa Binding and Inhibition of Platelet Aggregation by Reductions in the Concentration of Ionized Calcium in Plasma Anticoagulated With Citrate Circulation, September 2, 1997; 96(5): 1488 - 1494. [Abstract] [Full Text]
|
|
|
|
|
|
D. J. Kereiakes, N. Kleiman, J. J. Ferguson, J. P. Runyon, T. M. Broderick, N. A. Higby, L. H. Martin, G. Hantsbarger, S. McDonald, and R. J. Anders Sustained Platelet Glycoprotein IIb/IIIa Blockade With Oral Xemilofiban in 170 Patients After Coronary Stent Deployment Circulation, August 19, 1997; 96(4): 1117 - 1121. [Abstract] [Full Text]
|
|
|
|
|
|
J. J. Cook, G. R. Sitko, M. A. Holahan, M. T. Stranieri, J. D. Glass, B. C. Askew, C. J. McIntyre, D. A. Claremon, J. J. Baldwin, G. D. Hartman, et al. Nonpeptide Glycoprotein IIb/IIIa Inhibitors. 15. Antithrombotic Efficacy of L-738,167, a Long-Acting GPIIb/IIIa Antagonist, Correlates with Inhibition of Adenosine Diphosphate-Induced Platelet Aggregation but not with Bleeding Time Prolongation J. Pharmacol. Exp. Ther., May 1, 1997; 281(2): 677 - 689. [Abstract] [Full Text]
|
|
|
|
|
|
E. M. Ohman, N. S. Kleiman, G. Gacioch, S. J. Worley, F. I. Navetta, J. D. Talley, H. V. Anderson, S. G. Ellis, M. D. Cohen, D. Spriggs, et al. Combined Accelerated Tissue-Plasminogen Activator and Platelet Glycoprotein IIb/IIIa Integrin Receptor Blockade With Integrilin in Acute Myocardial Infarction: Results of a Randomized, Placebo-Controlled, Dose-Ranging Trial Circulation, February 18, 1997; 95(4): 846 - 854. [Abstract] [Full Text]
|
|
|
|
 |
|
 Y. Hiramatsu, N. Gikakis, H. L. Anderson III, J. H. Gorman III, C. Marcinkiewicz, R. J. Gould, S. Niewiarowski, and L. H. Edmunds Jr. TIROFIBAN PROVIDES ""PLATELET ANESTHESIA"" DURING CARDIOPULMONARY BYPASS IN BABOONS J. Thorac. Cardiovasc. Surg., January 1, 1997; 113(1): 182 - 193. [Abstract] [Full Text]
|
|
|
|
|
|
R. K. Aggarwal, D. C. Ireland, M. A. Azrin, M. D. Ezekowitz, D. P. de Bono, and A. H. Gershlick Antithrombotic Potential of Polymer-Coated Stents Eluting Platelet Glycoprotein IIb/IIIa Receptor Antibody Circulation, December 15, 1996; 94(12): 3311 - 3317. [Abstract] [Full Text]
|
|
|
|
|
|
S. P. Schulman, P. J. Goldschmidt-Clermont, E. J. Topol, R. M. Califf, F. I. Navetta, J. T. Willerson, N. C. Chandra, A. D. Guerci, J. J. Ferguson, R. A. Harrington, et al. Effects of Integrelin, a Platelet Glycoprotein IIb/IIIa Receptor Antagonist, in Unstable Angina: A Randomized Multicenter Trial Circulation, November 1, 1996; 94(9): 2083 - 2089. [Abstract] [Full Text]
|
|
|
|
|
|
D. J. Kereiakes, J. P. Runyon, N. S. Kleiman, N. A. Higby, L. C. Anderson, G. Hantsbarger, S. McDonald, and R. J. Anders Differential Dose-Response to Oral Xemilofiban After Antecedent Intravenous Abciximab: Administration for Complex Coronary Intervention Circulation, September 1, 1996; 94(5): 906 - 910. [Abstract] [Full Text]
|
|