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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)

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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.

Keywords

Arterial thrombosis - platelet inhibitors - GPIIb-IIIa - aspirin - thienopyridines
 

  • References

  • 1 Lefkovits J, Plow E, Topol E. Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995; 332: 1553-9.
    CrossrefPubMedGoogle Scholar
  • 2 Smith WL, Garavito RM, DeWitt DL. Prostaglandin endoperoxide H synthases (cyclooxygenases)-1 and-2. J Biol Chem 1996; 271: 33157-60.
    CrossrefPubMedGoogle Scholar
  • 3 Patrono C. Aspirin as an antiplatelet drug. N Engl J Med 1994; 330: 1287-94.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 13 Cattaneo M, Gachet C. ADP receptors and clinical bleeding disorders. Arterioscler Thromb Vasc Biol 1999; 19: 2281-5.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 16 Schror K. Antiplatelet drugs. A comparative review. Drugs 1995; 50: 7-28.
    CrossrefPubMedGoogle Scholar
  • 17 Quinn MJ, Fitzgerald DJ. Ticlopidine and clopidogrel. Circulation 1999; 100: 1667-72.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 19 Gent M, Blakely JA, Easton JD, Ellis DJ, Hachniski VC. The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke. Lancet 1989: 1215-20.
    PubMedGoogle Scholar
  • 20 Janzon L. The STIMS trial: the ticlopidine experience and its clinical applications. Swedish Ticlopidine Multicenter Study. Vasc Med 1996; 1: 141-3.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 33 Berger PB, Bell MR, Rihal CS. et al. Clopidogrel versus ticlopidine after intracoronary stent placement. J Am Coll Cardiol 1999; 34: 1891-4.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 35 Bennett CL, Conners JM, Carwile JM. et al. Thrombotic thrombocytopenic purpura associated with clopidogrel. N Engl J Med 2000; 342: 1773-7.
    CrossrefPubMedGoogle Scholar
  • 36 FitzGerald GA. Dipyridamole. N Engl J Med 1987; 316: 1240-7.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 38 Hervey PS, Goa KL. Extended-release dipyridamole/aspirin. Drugs 1999; 58: 469-75.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 40 Ikeda Y. Antiplatelet therapy using cilostazol, a specific PDE3 inhibitor. Thromb Haemost 1999; 82: 435-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 50 Tcheng JE. Differences among the parenteral platelet glycoprotein IIb/IIIa inhibitors and implications for treatment. Am J Cardiol 1999; 83: 7E-11E.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 61 Madan M, Berkowitz SD. Understanding thrombocytopenia and antigenicity with glycoprotein IIb-IIIa inhibitors. Am Heart J 1999; 138: 317-26.
    CrossrefPubMedGoogle Scholar
  • 62 Berkowitz SD, Harrington RA, Rund MM, Tcheng JE. Acute profound thrombocytopenia after C7E3 Fab (abciximab) therapy. Circulation 1997; 95: 809-13.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 66 IMPACT-II Investigators.. Randomised placebo-controlled trial of effect of eptifibatide on complications of percutaneous coronary intervention. Lancet 1997; 349: 1422-8.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 68 Cook JJ, Bednar B, Lynch Jr JL. et al. Tirofiban (Aggrastat®). Cardiovasc Drug Rev 1999; 17: 199-224.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 71 PRISM Investigators.. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina. N Engl J Med 1998; 338: 1498-505.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 75 Kereiakes DJ. Oral blockade of the platelet glycoprotein IIb/IIIa receptor: fact or fancy?. Am Heart J 1999; 138: S39-S46.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 78 Ferguson JJ. Meeting highlights. Highlights of the 48th scientific sessions of the American College of Cardiology. Circulation 1999; 100: 570-5.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar