Semin Vasc Med 2003; 03(4): 403-414
DOI: 10.1055/s-2004-817689

Copyright © 2003 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA. Tel.: +1(212) 584-4662

Antiplatelet Agents in Acute Coronary Syndromes

John W. Eikelboom1 , Sonia Anand2
  • 1Department of Haematology, Royal Perth Hospital and Department of Medicine, University of Western Australia, Crawley, WA, Australia
  • 2Division of Cardiology, Department of Medicine, McMaster University, Hamilton, ON, Canada
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03. Februar 2004 (online)


Plaque disruption, platelet activation, and intracoronary artery thrombus formation are the key events in the pathogenesis of acute coronary syndromes. Antiplatelet therapies significantly reduce the risk of ischemic complications both during the acute phase and in the long term in patients with acute coronary syndromes. Aspirin remains the cornerstone of antiplatelet therapy, but there is incremental benefit when clopidogrel or ticlopidine is added to aspirin. Dual antiplatelet therapy with the combination of clopidogrel and aspirin is becoming the new standard of care for the management of patients with non-ST-segment elevation acute coronary syndrome and undergoing percutaneous coronary intervention and is currently being further evaluated in ST-segment elevation acute coronary syndrome.


  • 1 Fuster V, Badimon L, Badimon J J, Chesebro J H. The pathogenesis of coronary artery disease and the acute coronary syndromes (1).  N Engl J Med . 1992;  326 242-250
  • 2 Fuster V, Badimon L, Badimon J J, Chesebro J H. The pathogenesis of coronary artery disease and the acute coronary syndromes (2).  N Engl J Med . 1992;  326 310-318
  • 3 Furie B, Furie B C. Molecular and cellular biology of blood coagulation.  N Engl J Med . 1992;  326 800-806
  • 4 Fuster V, Lewis A. Conner Memorial Lecture. Mechanisms leading to myocardial infarction: insights from studies of vascular biology.  Circulation . 1994;  90 2126-2146
  • 5 Falk E, Shah P K, Fuster V. Coronary plaque disruption.  Circulation . 1995;  92 657-661
  • 6 Weiss H J, Turitto V T, Baumgartner H R. Effect of shear rate on platelet interaction with subendothelium in citrated and native blood. I. Shear rate-dependent decrease of adhesion in von Willebrand's disease and the Bernard-Soulier syndrome.  J Lab Clin Med . 1978;  92 750-764
  • 7 Patrono C, Coller B, Dalen J E. et al . Platelet-active drugs: the relationships among dose, effectiveness, and side effects.  Chest . 2001;  119 39S-63S
  • 8 Antithrombotic Trialists' Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients.  BMJ . 2002;  324 71-86
  • 9 US Preventive Services Task Force. Aspirin for the primary prevention of cardiovascular events: recommendation and rationale.  Ann Intern Med . 2002;  136 157-160
  • 10 Yusuf S, Zhao F, Mehta S R, Chrolavicius S, Tognoni G, Fox K K. The Clopidogrel in Unstable Angina to Prevent Recurrent Events Trial Investigators. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.  N Engl J Med . 2001;  345 494-502
  • 11 White H D. on behalf of the Hirulog and Early Reperfusion or Occlusion (HERO) Study Group. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial.  Lancet . 2001;  358 1855-1863
  • 12 Ault K A, Cannon C P, Mitchell J. et al . Platelet activation after acute coronary syndrome. Results of the TIMI-12 trial.  J Am Coll Cardiol . 1999;  33 634-639
  • 13 Eikelboom J W, Weitz J I, Budaj A. for the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Study Investigators. et al. Clopidogrel does not suppress blood markers of coagulation activation in aspirin-treated patients with non-ST-elevation acute coronary syndromes.  Eur Heart J . 2002;  23 1771-1779
  • 14 Weitz J I, Hirsh J. New antithrombotic drugs. In: Colman RW, Hirsh J, Marder VJ, Clowes AW, George JN, eds. Hemostasis and Thrombosis }Basic Principles and Clinical Practice. Philadelphia: Lippincott Williams & Wilkins; 2001: 1529-1544
