Current Cardiology Reports

, Volume 6, Issue 4, pp 279–286

Current concepts in the antithrombotic management of non-ST-elevation acute coronary syndromes

  • David E. Kandzari
Article

Abstract

The recognition that thrombosis is fundamental to acute coronary syndromes (ACS) has inspired the development of novel therapies to inhibit platelet aggregation and thrombus formation. Several recent advances have been made in the management of patients with non-ST-segment elevation ACS (NSTE ACS) to improve early and late clinical outcomes. The research efforts leading to these improvements in care have focused on antiplatelet and anticoagulant therapies coupled with early invasive treatment options. In particular, ongoing clinical trials seek to refine treatment strategies for patients relative to individual risk presentation, the availability of facilities for invasive procedures, and the timing of revascularization. However, even despite the proven efficacy of currently available therapies to reduce the occurrence of death and/or myocardial infarction, still many eligible patients with high-risk NSTE ACS do not receive such treatments. This review provides a pathophysiologic rationale for antithrombotic therapies in ACS, examines the results of recent trials, and presents future directions for clinical investigation.

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References and Recommended Reading

  1. 1.
    Tufts Center for the Study of Drug Development: Cost of a new prescription medicine. Available at http://www.tufts.edu/med/ csdd/Nov30CostStudyPressRelease.html. November 30, 2001.Google Scholar
  2. 2.
    Peterson ED, Pollack CV, Roe MT, et al.: Early use of glycoprotein IIb/IIIa inhibitors in non-ST- elevation acute myocardial infarction. J Am Coll Cardiol 2003, 42:45–53. These observational data from the National Registry of Myocardial Infarction-4 indicate that among patients with NSTEMI, early treatment with intravenous GP IIb/IIIa inhibitors within 24 hours of presentation is associated with significant reductions in in-hospital mortality. Despite these proven benefits, only 25% of eligible patients received such treatment, underscoring the need for improvements in health care delivery and adherence to practice guidelines.PubMedCrossRefGoogle Scholar
  3. 3.
    Jencks SF, Huff ED, Cuerdon T: Change in the quality of care delivered to Medicare beneficiaries, 1998-1999 to 2000-2001. JAMA 2003, 289:305–312.PubMedCrossRefGoogle Scholar
  4. 4.
    Fuster V, Badimon L, Badimon JJ, Chesebro JH: The pathogenesis of coronary artery disease and the acute coronary syndrome. N Engl J Med 1992, 326:242–250, 310–318.PubMedCrossRefGoogle Scholar
  5. 5.
    Lefkovits J, Plow EF, Topol EJ: Platelet glycoprotein IIb/IIIa receptors in cardiovascular medicine. N Engl J Med 1995, 332:1553–1559.PubMedCrossRefGoogle Scholar
  6. 6.
    Naghavi M, Libby P, Falk E, et al.: From vulnerable plaque to vulnerable patient: a call for new definitions and risk assessment strategies: Part I. Circulation 2003, 108:1664–1672.PubMedCrossRefGoogle Scholar
  7. 7.
    Zarrabi A, Gul K, Willerson JT, et al.: Intravascular thermography: a novel approach for detection of vulnerable plaque. Curr Opin Cardiol 2002, 17:656–662.PubMedCrossRefGoogle Scholar
  8. 8.
    Heistad DD: Unstable coronary artery plaques. N Engl J Med 2003, 349:2285–2287.PubMedCrossRefGoogle Scholar
  9. 9.
    Kolodgie FD, Gold HK, Burke AP, et al.: Intraplaque hemorrhage and progression of coronary atheroma. N Engl J Med 2003, 349:2316–2325.PubMedCrossRefGoogle Scholar
  10. 10.
