Lancet 1988;349-360Background The introduction to the ISIS-2 manuscript opens with a remarkable statement from the authors:Reductions in mortality that are realistically moderate (eg, “only” 20-25%) are important, especially if produced by widely practicable treatments for common causes of death.At the time of this posting, January 2024, it’s amazing to think, how in 1988, a 20-25% reduction in mortality was considered moderate for a “widely practicable treatment for a common cause of death” and now the profession seems to grasp at almost anything, at nearly any cost, that reduces some composite of hard, soft and, in some cases, completely meaningless endpoints by the same amount. Regardless, ISIS-2 sought to test the hypothesis that streptokinase and aspirin, either alone or together, would reduce vascular mortality in patients with MI.Patients Patients with suspected myocardial infarction, who the responsible physician thought were within 24 hours of symptom onset and had no clear indication for, or contraindication to, streptokinase or aspirin. Absolute contraindications included: any history of stroke or of gastrointestinal ulcer. Possible contraindications included: recent arterial puncture, recent severe trauma, severe persistent hypertension, allergy to streptokinase or aspirin, low risk of cardiac death, or some other life-threatening disease. ECG changes at entry were not required.The design was meant to be pragmatic to facilitate patient enrollment; however, exclusion criteria was more extensive for ISIS-2 compared to ISIS-1, which reflects concern about hemorrhagic side effects associated with use of these agents. Like ISIS-1, there were no special procedures dictating patient follow-up after the hospitalization ended.Baseline characteristics Basic demographic information is not provided in the main manuscript but we can infer from the subgroup Forest plots that more than two thirds of patients were men, the overwhelming majority were less than 70 years of age, and nearly half were less than 60. Less than 20% had a previous MI and only around 7% had diabetes. Patients with inferior and anterior STEMI’s composed more than half of the cohort. About 43% of patients presented within 4 hours of symptom onset, another 42% presented between 5 and 12 hours, and the remaining 15% presented between 13 and 24 hours.Procedures A 2x2 factorial study design was used. All patients were randomly assigned to receive either streptokinase or a matching placebo. All patients were also randomly assigned to receive either aspirin or a matching placebo. This led to 4 distinct treatment groups: 1) streptokinase + aspirin placebo, 2) aspirin + streptokinase placebo, 3) streptokinase + aspirin, or 4) placebo onlyPatients allocated to receive streptokinase were immediately given 1.5 MU of ‘Streptase’ over 1 hour. Patients allocated to receive aspirin were immediately given 162.5 mg of an enteric coated tablet that was crushed, sucked, or chewed for a rapid anti-platelet effect. Thereafter, they took a 162.5 mg tablet daily for 1 month.Endpoints Vascular mortality over 5 weeks was the primary endpoint. Follow-up after discharge involved only mortality, through government records wherever possible.Results 17,187 participants were randomized from 417 hospitals in 16 countries. Compliance with the assigned treatments was estimated to be between 90-95%.The results of ISIS-2 are not reported in a standard results table, making vascular mortality as well as all-cause mortality impossible to infer over the duration of the trial. The number of non-vascular deaths are presented in a table but vascular deaths beyond 5 weeks are not formally provided in the original publication. The only evidence of vascular deaths beyond 5 weeks is presented in survival curves.Over 5 weeks, Streptokinase alone reduced vascular mortality compared to placebo by approximately 25% (9.2% vs 12.0%) and these results were highly significant. The difference remained highly sign