American Heart Journal
Volume 154, Issue 1 , Pages 3-11 , July 2007

Variation in the definitions of bleeding in clinical trials of patients with acute coronary syndromes and undergoing percutaneous coronary interventions and its impact on the apparent safety of antithrombotic drugs

  • Steven R. Steinhubl, MD

      Affiliations

    • Gill Heart Institute, University of Kentucky, Lexington, KY
    • Corresponding Author InformationReprint requests: Steven R. Steinhubl, MD, The Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky College of Medicine, 900 S. Limestone St., 326 C. T. Wethington Bldg., Lexington, KY 40536-0284.
  • ,
  • Adnan Kastrati, MD

      Affiliations

    • Deutsches Herzzentrum, Technische Universitat, Munich, Germany
  • ,
  • Peter B. Berger, MD

      Affiliations

    • Geisinger Medical Center, Danville, PA

Received 26 January 2007 ,Accepted 1 April 2007.

References 

  1. Randomised trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Lancet. 1988;2:349–360
  2. 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;334:1084–1089
  3. Rao SV, O'Grady K, Pieper KS, et al. A comparison of the clinical impact of bleeding measured by two different classifications among patients with acute coronary syndromes. J Am Coll Cardiol. 2006;47:809–816
  4. Eikelboom JW, Mehta SR, Anand SS, et al. Adverse impact of bleeding on prognosis in patients with acute coronary syndromes. Circulation. 2006;114:774–782
  5. Rao SV, O'Grady K, Pieper KS, et al. Impact of bleeding severity on clinical outcomes among patients with acute coronary syndromes. Am J Cardiol. 2005;96:1200–1206
  6. Rao SV, Jollis JG, Harrington RA, et al. Relationship of blood transfusion and clinical outcomes in patients with acute coronary syndromes. JAMA. 2004;292:1555–1562
  7. Rao AK, Pratt C, Berke A, et al. Thrombolysis In Myocardial Infarction (TIMI) trial—phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Coll Cardiol. 1988;11:1–11
  8. Bovill EG, Terrin ML, Stump DC, et al. Hemorrhagic events during therapy with recombinant tissue-type plasminogen activator, heparin, and aspirin for acute myocardial infarction. Results of the Thrombolysis In Myocardial Infarction (TIMI), phase II trial. Ann Intern Med. 1991;115:256–265
  9. The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. The GUSTO Investigators. N Engl J Med. 1993;329:673–682
  10. Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT) -3 Investigators . Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction. Lancet. 2001;358:605–613
  11. White H, Hirulog and Early Reperfusion or Occlusion (HERO) -2 trial Investigators . 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. Chen ZM, Jiang LX, Chen YP, et al. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet. 2005;366:1607–1621
  13. Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J. 2004;148:764–775
  14. Yusuf S, Zhao F, Mehta SR, et al. 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
  15. Yusuf S, Mehta SR, Fifth Organization to Access Strategies in Acute Ischemic Syndromes Investigators , et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:1464–1476
  16. Lincoff AM, Bittl JA, Harrington RA, et al. 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
  17. Montalescot G, White HD, Gallo R, et al. Enoxaparin versus unfractionated heparin in elective percutaneous coronary intervention. N Engl J Med. 2006;355:1006–1017
  18. Fuchs J, Cannon CP. Hirulog in the treatment of unstable angina. Results of the Thrombin Inhibition in Myocardial Ischemia (TIMI) 7 trial. Circulation. 1995;92:727–733
  19. Antman EM, McCabe CH, Braunwald E. Bivalirudin as a replacement for unfractionated heparin in unstable angina/non-ST-elevation myocardial infarction: observations from the TIMI 8 trial. The Thrombolysis In Myocardial Infarction. Am Heart J. 2002;143:229–234
  20. Antman EM, McCabe CH, Gurfinkel EP, et al. 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
  21. Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354:1477–1488
  22. Yusuf S, Mehta SR, Chrolavicius S, et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295:1519–1530
  23. Simoons ML, GUSTO IV-ACS Investigators . 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
  24. Ferguson JJ, Califf RM, Antman EM, et al. 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
  25. 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
  26. Fox KA, 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;110:1202–1208
  27. Kinnaird TD, Stabile E, Mintz GS, et al. Incidence, predictors, and prognostic implications of bleeding and blood transfusion following percutaneous coronary interventions. Am J Cardiol. 2003;92:930–935
  28. Califf RM, Pieper KS, Lee KL, et al. Prediction of 1-year survival after thrombolysis for acute myocardial infarction in the Global Utilization of Streptokinase and TPA for Occluded Coronary Arteries trial. Circulation. 2000;101:2231–2238
  29. McClure MW, Berkowitz SD, Sparapani R, et al. Clinical significance of thrombocytopenia during a non–ST-elevation acute coronary syndrome. The platelet glycoprotein IIb/IIIa in unstable angina: receptor suppression using integrilin therapy (PURSUIT) trial experience. Circulation. 1999;99:2892–2900
  30. DeGeare VS, Stone GW, Grines L, et al. Angiographic and clinical characteristics associated with increased in-hospital mortality in elderly patients with acute myocardial infarction undergoing percutaneous intervention (a pooled analysis of the primary angioplasty in myocardial infarction trials). Am J Cardiol. 2000;86:300–304
  31. Yang X, Alexander KP, Chen AY, et al. The implications of blood transfusions for patients with non–ST-segment elevation acute coronary syndromes: results from the CRUSADE National Quality Improvement Initiative. J Am Coll Cardiol. 2005;46:1490–1495
  32. Sabatine MS, Morrow DA, Giugliano RP, et al. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation. 2005;111:2042–2049
  33. Lincoff AM, Kleiman NS, Kereiakes DJ, et al. Long-term efficacy of bivalirudin and provisional glycoprotein IIb/IIIa blockade vs heparin and planned glycoprotein IIb/IIIa blockade during percutaneous coronary revascularization: REPLACE-2 randomized trial. JAMA. 2004;292:696–703
  34. Cohen M. Predictors of bleeding risk and long-term mortality in patients with acute coronary syndromes. Curr Med Res Opin. 2005;21:439–445
  35. Serebruany VL, Atar D. Assessment of bleeding events in clinical trials-proposal of a new classification. Am J Cardiol. 2007;99:288–290

 Disclosures: Dr Steinhubl received research support from and served as a consultant for Bristol-Myers Squibb, Sanofi-Aventis, and The Medicines Company and served as a consultant for AstraZeneca. Doctor Berger received consulting and lecture fees from Bristol-Myers Squibb, Sanofi-Aventis, Johnson & Johnson, Genentech, Guilford, Arginox, Schering-Plough, and Boston Scientific and is the medical director and owns equity in Lumen. Doctor Kastrati received lecture fees from Bristol-Myers Squibb, Lilly, and Sanofi-Aventis.

 Disclosures: Financial and editorial support for this publication has been provided by Sanofi-Aventis US Inc.

PII: S0002-8703(07)00287-6

doi: 10.1016/j.ahj.2007.04.009

American Heart Journal
Volume 154, Issue 1 , Pages 3-11 , July 2007