GUSTO

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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.
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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.[1][2] The first large study to demonstrate efficacy of thrombolytics in ACS was the unblinded GISSI trial[3] (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[4] (1992) and GISSI-2[5] (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[6] and has now become the standard of care.[7] Thrombolytic therapy remains an important back-up modality in the disease.

Guidelines

ACCF/AHA STEMI (2013, adapted)[7]

  • 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 (2014, adapted)[8]

  • 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.[9]
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[2]
  • Unclear cost effectiveness[2][10]
  • 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[11]
  • tPA was not compared to the "conventional" tPA regimen of the time[11]

Funding

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

Further Reading

  1. White HD and Van der Werf FJ. "Thrombolysis for acute myocardial infarction." Circulation. 1998:97(16):1632-1646.
  2. 2.0 2.1 2.2 Fuster V. "Editorial: Coronary thrombolysis -- A perspective for the practicing physician." The New England Journal of Medicine. 1993;329(10):723-724.
  3. GISSI trail authors. "Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction." The Lancet. 1986;1(8478):397-402.
  4. ISIS-3 group. "ISIS-3: A randomised comparison of streptokinase vs. tissue plasminogen activator vs. anistreplase and of aspirin plus heparin vs. aspirin alone among 41,299 cases of suspected acute myocardial infarction." The Lancet. 1992;339(8796):753-770.
  5. GISSI-2 group. "GISSI-2: A factorial randomised trial of alteplase versus streptokinase and heparin versus no heparin among 12,490 patients with acute myocardial infarction." The Lancet. 1990;336:65-71.
  6. Keeley EC, et al. "Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: A quantitative review of 23 randomised trials." The Lancet. 2003;361(9351:13-20.
  7. 7.0 7.1 O'Gara PT, et al. "2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines." Circulation. 2013;127(4):e362-e425.
  8. Amsterdam EA, et al. "2014 AHA/ACC guideline for the management of patients with non-ST-elevation acute coronary syndromes." Journal of the American College of Cardiology. 2014;epublished 2014-09-23. Accessed 2014-09-24.
  9. Topol EJ, et al. "Correspondence correction: More on the GUSTO trial." The New England Journal of Medicine. 1994;331:277-278.
  10. Multiple authors. "Correspondence: Thrombolytic therapy for acute myocardial infarction: GUSTO criticized." The New England Journal of Medicine. 1994;330:504-506.
  11. 11.0 11.1 Multiple authors. "Correspondence: Thrombolytic therapy for myocardial infarction." The New England Journal of Medicine. 1994;330:1089-1090.