The history of the TIMI, GISSI, and ISIS trials: the development of thrombolytic therapy in acute myocardial infarction

The introduction of thrombolytic therapy represents one of the most important advances in the history of cardiovascular medicine. Before the 1980s, treatment of acute myocardial infarction (AMI) was largely supportive, with limited opportunities to modify the natural course of the disease. The recognition that coronary thrombosis was the principal mechanism underlying ST-segment elevation myocardial infarction led to the development of reperfusion strategies aimed at restoring coronary blood flow and limiting myocardial damage. Among the landmark investigations that established the efficacy of thrombolytic therapy, the GISSI, ISIS, and TIMI trials occupy a central place. GISSI demonstrated for the first time on a large scale that intravenous streptokinase reduced mortality after AMI. ISIS confirmed and expanded these findings by documenting the additive benefits of aspirin, while TIMI advanced the understanding of coronary reperfusion through systematic angiographic assessment. Together, these programs transformed the management of acute myocardial infarction and established many of the principles that continue to guide reperfusion therapy today.