Clinical Trials of Novel Antithrombotics: Basic Concepts of Study Design and Methodology

  • Melvin E. Tan
  • Robert A. Harrington
Part of the Developments in Cardiovascular Medicine book series (DICM, volume 193)


When the normally smooth endothelial surface of a blood vessel is denuded by the rupture of an atherosclerotic plaque or during the course of percutaneous coronary intervention, this triggers a cascade of events culminating in thrombus formation. Endothelial disruption leads to exposure of adhesive glycoproteins, such as collagen, von Willebrand factor (vWF), fibronectin, laminin, vitronectin, and subendothelial thrombospondin, to which circulating inactivated platelets adhere. This occurs largely through membrane glycoprotein (GP) Ib-factor IX binding to vWF immobilized onto subendothelial structures. These platelets are then activated by local agonists, which include epinephrine, adenosine diphosphate (ADP), collagen, serotonin, and thrombin. Platelet activation induces an active conformational change in the surface GPIIb/IIIa receptors; conferring on them a high affinity for fibrinogen, vWF, and other adhesive glycoproteins; and resulting in platelet aggregation and consequent thrombosis. This conformational change in the platelet GPIIb/IIIa receptor is believed to be the final common pathway by which all agonists act to initiate platelet aggregation.


Percutaneous Coronary Intervention Acute Myocardial Infarction Unstable Angina Platelet Glycoprotein Abciximab Bolus 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Steele PM, Chesebro JH, Stanson AW, Holmes DR Jr, Dewanjee MK, Badimon L, Fuster V. Balloon angioplasty. Natural history of the pathophysiological response to injury in a pig model. Circ Res 57:105, 1985.PubMedGoogle Scholar
  2. 2.
    Badimon L, Badimon JJ, Galvez A, Chesebro JH, Fuster V. Influence of arterial damage and wall shear rate on platelet deposition. Ex vivo study in a swine model. Arteriosclerosis 6:312, 1986.PubMedGoogle Scholar
  3. 3.
    DeWood MA, Spores J, Notske R, et al. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 303:897, 1980.PubMedCrossRefGoogle Scholar
  4. 4.
    Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy — II: Maintenance of vascular graft or arterial patency by antiplatelet therapy. Br Med J 308:159, 1994.Google Scholar
  5. 5.
    Hirsh J, Fuster V. Guide to anticoagulant therapy. Part 1: Heparin. American Heart Association. Circulation 89:1449, 1994.PubMedGoogle Scholar
  6. 6.
    Akiyama T, Pawitan Y, Greenberg H, Kuo CS, Reynolds-Haertle RA. Increased risk of death and cardiac arrest from encainide and flecainide in patients after non-Q-wave acute myocardial infarction in the Cardiac Arrhythmia Suppression Trial: CAST investigators. Am J Cardiol 68:1551, 1991.PubMedCrossRefGoogle Scholar
  7. 7.
    Friedman LM, Furberg CD, DeMets DL. Fundamentals of Clinical Trials, 3rd ed. St. Louis, MO: Mosby-Year Book, 1996.Google Scholar
  8. 8.
    Topol EJ, Califf RM. Answers to complex questions cannot be derived from “simple” trials [see comments]. [Review] Br Heart J 68:348, 1992.PubMedCrossRefGoogle Scholar
  9. 9.
    1SIS-2. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. J Am Coll Cardiol 12:3A, 1988.CrossRefGoogle Scholar
  10. 10.
    GISSI. Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet 397, 1986.Google Scholar
  11. 11.
    The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med 329:673, 1993.CrossRefGoogle Scholar
  12. 12.
    The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med 329:1615, 1993.CrossRefGoogle Scholar
