Cardiovascular Drugs and Therapy

, Volume 24, Issue 1, pp 61–70 | Cite as

Antiplatelet and Anticoagulant Therapies in Acute Coronary Syndromes

  • Elias B. Hanna
  • David Luke Glancy
  • Jorge F. Saucedo


The combination of aspirin and clopidogrel is the mainstay antiplatelet therapy for acute coronary syndromes (ACS). However, the dosing of aspirin, the dosing of clopidogrel, the timing of clopidogrel initiation as well as the duration of clopidogrel therapy remain controversial matters. Clopidogrel resistance is an emerging concept with potential clinical implications. In the era of clopidogrel and bivalirudin, the role of glycoprotein IIb/IIIa antagonists is being challenged, yet they are still indicated in a select high-risk population. Concerning anticoagulant use in ACS, newer agents, bivalirudin and fondaparinux, have improved outcomes in comparison to heparin in patients managed with an invasive or conservative strategy, respectively. Combining multiple antiplatelet agents and an anticoagulant is the standard of care for ACS.

Key words

Acute coronary syndrome Myocardial infarction Antiplatelet Anticoagulant Aspirin Clopidogrel Prasugrel Ticagrelor Glycoprotein IIb/IIIa antagonist Unfractionated heparin Enoxaparin Bivalirudin Fondaparinux 