    Goldstein JA, Demetriou D, Grines CL, et al.: Multiple complex coronary plaques in patients with acute myocardial infarction. N Engl J Med 2000, 343:915–922.PubMedCrossRefGoogle Scholar
  11. 11.
    Maehara A, Mintz GS, Bui AB, et al.: Morphologic and angiographic features of coronary plaque rupture detected by intravascular ultrasound. J Am Coll Cardiol 2002, 40:902–910.CrossRefGoogle Scholar
  12. 12.
    Heeschen C, Dimmeler S, Hamm CW, et al., for the CAPTURE Study Investigators: Soluble CD40 ligand in acute coronary syndromes. N Engl J Med 2003, 348:1104–1111. In this substudy of 1088 patients with NSTE ACS, escalating levels of plasma CD40L were independently associated with the occurrence of death or MI from the time of initial hospitalization through 6 months. Treatment with abciximab attenuated the risk among patients with the highest CD40L concentrations to approximate the risk of those with the lowest CD40L levels. These findings highlight the nature of systemic inflammation in ACS and the predictive role of inflammatory markers.PubMedCrossRefGoogle Scholar
  13. 13.
    Buffon A, Biasucci LM, Liuzzo G, et al.: Widespread coronary inflammation in unstable angina. N Engl J Med 2002, 347:5–12.PubMedCrossRefGoogle Scholar
  14. 14.
    Kereiakes DJ: The fire that burns within: C-reactive protein. Circulation 2003, 107:373–374.PubMedCrossRefGoogle Scholar
  15. 15.
    Blankenberg S, Luc G, Ducimetière P, et al., on behalf of the PRIME study group: Interleukin-18 and the risk of coronary heart disease in European men: the Prospective Epidemiological Study of Myocardial Infarction (PRIME). Circulation 2003, 108:2453–2459.PubMedCrossRefGoogle Scholar
  16. 16.
    Varo N, de Lemos JA, Libby P, et al.: Soluble CD40L: risk prediction after acute coronary syndromes. Circulation 2003, 108:1049–1052.PubMedCrossRefGoogle Scholar
  17. 17.
    André P, Prasad KS, Denis CV, et al.: CD40L stabilizes arterial thrombi by a beta3 integrin-dependent mechanism. Nat Med 2002, 8:247–252.PubMedCrossRefGoogle Scholar
  18. 18.
    André P, Nannizzi-Alaimo L, Prasad SK, Phillips DR: Plateletderived CD40L: the switch-hitting player of cardiovascular disease. Circulation 2002, 106:896–899.PubMedCrossRefGoogle Scholar
  19. 19.
    Cipollone F, Ferri C, Desideri G, et al.: Preprocedural level of soluble CD40L is predictive of enhanced inflammatory response and restenosis after coronary angioplasty. Circulation 2003, 108:2776–2782.PubMedCrossRefGoogle Scholar
  20. 20.
    Vivekananthan DP, Bhatt DL, Chew DP, et al.: Clopidogrel pretreatment prior to percutaneous coronary intervention attenuates periprocedrual rise of C-reactive protein. J Am Coll Cardiol 2003, 41:24A.CrossRefGoogle Scholar
  21. 21.
    Zidar FJ, Quinn MJ, Bhatt DL, et al.: Clopidogrel pretreatment reduces platelet inflammatory marker expression in patients undergoing percutaneous coronary intervention. J Am Coll Cardiol 2003, 41:45A.CrossRefGoogle Scholar
  22. 22.
    The TIMI IIIB Investigators: Effects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q-wave myocardial infarction: results of the TIMI IIIB trial. Circulation 1994, 89:1545–1556.Google Scholar
  23. 23.
    The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators: A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996, 335:775–782.CrossRefGoogle Scholar
  24. 24.
    The Antiplatelet Trialists’ Collaboration: Collaborative overview of randomised trials of antiplatelet therapy-- I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. Br Med J 1994, 308:81–106.Google Scholar
  25. 25.
    The CAPRIE Steering Committee: A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet 1996, 348:1329–1339.CrossRefGoogle Scholar
