Clinical trials in thrombolytic therapy, Part 2: The open-artery hypothesis and RAPID-1 and RAPID-2

Abstract

The open-artery hypothesis as supported by thrombolytic study results is discussed. The open-artery hypothesis states that survival after acute myocardial infarction (AMI) is maximized by achieving early and sustained patency of the infarct-related artery. However, two large multicenter trials did not detect any difference in mortality between patients given alteplase and patients given streptokinase, despite previous evidence that alteplase led to earlier recanalization of infarct-related arteries. The Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-1) trial suggested that early and complete patency is essential for short-term survival after AMI. Subsequent observations indicated that an open infarct-related artery at the time of hospital discharge is associated with improved long-term survival. In the Reteplase Angiographic Phase II International Dose-Finding (RAPID-1) trial, complete patency was more frequent in patients who received a double-bolus regimen of reteplase than in patients who received standard-dose alteplase. Similar results were obtained in the Reteplase versus Alteplase Patency Investigation during Myocardial Infarction (RAPID-2) trial, which compared the same double-bolus reteplase regimen with an accelerated regimen of alteplase. In both RAPID studies, mortality was lower and other outcomes were more favorable in reteplase recipients. Reteplase seems more likely to produce normal blood flow soon after AMI than either standard-dose or accelerated alteplase and may be associated with a lower mortality rate. This lends further support to the open-artery hypothesis.