Global Utilization of Streptokinase and TPA for Ocluded Arteries-I - GUSTO-1

Description:

Accelerated t-PA vs. streptokinase for mortality in acute MI.

Hypothesis:

Newer, thrombolytic therapies can produce earlier and sustained reperfusion to improve survival.

Study Design

Study Design:

Patients Screened: Not given
Patients Enrolled: 41,021

Patient Populations:

Patients presenting to a participating hospital within six hours after the onset of symptoms.
Chest pain lasting at least 20 minutes.
ECG signs of >0.1 mV of ST-segment elevation in two or more limb leads or >0.2 mV in two or more contiguous precordial leads.

Exclusions:

Previous stroke
Active bleeding
Previous treatment with streptokinase (SK) or anistreplase
Recent trauma or major surgery
Previous participation in the trial
Non-compressible vascular punctures
Severe, uncontrolled hypertension (systolic blood pressure >180 mmHg, unresponsive to therapy

Primary Endpoints:

Death from any cause at 30 days of follow-up

Secondary Endpoints:

Death and nonfatal hemorrhagic stroke; death and nonfatal disabling stroke

Drug/Procedures Used:

SK, 1.5 million U in 100 mL over 60 minutes, plus 12,500 U of subcutaneous heparin bid, or
SK, 1.5 million U in 100 mL over 60 minutes, plus IV heparin as a bolus of 5000 U then 1000-1200 U/h adjusted to an activated partial thromboplastin time of 60--85 s, or
Accelerated recombinant tissue plasminogen activator (rt-PA) as a 15 mg bolus, then 0.75 mg/kg up to 50 mg over 30 min, and 0.5 mg/kg up to 35 mg over the next 60 min, with IV heparin as above, or
rt-PA, 1.0 mg/kg IV over 60 min, up to 90 mg, and SK, 1.9 million U over 60 min given simultaneously, and IV heparin as above

Concomitant Medications:

Aspirin, 160-325 mg/day; atenolol, 5 mg IV in two divided doses, then oral atenolol, 50-100 mg once daily. Other medication or treatment at the discretion of the physician

Principal Findings:

Mortality was 7.2% in the SK and subcutaneous heparin group, 7.4% for SK and IV heparin, 6.3% for accelerated rt-PA and IV heparin, and 7% for the combination of rt-PA and SK plus IV heparin. This corresponds to a 14% reduction in mortality for accelerated rt-PA compared to the two SK-only regimens (p = 0.001). There was a significant excess of hemorrhagic strokes in the accelerated rt-PA group (p = 0.03) and for the combination group (p <0.001), compared to SK only. However, a consistent pattern of fewer complications was seen in the accelerated rt-PA group. The combined endpoint of death or disabling stroke was significantly lower in the accelerated rt-PA group (6.9%) than in the SK-only groups (7.8%, p = 0.006). Patients >75 years had a higher mortality rate than patients <75 years, but absolute net benefit was still greater with accelerated rt-PA.

Two-year vital status (minimum, 688 days) was determined for 2375 patients. There was a substantial mortality advantage for early complete reperfusion (TIMI grade 3) and for preserved ejection fraction beyond 30 days. Early TIMI 3 flow was associated with approximately a 3% mortality reduction the first month with an additional 5% from 30 days to 2 years.

Multivariable analysis identified age as the most significant factor influencing 30-day mortality. Other factors most significantly associated with increased mortality were lower systolic blood pressure, higher Killip class, elevated heart rate, and anterior infarction. Together, these five characteristics contained 90% of the prognostic information in the baseline clinical data.

Bypass surgery was a significant independent predictor of 30-day mortality (risk ratio 1.87) and a weaker predictor of 1-year mortality (risk ratio 1.21).

A case-control retrospective analysis of 198 patients undergoing rescue PTCA showed that successful rescue PTCA resulted in superior left ventricular function and 30-day mortality outcomes, comparable to outcomes in patients with closed IRAs managed conservatively, but less favorable than in patients in whom thrombolytic therapy was initially successful. The mortality rate after a failed rescue attempt was 30.4%; however, five of the seven patients who died after failed rescue PTCA were in cardiogenic shock before the procedure.

Interpretation:

The GUSTO-I study established accelerated rt-PA combined with IV heparin as the optimal thrombolytic strategy for patients with AMI. The benefit of rt-PA over streptokinase was not detected in ISIS-3 or GISSI-2, likely because of lower doses of concomitant heparin. Successful reperfusion and myocardial salvage produce significant mortality benefits that are amplified beyond the initial 30 days.

References:

1. N Engl J Med 1993;329:673-82. Design and baseline results
2. Circulation 1995;91:1659-68. Predictors of 30-day mortality
3. Circulation 1995;91:1923-8. Angiographic substudy
4. Circulation 1996;94:1233-8. Final results (1-year follow-up)
5. JAMA 1996;275:777-82. Gender subgroups
6. J Am Coll Cardiol 1997;29:240-249. CABG and mortality
7. Circulation 1998;97:1549-56. 2-year survival analysis
8. J Am Coll Cardiol 1998;31:1511-7. Rescue PTCA

Clinical Topics: Anticoagulation Management, Dyslipidemia, Heart Failure and Cardiomyopathies, Lipid Metabolism, Acute Heart Failure

Keywords: Thrombolytic Therapy, Stroke, Myocardial Infarction, Ventricular Function, Left, Heparin, Blood Pressure, Electrocardiography, Heart Rate, Shock, Cardiogenic, Streptokinase, Chest Pain, Partial Thromboplastin Time, Tissue Plasminogen Activator


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