  1. 1.
    Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics—2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007;115:e69–e171.CrossRefPubMedGoogle Scholar
  2. 2.
    Théroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med. 1988;319:1105–11.PubMedCrossRefGoogle Scholar
  3. 3.
    The RISC group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary disease. Lancet 1990;336:827–30.CrossRefGoogle Scholar
  4. 4.
    Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomized trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324:71–86.CrossRefGoogle Scholar
  5. 5.
    Peters RJ, Mehta SR, Fox KA, 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 N Engl J Med 2001;345:494–502.Google Scholar
  6. 6.
    Mehta SR, Bassand JP, Chrolavicius S, et al. CURRENT-OASIS 7: a randomized, 2 × 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Presented at the European Society of Cardiology Congress, Barcelona, Spain, August 2009.Google Scholar
  7. 7.
    Anderson JL, Adams CD, Antman EM, et al. ACC/AHA 2007 guidelines for the management of patients with unstable angina/non ST elevation myocardial infarction. J Am Coll Cardiol. 2007;50:1–157.CrossRefGoogle Scholar
  8. 8.
    King 3rd SB, Smith Jr SC, Hirshfeld Jr JW, Jacobs AK, Morrison DA, Williams DO, et al. 2007 focused update of the ACC/AHA/SCAI 2005 guideline update for percutaneous coronary intervention: a report of the American College of Cardiology/American Heart Association Task Force on Practice guidelines. J Am Coll Cardiol. 2008;51:172–209.CrossRefPubMedGoogle Scholar
  9. 9.
    Gurbel PA, Becker RC, Mann KG, et al. Platelet function monitoring in patients with coronary artery disease. J Am Coll Cardiol. 2007;50:1822–34.CrossRefPubMedGoogle Scholar
  10. 10.
    Nguyen TA, Diodati JG, Pharand C. Resistance to clopidogrel: a review of the evidence. J Am Coll Cardiol. 2005;45:1157–64.CrossRefPubMedGoogle Scholar
  11. 11.
    Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK. 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.CrossRefPubMedGoogle Scholar
  12. 12.
    Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, et al. Addition of clopidogrel to aspirin in 45852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet 2005;366:1607–21.CrossRefPubMedGoogle Scholar
  13. 13.
    Sabatine MS, Cannon CP, Gibson CM, López-Sendón JL, Montalescot G, Theroux P, et al. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:1179–89.CrossRefPubMedGoogle Scholar
  14. 14.
    Steinhubl SR, Berger PB, Brennan DM, Topol EJ, for the CREDO Investigators. Optimal timing for the initiation of pre-treatment with 300 mg clopidogrel before percutaneous coronary intervention. J Am Coll Cardiol. 2006;47:939–43.CrossRefPubMedGoogle Scholar
  15. 15.
    Fox KAA, Mehta SR, Peters R, et al. Benefits and risks of the combination of clopidogrel and aspirin in patients undergoing surgical revascularization for non-ST-elevation acute coronary syndrome. The Clopidogrel in Unstable angina to prevent Recurrent ischemic Events (CURE) Trial. Circulation 2004;110:1202–8.CrossRefPubMedGoogle Scholar
  16. 16.
    Bhatt DL, Flather MD, Hacke W, et al. Patients with prior myocardial infarction, stroke, or symptomatic peripheral arterial disease in the CHARISMA trial. J Am Coll Cardiol. 2007;49:1982–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Steinhubl SR, Berger PB, Mann 3rd JT, et al. Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002;288:2411–20.CrossRefPubMedGoogle Scholar
  18. 18.
    Mehta SR, Yusuf S, Peters RJ, 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;358:527–33.CrossRefPubMedGoogle Scholar
  19. 19.
    Ong ATL, McFadden EP, Regar E, et al. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol. 2005;45:2088–92.CrossRefPubMedGoogle Scholar
  20. 20.
    Berger JS, Frye CB, Harshaw Q, Edwards FH, Steinhubl SR, Becker RC. Impact of clopidogrel in patients with acute coronary syndromes requiring coronary artery bypass surgery: a multicenter analysis. J Am Coll Cardiol. 2008;52:1693–701.CrossRefPubMedGoogle Scholar
  21. 21.
    Ebrahimi R, Dyke C, Mehran R, et al. Outcomes following pre-operative clopidogrel administration in patients with acute coronary syndromes undergoing coronary artery bypass surgery: the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol. 2009;53:1965–72.CrossRefPubMedGoogle Scholar
  22. 22.
    Serebruany VL, Steinhubl SR, Berger PB, et al. Variability in platelet responsiveness to clopidogrel among 544 individuals. J Am Coll Cardiol. 2005;45:246–51.CrossRefPubMedGoogle Scholar
  23. 23.
    Sibbing D, Braun S, Morath T, et al. Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis. J Am Coll Cardiol. 2009;53:849–56.CrossRefPubMedGoogle Scholar
  24. 24.
    von Beckerath N, von Beckerath O, Koch W, Eichinger M, Schömig A, Kastrati A. P2Y12 gene H2 haplotype is not associated with increased adenosine diphosphate-induced platelet aggregation after initiation of clopidogrel therapy with a high loading dose. Blood Coagul Fibrinolysis. 2005;16:199–204.CrossRefGoogle Scholar
  25. 25.