  26. 26.
    The CURE Study 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. In a randomized trial of 12,562 NSTE ACS patients, the CURE trial demonstrated that long-term treatment with combined aspirin and clopidogrel was associated with significant reductions in the 1-year occurrence of death, MI, or stroke (9.3% with clopidogrel and aspirin vs 11.5% with aspirin alone; P = 0.00005).CrossRefGoogle Scholar
  27. 27.
    Braunwald E, Antman EM, Beasley JW, et al.: ACC/AHA guidelines for the management of patients with unstable angina and non- ST-segment elevation myocardial infarction. J Am Coll Cardiol 2000, 36:970–1062. Adherence to treatment guidelines recommended by the ACC and AHA is fundamental to the application of evidence-based therapies for NSTE ACS patients. The guidelines summarize clinical trials evidence for therapies in NSTE ACS and provide graded recommendations.PubMedCrossRefGoogle Scholar
  28. 28.
    Hongo RH, Ley J, Dick SE, Yee RR: The effect of clopidogrel in combination with aspirin when given before coronary artery bypass grafting. J Am Coll Cardiol 2002, 40:231–237.PubMedCrossRefGoogle Scholar
  29. 29.
    Mehta SR, Yusuf S, Peters RJG, et al., for theCURE Investigators: Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001, 358:526–533.CrossRefGoogle Scholar
  30. 30.
    Steinhubl SR, Berger PB, Mann III JT, et al., for the CREDO Investigators: Early and sustained dual oral antiplatelet therapy following percutaneous coronary intervention: a randomized controlled trial. JAMA 2002, 288:2411–2420. Although the CREDO trial did not demonstrate a statistically significant early benefit with clopidogrel pretreatment before PCI, long-term therapy with clopidogrel and aspirin was associated with a 27% relative reduction in 1-year ischemic adverse events (11.5% vs 8.5%; P = 0.02).PubMedCrossRefGoogle Scholar
  31. 31.
    Thebault JJ, Kieffer G, Cariou R: Single-dose pharmacodynamics of clopidogrel. Semin Thromb Hemost 1999, 25(Suppl 2):3–8.PubMedGoogle Scholar
  32. 32.
    Kastrati A, Mehilli J, Schühlen H, et al., for the Intracoronary Stenting and Antithrombotic Regimen-Rapid Early Action for Coronary Treatment (ISAR-REACT) Study Investigators: A clinical trial of abciximab in elective percutaneous coronary intervention after pretreatment with clopidogrel. N Engl J Med 2004, 350:232–238. The ISAR-REACT trial demonstrated no significant differences regarding 30-day adverse events among a relatively lower-risk cohort of patients undergoing PCI who received a 600-mg oral loading dose of clopidogrel followed by randomization to abciximab or placebo.PubMedCrossRefGoogle Scholar
  33. 33.
    Kong DF, Califf RM, Miller DP, et al.: Clinical outcomes of therapeutic agents that block the platelet glycoprotein IIb/ IIIa integrin in ischemic heart disease. Circulation 1998, 98:2829–2835.PubMedGoogle Scholar
  34. 34.
    The ESPRIT Investigators: Novel dosing regimen of eptifibatide in planned coronary stent implantation (Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy.): a randomised, placebo-controlled trial. Lancet 2000, 356:2037–2044.CrossRefGoogle Scholar
  35. 35.
    Topol EJ, Moliterno DJ, Herrmann HC, et al.: Comparison of two platelet glycoprotein IIb/IIIa inhibitors, tirofiban and abciximab, for the prevention of ischemic events with percutaneous coronary revascularization. N Engl J Med 2001, 344:1888–1894.PubMedCrossRefGoogle Scholar
  36. 36.