  • 15 Awtry E H, Loscalzo J. Aspirin.  Circulation . 2000;  101 1206-1218
  • 16 Clarke R J, Mayo G, Price P, Fitzgerald G A. Suppression of thromboxane A2 but not of systemic prostacyclin by controlled-release aspirin.  N Engl J Med . 1991;  325 1137-1141
  • 17 Jaffe E A, Weksler B B. Recovery of endothelial cell prostacyclin production after inhibition by low doses of aspirin.  J Clin Invest . 1979;  63 532-535
  • 18 Ratnatunga C P, Edmondson S F, Rees G M, Kovacs I B. High-dose aspirin inhibits shear-induced platelet reaction involving thrombin generation.  Circulation . 1992;  85 1077-1082
  • 19 Buchanan M R, Rischke J A, Hirsh J. Aspirin inhibits platelet function independent of the acetylation of cyclo-oxygenase.  Thromb Res . 1982;  25 363-373
  • 20 Santos M T, Moscardo A, Valles J. et al . Participation of tyrosine phosphorylation in cytoskeletal reorganization, alpha(IIb) beta(3) integrin receptor activation, and aspirin-insensitive mechanisms of thrombin-stimulated human platelets.  Circulation . 2000;  102 1924-1930
  • 21 Moroz L A. Increased blood fibrinolytic activity after aspirin ingestion.  N Engl J Med . 1977;  296 525-529
  • 22 Szczeklik A, Krzanowski M, Gora P, Radwan J. Antiplatelet therapy and the generation of thrombin in clotting blood.  Blood . 1992;  80 2006-2011
  • 23 Kessels H, Beguin S, Andree H, Hemker H C. Measurement of thrombin generation in whole blood: the effect of heparin and aspirin.  Thromb Haemost . 1994;  72 78-83
  • 24 Szczeklik A, Musial J, Undas A. et al . Inhibition of thrombin generation by aspirin is blunted in hypercholesterolemia.  Arterioscler Thromb Vasc Biol . 1996;  16 948-954
  • 25 Santos M T, Valles J, Aznar J, Marcus A J, Broekman M J, Safier L B. Prothrombotic effects of erythrocytes on platelet reactivity: reduction by aspirin.  Circulation . 1997;  95 63-68
  • 26 Valles J, Santos M T, Aznar J. et al . Erythrocyte promotion of platelet reactivity decreases the effectiveness of aspirin as an antithrombotic therapeutic modality: the effect of low-dose aspirin is less than optimal in patients with vascular disease due to prothrombotic effects of erythrocytes on platelet reactivity.  Circulation . 1998;  97 350-355
  • 27 Podhaisky H P, Abate A, Polte T, Oberle S, Schroder H. Aspirin protects endothelial cells from oxidative stress: possible synergism with vitamin E.  FEBS Lett . 1997;  417 349-351
  • 28 Husain S, Andrews N P, Mulcahy D, Panza J A, Quyyumi A A. Aspirin improves endothelial dysfunction in atherosclerosis.  Circulation . 1998;  97 716-720
  • 29 Ridker P M, Cushman M, Stampfer M J, Tracy R P, Hennekens C H. Inflammation, aspirin, and the risk of cardiovascular disease in apparently healthy men.  N Engl J Med . 1997;  336 973-979
  • 30 Aukrust P, Waehre T, Damas J K, Gullestad L, Solum N O. Inflammatory role of platelets in acute coronary syndromes.  Heart . 2001;  86 605-606
  • 31 Jimenez A H, Stubbs M E, Tofler G H, Winther K, Williams G H, Muller J E. Rapidity and duration of platelet suppression by enteric-coated aspirin in healthy young individuals.  Am J Cardiol . 1992;  69 258-262
  • 32 Weksler B B, Pett S B, Alonso D. et al . Differential inhibition by aspirin of vascular and platelet prostaglandin synthesis in atherosclerotic patients.  N Engl J Med . 1983;  308 800-805
  • 33 Quinn M J, Fitzgerald D J. Ticlopidine and clopidogrel.  Circulation . 1999;  100 1667-1672
  • 34 Foster C J, Prosser D M, Agans J M. et al . Molecular identification and characterization of the platelet ADP receptor targeted by thienopyridine antithrombotic drugs.  J Clin Invest . 2001;  107 1591-1598
  • 35 Savi P, Pereillo J M, Uzabiaga J. et al . Identification and biological activity of the active metabolite of clopidogrel.  Thromb Haemost . 2000;  84 891-896
  • 36 Pereillo J M, Maftouh M, Andrieu A. et al . Structure and stereochemistry of the active metabolite of clopidogrel.  Drug Metab Dispos . 2002;  30 1288-1295
