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, up to 24 hours (median 5 hours) after the onset of symptoms. With placebo controls, patients were randomized to a one-hour intravenous infusion of 1.5 million units of streptokinase, enteric-coated 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 the odds of vascular death at five weeks by 23 percent (9.4 percent against 11.8 percent), and streptokinase alone by 25 percent (9.2 against 12.0 percent). Given together, they cut the odds by 42 percent (8.0 against 13.2 percent), and their effects appeared to be additive. Aspirin also halved nonfatal reinfarction (1.0 against 2.0 percent) without a significant increase in cerebral hemorrhage or bleeds needing transfusion.

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. ISIS-2 settled the question with a mortality endpoint in a large trial, and a cheap, widely available drug entered guidelines for acute MI. Aspirin became part of routine early treatment of suspected MI. The benefit held even for patients treated 13 to 24 hours after the onset of pain.

ISIS-2 also contributed to the methodology of large, simple cardiovascular trials. The factorial design, wide eligibility criteria and a mortality endpoint, not a surrogate measure, were deliberate choices by Collins and Peto that set the ISIS trials apart from smaller, more selected 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.