GUSTO

Published

Topol E, et al. "An international randomized trial comparing four thrombolytic strategies for acute myocardial infarction". The New England Journal of Medicine. 1993. 329(10):673-682.
PubMed • Full text • PDF

Clinical Question

Among patients with ACS, does administration of streptokinase, tPA, or both in addition to heparin and ASA reduce all-cause mortality at 30 days?

Bottom Line

Among patients with ACS, rapidly administered tPA in addition to heparin and ASA reduces all-cause mortality at 30 days when compared ASA and heparin with either streptokinase or slowly-administered tPA and streptokinase.

Major Points

Restoration of coronary perfusion in MI was identified as a potential therapeutic intervention as early as 1912, with the first studies of thrombolytics/fibrinolytics (originally streptokinase [SK]) occurring in the 1950s. The first large study to demonstrate efficacy of thrombolytics in ACS was the unblinded GISSI trial (1986). This was confirmed in the double-blinded ISIS-2 trial (1988).

Tissues plasminogen activator (tPA) is a novel thrombolytic that was found to improve reperfusion over SK in TIMI-1 (1987). Its role in ACS was demonstrated in ISIS-3 (1992) and GISSI-2 (1992). There was no mortality benefit from tPA, which was infused over 3-4 hours. Whether more rapid infusion of tPA would provide a survival advantage was unknown.

The 1993 Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO) trial randomized 41,021 patients with ACS at 1,081 hospitals to SK+heparin sub-q, SK+heparin IV, rapid administration of "accelerated" tPA+heparin IV, or a combination of SK+tPA+heparin IV (with a slower administration of the tPA). The group receiving tPA+heparin had a 1% absolute risk reduction of death at 30 days over both SK+heparin groups (6.3% vs 7.2% and 7.4%; NNT 100). The tPA+heparin group had more hemorrhagic strokes and bleeding. Therapy with tPA+SK+heparin did not confer a survival benefit over SK+heparin.

Subsequent to GUSTO, PCI has been found to be superior to thombolysis in STEMI and has now become the standard of care. Thrombolytic therapy remains an important back-up modality in the disease.

Guidelines

ACCF/AHA STEMI Guidelines (2013, adapted)

• If >120 minute delay from first medical contact until PCI, the following are indications for thrombolytics in STEMI:
  • No contraindications to the therapy, ischemic symptoms <12 hours duration (class I, level A)
  • No contraindications to the therapy, ongoing ischemia between 12-24 hours of onset of symptoms (class IIa, level C)
• Do not administer thrombolytics if ST depression unless suspicion of a posterior/inferobasal MI or also ST-elevations in aVR (class III, level B)

ACCF/AHA NSTE-ACS Guidelines (2014, adapted)

• If NSTE-ACS (examples include no ST elevation, no posterior MI, or LBBB known to be old), do not administer IV thombolytics (class III, level A)

Design

• Multicenter, randomized, open label, comparative trial
• N=41,021
  • SK+heparin sub-q(n=9,841)
  • SK+heparin IV (n=10,410)
  • tPA+heparin IV (n=10,396)
  • tPA+SK+heparin IV (10,374)
• Setting: 1,081 hospitals in N. America, Europe, the Middle East, and Australia/New Zealand
• Enrollment: 1990-1993
• Follow-up: 30 days
• Analysis: Not defined, presumably intention-to-treat
• Primary outcome: All-cause mortality at 30 days

Population

Inclusion Criteria

• Presentation to a hospital <6 hours after start of ≥20 minutes of chest pain
• ST elevations ≥0.1 mV in ≥2 limb leads or ≥0.2 mV in ≥2 contiguous precordial leads

Exclusion Criteria

• Prior stroke
• Active bleeding
• Prior SK or anistreplase therapy
• Recent major surgery or trauma
• Prior GUSTO participation
• Noncompressable blood vessels on vascular punctures

The authors define a SBP≥180 mmHg unresponsive to therapy was a relative contraindication to enrollment but not an overt criterion for exclusion.

Baseline Characteristics

From the SK+heparin sub-q group.

