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Therapeutics

Accelerated tissue plasminogen activator with intravenous heparin was most effective in reducing mortality from acute myocardial infarction

ACP J Club. 1994 Mar-April;120:33. doi:10.7326/ACPJC-1994-120-2-033


Source Citation

The GUSTO Investigators. An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction. N Engl J Med. 1993 Sep 2;329:673-82.


Abstract

Objective

To compare the effectiveness of 4 thrombolytic strategies in reducing mortality in patients with acute myocardial infarction.

Design

Randomized controlled trial with 30-day follow-up (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries [GUSTO] Trial).

Setting

1081 hospitals in 15 countries.

Patients

41 021 patients (mean age 62 y, 75% men) who were seen at a hospital < 6 hours after the onset of symptoms of chest pain lasting ≥ 20 minutes and who had electrocardiographic signs of ≥ 0.1 mV of ST-segment elevation in ≥ 2 limb leads or ≥ 0.2 mV in ≥ 2 contiguous precordial leads. Exclusion criteria were previous stroke, active bleeding, previous treatment with streptokinase or anistreplase, recent trauma or major surgery, severe uncontrolled hypertension, or noncompressible vascular punctures.

Intervention

Patients were allocated to receive streptokinase, 1.5 million U over 60 minutes, with subcutaneous heparin, 12 500 U twice daily beginning 4 hours after the start of thrombolytic therapy (n = 9841); streptokinase, 1.5 million U over 60 minutes, with adjustment for activated partial thromboplastin time after intravenous heparin in a bolus dose (n = 10 410); accelerated tissue plasminogen activator (tPA) in a bolus dose of 15 mg, 0.75 mg/kg over 30 minutes, and 0.5 mg/kg over the next 60 minutes using the previous intravenous heparin regimen (n = 10 396); or the combination of intravenous tPA, 1.0 mg/kg over 60 minutes, and streptokinase, 1.0 million U over 60 minutes, given through separate intravenous catheters, along with the same intravenous heparin regimen (n = 10 374).

Main outcome measures

Death from any cause at 30 days and stroke.

Main results

For 30-day mortality, no difference existed between the streptokinase groups (P = 0.73). A reduction in mortality occurred with tPA compared with the 2 streptokinase groups (10 lives saved per 1000 patients treated; risk reduction 14%, 95% CI 5.9% to 21.3%, P = 0.001). There was an excess of 2 hemorrhagic strokes per 1000 patients treated with tPA compared with streptokinase (P = 0.03) and an excess of 4 hemorrhagic strokes per 1000 for the combination of thrombolytic agents (P < 0.001). The combined end point of death or disabling stroke was lower in the tPA group than in the streptokinase-only groups (6.9% vs 7.8%, P = 0.006).

Conclusion

Accelerated tissue plasminogen activator with intravenous heparin was superior to streptokinase with subcutaneous heparin or intravenous heparin in reducing mortality in patients with acute myocardial infarction.

Sources of funding: Bayer; CIBA-Corning; Genentech; ICI Pharmaceuticals; Sanofi Pharmaceuticals.

For article reprint: Dr. E. Topol, Department of Cardiology, One Clinic Center, Cleveland Clinic Foundation, Cleveland, OH 44195, USA. FAX 216-444-8050.


Commentary

The study by the GUSTO investigators shows that an accelerated regimen of tPA with intravenous heparin achieves a moderate further reduction in mortality when compared with conventional streptokinase treatment, but with a small increased risk for stroke. The combined end point of death or disabling stroke was reduced by 9 per 1000 patients treated with accelerated tPA. The contribution of heparin to either benefit or risk, unfortunately, cannot be assessed. Accelerated tPA is 7 times more expensive than streptokinase and requires laboratory monitoring of heparin. The 90-minute patency rate seen with accelerated tPA, however, was significantly higher than that seen with streptokinase, and patency predicted left ventricular function and 30-day mortality (1). The mortality advantage for the tPA group was evident only among patients treated within 4 hours (a prespecified subgroup analysis), and the overall mortality benefit seen with tPA relative to streptokinase was about a third better than that previously seen between streptokinase and placebo (2, 3).

Only a minority of patients admitted to the hospital with myocardial infarction receive any thrombolytic agent. Clinical priorities, therefore, should be to maximize the use of conventional thrombolytic therapy and to minimize treatment delay. Use of accelerated tPA rather than streptokinase ranks below these clinical priorities for cost-effectiveness and, if adopted, should be reserved for patients presenting within 4 hours of symptom onset. Beyond that time, the excess risk for stroke is likely to outweigh any mortality benefit.

Kent L. Woods, MD
University of LeicesterLeicester, England, UK


References

1. 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. 1993;329:1615-22.

2. Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI). Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction. Lancet. 1986;1:397-402.

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