    Wallentin L, Varenhorst C, James S, et al. Prasugrel achieves greater and faster P2Y12receptor-mediated platelet inhibition than clopidogrel due to more efficient generation of its active metabolite in aspirin-treated patients with coronary artery disease. Eur Heart J. 2008;29:21–30.CrossRefPubMedGoogle Scholar
  26. 26.
    Trenk D, Hochholzer W, Fromm MF, et al. Cytochrome P450 2C19 polymorphism and high on-clopidogrel platelet reactivity associated with adverse 1-year clinical outcome of elective percutaneous coronary intervention with drug-eluting or bare-metal stents. J Am Coll Cardiol. 2008;51:1925–34.CrossRefPubMedGoogle Scholar
  27. 27.
    Simon T, Verstuyft C, Mary-Krause M. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009;360:363–75.CrossRefPubMedGoogle Scholar
  28. 28.
    Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009;360:354–62.CrossRefPubMedGoogle Scholar
  29. 29.
    Ho PM, Maddox TM, Wang L, et al. Risk of adverse outcomes associated with concomitant use of clopidogrel and proton pump inhibitors following acute coronary syndrome. JAMA 2009;301:937–44.CrossRefPubMedGoogle Scholar
  30. 30.
    O’Donoghue ML, Braunwald E, Antman EM, et al. Pharmacodynamic effect and clinical efficacy of clopidogrel and prasugrel with or without a proton-pump inhibitor: an analysis of two randomised trials. Lancet 2009;374:989–97.CrossRefPubMedGoogle Scholar
  31. 31.
    Clopidogrel and the optimization of gastro-intestinal events trial (COGENT trial). Presented by Bhatt D at the Transcatheter Cardiovascular Therapeutics meeting (TCT 2009), San Francisco, CA, September 24, 2009.Google Scholar
  32. 32.
    Saw J, Steinhubl SR, Berger PB, et al. Lack of adverse clopidogrel-atorvastatin clinical interaction from secondary analysis of a randomized, placebo-controlled clopidogrel trial. Circulation 2003;108:921–4.CrossRefPubMedGoogle Scholar
  33. 33.
    Campo J, Valgimigli M, Gemmati D. Poor responsiveness to clopidogrel: drug-specific or class-effect mechanism? Evidence from a clopidogrel-to-ticlopidine crossover study. J Am Coll Cardiol. 2007;50:1132–7.CrossRefPubMedGoogle Scholar
  34. 34.
    Bonello L, Camoin-Jau L, Arques S, et al. Adjusted clopidogrel loading doses according to vasodilator-stimulated phosphoprotein phosphorylation index decrease rate of major adverse cardiovascular events in patients with clopidogrel resistance: a multicenter randomized prospective study. J Am Coll Cardiol. 2008;51:1404–11.CrossRefPubMedGoogle Scholar
  35. 35.
    Chen W, Lee P, Ng W, et al. Aspirin resistance is associated with a high incidence of myonecrosis after non-urgent percutaneous coronary intervention despite clopidogrel pretreatment. J Am Coll Cardiol. 2004;43:1122–6.CrossRefPubMedGoogle Scholar
  36. 36.
    Brandt JT, Payne CD, Wiviott SD, et al. A comparison of prasugrel and clopidogrel loading doses on platelet function: magnitude of platelet inhibition is related to active metabolite formation. Am Heart J. 2007;153:66.e9–66.e16.CrossRefGoogle Scholar
  37. 37.
    Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357:2001–15.CrossRefPubMedGoogle Scholar
  38. 38.
    O'Donoghue M, Antman EM, Braunwald E, et al. The efficacy and safety of prasugrel with and without a glycoprotein IIb/IIIa inhibitor in patients with acute coronary syndromes undergoing percutaneous interventionA TRITON–TIMI 38 (Trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel–thrombolysis in myocardial infarction 38) analysis. J Am Coll Cardiol. 2009;54:678–85.Google Scholar
  39. 39.
    Wiviott SD, Braunwald E, Angiolillo DJ, et al. Greater clinical benefit of more intensive oral antiplatelet therapy with prasugrel in patients with diabetes mellitus in the trial to assess improvement in therapeutic outcomes by optimizing platelet inhibition with prasugrel-thrombolysis in myocardial infarction 38. Circulation 2008;118:1626–36.CrossRefPubMedGoogle Scholar
  40. 40.
    Montalescot G, Wiviott SD, Braunwald E, et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. Lancet 2009;373:723–31.CrossRefPubMedGoogle Scholar
  41. 41.
    Bhatt DL. Prasugrel in clinical practice. N Engl J Med. 2009;361:940–2.CrossRefPubMedGoogle Scholar
  42. 42.
    Husted S, Emanuelsson H, Heptinstall S, Sandset PM, Wickens M, Peters G. Pharmacodynamics, pharmacokinetics, and safety of the oral reversible P2Y12 antagonist AZD6140 with aspirin in patients with atherosclerosis: a double-blind comparison to clopidogrel with aspirin. Eur Heart J. 2006;27:1038–47.CrossRefPubMedGoogle Scholar
  43. 43.
    Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361:1045–57.CrossRefPubMedGoogle Scholar
  44. 44.
    The 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.CrossRefGoogle Scholar
  45. 45.
    The 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, 199730.Google Scholar
  46. 46.
    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;338:1488–97.CrossRefGoogle Scholar
  47. 47.
    Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet 2002;359:189–98.CrossRefPubMedGoogle Scholar
  48. 48.