• Demographics: Age 62 years, female 25%
• PMH: Diabetes 15%, smoker 43%, HTN 39%, MI 16%
• PSH: CABG 4%
• Baseline health data: BP 130/73
• Duration until study events:
  • Randomization: 120 minutes
  • Treatment: 164 minutes
  • Time from symptoms to treatment: 5 minutes longer in the tPA+SK+heparin IV group (P<0.001)

Interventions

• Randomization to a group:
  • SK+heparin sub-q:
    • SK 1.5 million units IV over 60 minutes
    • Heparin 12,500 units subcutaneously twice daily with first dose 4 hours after initiation of thrombolysis and was continued for 7 days or until hospital discharge
      • Of note, this was the regimen used in ISIS-3 and was added as a treatment arm 4 months after initiation of the trial
  • SK+heparin IV:
    • SK 1.5 million units IV over 60 minutes
    • Simultaneous administration of heparin bolus at 5000 units x1 IV then a weight-based heparin gtt at 1000-1200 units per hour IV titrated to an aPTT 60-85 seconds, continued for ≥48 hours
  • tPA+heparin IV:
    • Accelerated tPA bolus of 15 mg IV then 0.75 mg/kg (maximum 50 mg) over 30 minutes then 0.5 mg/kg (maximum 35 mg) over the next 60 minutes
    • Heparin bolus at 5000 units x1 IV then a weight-based heparin gtt at 1000-1200 units per hour IV titrated to an aPTT 60-85 seconds, continued for ≥48 hours
      • The heparin therapy was initiated while the tPA was being given at 0.5 mg/kg
  • tPA+SK+heparin IV:
    • tPA 1 mg/kg IV over 60 minutes (maximum 90 mg) with 10% of total dose give an a bolus
    • SK 1 million units over 60 minutes
    • Heparin bolus at 5000 units x1 IV then a weight-based heparin gtt at 1000-1200 units per hour IV titrated to an aPTT 60-85 seconds, continued for ≥48 hours
      • All therapies were started simultaneously
• All patients received:
  • ASA - Chewable ASA ≥160 mg at presentation then were continued on daily ASA 160-325 mg PO qday
  • Beta blockers - if no contraindications, atenolol 2.5 mg IV x 2 then 50-100 mg PO qday
  • Other medications and interventions were performed at the discretion of the treating physician

Outcomes

Presented as SK+heparin sub-q vs. SK+heparin IV vs. tPA+heparin IV vs. tPA+SK+heparin IV. P value is tPA+heparin IV vs. SK+heparin sub-q and SK+heparin IV. NNT/NNH compares tPA+heparin IV vs. average outcome between both SK+heparin groups.

Primary Outcome

All-cause mortality at 30 days

7.2% vs. 7.4% vs. 6.3% vs. 7.0% (risk reduction 14%; 95% CI 5.9-21.3%; P=0.001; NNT=100)

No difference between groups receiving SK, P=0.731

tPA+heparin better than tPA+SK+heparin with risk reduction 10%, 95% CI 6.3-7.0%, P=0.04

Secondary Outcomes

All-cause mortality at 30 days

Or nonfatal stroke: 7.9% vs. 8.2% vs. 7.2% vs. 7.9% (P=0.006; NNT 118)

Or nonfatal hemorrhagic stroke: 7.4% vs. 7.6% vs. 6.6% vs. 7.4% (P=0.004; NNT 111)

Or nonfatal disabling stroke: 7.7% vs. 7.9% vs. 6.9% vs. 7.6% (P=0.006; NNT 111)

Adverse Events

Stroke

1.22% vs. 1.40% vs. 1.55% vs. 1.64% (P=0.09)

Hemorrhagic: 0.49% vs. 0.54% vs. 0.72% vs. 0.94% (P=0.03; NNH 489)

Non-hemorrhagic: 0.53% vs. 0.65% vs. 0.64% vs. 0.53% (P=0.57)

Hemorrhagic conversion: 0.04% vs. 0.05% vs. 0.06% vs. 0.08% (P=0.62)

Unknown: 0.15% vs. 0.16% vs. 0.13% vs. 0.10% (P=0.54)

Bleeding

Severe or life-threatening: 0.3% vs. 0.5% vs. 0.4% vs. 0.6% (P=0.31)

Moderate: 5.6% vs. 5.8% vs. 5.1% vs. 5.6% (P=0.04; NNH 167)

Moderate or worse: 5.8% vs. 6.3% vs. 5.4% vs. 6.1% (P=0.02; NNH 154)

Units transfused:

None: 89% vs. 88% vs. 90% vs. 88%

1-2: 5% vs. 6% vs. 5% vs. 6%

3-4: 3% vs. 3% vs. 3% vs. 3%

≥5: 3% vs. 3% vs. 2% vs. 3%

Lowest median HCT: 37% s. 37% vs. 37% vs. 37%

Other adverse events

Allergic reaction: 5.7% vs. 5.8% vs. 1.6% vs. 5.4% (P<0.001)

