Thromb Haemost 2001; 85(03): 395-400
DOI: 10.1055/s-0037-1615595
Review Article
Schattauer GmbH

Platelet Function Inhibitors in the Year 2000

Joel S. Bennett
1   Hematology-Oncology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, and DuPont Pharmaceuticals, Wilmington, DE, USA
,
Shaker Mousa
1   Hematology-Oncology Division, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA, USA, and DuPont Pharmaceuticals, Wilmington, DE, USA
› Author Affiliations
Further Information

Publication History

Received 26 June 2000

Accepted after revision 04 August 2000

Publication Date:
08 December 2017 (online)

Summary

Platelet thrombi are responsible for much of the morbidity and mortality of arterial vascular disease (1). Because platelet inhibitors such as aspirin have proven to be of benefit to patients with these disorders, there has been a directed search for more potent anti-platelet agents. The following discussion addresses the mechanism of action and clinical utility of the currently available platelet function inhibitors. Although in theory these agents could impair platelet adhesion, aggregation, secretion, or platelet procoagulant activity, in practice they are focused almost exclusively on the biochemical events that proceed from platelet stimulation to ligand binding to the platelet fibrinogen receptor GPIIb-IIIa.

 
  • References

  • 1 Lefkovits J, Plow E, Topol E. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995; 332: 1553-9.
  • 2 Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and-2. J Biol Chem 1996; 271: 33157-60.
  • 3 Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994; 330: 1287-94.
  • 4 Clarke RJ, Mayo G, Price P, FitzGerald GA. Suppression of thromboxane A2 but not systemic prostacyclin by controlled-release aspirin. N Engl J Med 1991; 325: 1137-41.
  • 5 RISC Group.. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet 1990; 336: 827-30.
  • 6 ISIS-2 Collaborative Group.. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17187 cases of suspected myocardial infarction: ISIS-2. Lancet 1988; 2: 349-60.
  • 7 Antiplatelet Trialists’ Collaboration.. Collaborativer overview of randomized trials of antiplatelet therapy-I: Prevention of death, myocardial infarction, stroke by prolonged antiplatelet therapy in various categories of patients. Brit Med J 1994; 308: 81-106.
  • 8 Peto R, Gray R, Collins R. et al. Randomized trial of prophylactic daily aspirin in British male doctors. Brit Med J 1988; 296: 313-6.
  • 9 Steering Committee of the Physicans’ Health Study Research Group.. Final report on the aspirin component of the ongoing physicians’ health study. N Engl J Med 1989; 321: 129-35.
  • 10 Ridker PM, Manson JE, Gaziano M, Buring JE, Hennekens CH. Low dose aspirin therapy for chronic stable angina. Ann Int Med 114 1991; 835-9.
  • 11 Serruys PW, Rutsch W, Heyndrickx GR. et al. Prevention of restenosis after percutaneous transluminal coronary angioplasty with thromboxane A2-receptor blockade. Circulation 1991; 84: 1568-80.
  • 12 RAPT Investigators.. Coronary heart disease/thrombolysis/lipids: Randomized trial of ridogrel, a combined thromboxane A2 synthase inhibitor and thromboxane A2/prostaglandin endoperoxide receptor antagonist, versus aspirin as adjunct to thrombolysis in patients with acute myocardial infarction: the Ridogrel versus aspirin patency trial (RAPT). Circulation 1994; 89: 588-95.
  • 13 Cattaneo M, Gachet C. ADP receptors and clinical bleeding disorders. Arterioscler Thromb Vasc Biol 1999; 19: 2281-5.
  • 14 Geiger J, Honig-Liedl P, Schanzenbacher P, Walter U. Ligand specificity and ticlopidine effects distinguish three human platelet ADP receptors. Eur J. Pharmacol 1998; 351: 235-46.
  • 15 Geiger J, Brich J, Honig-Liedl P. et al. Specific impairment of human platelet P2Y(AC) ADP receptor-mediated signaling by the antiplatelet drug clopidogrel. Arterioscler Thromb Vasc Biol 1999; 19: 2007-11.
  • 16 Schror K. Antiplatelet drugs. A comparative review. Drugs 1995; 50: 7-28.
