Immediate Pharmacology in the Current Era of Reperfusion Therapy

Login or register to view PDF.

Pages

In contrast, the evidence for combining abciximab and eptifibatide with either full-dose or half-dose fibrinolysis suggests improved rates and initial restoration of epicardial blood flow, but no reductions in mortality and an increased risk of bleeding events.5,6 Hence, these combined approaches to pharmacologic reperfusion cannot be recommended.

More recent evidence with clopidogrel, a thienopyridine adenosine diphosphate (ADP) antagonist, has rekindled interest in the dual antiplatelet approach as adjunctive pharmacology for fibrinolysis. In the Clopidogrel as Adjunctive Reperfusion Therapy (CLARITY) trial, a 300 mg loading dose of clopidogrel followed by a 75 mg daily dose was associated with an improvement in coronary artery patency at 3.5 days (and death or MI before angiography) (0.64, 95% confidence interval (CI) 0.53-0.76, p<0.001), with reductions in recurrent MI and recurrent ischemia without an overall reduction in death.7 Supporting these data is the large-scale clinical experience among 45,852 STEMI patients in China. Despite the fact that only ~54% of patients received fibrinolytic therapy, clopidogrel in addition to aspirin was associated with a 7% reduction in all-cause mortality (odds ratio 0.93, 95% CI 0.87-0.99, p=0.03).8 In contradistinction to the intravenous glycoprotein IIb/IIIa inhibitor experience, adequately designed and powered studies of administration of clopidogrel prior to primary PCI have not been conducted. While the use of dual antiplatelet therapy following stent placement has become routine, whether upfront or even pre-hospital administration of large clopidogrel loading doses among patients destined for primary PCI leads to incremental reductions in death or MI is unknown and may not be expected given the relatively delayed onset of action (> 2-3 hours).

Innovations in antithrombin therapies in the management of STEMI have demonstrated reductions in MI, but reductions in short-term mortality remains elusive and bleeding has increased. Extending the experience of enoxaparin, an indirect inhibitor of thrombin and factor X through its interaction with antithrombin, in non-ST-segment acute coronary syndrome (ACS) to the management of STEMI patients undergoing fibrinolysis in the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment (EXTRACT) trial demonstrates a 17% reduction in the 30-day rate of death or nonfatal MI (odds ratio 0.87, CI 0.77-0.90, p<0.001), with this difference largely driven by reductions in non-fatal MI.9 These benefits were achieved with a modest increase in bleeding (heparin 1.4% versus enoxaparin 2.1%, p<0.001). In the EXTRACT study the dose of enoxaparin was adjusted in the elderly with elimination of the 30 mg intravenous bolus of enoxaparin and reduction of the twice-daily regimen of 1 mg/kg enoxaparin given subcutaneously (SC) to 0.75 mg/kg twice daily.