Anaphylaxis: 0.7% vs. 0.6% vs. 0.2% vs. 0.6% (P<0.001)

HF: 17.5% vs. 16.8% vs. 15.2% vs. 16.8% (P<0.001)

Cardiogenic shock: 6.9% vs. 6.3% vs. 5.1% vs. 6.1% (P<0.001)

Persistent hypotension: 13.3% vs. 12.5% vs. 10.1% vs. 12.4% (P<0.001)

2nd or 3rd AV block: 9.5% vs. 8.7% vs. 7.3% vs. 8.4% (P<0.001)

Sutained V-tach: 6.8% vs. 6.5% vs. 5.6% vs. 6.1% (P=0.001)

V-fib: 7.1% vs. 6.9% vs. 6.3% vs. 6.9% (P=0.02)

Asystole: 6.0% vs. 6.4% vs. 5.3% vs. 6.4% (P=0.003)

AF or a-flutter: 9.9% vs. 9.8% vs. 8.6% vs. 9.1% (P=0.001)

Reinfarction: 3.4% vs. 4.0% vs. 4.0% vs. 4.0% (P=0.26)

Recurrent ischemia: 19.9% vs. 19.6% vs. 19.0% vs. 18.8% (P=0.14)

Acute MR: 1.6% vs. 2.6% vs. 1.3% vs. 1.4% (P=0.11)

Acute VSD: 0.5% vs. 0.4% vs. 0.4% vs. 0.6% (P=0.59)

Additional Outcomes

All-cause morality at 24 hours

2.8% vs. 2.9% vs. 2.3% vs. 2.8% (P=0.005; NNT 182)

Therapy compliance

Thrombolytics: 97% - 98% in all groups

Aspirin:

Initial: 97% of all patients

Daily: 93% of all patients

Heparin:

Day 1: 99.5% of all patients

≥40 hours: 86% of all patients

Beta blockers:

IV administration: 46% of all patients

Orally: 71% of all patients

Additional therapies

Lidocaine: 18% of all patients

CCB: 31% of all patients

Digoxin: 14% of all patients

Other inotropes: 19% of all patients

IV nitroglycerin: 77% of all patients

ACE-inhibitor: 21% of all patients

Subgroup Analysis

Presented as both SK+heparin groups vs. tPA+heparin IV.

All-cause mortality at 30 days

≤75 years: 5.5% vs. 4.4% (OR 0.79; 95% CI 0.70-0.89)

>75 years: 20.6% vs. 19.3% (OR 0.92; 95% CI 0.78-1.10)

P-value for interaction by age group 0.098

Anterior infarct: 10.5% vs. 8.6% (OR 0.81; 95% CI 0.71-0.92)

Non-anterior infarct: 5.3% vs. 4.7% (OR 0.89; 95% CI 0.78-1.03)

0-2 hours until thrombolytics: 5.4% vs. 4.3% (tPA better)

2-4 hours until thrombolytics: 6.7% vs. 5.5% (tPA better)

4-6 hours until thrombolytics: 9.3% vs. 8.9% (no difference)

>6 hours until thrombolytics: 8.3% vs. 10.4% (no difference)

P-value for interaction for duration of time 0.015

The authors note in a follow-up letter that this P-value for interaction lost significance (P=0.38) with complete follow-up.

Any stroke

≤75 years: 1.08% vs. 1.20% (OR 1.21; 95% CI 0.88-1.42)

>75 years: 3.05% vs. 3.93% (OR 1.30; 95% CI 0.90-1.87)

Hemorrhagic stroke

≤75 years: 0.42% vs. 0.52% (0R 1.24; 95% CI 0.86-1.78)

>75 years: 1.23% vs. 2.08% (OR 1.71; 95% CI 1.01-2.88)

All-cause mortality or non-fatal disabling stroke

≤75 years: 6.0% vs. 5.0% (OR 0.83; 95% CI 0.74-0.93)

>75 years: 21.5% vs. 20.2% (OR 0.93; 95% CI 0.78-1.10)

Criticisms

• Lacked power to detect benefit in subgroups
• Unclear cost effectiveness
• No difference in LV function between the groups, which would be expected if the survival benefit in the tPA+heparin group was related to improved patency
• tPA was not compared to the "conventional" tPA regimen of the time

Funding

• Private funding from Bayer, CIBA-Corning, Genentech, ICI Pharmaceuticals, and Sanofi Pharmaceuticals