  • 17 Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667-72.
  • 18 Balsano F, Rizzon P, Violi F. et al. Antiplatelet treatment with ticlopidine in unstable angina. A controlled multicenter clinical trial. Circulation 1990; 82: 17-26.
  • 19 Gent M, Blakely JA, Easton JD, Ellis DJ, Hachniski VC. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989: 1215-20.
  • 20 Janzon L. The STIMS trial: the ticlopidine experience and its clinical applications. Swedish Ticlopidine Multicenter Study. Vasc Med 1996; 1: 141-3.
  • 21 Hass WK, Easton JD, Adams HP. et al. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med 1989; 321: 501-7.
  • 22 Becquemin JP. Effect of ticlopidine on the long-term patency of saphenous-vein bypass grafts in the legs. N Engl J Med 1997; 337: 1726-31.
  • 23 Schomig A, Neumann FJ, Kastrati A. et al. A randomized comparison of antiplatelet and anticoagulant therapy after the placement of coronary-artery stents. N Engl J Med 1996; 334: 1084-9.
  • 24 Leon MB, Baim DS, Popma JJ. et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med 1998; 339: 1665-71.
  • 25 Albiero R, Hall P, Itoh A. et al. Results of a consecutive series of patients receiving only antiplatelet therapy after optimized stent implantation. Comparison of aspirin alone versus combined ticlopidine and aspirin therapy. Circulation 1997; 95: 1145-56.
  • 26 Yeh SP, Hsueh EJ, Wu H, Wang YC. Ticlopidine-associated aplastic anemia. A case report and review of literature. Ann Hematol 1998; 76: 87-90.
  • 27 Bennett CL, Davidson CJ, Raisch DW, Weinberg PD, Bennett RH, Feldman MD. Thrombotic thrombocytopenic purpura associated with ticlopidine in the setting of coronary artery stents and stroke prevention. Arch Intern Med 1999; 159: 2524-8.
  • 28 Steinhubl SR, Tan WA, Foody JM, Topol EJ. Incidence and clinical course of thrombotic thrombocytopenic purpura due to ticlopidine following coronary stenting. EPISTENT Investigators. Evaluation of Platelet IIb/IIIa Inhibitor for Stenting . J Am Med Assoc 1999; 281: 806-10.
  • 29 Bennett CL, Weinberg PD, Rozenberg-Ben-Dror K, Yarnold PR, Kwaan HC, Green D. Thrombotic thrombocytopenic purpura associated with ticlopidine. A review of 60 cases. Ann Int Med 1998; 128: 541-4.
  • 30 CAPRIE Steering Committee.. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996; 348: 1329-39.
  • 31 Moussa I, Oetgen M, Roubin G. et al. Effectiveness of clopidogrel and aspirin versus ticlopidine and aspirin in preventing stent thrombosis after coronary stent implantation. Circulation 1999; 99: 2364-6.
  • 32 Muller C, Buttner HJ, Petersen J, Roskamm H. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents. Circulation 2000; 101: 590-3.
  • 33 Berger PB, Bell MR, Rihal CS. et al. Clopidogrel versus ticlopidine after intracoronary stent placement. J Am Coll Cardiol 1999; 34: 1891-4.
  • 34 Mishkel GJ, Aguirre FV, Ligon RW, Rocha-Singh KJ, Lucore CL. Clopidogrel as adjunctive antiplatelet therapy during coronary stenting. J Am Coll Cardiol 1999; 34: 1884-90.
  • 35 Bennett CL, Conners JM, Carwile JM. et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000; 342: 1773-7.
  • 36 FitzGerald GA. Dipyridamole. N Engl J Med 1987; 316: 1240-7.
  • 37 Diener HC, Cunha L, Forbes C, Sivenius J, Smets P, Lowenthal A. European Stroke Prevention Study. 2. Dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci 1996; 143: 1-13.
  • 38 Hervey PS, Goa KL. Extended-release dipyridamole/aspirin. Drugs 1999; 58: 469-75.
  • 39 Sudo T, Tachibana K, Toga K. et al. Potent effects of novel anti-platelet aggregatory cilostamide analogues on recombinant cyclic nucleotide phosphodiesterase isozyme activity. Biochem Pharmacol 2000; 59: 347-56.
  • 40 Ikeda Y. Antiplatelet therapy using cilostazol, a specific PDE3 inhibitor. Thromb Haemost 1999; 82: 435-8.
  • 41 Money SR, Herd JA, Isaacsohn JL. et al. Effect of cilostazol on walking distances in patients with intermittent claudication caused by peripheral vascular disease. J Vasc Surg 1998; 27: 267-74.