  13. 13.
    Simes RJ, Califf RM, Mark DB, on behalf of the GUSTO Investigators. Tradeoffs between stroke and mortality after acute myocardial infarction: Net clinical benefit of accelerated tissue plasminogen activator compared with streptokinase (abstr). Circulation 88(Suppl. I):I291, 1993.Google Scholar
  14. 14.
    Jang Y, Lincoff AM, Plow EF, Topol EJ. Cell adhesion molecules in coronary artery disease. J Am Coll Cardiol 24:1591, 1994.PubMedGoogle Scholar
  15. 15.
    Phillips DR, Charo IF, Parise LV, Fitzgerald LA. The platelet membrane glycoprotein IIb-IIIa complex. Blood 71:831, 1988.PubMedGoogle Scholar
  16. 16.
    Phillips DR, Charo IF, Scarborough RM. GPIIb-IIIa: The responsive integrin. Cell 65:359, 1991.PubMedCrossRefGoogle Scholar
  17. 17.
    Coller BS, Scudder LE. Inhibition of dog platelet function by in vivo infusion of F(ab’)2 fragments of a monoclonal antibody to the platelet glycoprotein IIb/IIIa receptor. Blood 66:1456, 1985.PubMedGoogle Scholar
  18. 18.
    Scarborough RM, Rose JW, Naughton MA, Phillips DR, Nannizzi L, Arfsten A, Campbell AM, Charo IF. Characterization of the integrin specificities of disintegrins isolated from American pit viper venoms. J Biol Chem 268:1058, 1993.PubMedGoogle Scholar
  19. 19.
    Tardiff BE, Miller J, Harrington RA, Tcheng JE, Califf RM. Integrilin (tm)-synthetic peptides against the platelet glycoprotein IIb/IIIa receptor. In Sasahara, Loscalzo (eds). New Therapeutic Agents in Thrombosis and Thrombolysis. New York: Marcel Dekker, in press.Google Scholar
  20. 20.
    Scarborough RM, Naughton MA, Teng W, Rose JW, Phillips DR, Nannizzi L, Arfsten A, Campbell AM, Charo IF. Design of potent and specific integrin antagonists. Peptide antagonists with high specifictity for glycoprotein IIb-IIIa. J Biol Chem 268:1066, 1993.PubMedGoogle Scholar
  21. 21.
    Kereiakes DJ, Runyon JP, Kleiman NS, Higby NA, Anderson LC, Hantsbarger G, McDonald S, Anders RJ. Differential dose response to oral Xemlofiban after antecedent intravenous abciximab: Administration for complex coronary Intervention. Circulation 94:906, 1996.PubMedGoogle Scholar
  22. 22.
    Theroux P, White H, David D, Van De Werf F, Nienaber CA, Charbonnier B, et al. A heparincontrolled study of MK-383 in unstable angina (abstr). Circulation 90(Suppl. I):I231, 1994.Google Scholar
  23. 23.
    Alig L, Edenhofer A, Hadvary P, Hurzeler M, Knopp D, Muller M, Steiner B, Trzeciak A, Weller T. Low molecular weight, non-peptide fibrinogen receptor antagonists. J Med Chem 35:4393, 1992.PubMedCrossRefGoogle Scholar
  24. 24.
    Berdan LG, Holmes DR, Davidson-Ray L, Lam LC, Talley JD, Mark DB, for the CAVEAT Investigators. Economic impact of abrupt closure following percutaneous intervention: The CAVEAT experience. J Am Coll Cardiol 23:434A, 1994.Google Scholar
  25. 25.
    Mark DB, Talley JD, Topol EJ, Bowman L, Lam LC, Anderson KM, Jollis JG, Cleman MW, Lee KL, Aversano T, Untereker WJ, Davidson-Ray L, Califf RM, for the EPIC Investigators. Economic assessment of platelet glycoprotein IIb/IIIa inhibition for prevention of ischemic complications of high-risk coronary angioplasty. Circulation 94:629, 1996.PubMedGoogle Scholar
  26. 26.
    Ellis SG, Tcheng JE, Navetta FI, Muller DW, Weisman HF, Smith C, Anderson KM, Califf RM, Topol EJ. Safety and antiplatelet effect of murine monoclonal antibody 7E3 Fab directed against platelet glycoprorein IIb/IIIa in patients undergoing elective coronary angioplasty. Cor Art Dis 4:167, 1993.CrossRefGoogle Scholar
  27. 27.