    Karvouni E, Katritsis DG, Ioannidis JPA: Intravenous glycoprotein IIb/IIIa receptor antagonists reduce mortality after percutaneous coronary interventions. J Am Coll Cardiol 2003, 41:26–32. This meta-analysis of 19 randomized, placebo-controlled trials examined the benefit of GP IIb/IIIa inhibitors as adjunctive therapy to PCI. The study demonstrated significant reductions in 30-day and 6-month mortality among patients treated with GP IIb/IIIa inhibition. In addition, major bleeding complications were not increased when heparin was discontinued immediately post-PCI.PubMedCrossRefGoogle Scholar
  37. 37.
    Kong DF, Hasselblad V, Harrington RA, et al.: Meta-analysis of survival with platelet glycoprotein IIb/IIIa antagonists for percutaneous coronary interventions. Am J Cardiol 2003, 92:651–655.PubMedCrossRefGoogle Scholar
  38. 38.
    Cannon CP, Weintraub WS, Demopoulos L, et al.: Comparison of invasive versus conservative strategy in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban: the Treat Angina with Aggrastat and Determine the Cost of Therapy with an Invasive of Conservative Strategy (TACTICS-TIMI 18) Investigators. N Eng J Med 2001, 344:1879–1887.CrossRefGoogle Scholar
  39. 39.
    Mahaffey KW, Alexander JH, Roe MT, et al.: Characterization of types of myocardial infarctions in two large acute coronary syndrome trials. Circulation 2001, 104:II-697. [Author: please verify page range]Google Scholar
  40. 40.
    The Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Study Investigators: Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients with acute coronary syndromes. N Engl J Med 1998, 339:436–443.CrossRefGoogle Scholar
  41. 41.
    The GUSTO IV-ACS Investigators: Effect of glycoprotein IIb/ IIIa receptor blocker abciximab on outcome in patients with acute coronary syndromes without early coronary revascularization: the GUSTO-IV ACS randomised trial. Lancet 2001, 357:1915–1924.CrossRefGoogle Scholar
  42. 42.
    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, 359:189–198. This landmark meta-analysis involving more than 30,000 patients in trials of GP IIb/IIIa inhibition confirmed the benefit of these agents in ACS patients not routinely scheduled to undergo PCI. In particular, a greater treatment effect was observed among the highest-risk, troponin-positive patients.PubMedCrossRefGoogle Scholar
  43. 43.
    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. JAMA 1996, 276:811–815.PubMedCrossRefGoogle Scholar
  44. 44.
    Lauer MA, Houghtaling PL, Peterson JG, et al.: Attenuation of rebound ischemia after discontinuation of heparin therapy by glycoprotein IIb/IIIa inhibition with eptifibatide in patients with acute coronary syndromes: observations from the Platelet IIb/IIIa in Unstable Angina: Receptor Suppression Using Integrilin Therapy (PURSUIT) Trial. Circulation 2001, 104:2772–2777.PubMedGoogle Scholar
  45. 45.
    Cohen M, Demers C, Gurfinkel EP, et al., for the Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events Study Group. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med 1997, 337:447–452.PubMedCrossRefGoogle Scholar
  46. 46.
    Antman EM, McCabe CH, Gurfinkel EP, et al., for the TIMI (Thrombolysis In Myocardial Infarction) 11B Investigators: Enoxaparin prevents death and cardiac ischemic events in unstable angina/non-Q-wave myocardial infarction: results of the Thrombolysis In Myocardial Infarction (TIMI) 11B Trial. Circulation 1999, 100:1593–1601.PubMedGoogle Scholar
  47. 47.
    SoRelle R: Cardiovascular news. Aggrastat to Zocor trial. Circulation 2003, 107:9024e-9032e.CrossRefGoogle Scholar
  48. 48.
