Lancet 1994;343:1115-22.Background By the time GISSI-3 was undertaken, evidence had emerged suggesting afterload reduction with angiotensin-converting-enzyme (ACE) inhibitors improved morbidity and mortality in patients with chronic systolic heart failure and these agents were already an established treatment for acute, severe heart failure based on theoretical grounds, despite lack of evidence from large scale RCTs. There was also lower level evidence that nitrates reduced mortality in patients with acute MI and these drugs were broadly used in coronary care units at the time. The GISSI-3 trial was undertaken to test the hypotheses that 6 weeks of treatment with lisinopril alone or transdermal glyceryl trinitrate (GTN) alone reduced the combined endpoint of mortality and severe LV dysfunction at 6 months compared to controls.Cardiology Trial’s Substack is a reader-supported publication. To receive new posts and support our work, consider becoming a free or paid subscriber.Patients Patients were eligible if they presented with chest pain and ST segment elevations of ≥1 mm in any limb lead of the electrocardiogram and/or ≥2 mm in any precordial leads and were admitted to the cardiac intensive care unit (CCU) within 24 hr from the onset of symptoms. Absolute contraindications included: severe heart failure requiring any of the study treatments, Killip class 4, high risk of hemodynamic deterioration after treatment with vasodilators (SBP <100 mmHg), specific contraindications to the study drug such as a history of renal failure or bilateral renal artery stenosis, documented allergy to one of the study drugs, or other life-threatening diseases like cancer or serious respiratory disease.Baseline characteristics The number of patients who were admitted to CCUs over the study period was 43,047 and 19,394 (45%) were randomized. Reasons for exclusion included: more than 24 hr from onset of symptoms (33%), contraindications to study treatment (23%), persistent hemodynamic instability (15%), and administrative reasons (28%). Similar to other GISSI trials, which also provided information on patients enrolled versus those who were not, women were more likely to be excluded (31% of excluded vs 22% of enrolled) as were patients >70 years of age (41% of excluded vs 27% of enrolled). As expected, excluded patients had higher in-hospital mortality (12% of excluded vs 6% of enrolled).Seventy-eight percent of patients enrolled were men and nearly three quarters were under the age of 70. Patients with anterior STEMI accounted for approximately 27%, those with inferior 32% and non-Q-wave MI’s approximately 19%. Time from symptom onset was between 12-24 hours in 40%, between 6-12 hours in 25% and less than 6 hours in 35%. The vast majority of patients had a Killip score of 1 (85%) with the remainder having a Killip score of 2 (14%). Procedures The study used a 2x2 factorial design, resulting in 4 treatment groups: lisinopril alone, transdermal GTN alone, combination therapy with lisinopril and transdermal GTN, or no trial therapy.Patients randomized to oral lisinopril received 5 mg at the time of randomization, followed by 5 mg 24 hours later and 10 mg 48 hours later to be continued at a dose of 10 mg daily for 6 weeks. Patients with SBP <120 mmHg could be started on 2.5 and titrated up and if at any time in the trial SBP was <100 mmHg; a maintenance dose of 5 mg daily could be adopted and temporary reductions to 2.5 mg daily were allowed. Those randomized to control received no treatment.Those assigned to transdermal GTN were administered a continuous infusion over the first 24 hours. It was started at 5 mcg/min and increased by 5-20 mcg/min every 5 minutes for the first 30 minutes until SBP fell by at least 10%, provided it remained over 90 mmHg. After 24 hours, the IV infusion was replaced with a transdermal patch providing 10 mg daily. The patch was applied every morning and removed at bedtime, to provide a 10 hour nitrate-free interval, so as t