    Kastrati A, Mehilli J, Neumann FJ, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: the ISAR REACT 2 randomized trial. JAMA 2006;295:1531–8.CrossRefPubMedGoogle Scholar
  49. 49.
    Stone GW, McLaurin BT, Cox DA, et al. Bivalirudin for patients with acute coronary syndromes. N Engl J Med. 2006;355:2203–16, (ACUITY trial).CrossRefPubMedGoogle Scholar
  50. 50.
    Ellis SG, Tendera M, de Belder MA, et al. Facilitated PCI in patients with ST-elevation myocardial infarction. N Engl J Med. 2008;358:2205–17.CrossRefPubMedGoogle Scholar
  51. 51.
    Giugliano RP, White JA, Boden C, et al. Early versus delayed, provisional eptifibatide in acute coronary syndromes. N Engl J Med. 2009;360:2176–90.CrossRefPubMedGoogle Scholar
  52. 52.
    Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin reduces the incidence of myocardial infarction and death in patients with unstable angina. A meta-analysis. JAMA 1996;276:811–5.CrossRefPubMedGoogle Scholar
  53. 53.
    Goodman SG, Barr A, Sobtchouk A, et al. Low molecular weight heparin decreases rebound ischemia in unstable angina or non-Q-wave myocardial infarction: the Canadian ESSENCE ST segment monitoring substudy. J Am Coll Cardiol. 2000;36:1507–13.CrossRefPubMedGoogle Scholar
  54. 54.
    Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. Efficacy and safety of subcutaneous enoxaparin in non-Q-wave coronary events study group. N Engl J Med. 1997;337:447–52.CrossRefPubMedGoogle Scholar
  55. 55.
    Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Qwave myocardial infarction: results of the Thrombolysis In Myocardial Infarction (TIMI) 11B trial. Circulation 1999;100:1593–601.PubMedGoogle Scholar
  56. 56.
    SYNERGY Trial Investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA 2004;292:45–54.CrossRefGoogle Scholar
  57. 57.
    Sanderink G, Le Liboux A, Jariwala N, et al. The pharmacokinetics and pharmacodynamics of enoxaparin in obese volunteers. Clin Pharmacol Ther. 2002;72:308–18.Google Scholar
  58. 58.
    Levine GN, Ferrando T. Degree of anticoagulation after one subcutaneous and one subsequent intravenous booster dose of enoxaparin: implications for patients with acute coronary syndromes undergoing early percutaneous coronary intervention. J Thromb Thrombolysis. 2004;17:167–71.CrossRefPubMedGoogle Scholar
  59. 59.
    Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354:1477–88.CrossRefPubMedGoogle Scholar
  60. 60.
    Antman E, Hand M, Armstrong PW, et al. Focused update of the ACC/AHA 2004 guidelines for the management of patients with ST-elevation myocardial infarction. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2008;51:210–47.CrossRefPubMedGoogle Scholar
  61. 61.
    Feit F, Manoukian SV, Ebrahimi R, et al. Safety and efficacy of bivalirudin monotherapy in patients with diabetes mellitus and acute coronary syndromes: a report from the ACUITY (Acute Catheterization and Urgent Intervention Triage Strategy) trial. J Am Coll Cardiol. 2008;51:1645–52.CrossRefPubMedGoogle Scholar
  62. 62.
    White HD, Chew DP, Hoekstra JW, et al. Safety and efficacy of switching from either unfractionated heparin or enoxaparin to bivalirudin in patients with non-ST-segment elevation acute coronary syndromes managed with an invasive strategy: results from the ACUITY (Acute Catheterization and Urgent Intervention Triage strategY) trial. J Am Coll Cardiol. 2008;51:1734–41.CrossRefPubMedGoogle Scholar
  63. 63.
    Stone GW, Witzenbichler B, Guagliumi G, et al. Bivalirudin during primary PCI in acute myocardial infarction. N Engl J Med. 2008;358:2218–30.CrossRefPubMedGoogle Scholar
  64. 64.
    Mehran R, Lansky AJ, Witzenbichler B, et al. Bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction (HORIZONS-AMI): 1-year results of a randomised controlled trial. Lancet 2009;374:1149–59.CrossRefPubMedGoogle Scholar
  65. 65.
    Yusuf S, Mehta SR, Chrolavicius S, et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:1464–76, (OASIS 5 trial).CrossRefPubMedGoogle Scholar
  66. 66.
    Mehta SR, Boden WE, Eikelboom JW, et al. Antithrombotic therapy with fondaparinux in relation to interventional management strategy in patients with ST- and non-ST-segment elevation acute coronary syndromes: an individual patient-level combined analysis of the fifth and sixth organization to assess strategies in ischemic syndromes (OASIS 5 and 6) randomized trials. Circulation 2008;118:2038–46.CrossRefPubMedGoogle Scholar
  67. 67.
    The OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 2006;295:1519–30.CrossRefGoogle Scholar
  68. 68.
    Fox KA, Antman EM, Montalescot G, et al. The impact of renal dysfunction on outcomes in the ExTRACT-TIMI 25 trial. J Am Coll Cardiol. 2007;49:2249–55.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Elias B. Hanna
    • 1
  • David Luke Glancy
    • 2
  • Jorge F. Saucedo
    • 3
  1. 1.Cardiology DepartmentOklahoma UniversityOklahoma CityUSA
  2. 2.Cardiology DepartmentLouisiana State UniversityNew OrleansUSA
  3. 3.Cardiology DepartmentOklahoma UniversityOklahoma CityUSA

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