Pages

References
  1. Montalescot G, Barragan P, Wittenberg O et al., Platelet glycoprotein IIb/IIIa inhibition with coronary stenting for acute myocardial infarction , N Engl J Med (2001);344: pp. 1895-1903.
    Crossref | PubMed
  2. Stone GW,Grines CL, Cox DA et al., Comparison of angioplasty with stenting, with or without abciximab, in acute myocardial infarction , N Engl J Med (2002);346: pp. 957-966.
    Crossref | PubMed
  3. De Luca G, Suryapranata H, Stone GW et al., Abciximab as adjunctive therapy to reperfusion in acute ST-segment elevation myocardial infarction: a meta-analysis of randomized trials , JAMA (2005);293: pp. 1759-1765.
    Crossref | PubMed
  4. Gibson CM, Kirtane AJ, Murphy SA et al., Early initiation of eptifibatide in the emergency department before primary percutaneous coronary intervention for ST-segment elevation myocardial infarction: results of the Time to Integrilin Therapy in Acute Myocardial Infarction (TITAN)-TIMI 34 trial', Am Heart J (2006);152: pp. 668-675.
    Crossref | PubMed
  5. Giugliano RP, Roe MT, Harrington RA et al., Combination reperfusion therapy with eptifibatide and reduced-dose tenecteplase for ST-elevation myocardial infarction: results of the integrilin and tenecteplase in acute myocardial infarction (INTEGRITI) Phase II Angiographic Trial , J Am Coll Cardiol (2003);41: pp. 1251-1260.
    Crossref | PubMed
  6. Topol EJ, 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: pp. 1905-1914.
    Crossref | PubMed
  7. Sabatine MS, Cannon CP, Gibson CM et al., CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation , N Engl J Med (2005);352: pp. 1179-1189.
    Crossref | PubMed
  8. 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: pp. 1607-1621.
    Crossref | PubMed
  9. 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: pp. 1477-1488.
    Crossref | PubMed
  10. Cohen M, Gensini GF, Maritz F et al., The safety and efficacy of subcutaneous enoxaparin versus intravenous unfractionated heparin and tirofiban versus placebo in the treatment of acute ST-segment elevation myocardial infarction patients ineligible for reperfusion (TETAMI): a randomized trial , J Am Coll Cardiol (2003);42: pp. 1348-1356.
    Crossref | PubMed
  11. Labeque JN, Jais C, Dubos O et al., Prehospital administration of enoxaparin before primary angioplasty for ST-elevation acute myocardial infarction , Catheter Cardiovasc Interv (2006);67: pp. 207-213.
    Crossref | PubMed
  12. Yusuf S, Mehta SR, Chrolavicius S et al., Effects of fondaparinux on mortality and reinfarction in patients with acute STsegment elevation myocardial infarction: the OASIS-6 randomized trial , JAMA (2006);295: pp. 1519-1530.
    Crossref | PubMed
  13. Yusuf S, Mehta SR, Chrolavicius S et al., Comparison of fondaparinux and enoxaparin in acute coronary syndromes , N Engl J Med (2006);354: pp. 1464-1476.
    Crossref | PubMed
  14. White H, Thrombin-specific anticoagulation with bivalirudin versus heparin in patients receiving fibrinolytic therapy for acute myocardial infarction: the HERO-2 randomised trial , Lancet (2001);358: pp. 1855-1863.
    Crossref | PubMed
  15. Antman EM, Hirudin in acute myocardial infarction.Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial , Circulation (1996);94: pp. 911-921.
    Crossref | PubMed
  16. A clinical trial comparing primary coronary angioplasty with tissue plasminogen activator for acute myocardial infarction.The Global Use of Strategies to Open Occluded Coronary Arteries in Acute Coronary Syndromes (GUSTO IIb) Angioplasty Substudy Investigators , N Engl J Med (1997);336: pp. 1621-1628.
    Crossref | PubMed
  17. Stella JF, Stella RE, Laffaldano RA et al., Anticoagulation with bivalirudin during percutaneous coronary intervention for STsegment elevation myocardial infarction , J Invasive Cardiol (2004);16: pp. 451-454.
    PubMed
  18. Lincoff AM, Kleiman NS, Kereiakes DJ et al., REPLACE-2 Investigators. 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: pp. 696-703.
    Crossref | PubMed
  19. White HD, Kleiman NS, Mahaffey KW et al., Efficacy and Safety of Enoxaparin Compared to Unfractionated Heparin in High Risk Patients with Non-ST Elevation Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention in the Superior Yield of the New Strategy of Enoxaparin, Revascularization and Glycoprotein IIb/IIIa Inhibitors (SYNERGY) Trial , Am Heart J (2006), in press.
  20. Stone GW,McLaurin BT, Cox DA et al., for the ACUITY Investigators, Prospective, randomized comparison of heparin plus glycoprotein IIb/IIIa inhibition and bivalirudin with or without glycoprotein IIb/IIIa inhibition in patients with acute coronary syndromes: the ACUITY trial , N Engl J Med (2006), in press.