    Tcheng JE, Ellis SG, George BS, Keereiakes DJ, Kleiman NS, Talley JD, Wang AL, Weisman HF, Califf RM, Topol EJ. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody fab 7E3 in high-risk coronary angioplasty. Circulation 90:1757, 1994.PubMedGoogle Scholar
  28. 28.
    The EPIC Investigators. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 330:956, 1994.CrossRefGoogle Scholar
  29. 29.
    Lincoff AM, Califf RM, Anderson K, Weisman HF, Topol EJ, for the EPIC Investigators. Striking clinical benefir with platelet GP IIb/IIIa inhibition by c7E3 among patients with unstabel angina: Outcome in the EPIC trial (abstr). Circulation 90(Suppl. I):I21, 1994.Google Scholar
  30. 30.
    Lefkovits J, Ivanhoe RJ, Califf RM, Bergelson BA, Anderson KM, Stoner GL, Weisman HF, Topol EJ. Effects of platelet glycoprotein IIb/IIIa receptor blockade by a chimeric monoclonal antibody (abciximab) on acute and six-month outcomes after percutaneous transluminal coronary angioplasry for acute myocardial infarction. EPIC investigators. Am J Cardiol 77:1045, 1996.PubMedCrossRefGoogle Scholar
  31. 31.
    Topol EJ, Califf RM, Weisman HF, Ellis SG, Tcheng JE, Worley S, Ivanhoe R, George BS, Fintel D, Weston M, Sigmon K, Anderson KM, Lee KL, Willerson JT, on behalf of The EPIC Investigatiors. Randomised trial of coronary intervention with antibody against platelet IIb/IIIa integrin for reduction of clinical restenosis: Results at six months. Lancet 343:881, 1994.PubMedCrossRefGoogle Scholar
  32. 32.
    Aguirre FV, Topol EJ, Ferguson JJ, Anderson K, Blankenship JC, Heuser RR, Sigmon K, Taylor M, Gottlieb R, Hanovich G, Rosenberg M, Donohue TJ, Weisman HF, Califf RM, for the EPIC Investigators. Bleeding complications with the chimeric antibody to paltelet glycoprotein IIb/IIIa integrin in patients undergoing percutaneous coronary intervention. Circulation 91:2882, 1995.PubMedGoogle Scholar
  33. 33.
    Lincoff AM, Tcheng JE, Bass TA, Popma JJ, Tcirstein PS, Kleiman NS, Weisman HF, Musco MH, Cabot CF, Berdan LG, Califf RM, Topol EJ, PROLOG Investigators. A multicenter, randomized, double-blind pilot trial of standard versus low dose weight-adjusted heparin in patients treated with the platelet GP IIb/IIIa receptor antibody c7E3 during percutaneous coronary revascularization (abstr). J Am Coll Cardiol 25:80A, 1995.CrossRefGoogle Scholar
  34. 34.
    Ferguson JJ. Meeting highlights: American College of Cardiology 45th Annual Scientific Session, Orlando, Florida, March 24 to 27, 1996. Circulation 94:1, 1996.PubMedGoogle Scholar
  35. 35.
    Simoons ML. Refractory unstable angina: Reduction of events by C-7E3: The CAPTURE study. Presented at the 45th Annual Scientific Session of the American College of Cariology, Orlando, Florida, March 24, 1996.Google Scholar
  36. 36.
    Tcheng JE, Harrington RA, Kottke-Marchant K, Kleiman NS, Ellis SG, Kereiakes DJ, Mick MJ, Navetta FI, Smith JE, Worley SJ, Miller JA, Joseph DM, Sigmon KN, Kitt MM, du Mee CP, Califf RM, Topol EJ, for the IMPACT Investigators. Multicenter, randomized, double-blind, placebo-controlled trial of the platelet integrin glycoprotein IIb/IIIa blocker integrelin in elective coronary intervention. Circulation 91:2151, 1995.PubMedGoogle Scholar
  37. 37.
    Harrington RA, Kleiman NS, Kottke-Marchant K, Lincoff AM, Tcheng JE, Sigmon KN, Joseph D, Rios G, Trainor K, Rose D, Greenberg CS, Kitt MM, Topol F.J, Cahft RM. Immediate and reversible platelet inhibition after intravenous administration of a pepride glycoprotein IIb/IIIa inhibitor during percutaneous coronary intervention. Am J Cardiol 76:1222, 1995.PubMedCrossRefGoogle Scholar
  38. 38.
