A marriage of enhancement: fibrinolysis and conjunctive therapy

Summary

Pharmacologic reperfusion of patients with acute ST segment elevation myocardial infarction is designed to achieve prompt high-quality reperfusion, prevent recurrent ischemia and reinfarction, maintain long-term patency, and to enhance patient survival and quality of life. Because monotherapy with fibrinolytics is by itself unable to achieve all of these objectives, antithrombotic, anti-platelet, and other novel agents are required. We discuss herein the role of unfractionated and enoxaparin, the potential added value of direct thrombin inhibitors, and the importance of aspirin. Despite the promise of glycoprotein IIb/IIIa inhibitors, risks associated with intracranial hemorrhage in the elderly have led to restraint in their application to broad populations. Facilitation of urgent percutaneous coronary intervention with combination reduced-dose fibrinolytic and glycoprotein IIb/IIIa inhibitors remains a promising potential future path. The future is likely to emphasize greater application of the already effective therapies at our disposal and the development of novel anti-platelet and anti-thrombin agents as well as those directed toward inflammation.

Keywords

Clinical trials - fibrinolytic therapy - clinical trials - heparins / LMWH

• References

• 1 The GISSI Group (Gruppo Italiano per lo Studio della Streptochinasi nell’infarto Miocardio). Effectiveness of intravenous thrombolytic treatment of myocardial infarction. Lancet 1986; 01: 397-401.
• 2 Sherry S. The origin of thrombolytic therapy. J Am Coll Cardiol 1989; 14: 1085-92.
• 3 Topol EJ. Towards a new frontier in myocardial reperfusion therapy: Emerging platelet pre-eminence [Review]. Circulation 1998; 97 (02) 211-8.
• 4 Coller BS. Platelets and thrombolytic therapy. N Eng J Med 1990; 322: 33-42.
• 5 Armstrong PW. Heparin in acute coronary disease: Requiem for a heavyweight?. N Eng J Med 1997; 337: 492-4.
• 6 The In-TIME-II Investigators. Intravenous NPA for the treatment of infarcting myocardium early; In TIME-II, a double-blind comparison of single-bolus lanoteplase vs accelerated alteplase for the treatment of patients with acute myocardial infarction. Eur Heart J 2000; 21 (24) 2005-13.
• 7 Ryan TJ, Antman EM, Brooks NH. et al. 1999 Update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: Executive summary and recommendations. 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: 1016-30.
• 8 The ASSENT 3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomized trial in acute myocardial infarction. Lancet 2001; 358 9282 605-13.
• 9 The ASSENT-II Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double blind randomized trial. Lancet 2002; 354: 716-22.
• 10 The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Eng J Med 1993; 329: 673-82.
• 11 Antman EM, Louwerenburg HW, Baars HF. et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE-Thrombolysis in Myocardial Infarction (TIMI) 23 Trial. Circulation 2002; 105 (14) 1642-9.
• 12 Armstrong PW, Wallentin L, Goldstein P. et al. for the ASSENT 3 and ASSENT 3+. Metaanalysis of the Efficacy and Safety of Unfractionated Heparin versus Enoxaparin In Conjunction with tenecteplase for ST Elevation Myocardial Infarction: Insights from ASSENT 3 and ASSENT 3+. Circulation. 2003 18. (17 suppl IV): IV580-IV581.
• 13 Wallentin L, Goldstein P, Armstrong PW. et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting: the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-3 PLUS randomized trial in acute myocardial infarction. Circulation 2003; 108 (02) 135-42.
• 14 Weitz JI, Buller HR. Direct thrombin inhibitors in acute coronary syndromes: present and future. Circulation 2002; 105 (08) 1004-11.
• 15 White HD, Aylward PE, Frey MJ. et al. Randomized, double-blind comparison of hirulog versus heparin in patients receiving streptokinase and aspirin for acute myocardial infarction (HERO). Circulation 1997; 96 (07) 2155-61.
• 16 The HERO-II Investigators. Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: The HERO-2 randomized trial. Lancet 2001; 358: 1855-63.
• 17 The ISIS-2 Collaborative Group (Second International Study of Infarct Survival). Randomized trial of intravenous streptokinase, oral aspirin, both or neither among 17,187 cases of suspected acute myocardial infarction: ISIS-2. Lancet 1988; 02 8607 349-60.
• 18 Coller BS, Peerschke EI, Scudder LE. et al. A murine monoclonal antibody that completely blocks the binding of fibrinogen to platelets produces a thrombasthenic-like state in normal platelets and binds to glycoproteins IIb and/or IIIa. J Clin Invest 1983; 72 (01) 325-38.
• 19 Antman EM, Giugliano RP, Gibson CM. et al. Abciximab facilitates the rate and extent of thrombolysis: results of the thrombolysis in myocardial infarction (TIMI) 14 trial. The TIMI 14 Investigators. Circulation 1999; 99 (21) 2720-32.
• 20 The SPEED Group (Strategies for Patency Enhancement in the Emergency Department). Trial of abciximab with and without low dose reteplase for acute myocardial infarction. Circulation 2000; 101: 2788-94.
• 21 Brener SJ, Zeymer U, Adgey AA. et al. Eptifibatide and low-dose tissue plasminogen activator in acute myocardial infarction: the integrilin and low-dose thrombolysis in acute myocardial infarction (INTRO AMI). J Am Coll Cardiol 2002; 39 (03) 377-86.
• 22 Armstrong PW. Reperfusion synergism: Will it be both sustained and safe?. [Editorial] Eur Heart J 2000; 21: 1913-6.
• 23 The GUSTO V Investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomized trial. Lancet 2001; 357: 1905-14.
• 24 Lincoff AM, Califf RM, Van de Werf F. et al. Mortality at 1 year with combination platelet glycoprotein Iib/IIIa inhibition and reduceddose fibrinolytic therapy vs conventional fibrinolytic therapy for acute myocardial infarction: GUSTO V randomized trial. JAMA 2002; 288 (17) 2130-5.
• 25 Sinnaeve PR, Alexander JH, Bogaerts K. et al. Efficacy of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: one-year follow-up results of the ASSENT-3 randomized trial in acute myocardial infarction. Am Heart J. [In Press].
• 26 Kastrati A, Mehilli J, Schlotterbeck K. et al. Early administration of reteplase plus abciximab vs. abciximab alone in patients with acute myocardial infarction referred for percutaneous coronary intervention. JAMA 2004; 291 (08) 947-54.
• 27 Yusuf S, Zhao F, Mehta SR. et al. 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 Eng J Med 2001; 345 (07) 494-502.
• 28 Steinhubl SR, Berger PB, Mann 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: 2411-20.
• 29 Bhatt DL, Topol EJ. Scientific and therapeutic advances in antiplatelet therapy. Nat Rev Drug Discov 2003; 02 (01) 15-28.
• 30 Hirsh J, Weitz JI. New antithrombotic agents. Lancet 1999; 353 9162 1431-6.
• 31 Granger CB, Mahaffey KW, Weaver WD. et al. Pexelizumab, an anti-C5 complement antibody, as adjunctive therapy to primary percutaneous coronary intervention in acute myocardial infarction: the COMplement Inhibition in Myocardial infarction treated with Angioplasty (COMMA) Trial. Circulation 2003; 108: 1184-90.
• 32 Yarbrough WM, Mukherjee R, Escobar GP. et al. Selective targeting and timing of matrix metalloproteinase inhibition in post-myocardial infarction remodeling. Circulation 2003; 108: 1753-9.