  • 37 Gent M, Blakely J A, Easton J D. et al . The Canadian American Ticlopidine Study (CATS) in thromboembolic stroke.  Lancet . 1989;  1 1215-1220
  • 38 Bhatt D L, Bertrand M E, Berger P B. et al . Meta-analysis of randomized and registry comparisons of ticlopidine with clopidogrel after stenting.  J Am Coll Cardiol . 2002;  39 9-14
  • 39 CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.  Lancet . 1996;  348 1329-1339
  • 40 Harker L A, Boissel J-P, Pilgrim A J, Gent M, on behalf of the CAPRIE steering committee and investigators. Comparative safety and tolerability of clopidogrel and aspirin. Results from CAPRIE.  Drug Saf . 1999;  21 325-335
  • 41 Boneu B, Destelle G. Platelet anti-aggregatory activity and tolerance of clopidogrel in atherosclerotic patients.  Thromb Haemost . 1996;  76 939-943
  • 42 Pache J, Kastrati A, Mehilli J. et al . Clopidogrel therapy in patients undergoing coronary stenting: value of a high-loading-dose regimen.  Catheter Cardiovasc Interv . 2002;  55 436-441
  • 43 Simoons M L. Effect of glycoprotein IIb/IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularisation: the GUSTO IV-ACS randomised trial.  Lancet . 2001;  357 1915-1924
  • 44 Topol E J. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial.  Lancet . 2001;  357 1905-1914
  • 45 PURSUIT trial investigators. Inhibition of glycoprotein IIb/ IIIa with eptifibatide in patients with acute coronary syndromes.  N Engl J Med . 1998;  339 436-443
  • 46 Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) Study Investigators. A comparison of aspirin plus tirofiban with aspirin plus heparin for unstable angina.  N Engl J Med . 1998;  338 1498-1505
  • 47 Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) Study 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 1488-1497
  • 48 Bhatt D L, Topol E J. Current role of platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes.  JAMA . 2000;  284 1549-1558
  • 49 Boersma E, Harrington R A, Moliterno D J. et al . Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials.  Lancet . 2002;  359 189-198
  • 50 Chew D P, Bhatt D L, Sapp S, Topol E J. Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials.  Circulation . 2001;  103 201-206
  • 51 Leebeek F W, Boersma E, Cannon C P, van de Werf J F, Simoons M L. Oral glycoprotein IIb/IIIa receptor inhibitors in patients with cardiovascular disease: why were the results so unfavourable.  Eur Heart J . 2002;  23 444-457
  • 52 Quinn M J, Plow E F, Topol E J. Platelet glycoprotein IIb/IIIa inhibitors: recognition of a two-edged sword?.  Circulation . 2002;  106 379-385
  • 53 Maree A, Fitzgerald D. Glycoprotein IIb/IIIa inhibitors in acute coronary syndromes. Semin Vasc Med 3:385-390
  • 54 Elwood P C, Williams W O. A randomised controlled trial of aspirin in the prevention of early mortality in myocardial infarction.  J R Coll Gen Pract . 1979;  29 413-416
  • 55 Elwood P C. Early use of aspirin.  Lancet . 1990;  335 486
  • 56 Verheugt F W, Kupper A J, Galema T W, Roos J P. Low dose aspirin after early thrombolysis in anterior wall acute myocardial infarction.  Am J Cardiol . 1988;  61 904-906
  • 57 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised factorial trial of high-dose intravenous streptokinase, or oral aspirin and of intravenous heparin in acute myocardial infarction.  Eur Heart J . 1987;  8 634-642
  • 58 ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2.  Lancet . 1988;  2 349-360
  • 59 Baigent C, Collins R, Appleby P, Parish S, Sleight P, Peto R. ISIS-2: 10 year survival among patients with suspected acute myocardial infarction in randomised comparison of intravenous streptokinase, oral aspirin, both, or neither.  BMJ . 1998;  316 1337-1343
  • 60 Elwood P C, Cochrane A L, Burr M L. et al . A randomized controlled trial of acetylsalicylic acid in the secondary prevention of mortality from myocardial infarction.  BMJ . 1974;  1 436-440
