ISIS-2 showed that aspirin and streptokinase each independently reduced early vascular mortality in acute MI, with the greatest benefit when used together. It is one of the landmark trials that established aspirin and reperfusion therapy as foundational acute MI treatment.
Study design
- Large, randomized, placebo-controlled trial
- 2x2 factorial design
- N = 17,187
- Patients with suspected acute myocardial infarction
- Randomized to streptokinase, aspirin, both, or placebo
- Primary outcome: vascular mortality at 5 weeks
Population
Included
- Suspected acute MI
- Presentation within 24 hours of symptom onset
- No clear contraindication to streptokinase or aspirin
- Broad real-world MI population
Clinical context
- Pre-primary PCI era
- Thrombolysis was the major reperfusion strategy
- Aspirin was not yet universally established for acute MI
- Trial tested simple, scalable acute MI therapies
Acute MI
N = 17,187
2x2 factorial
Aspirin
Streptokinase
5-week mortality
Interventions
Streptokinase
- 1.5 million units IV over 1 hour
- Compared with placebo
- Tested as early reperfusion therapy
Aspirin
- 162.5 mg daily for 1 month
- Compared with placebo
- Tested as early antiplatelet therapy
Primary outcome
- Primary outcome: vascular mortality at 5 weeks
- Streptokinase reduced vascular mortality: 9.2% vs 12.0%
- Aspirin reduced vascular mortality: 9.4% vs 11.8%
- Combination therapy had the largest benefit: 8.0% vs 13.2% with double placebo
- Aspirin + streptokinase produced an approximate 42% relative reduction in vascular death vs placebo
Aspirin + streptokinase vs placebo
Vascular mortality at 5 weeks
15%
11.25%
7.5%
3.75%
0%
8.0% vs 13.2% | Approx 42% relative mortality reduction
Primary endpoint: vascular mortality at 5 weeks. ASA = aspirin. SK = streptokinase.
Secondary outcomes
| Outcome | Finding | Interpretation |
|---|---|---|
| Streptokinase alone | 9.2% vs 12.0% vascular mortality | Reduced early death after acute MI |
| Aspirin alone | 9.4% vs 11.8% vascular mortality | Reduced early death after acute MI |
| Aspirin + streptokinase | 8.0% vs 13.2% vascular mortality | Combination produced the largest mortality benefit |
| Reinfarction | Reduced with aspirin | Supported early antiplatelet therapy in MI |
| Stroke | Reduced ischemic events but small hemorrhagic risk with lytic therapy | Benefit favored treatment in appropriate patients |
Safety
| Safety issue | Finding | Clinical point |
|---|---|---|
| Bleeding | More bleeding with streptokinase | Expected tradeoff with thrombolytic therapy |
| Hemorrhagic stroke | Small excess risk with streptokinase | Screen for contraindications before lysis |
| Aspirin | Large mortality benefit with low cost and broad usability | Became standard acute MI therapy |
Practical point: ISIS-2 was a pre-PCI trial, so streptokinase is no longer the default reperfusion strategy where timely PCI is available. The aspirin finding remains foundational and directly relevant.
Interpretation
- ISIS-2 proved that early aspirin saves lives in acute MI.
- It also confirmed that thrombolytic reperfusion reduces early MI mortality.
- The combination of aspirin and streptokinase had additive benefit.
- The trial changed acute MI care because both treatments were simple, cheap, and rapidly deployable.
- Modern STEMI care now prioritizes PCI when available, but ISIS-2 remains one of the most important cardiology trials ever performed.
Citation: ISIS-2 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;2:349-360.
PubMed