  • 42 Beebe HG, Dawson DL, Cutler BS. et al. A new pharmacological treatment for intermittent claudication: results of a randomized, multicenter trial. Arch Intern Med 1999; 159: 2041-50.
  • 43 Dawson DL, Cutler BS, Meissner MH, Strandness Jr DE. Cilostazol has beneficial effects in treatment of intermittent claudication: results from a multicenter, randomized, prospective, double-blind trial. Circulation 1998; 98: 678-86.
  • 44 Cohn JN, Goldstein SO, Greenberg BH. et al. A dose-dependent increase in mortality with vesnarinone among patients with severe heart failure. Vesnarinone Trial Investigators. N Engl J Med 1998; 339: 1810-6.
  • 45 Yoon Y, Shim WH, Lee DH. et al. Usefulness of cilostazol versus ticlopidine in coronary artery stenting. Am J Cardiol 1999; 84: 1375-80.
  • 46 Park SW, Lee CW, Kim HS. et al. Comparison of cilostazol versus ticlopidine therapy after stent implantation. Am J Cardiol 1999; 84: 511-4.
  • 47 Coller BS. A new murine monoclonal antibody reports an activation-dependent change in the conformation and/or microenvironment of the platelet glycoprotein IIb-IIIa complex. J Clin Invest 1985; 76: 101-8.
  • 48 Coller BS. Binding of abciximab to αVβ3 and activated αMβ2 receptors: with a review of platelet-leukocyte interactions. Thromb Haemost 1999; 82: 326-36.
  • 49 Tcheng J, Ellis S, George B. et al. Pharmacodynamics of chimeric glycoprotein IIb/IIIa integrin antiplatelet antibody Fab 7E3 in high-risk coronary angioplasty. Circulation 1994; 90: 1757-64.
  • 50 Tcheng JE. Differences among the parenteral platelet glycoprotein IIb/IIIa inhibitors and implications for treatment. Am J Cardiol 1999; 83: 7E-11E.
  • 51 Mascelli MA, Lance ET, Damaraju L, Wagner CL, Weisman HF, Jordan RE. Pharmacodynamic profile of short-term abciximab treatment demonstrates prolonged platelet inhibition with gradual recovery from GP IIb/IIIa receptor blockade. Circulation 1998; 97: 1680-8.
  • 52 EPIC Investigators.. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high-risk coronary angioplasty. N Engl J Med 1994; 330: 956-61.
  • 53 CAPTURE Investigators.. Randomised placebo-controlled trial of abciximab before and during coronary intervention in refractory unstable angina: the CAPTURE Study. Lancet 1997; 349: 1429-35.
  • 54 Hamm CW, Heeschen C, Goldmann B. et al. Benefit of abciximab in patients with refractory unstable angina in relation to serum troponin T levels. c7E3 Fab Antiplatelet Therapy in Unstable Refractory Angina (CAPTURE) Study Investigators. N Engl J Med 1999; 340: 1623-9.
  • 55 EPILOG Investigators.. Platelet glycoprotein IIb/IIIa receptor blockade and low-dose heparin during percutaneous coronary revascularization. N Engl J Med 1997; 336: 1689-96.
  • 56 EPISTENT Investigators.. Randomised placebo-controlled and balloon-angioplasty-controlled trial to assess safety of coronary stenting with use of platelet glycoprotein-IIb/IIIa blockade. Lancet 1998; 352: 87-92.
  • 57 Lincoff AM, Califf RM, Moliterno DJ. et al. Complementary clinical benefits of coronary-artery stenting and blockade of platelet glycoprotein IIb/IIIa receptors. N Engl J Med 1999; 341: 319-27.
  • 58 Topol EJ, Mark DB, Lincoff AM. et al. Outcomes at 1 year and economic implications of platelet glycoprotein IIb/IIIa blockade in patients undergoing coronary stenting: results from a multicentre randomised trial. Lancet 1999; 354: 2019-24.
  • 59 Lincoff AM. Potent complementary clinical benefit of abciximab and stenting during percutaneous coronary revascularization in patients with diabetes mellitus: results of the EPISTENT trial. Am Heart J 2000; 139: S46-S52.
  • 60 Marso SP, Lincoff AM, Ellis SG. et al. Optimizing the percutaneous interventional outcomes for patients with diabetes mellitus: results of the EPISTENT (Evaluation of platelet IIb/IIIa inhibitor for stenting trial) diabetic substudy. Circulation 1999; 100: 2477-84.
  • 61 Madan M, Berkowitz SD. Understanding thrombocytopenia and antigenicity with glycoprotein IIb-IIIa inhibitors. Am Heart J 1999; 138: 317-26.