  • 61 The Coronary Drug Project Research Group. Aspirin in coronary heart disease.  J Chronic Dis . 1976;  29 625-642
  • 62 Elwood P C, Sweetnam P M. Aspirin and secondary mortality after myocardial infarction.  Lancet . 1979;  2 1313-1315
  • 63 The Persantine-Aspirin Reinfarction Study Research Group. Persantine and aspirin in coronary heart disease.  Circulation . 1980;  62 449-461
  • 64 The Aspirin Myocardial Infarction Study Research Group. The Aspirin Myocardial Infarction Study: final results.  Circulation . 1980;  62 (suppl V) 79-84
  • 65 Breddin K, Loew D, Lechner K, Oberla K, Walter E. The German-Austrian Aspirin Trial: a comparison of acetylsalicylic acid, placebo, and phenprocoumon in secondary prevention of myocardial infarction. On behalf of the German-Austrian Study Group.  Circulation . 1980;  62(6 Pt 2) V63-72
  • 66 The EPSIM Research Group. A controlled comparison of aspirin and oral anticoagulants in prevention of death after myocardial infarction.  N Engl J Med . 1982;  307 701-708
  • 67 Julian D G, Chamberlain D A, Pocock S J. A comparison of aspirin and anticoagulation following thrombolysis for myocardial infarction (the AFTER study): a multicentre unblinded randomised clinical trial.  BMJ . 1996;  313 1429-1431
  • 68 Hurlen M, Abdelnoor M, Smith P, Erikssen J, Arnesen H. Warfarin, aspirin, or both after myocardial infarction.  N Engl J Med . 2002;  347 969-974
  • 69 Van Es F R, Jonker J JC, Verheugt F WA, Deckers J W, Grobbee D E. for the Antithrombotics in the Secondary Prevention of Events in Coronary Thrombosis-2 (ASPECT-2) Research Group. Aspirin and coumadin after acute coronary syndromes (the ASPECT-2 study): a randomised controlled trial.  Lancet . 2002;  360 109-113
  • 70 Anand S S, Yusuf S. Oral anticoagulant therapy in patients with coronary artery disease: a meta-analysis.  JAMA . 1999;  282 2058-2067
  • 71 Ryan T J, Antman E M, Brooks N H. et al . ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary and recommendation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction).  Circulation . 1999;  100 1016-1030
  • 72 Cairns J A, Theroux P, Lewis H D, Ezekowitz M, Meade T W. Antithrombotic agents in coronary artery disease.  Chest . 2001;  119 228S-252S
  • 73 Lewis H D, Davis J W, Archibald D G. et al . Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina.  N Engl J Med . 1983;  309 396-403
  • 74 Cairns J A, Gent M, Singer J. et al . Aspirin, sulfinpyrazone, or both in unstable angina: results of a Canadian multicenter trial.  N Engl J Med . 1985;  313 1369-1375
  • 75 Théroux P, Ouimet H, McCans J. et al . Aspirin, heparin, or both to treat acute unstable angina.  N Engl J Med . 1988;  319 1105-1111
  • 76 The 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;  336 827-830
  • 77 Wallentin L C. and the Research Group on Instability in Coronary Artery Disease in Southeast Sweden. Aspirin (75 mg/day) after an episode of unstable coronary artery disease: long-term effects on the risk for myocardial infarction, occurrence of severe angina and the need for revascularization.  J Am Coll Cardiol . 1991;  18 1587-1593
  • 78 Nyman I, Larsson H, Wallentin L. and the Research Group on Instability in Coronary Artery Disease in Southeast Sweden. Prevention of serious cardiac events by low-dose aspirin in patients with silent myocardial ischaemia.  Lancet . 1992;  340 497-501
  • 79 Theroux P, Waters D, Qiu S, McCans J, de Guise P, Juneau M. Aspirin versus heparin to prevent myocardial infarction during the acute phase of unstable angina.  Circulation . 1993;  88(5 Pt 1) 2045-2048
  • 80 Serneri G GN, Gensini G F, Poggesi L. et al . Effect of heparin, aspirin, or alteplase in reduction of myocardial ischaemia in refractory unstable angina.  Lancet . 1990;  335 615-618