    Tcheng JE, Lineoff AM, Sigmon KN, Kitt MM, Califf RM, Topol FJ, for the IMPACT II Investigators. Platelet glycoprotein IIb/IIIa inhibition with integrelin™ during percutaneous coronary intervention: The IMPACT II trial (abstr). Circulation 92(Suppl. I):I543, 1995.Google Scholar
  39. 39.
    Gold HK, Gimple LW, Yasuda T, Lembach RC, Werner W, Holt R, Jordan R, Berger H, Collen D, Coller BS. Pharmacodynamic study of F(ab’)2 fragments of munne monoclonal antibody 7E3 directed against human platelet glycoprotein IIb/IIIa in patients with unstable angina pectoris. J Clin Invest 86:651, 1990.PubMedGoogle Scholar
  40. 40.
    Schulman SP, Goldschmidt-Clermont PJ, Navetta FI, Chandra NC, Guerci AD, Califf RM, Ferguson JJ, Willerson JT, Wolfe CL, Bahr R, Yakubov SJ, Nyggard TW, Mason SJ, Brashears L, Charo I, du Mee C, Kitt MM, Gerstenblith GG. Integrelin in unstable angina: A double-blind randomized trial (abstr). Circulation 88(Suppl. I):I608, 1993.Google Scholar
  41. 41.
    Harrington RA. Schulman SP, Kleiman NS, Lincoff AM, Goldschmidt-Clermont PJ, Joseph D, Sigmon KN, Parker J, Marchant K, Kitt MM. Profound, sustained and reversible platelet inhibition following administration of a glycoprotein IIb/IIIa inhibitor with and without heparin in patients with unstable angina (abstr). Circulation 90(Suppl. I):I232, 1994.Google Scholar
  42. 42.
    Theroux P, Kouz, Roy L, Knudtson ML, Diodati JG, Marquis JF, et al. Platelet Membrane Receptor Glycoprotien IIb/IIIa Antagonism in Unstable Angina: The Canadian Lamifiban Study. Circulation 94:899, 1996.PubMedGoogle Scholar
  43. 43.
    Ohman EM, Califf RM, Topol EJ, Candela R, Abbottsmith C, Ellis S, Sigmon KN, Kereiakes D, George B, Stack R, the TAMI Study Group. Consequences of reocclusion after successful reperfusion therapy in acute myocardial infarction. Circulation 82:781, 1990.PubMedGoogle Scholar
  44. 44.
    Yasuda T, Gold HK, Fallon JT, Leinbach RC, Guerrero JL, Scudder LE, Kanke M, Shealy D. Ross MJ, Collen D, et al. Monoclonal antibody against the platelet glycoprotein (GP) IIb/IIIa receptor prevents corconary artery retocclusion after reperfusion with recombinant tissue-type plasminogen activator in dogs. J Clin Invest 81:1284, 1988.PubMedGoogle Scholar
  45. 45.
    Kleiman NS, Ohman EM, Kereiakes DJ, Ellis SG, Weisman HF, Topol EJ, for the TAMI 8 Investigators. Profound platelet inactivation with 7E3 shortly after thrombolytic therapy for acute myocardial infarction (abstr). Circulation 84:II522, 1991.Google Scholar
  46. 46.
    Ohman EM, Kleiman NS, Gacioch G, Talley D, Navetta FI, Worley S, Anderson RD, Cohen J, Kereiakes DJ, Sigmon KN, Krucoff MW, Califf RM, Topol EJ, for the IMPACT-AMI Investigators. Combined accelerated tissue plasminogen activator and platelet glycoprotein IIb-IIIa integrin blockade with Integrilin(TM) in acute myocardial infarction: Results from a randomized, placebo-controlled, doseranging trial. Circulation 1996, in press.Google Scholar
  47. 47.
    Moliterno DJ, Harrington RA, Califf RM, Rapold HJ, Topol EJ, for the PARADIGM Investigators. Randomized, placebo-controlled study of Lamifiban with thrombolytic therapy for the treatment of acute myocardial infarction: Rarionale and design for the Platelet Aggregation Receptor Antagonist Dose Investigation and Reperfusion Gain in Myocardial Infarction (PARADIGM) study. J Thromb Thromboly 2:165, 1995.Google Scholar

Copyright information

© Kluwer Academic Publishers 1997

Authors and Affiliations

  • Melvin E. Tan
  • Robert A. Harrington

There are no affiliations available

Personalised recommendations