  • 62 Berkowitz SD, Harrington RA, Rund MM, Tcheng JE. Acute profound thrombocytopenia after C7E3 Fab (abciximab) therapy. Circulation 1997; 95: 809-13.
  • 63 Bednar B, Cook JJ, Holahan MA. et al. Fibrinogen receptor antagonist-induced thrombocytopenia in chimpanzee and rhesus monkey associated with preexisting drug-dependent antibodies to platelet glycoprotein IIb/IIIa. Blood 1999; 94: 587-99.
  • 64 Tcheng JE, Kereiakes DJ, Braden GA. et al. Readministration of abciximab: interim report of the ReoPro readministration registry. Am Heart J 1999; 138: S33-S38.
  • 65 Phillips DR, Teng W, Arfsten A. 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 1997; 96: 1488-94.
  • 66 IMPACT-II Investigators.. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention. Lancet 1997; 349: 1422-8.
  • 67 Harrington RA. Design and methodology of the PURSUIT trial: evaluating eptifibatide for acute ischemic coronary syndromes. Platelet Glycoprotein IIb-IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy. Am J Cardiol 1997; 80: 34B-38B.
  • 68 Cook JJ, Bednar B, Lynch Jr JL. et al. Tirofiban (Aggrastat®). Cardiovasc Drug Rev 1999; 17: 199-224.
  • 69 RESTORE Investigators.. Effects of platelet glycoprotein IIb/IIIa blockade with tirofiban on adverse cardiac events in patients with unstable angina or acute myocardial infarction undergoing coronary angioplasty. Circulation 1997; 96: 1445-53.
  • 70 Gibson CM, Goel M, Cohen DJ. et al. Six-month angiographic and clinical follow-up of patients prospectively randomized to receive either tirofiban or placebo during angioplasty in the RESTORE trial. J Am Coll Cardiol 1998; 32: 28-34.
  • 71 PRISM Investigators.. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998; 338: 1498-505.
  • 72 Heeschen C, Hamm CW, Goldmann B, Deu A, Langenbrink L, White HD. Troponin concentrations for stratification of patients with acute coronary syndromes in relation to therapeutic efficacy of tirofiban. Lancet 1999; 354: 1757-62.
  • 73 PRISM-PLUS Investigators.. Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban in unstable angina and non-Q-wave myocardial infarction. N Engl J Med 1998; 338: 1488-97.
  • 74 Theroux P. Oral inhibitors of platelet membrane receptor glycoprotein IIb/IIIa in clinical cardiology: issues and opportunities. Am Heart J 1998; 135: S107-S112.
  • 75 Kereiakes DJ. Oral blockade of the platelet glycoprotein IIb/IIIa receptor: fact or fancy?. Am Heart J 1999; 138: S39-S46.
  • 76 SYMPHONY Investigators.. Comparison of sibrafiban with aspirin for prevention of cardiovascular events after acute coronary syndromes: a randomized trial. Lancet 2000; 355: 337-45.
  • 77 O’Neill WW, Serruys P, Knudtson M. et al. Long-term treatment with a platelet glycoprotein-receptor antagonist after percutaneous coronary revascularization. N Engl J Med 2000; 342: 1316-24.
  • 78 Ferguson JJ. Meeting highlights. Highlights of the 48th scientific sessions of the American College of Cardiology. Circulation 1999; 100: 570-5.
  • 79 Topol EJ, Easton JD, Amarenco P. et al. Design of the Blockade of the Glycoprotein IIb/IIIa Receptor to Avoid Vascular Occulsion (BRAVO) trial. Am Heart J 2000; 139: 927-33.
  • 80 Akkerhuis M, van den Zwaan C, Wilcox RG. et al. Troponin-I identifies patients with unstable coronary artery disease who benefit from long-term oral glycoprotein IIb/IIIa inhibition: the FROST study.. Circulation 1999; 100 I I-292.
  • 81 Mousa SA, Forsythe M, Bozarth J, Youssef A, Wityak J, Olson R, Sielecki T. XV454, a novel nonpeptide small-molecule platelet GIIb/IIIa antagonist with comparable platelet αIIbβ3-binding kinetics to c7E3. J Cardiovasc Pharmacol 1998; 32: 736-44.
  • 82 Peter K, Schwarz M, Ylanne J. et al. Induction of fibrinogen binding and platelet aggregation as a potential intrinsic property of various glycoprotein IIb/IIIa (αIIbβ3) inhibitors. Blood 1998; 92: 3240-9.
  • 83 Holmes MB, Sobel BE, Cannon CP, Schneider DJ. Increased platelet reactivity in patients given orbofiban after an acute coronary syndrome: an OPUS-TIMI 16 substudy. Am J Cardiol 2000; 85: 491-3.