    Goodman SG, Fitchett D, Armstrong PW, et al., for the Integrilin and Enoxaparin Randomized Assessment of Acute Coronary Syndrome Treatment (INTERACT) Trial Investigators: Randomized evaluation of the safety and efficacy of enoxaparin versus unfractionated heparin in high-risk patients with non- ST-segment elevation acute coronary syndromes receiving the glycoprotein IIb/IIIa inhibitor eptifibatide. Circulation 2003, 107:238–244.PubMedCrossRefGoogle Scholar
  49. 49.
    Moliterno DJ, Hermiller JB, Kereiakes DJ, et al.: A novel point-ofcare enoxaparin monitor for use during percutaneous coronary intervention. J Am Coll Cardiol 2003, 42:1132–1139.PubMedCrossRefGoogle Scholar
  50. 50.
    The Direct Thrombin Inhibitor Trialists’ Collaborative Group: Direct thrombin inhibitors in acute coronary syndromes: principal results of a meta-analysis based on individual patients’ data. Lancet 2002, 359:294–302.CrossRefGoogle Scholar
  51. 51.
    Lincoff AM, Bittl JA, Harrington RA, et al., for the REPLACE-2 Investigators: Bivalirudin and provisional glycoprotein IIb/IIIa blockade compared with heparin and planned glycoprotein IIb/ IIIa blockade during percutaneous coronary intervention: REPLACE-2 randomized trial. JAMA 2003, 289:853–863. In REPLACE-2, treatment with bivalirudin was statistically not inferior to UFH plus planned GP IIb/IIIa inhibition in PCI with regard to early ischemic events and was associated with significantly less bleeding (4.2% vs 2.4%; P < 0.001). These findings not only emphasize the limitations associated with UFH, but like the ISARREACT trial [32], they also imply that selected low- or moderate-risk patients may be appropriate candidates for alternative antithrombotic therapies than UFH with planned GP IIb/IIIa inhibition.PubMedCrossRefGoogle Scholar
  52. 52.
    Chew DP, Bhatt DL, Sapp S, Topol EJ: Increased mortality with oral platelet glycoprotein IIb/IIIa antagonists: a meta-analysis of phase III multicenter randomized trials]. Circulation 103:201–206.Google Scholar
  53. 53.
    Francis CW, Berkowitz SD, Comp PC, et al., for the EXULT A Study Group: Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003, 349:1703–1712.PubMedCrossRefGoogle Scholar
  54. 54.
    SoRelle R: Cardiovascular news: Stroke prevention using an oral thrombin inhibitor in atrial fibrillation V (SPORTIF V). Circulation 2003, 108:9051e-9065e.CrossRefGoogle Scholar
  55. 55.
    Wallentin L, Wilcox RG, Weaver WD, et al., for the ESTEEM Investigators: Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet 2003, 362:789–797.PubMedCrossRefGoogle Scholar
  56. 56.
    Eriksson BI, Bauer KA, Lassen MR, Turpie AGG, for the Steering Committee of the Pentasaccharide in Hip-Fracture Surgery Study: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001, 345:1298–1304.PubMedCrossRefGoogle Scholar
  57. 57.
    Bauer KA, Eriksson BI, Lassen MR, Turpie AGG, for the Steering Committee of the Pentasaccharide in Major Knee Surgery Study: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001, 345:1305–1310.PubMedCrossRefGoogle Scholar
  58. 58.
    Dyke CK, Becker RC, Kleiman NS, et al.: First experience with direct factor Xa inhibition in patients with stable coronary disease: a pharmacokinetic and pharmacodynamic evaluation. Circulation 2002, 105:2385–2391.PubMedCrossRefGoogle Scholar
  59. 59.
    Roe MT, Ohman EM, Pollack CV, et al.: Changing the model of care for patients with acute coronary syndromes-implementing practice guidelines and altering physician behavior. Am Heart J 2003, 146:605–612.PubMedCrossRefGoogle Scholar

Copyright information

© Current Science Inc. 2004

Authors and Affiliations

  • David E. Kandzari
    • 1
  1. 1.Division of CardiologyDuke Clinical Research UnitDurhamUSA

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