  • 81 Eikelboom J W, Anand S, Malmberg K, Weitz J, Ginsberg J, Yusuf S. Unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) in unstable angina and non-Q-wave myocardial infarction (NQMI): a meta-analysis.  Lancet . 2000;  355 1936-1942
  • 82 Balsano F, Rizzon P, Violi F. et al . Antiplatelet treatment with ticlopidine in unstable angina: a controlled multicenter clinical trial. The studio della Ticlopidina nell'Angina Instabile Group.  Circulation . 1990;  82 17-26
  • 83 Peters R J, Mehta S R, Fox K A. et al . Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study.  Circulation . 2003;  108 1682-1687
  • 84 Braunwald E, Antman E M, Beasley J W. et al . ACC/AHA 2002 guideline updates for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina).  Circulation . 2002;  106 1893-1900
  • 85 Popma J J, Ohman M, Weitz J, Lincoff M, Harrington R A, Berger P. Antithrombotic therapy in patients undergoing percutaneous coronary intervention.  Chest . 2001;  119 321-336
  • 86 Serruys P W, Strauss B H, Beatt K J. et al . Angiographic follow-up after placement of a self-expanding coronary artery stent.  N Engl J Med . 1991;  324 13-17
  • 87 Schwartz L, Bourassa M G, Lesperance J. et al . Aspirin and dipyridamole in the prevention of restenosis after percutaneous transluminal coronary angioplasty.  N Engl J Med . 1988;  318 1714-1719
  • 88 Lembo N J, Black A J, Roubin G S. et al . Effect of pretreatment with aspirin versus aspirin plus dipyridamole on frequency and type of acute complications of percutaneous transluminal coronary angioplasty.  Am J Cardiol . 1990;  65 422-426
  • 89 Smith S C, Dove J T, Jacobs A K. et al . ACC/AHA guidelines for percutaneous coronary intervention: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1993 Guidelines for Percutaneous Transluminal Coronary Angioplasty).  Circulation . 2001;  103 3019-3041
  • 90 Urban P, Macaya C, Rupprecht H J. et al . Randomized evaluation of anticoagulation versus antiplatelet therapy after coronary stent implantation in high-risk patients: the Multicenter Aspirin and Ticlopidine Trial after Intracoronary Stenting (MATTIS).  Circulation . 1998;  98 2126-2132
  • 91 Bertrand M E, Legrand V, Boland J. et al . Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (fantastic) study.  Circulation . 1998;  98 1597-1603
  • 92 Leon M B, Baim D S, Popma J J. 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 1665-1671
  • 93 Schomig A, Neumann F J, 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 1084-1089
  • 94 Berger P B, Bell M R, Grill D E, Melby S, Holmes Jr R D. Frequency of adverse clinical events in the 12 months following successful intracoronary stent placement in patients treated with aspirin and ticlopidine (without warfarin).  Am J Cardiol . 1998;  81 713-718
  • 95 Steinhubl S, Lauer M, Mukherjee D. et al . The duration of pretreatment with ticlopidine prior to stenting is associated with the risk of procedure-related non-Q-wave myocardial infarctions.  J Am Coll Cardiol . 1998;  32 1366-1370
  • 96 Bertrand M E, Rupprecht H-J, Urban P, Gershlick A H, for the CLASSICS Investigators. Double-blind study of the safety of clopidogrel with and without a loading dose in combination with aspirin compared with ticlopidine in combination with aspirin after coronary stenting. The Clopidogrel Aspirin Stent International Cooperative Study (CLASSICS).  Circulation . 2000;  102 624-629
  • 97 Muller C, Buttner H J, Petersen J, Roskamm H. A randomized comparison of clopidogrel and aspirin versus ticlopidine and aspirin after the placement of coronary-artery stents.  Circulation . 2000;  101 590-593
  • 98 Steinhubl S R, Berger P B, Mann J T, for the CREDO Investigators. et al . Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention. A randomized controlled trial.  JAMA . 2002;  288 2411-2420
  • 99 Mehta S R, Yusuf S, Peters R J. and the Clopidogrel in Unstable angina to prevent Recurrent Events trial (CURE) Investigators et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study.  Lancet . 2001;  358 527-533