Cardiology · 1988
ISIS-2 (Second International Study of Infarct Survival)
Through most of the 1980s, the treatment of acute MI was in active transformation. Streptokinase had been shown to reduce mortality, but thrombolysis required intravenous infusion in a monitored setting. Aspirin had been used empirically in coronary patients for years, and some smaller trials suggested a benefit in secondary prevention, but no large trial had directly tested whether aspirin given acutely at the time of MI reduced short-term mortality. The question had practical importance: aspirin was cheap, widely available, and could be administered anywhere, including ambulances and primary care offices.
ISIS-2 was designed by Rory Collins and Richard Peto at the University of Oxford, who had already led the first ISIS trial of intravenous atenolol in MI. The second trial used a two-by-two factorial design, enrolling 17,187 patients with suspected acute MI at 417 hospitals across 16 countries. Patients were randomized to intravenous streptokinase, oral aspirin 160 mg daily for one month, both, or neither. The factorial structure allowed the investigators to test both interventions simultaneously in a single trial without requiring a doubled sample size. Peter Sleight at Oxford co-led clinical operations.
The results, published in the Lancet in 1988, were clear on all four arms. Aspirin alone reduced five-week vascular mortality by approximately 23% relative to placebo. Streptokinase alone achieved a similar reduction. The combination produced roughly a 42% reduction, and the two benefits were additive with no meaningful interaction. Equally important, aspirin's mortality benefit came without a clinically significant increase in major bleeding, which had been a concern given its antiplatelet mechanism.
Before ISIS-2, most cardiologists knew aspirin was used after MI, but this empirical practice lacked the support of a mortality endpoint in a large trial. The ISIS-2 result removed any ambiguity: a substantial reduction in mortality from a drug costing fractions of a penny per dose was compelling, and the result appeared in guidelines rapidly. Aspirin became part of the standard first-responder protocol for suspected MI, given at first contact before any diagnostic confirmation.
ISIS-2 also contributed to the methodology of large, simple cardiovascular trials. The factorial design, the use of wide eligibility criteria to maximize generalizability, and the reliance on a mortality endpoint rather than surrogate measures were deliberate choices by Collins and Peto that distinguished the ISIS trials from smaller, more selected academic studies. The trial helped establish antiplatelet therapy across the spectrum of acute coronary syndromes; subsequent trials of clopidogrel and other agents were built on the platform of aspirin as a universal background therapy that ISIS-2 had established.
Key People
- Rory Collins — Oxford epidemiologist and ISIS-2 principal investigator
- Richard Peto — Oxford statistician and co-principal investigator who designed the ISIS trials
- Peter Sleight — Oxford cardiologist who co-led ISIS-2 clinical operations
- Salim Yusuf — Cardiologist and trialist who contributed to the ISIS data infrastructure and analysis
Lancet. 1988;2(8607):349-360.
Related landmarks
- 1987 · CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study) (Cardiology)
- 1987 · FDA approval of lovastatin, the first statin (HMG-CoA reductase inhibitor) (Cardiology)
- 1986 · GISSI-1 (Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction) (Cardiology)
- 1991 · SOLVD Treatment Trial (Cardiology)