Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Hirudin was no more effective than unfractionated heparin for acute MI

ACP J Club. 1997 Mar-Apr;126:32. doi:10.7326/ACPJC-1997-126-2-032

Related Content in this Issue
• Companion Abstract and Commentary: Hirudin reduced death or MI more than heparin at 48 hours but not at 30 days


Source Citation

Antman EM, for the TIMI 9B Investigators. Hirudin in acute myocardial infarction. Thrombolysis and thrombin inhibition in myocardial infarction (TIMI) 9B trial. Circulation. 1996 Sep 1;94:911-21.


Abstract

Objective

To compare the effectiveness and safety of hirudin with intravenous heparin when combined with aspirin and either accelerated tissue plasminogen activator (t-PA) or streptokinase in patients with acute myocardial infarction (MI).

Design

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

Setting

150 centers in the United States, Canada, the United Kingdom, Israel, and Germany.

Patients

3002 patients (mean age 60 y, 75% men) who had had an acute MI ≥ 0.1 mV ST-segment elevation in ≥ 2 leads or new left bundle branch block on electrocardiogram. Exclusion criteria were age < 21 years, contraindications to thrombolysis, serum creatinine level > 2.0 mg/dL, cardiogenic shock, receipt of therapeutic doses of anticoagulants, or potential for pregnancy. Follow-up was 99.5%.

Intervention

All patients received aspirin, 150 to 325 mg, and either front-loaded, weight-adjusted t-PA (maximum 100 mg) for 90 minutes or streptokinase, 1.5 million units for 1 hour. Patients were allocated within 1 hour of starting thrombolysis to unfractionated heparin, 5000 U bolus and a continuous infusion of 1000 U/h (n = 1491), or to hirudin, 0.1 mg/kg bolus and a continuous infusion of 0.1 mg/kg per hour (n = 1511). The target activated partial thromboplastin time was 55 to 85 seconds.

Main outcome measures

The composite end point of unsatisfactory outcome within 30 days was defined as death, recurrent infarction, or the development of congestive heart failure or cardiogenic shock ≥ 4 hours after the start of thrombolysis. Safety outcomes were major hemorrhage or severe anaphylaxis.

Main results

The study had 90% power to detect a 25% reduction in events with hirudin. Efficacy analysis showed no differences between hirudin and heparin. The composite end point occurred in 12.9% of patients who received hirudin and 11.9% of patients who received heparin {95% CI for the 1% absolute difference -3.3% to 1.4%, P = 0.42}*. Adjusting for age, time to treatment, or type of thrombolytic agent administered did not appreciably alter these results. The groups did not differ for safety outcomes. Major hemorrhage occurred in 4.6% of hirudin recipients compared with 5.3% of heparin recipients {CI for the 0.7% absolute difference -0.9% to 2.3%, P = 0.4}*.

Conclusion

Heparin and hirudin were similar in effectiveness and safety when used in conjunction with thrombolytic therapy that included accelerated tissue plasminogen activator or streptokinase for patients with acute myocardial infarction.

Sources of funding: Ciba-Geigy Corporation and Genentech.

For article reprint: Dr. E.M. Antman, Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. FAX 617-732-7134.

*Numbers calculated from data in article


Commentary

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


References

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.