What are the implications of the GUSTO I (Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries) trial on the use of thrombolytic therapy with tissue plasminogen activator (tPA) in adults with acute coronary syndrome (ACS) and a history of cardiovascular disease or risk factors?

GUSTO I Trial: Implications for Thrombolytic Therapy in Acute Myocardial Infarction

Primary Finding and Recommendation

Accelerated tissue plasminogen activator (tPA/alteplase) reduces mortality by 10 additional deaths per 1,000 patients treated compared to streptokinase in acute myocardial infarction with ST-segment elevation, making it the preferred thrombolytic agent despite a small increase in stroke risk. 1, 2

Mortality Benefit

The GUSTO I trial enrolled 41,021 patients and demonstrated that accelerated tPA achieved a 30-day mortality rate of 6.3% compared to 7.2-7.4% with streptokinase regimens, representing a 15% relative risk reduction (95% CI: 5.9-21.3%, p=0.001). 1, 3, 4 This mortality advantage was consistent across virtually all subgroups, including elderly patients, those with non-anterior infarctions, patients requiring bypass surgery, and hypertensive patients. 3

• The survival benefit stems from accelerated tPA achieving superior early coronary artery patency, specifically TIMI grade 3 (normal) flow at 90 minutes in 54% of patients versus less than 40% with streptokinase regimens (p<0.001). 1, 4
• Patients with TIMI grade 3 flow at 90 minutes had 30-day mortality of 4.4% compared to 8.9% in those with no flow (p=0.009). 4
• The angiographic substudy demonstrated that 92% of the mortality difference between treatments could be explained by differences in achieving early, complete coronary perfusion (R²=0.92). 5

Stroke Risk Trade-off

The mortality benefit comes at the cost of 3 additional strokes per 1,000 patients treated with accelerated tPA compared to streptokinase, but critically, only 1 of these 3 additional strokes results in residual neurological deficit. 1, 2

• Intracranial hemorrhage rates were 0.70% with accelerated tPA versus 0.51% with streptokinase in GUSTO I. 1
• More recent trials show ICH rates of 0.87-0.94% with tPA as higher-risk populations (older age, more females) are now treated. 1
• The combined endpoint of death or disabling stroke remained significantly reduced with accelerated tPA (p=0.006). 3

Patient Selection Algorithm

Use streptokinase preferentially over tPA in patients with:

• Age >75 years 2
• Body weight <70 kg 2
• Female gender 2
• Prior cerebrovascular disease 2
• Uncontrolled hypertension on admission 2

These populations have substantially increased risk of intracranial hemorrhage that may outweigh the mortality benefit. 2

Use accelerated tPA preferentially in:

• Patients presenting within 2 hours of symptom onset (greatest absolute mortality reduction) 1
• Large anterior myocardial infarctions 1
• Patients at low risk for intracranial hemorrhage 1
• Late presenters (tPA may be more effective than streptokinase beyond 4-6 hours) 2

Dosing Protocols

Accelerated tPA regimen (the GUSTO protocol): 2

• 15 mg IV bolus
• Then 0.75 mg/kg over 30 minutes (maximum 50 mg)
• Then 0.5 mg/kg over 60 minutes (maximum 35 mg)
• Total dose not to exceed 100 mg
• Concurrent IV heparin for 24-48 hours with aPTT-adjusted dosing 1

Streptokinase regimen: 2

• 1.5 million units in 100 mL over 30-60 minutes
• Subcutaneous heparin has lowest ICH rate (0.51%) but IV heparin may be used 1

Critical Pitfalls to Avoid

• Never use 3-hour tPA infusion protocols - only the accelerated 90-minute regimen demonstrated mortality benefit in GUSTO I. 1, 2
• Never readminister streptokinase if prior exposure within 10 years due to antibody formation and allergic reaction risk. 1, 2 tPA can be safely readministered. 2
• Do not delay treatment for low-risk patients - the ACC/AHA guidelines note that stroke risk may outweigh benefit in patients at low risk of death from cardiac causes. 6
• Monitor for hypotension with streptokinase - occurs commonly but is usually manageable; severe allergic reactions are rare. 1, 2

Newer Thrombolytic Agents

Subsequent trials demonstrated that tenecteplase (TNK-tPA) is equivalent to accelerated tPA for 30-day mortality (6.17% vs 6.18%) with similar ICH rates (0.93% vs 0.94%) but significantly less non-cerebral bleeding (26% vs 28.1%, p<0.002). 1 The single-bolus administration of TNK-tPA offers practical advantages for pre-hospital use. 1, 2

Reteplase showed no additional survival benefit over accelerated tPA (7.5% vs 7.2% mortality at 30 days) despite ease of bolus administration. 1

Cost-Benefit Considerations

The ACC/AHA guidelines emphasize that accelerated tPA and reteplase are substantially more expensive than streptokinase, so the cost-benefit ratio is greatest in patients presenting early after symptom onset with large areas of myocardial injury and low risk of intracranial hemorrhage. 1