GISSI-1 (Effectiveness of intravenous thrombolytic treatment in acute myocardial infarction)

Through the first half of the 1980s, the management of acute myocardial infarction remained largely supportive. Nitrates, beta-blockers, and lidocaine prophylaxis against arrhythmias were the working tools in coronary care units; in GISSI's control group, 13 percent of patients died in hospital within 21 days. The thrombotic basis of most acute infarctions was understood, and small trials of intracoronary streptokinase had shown angiographic evidence of recanalization, but those trials were too small to detect a mortality effect with confidence and required catheterization laboratory access that most hospitals did not have.

The Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico network assembled 176 coronary care units across Italy and enrolled patients with suspected acute MI presenting within 12 hours of symptom onset. Over 17 months in 1984 and 1985, 11,806 patients were randomized, without blinding, to intravenous streptokinase plus usual treatment or usual treatment alone. The design was deliberately simple: IV streptokinase required no catheterization laboratory, only a peripheral line, making it deployable at any hospital running a coronary care unit. Fausto Rovelli coordinated the multicenter network throughout the enrollment period.

The results, published in the Lancet in 1986, showed 21-day mortality of 10.7 percent in the streptokinase group versus 13.0 percent in the control group, an absolute reduction of 2.3 percentage points and a relative reduction of approximately 18 percent. The benefit depended on time from the onset of pain: the relative risk of death was 0.74 for patients treated within 3 hours, 0.80 at 3 to 6 hours, 0.87 at 6 to 9 hours and 1.19 at 9 to 12 hours. That gradient turned speed of treatment into a clinical priority.

At that scale the mortality finding was clear (p = 0.0002): about 23 fewer deaths for every 1,000 patients treated, and the authors judged streptokinase safe for routine use. ISIS-2, published two years later, confirmed the finding with streptokinase and extended it to aspirin, showing additive benefit. In ISIS-2, streptokinase alone cut the odds of vascular death at five weeks by 25 percent and the combination with aspirin by 42 percent, and intravenous thrombolysis became standard care for acute myocardial infarction.

GISSI-1 also reshaped how the cardiology community thought about conducting large, simple randomized trials. Its design, enrolling broad, unselected populations across many centers with a minimal protocol, produced an answer that previous small trials had been unable to generate. ISIS-3 later pooled its heparin results with those of GISSI-2. Percutaneous coronary intervention eventually replaced thrombolysis as the preferred reperfusion strategy where catheterization laboratories were available around the clock, while drug reperfusion is still used where they are not.