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Hirudin reduced death or MI more than heparin at 48 hours but not at 30 days

ACP J Club. 1997 Mar-Apr;126:33. doi:10.7326/ACPJC-1997-126-2-033

Related Content in this Issue
• Companion Abstract and Commentary: Hirudin was no more effective than unfractionated heparin for acute MI

Source Citation

The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb Investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med. 1996 Sep 12;335:775-82.



To compare the effectiveness of hirudin with heparin in patients with various acute coronary syndromes.


Randomized, double-blind, placebo-controlled trial with 30-day follow-up.


373 hospitals in 13 countries.


12 142 patients (mean age 65 y, 70% men) who had chest discomfort within 12 hours of randomization that was associated with either transient or persistent ST-segment elevation or depression > 0.5 mm or with persistent, definite T-wave inversion > 1 mm. Exclusion criteria were receipt of warfarin at the time of enrollment, active bleeding, history of stroke, contraindication to heparin therapy, renal insufficiency, systolic blood pressure > 200 mm Hg or diastolic blood pressure > 110 mm Hg, or potential for pregnancy. Follow-up was complete.


Patients were stratified by ST-segment status and allocated to hirudin plus heparin placebo (n = 6069) or to heparin plus hirudin placebo (n = 6073). Hirudin was given as a bolus dose of 0.1 mg/kg of body weight intravenously and then as a continuous infusion of 0.1 mg/kg per hour. Heparin was given as a bolus dose of 5000 U intravenously and then as a continuous infusion of 1000 U/hr. Both drugs were infused for a minimum of 3 days and a maximum of 5 days.

Main outcome measures

The primary composite end point was death or nonfatal myocardial infarction (MI) at 30 days. Bleeding complications were compared.

Main results

Analysis was by intention to treat. The groups did not differ for the primary end point. Death or MI within 30 days occurred in 8.9% of patients who received hirudin and in 9.8% of patients who received heparin ({95% CI for the 0.9% absolute difference -0.4% to 2.0%}*, P = 0.058). Fewer patients who received hirudin died or had an MI within 24 or 48 hours than did patients who received heparin (1.3% vs 2.1%, P = 0.001 and 2.3% vs 3.1%, P = 0.001, respectively). {This means that 125 patients would need to be treated (NNT) with hirudin (rather than heparin) to prevent 1 additional death or MI within 24 hours, CI 77 to 277; the relative risk reduction (RRR) was 38%, CI 19% to 53%. For death or MI within 48 hours, the NNT was 125, CI 71 to 407; RRR 26%, CI 8.7% to 41%.}* The groups did not differ for severe bleeding. The moderate bleeding rate was higher in hirudin recipients than in heparin recipients (8.8% vs 7.7%, P = 0.03). The results were not affected by ST-segment status.


In patients with various acute coronary syndromes, hirudin was more effective than heparin in preventing death or myocardial infarction within 48 hours but was not more beneficial than heparin within 30 days.

Sources of funding: Ciba-Geigy; Boehringer Mannheim; Guidant.

For article reprint: Dr. E.J. Topol, The Cleveland Clinic Foundation, Department of Cardiology F/25, 9500 Euclid Avenue, Cleveland, OH 44195, USA. FAX 216-445-9595.

*Numbers calculated from data supplied by author.


Coronary thrombosis is a crucial event that underlies acute MI and unstable angina. Consequently, the development of anti-thrombotic interventions for acute coronary syndromes has been intensely studied. During the era before thrombolytics, the use of heparin in conjunction with oral anticoagulation was shown to reduce total mortality. Pharmacologically, however, heparin is not an optimal intervention for patients with acute MI. Heparin is an indirect inhibitor of thrombin and requires the presence of antithrombin III. Its activity is inhibited by the presence of platelet factor IV, and it does not suppress continuing thrombus formation stimulated by clot-bound thrombin. Consequently, other antithrombotic agents have been studied that promote arterial patency and prevent reocclusion.

Aspirin alone, streptokinase alone, and aspirin in conjunction with streptokinase have been shown to improve survival in selected patients with acute MI (1). The benefit of combined aspirin and thrombolytic therapy for survival exceeds the benefit of either treatment alone. Despite a 42% reduction in mortality with combined therapy, additional improvement is possible. The infarction-associated artery remains occluded in 15% to 20% of patients with acute MI who are treated with aspirin, thrombolytics, and IV heparin (2, 3). Another 15% to 20% achieve only subnormal perfusion. In addition, 5% to 10% of patients who obtain initial patency develop reocclusion or reinfarction. Success in reestablishing patency, achieving normal flow, and maintaining patency is associated with reduced mortality (3).

Although it is routinely administered after thrombolysis, heparin has not been shown to consistently improve patency or patient survival. Hirudin, a direct thrombin inhibitor, has received considerable interest. Hirudin achieves more consistent anticoagulation than does heparin and has been shown to improve coronary reperfusion and patency (4). Hirudin, however, like heparin given at higher doses, has been associated with an increased risk for major bleeding. As a result, the TIMI 9A and GUSTO IIa trials were revised. The results of these revised protocols are now available.

Unfortunately, the theoretical advantages of hirudin were not substantiated. Patients who received hirudin showed no survival advantage. The risk for major bleeding complications did not differ by treatment. In the GUSTO IIb trial, 74% of patients with ST-segment elevation received thrombolytic agents; the agents were not used in those without ST-segment elevation. Hirudin had no advantage over heparin based on the ST-segment stratification. The patients in the TIMI 9B trial had ST-elevation and received thrombolytic therapy. Neither study addressed the efficacy of heparin given after thrombolysis compared with controls. Given the current practice of anticoagulation therapy with heparin after thrombolysis, hirudin is an alternative approach in patients with heparin-associated thrombocytopenia. For other patients, the higher cost of hirudin and lack of a clear survival or adverse risk advantage supports the continued use of heparin as an anticoagulant. It is hoped that the results of the GUSTO IIb and the TIMI 9B trials may stimulate antithrombotic research on other mechanisms, such as platelet glycoprotein IIb/IIIa inhibition to reduce thrombosis, maintain patency, and improve survival.

Brian P. Schmitt, MD
Northwestern University Medical SchoolChicago, Illinois, USA

Brian P. Schmitt, MD
Northwestern University Medical School
Chicago, Illinois, USA


1. ISIS-2 (Second International Study of Infarct Survival) Collaborative Group. Randomized trial of intravenous streptokinase, oral aspirin, both, or neither among 17,187 cases of suspected acute myocardial infarction. Lancet. 1988;2:349-60.

2. TIMI Study Group. The thrombolysis in myocardial infarction (TIMI) Trial: phase I findings. N Engl J Med. 1985;312:932-6.

3. The GUSTO Angiographic Investigators. The effects of tissue plasminogen activator, streptokinase, or both on coronary-artery patency, ventricular function, and survival after acute myocardial infarction. N Engl J Med. 1994;330:516.

4. Cannon CP, McCabe CH, Henry TD, et al. 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. J Am Coll Cardiol. 1994;23:993-1003.