A pilot trial of recombinant desulfatohirudin compared with heparin in conjunction with tissue-type plasminogen activator and aspirin for acute myocardial infarction: results of the Thrombolysis in Myocardial Infarction (TIMI) 5 trial.

Abstract

OBJECTIVES:

The purpose of this study was to assess the value of recombinant desulfatohirudin (hirudin) as adjunctive therapy to thrombolysis in acute myocardial infarction.

BACKGROUND:

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.

METHODS:

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.

RESULTS:

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).

CONCLUSIONS:

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.

• Authors: C P Cannon, C H McCabe, T D Henry, M J Schweiger, R S Gibson, H S Mueller, R C Becker, N S Kleiman, J M Haugland, J L Anderson
• Journal: Journal of the American College of Cardiology (J Am Coll Cardiol) Vol. 23 Issue 5 Pg. 993-1003 (Apr 1994) ISSN: 0735-1097 [Print] United States
• PMID: 8144799 (Publication Type: Clinical Trial, Clinical Trial, Phase II, Comparative Study, Journal Article, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)

Chemical References

• Adjuvants, Pharmaceutic
• Fibrinolytic Agents
• Hirudins
• Recombinant Proteins
• Heparin
• Tissue Plasminogen Activator
• Aspirin
• desirudin

Topics

• Adjuvants, Pharmaceutic (therapeutic use)
• Adult
• Aged
• Aspirin (therapeutic use)
• Coronary Angiography
• Dose-Response Relationship, Drug
• Female
• Fibrinolytic Agents (therapeutic use)
• Heparin (therapeutic use)
• Hirudin Therapy
• Hirudins (analogs & derivatives)
• Humans
• Male
• Middle Aged
• Myocardial Infarction (diagnostic imaging, drug therapy)
• Partial Thromboplastin Time
• Pilot Projects
• Recombinant Proteins (therapeutic use)
• Survival Rate
• Thrombolytic Therapy (methods)
• Tissue Plasminogen Activator (therapeutic use)
• Treatment Outcome
• Vascular Patency