cgp-39393 and Myocardial-Infarction

A large proportion of deaths among patients with myocardial infarction occurs within the first 24 hours after presentation. It is not clear whether this phenomenon is also true of patients without ST-segment elevation who may or may not have infarction at the time of presentation. Thrombin activity may also be greatest during the first 24 hours after plaque rupture. Accordingly, this study was designed to examine the pattern of early ischemic events among patients with acute coronary syndromes and to determine whether the direct thrombin inhibitor desirudin (r-hirudin) would be most effective during this period.. Among the 11,142 patients enrolled in GUSTO-II, death or (re)infarction occurred within 24 hours in 210 patients (1.7%), representing 19% of the 1135 deaths that had occurred by 30 days. Death or (re)infarction occurred within 24 hours in 113 patients (2. 7%) with ST-segment elevation and in 97 patients without ST-segment elevation (1.2%, P <.001), representing 26% and 14% of the 30-day event rates, respectively, for the 2 enrollment strata. Among patients with ST-segment elevation, most of these events were deaths, whereas among patients without ST-segment elevation, most events were (re)infarctions. Death or (re)infarction by 24 hours occurred in 80 (1.3%) patients treated with desirudin and 130 (2.1%) patients treated with heparin (P =.01). This finding predominantly consisted of prevention of death among patients with ST-segment elevation and of (re)infarction among patients without ST-segment elevation.. These findings have important implications for early triage of patients with acute coronary syndromes and for the development of new therapies directed at stabilizing the unstable atherosclerotic plaque.

Topics: Aged; Disease-Free Survival; Female; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Multivariate Analysis; Myocardial Infarction; Recombinant Proteins; Recurrence; Survival Analysis; Treatment Outcome

The purpose of this study was to assess the value of recombinant desulfatohirudin (hirudin) as adjunctive therapy to thrombolysis in acute myocardial infarction.. Failure to achieve initial reperfusion and reocclusion of the infarct-related artery remain major limitations of thrombolytic therapy despite aggressive regimens of heparin and aspirin. Hirudin, a direct thrombin inhibitor, has been shown in experimental models to enhance thrombolysis and reduce reocclusion.. The Thrombolysis in Myocardial Infarction (TIMI) 5 trial was a randomized, dose-ranging, pilot trial of hirudin versus heparin, given with front-loaded tissue-type plasminogen activator and aspirin to 246 patients with acute myocardial infarction. Patients received either intravenous heparin or hirudin at one of four ascending doses for 5 days. Patients underwent coronary angiography at 90 min and at 18 to 36 h, unless rescue angioplasty was performed.. The primary end point, TIMI grade 3 flow in the infarct-related artery at 90 min and 18 to 36 h without death or reinfarction before the 18- to 36-h catheterization was achieved in 97 (61.8%) of 157 evaluable hirudin-treated patients compared with 39 (49.4%) of 79 evaluable heparin-treated patients (p = 0.07). All four doses of hirudin led to similar findings in the angiographic and clinical end points. At 90 min, TIMI grade 3 flow was present in 105 (64.8%) of 162 hirudin-treated patients compared with 48 (57.1%) of 84 heparin-treated patients (p = NS). Infarct-related artery patency (TIMI grade 2 or 3 flow) was similar in the two groups (82.1% and 78.6%, respectively). At 18 to 36 h, 129 (97.8%) of 132 hirudin-treated patients had a patent infarct-related artery compared with 58 (89.2%) of 65 heparin-treated patients (p = 0.01). Reocclusion by 18 to 36 h occurred in 2 (1.6%) of 123 hirudin-treated patients versus 4 (6.7%) of 60 heparin-treated patients (p = 0.07). Death or reinfarction occurred during the hospital period in 11 (6.8%) of 162 hirudin-treated patients compared with 14 (16.7%) of 84 heparin-treated patients (p = 0.02). Major spontaneous hemorrhage occurred in 1.2% of hirudin-treated patients versus 4.7% of heparin-treated patients (p = 0.09), and major hemorrhage at an instrumented site occurred in 16.3% and 18.6%, respectively (p = NS).. Hirudin is a promising agent compared with heparin as adjunctive therapy with thrombolysis for acute myocardial infarction, and its evaluation in larger trials is warranted.

Topics: Adjuvants, Pharmaceutic; Adult; Aged; Aspirin; Coronary Angiography; Dose-Response Relationship, Drug; Female; Fibrinolytic Agents; Heparin; Hirudin Therapy; Hirudins; Humans; Male; Middle Aged; Myocardial Infarction; Partial Thromboplastin Time; Pilot Projects; Recombinant Proteins; Survival Rate; Thrombolytic Therapy; Tissue Plasminogen Activator; Treatment Outcome; Vascular Patency

Desirudin, a recombinant hirudin used in the prevention and management of thromboembolic disease, is a thrombin inhibitor which binds directly and with high affinity to clot-bound and fluid phase thrombin. As a prophylaxis in patients undergoing hip replacement surgery, desirudin was significantly more effective in reducing the incidence of deep vein thrombosis (DVT) than either unfractionated or low molecular weight heparin. However, results in patients with acute coronary syndromes are less conclusive. A significant reduction with desirudin compared with heparin in the incidence of death or non-fatal (re)infarction at 24 hours in patients with acute myocardial infarction (MI) was reported in the GUSTO (Global Use of Strategies to Open Occluded Coronary Arteries) IIb trial but not in the TIMI (Thrombolysis and Thrombin Inhibition in Myocardial Infarction) 9B trial. Despite the early reduction shown in GUSTO IIb, desirudin was not associated with an improved long term clinical benefit at 30 days compared with heparin. Similar results were seen in patients with unstable angina/non-Q-wave MI enrolled in the GUSTO IIb trial. In addition, desirudin and heparin showed similar efficacy in preventing restenosis 30 weeks after coronary angioplasty for unstable angina, despite desirudin being associated with a significant reduction in the rate of cardiac events within the first 96 hours. Desirudin is as well tolerated as heparin with a similar incidence of moderate and severe bleeding, intracranial haemorrhage or stroke reported when trialled in the prevention of DVT associated with hip replacement surgery or the treatment of acute coronary syndromes. However, in the GUSTO IIb trial a significantly higher incidence of transfusions was observed in patients with unstable angina/non-Q-wave MI.. Desirudin is clearly more effective than heparin in the prevention of DVT in patients undergoing elective hip replacement, although cost factors may influence its ultimate place in therapy. In the treatment of acute coronary syndromes the role of desirudin is less certain; however, it may be useful for patients in whom heparin therapy is not a viable option.

Topics: Angina Pectoris; Anticoagulants; Arthroplasty, Replacement, Hip; Drug Administration Schedule; Hirudins; Humans; Myocardial Infarction; Postoperative Complications; Recombinant Proteins; Thromboembolism

Data relevant to economic evaluation are being collected alongside clinical trials with increasing frequency. When these trials involve health outcomes and resource utilization in many different countries, numerous methodologic problems arise. This paper describes and discusses the methodology for economic evaluation that will be used in the Economic Substudy of GUSTO IIb, as an example of how to address the problems that arise in economic evaluations linked to international trials.

Topics: Canada; Clinical Trials as Topic; Cost-Benefit Analysis; Europe; Fibrinolytic Agents; Health Resources; Heparin; Hirudin Therapy; Hirudins; Humans; International Cooperation; Multicenter Studies as Topic; Myocardial Infarction; Outcome Assessment, Health Care; Quality of Life; Quality-Adjusted Life Years; Recombinant Proteins; Research Design; United States