Thrombolytic therapy in acute myocardial infarction

Infarct size limitation has been a therapeutic aim for many years, particularly in view of the known close relationship between the extent of myocardial damage occurring at the time of the infarction, and future morbidity and mortality. It is only in the last decade, however, since the pathophysiology of myocardial infarction has been better understood, that this aim has become a clinical reality. Thus, it is now well established that myocardial infarction is caused by intracoronary thrombosis, usually at the site of a ruptured atheromatous plaque,' and this occlusive thrombus can be dissolved by the administration of intracoronary or intravenous thrombolytic agents.4-6 Although this clinical breakthrough has come in the last 10 years, the pioneering work on this subject was in fact performed in the late 1950s and early 1960s, using open chested anaesthetized dogs to study the effects of reperfusion on ischaemic myocardium.7-1' The results of these early studies demonstrated the experimental basis for the theory that ischaemic cell death has an early reversible and later irreversible phase. However, it was not until the late 1970s that a full analysis of the timing of cell death was complete and a time frame for intervention to reduce infarct size established. 2-14 Reimer and Jennings,14 in a classical paper, were at this time able to produce, from animal studies, a plot of the percentage of myocardium salvageable (by reperfusion) against duration of occlusion of a coronary artery. This work clearly demonstrated a therapeutic time window in which intervention was able to modify infarct size and it was from this paper, together with work showing the role of occlusive thrombus resulting in myocardial infarction,1 3 that a number of clinical studies on infarct size limitation were moulded. Initial human work on this subject in the early 1980s was largely confined to the administration of intracoronary streptokinase4'6,'1516 and it therefore required that medical practitioners involved in the work had access to a cardiac catheterization laboratory. In these studies, intracoronary streptokinase was infused into the occluded coronary artery at a standard rate, and patency rates achieved were in the region of 70-80% after 20-30 minutes perfusion. It was realized early on however that the assessment of success in restoring coronary patency was complicated by the phenomenon of spontaneous reperfusion. 17,18 However, in the many studies performed at this time, coronary patency rates were consistently significantly higher after the administration of thrombolytic therapy than in patients treated conventionally. Because of logistic problems with intracoronary infusions the obvious next development for thrombolytic therapy was the utilization of the intravenous route of administration. Streptokinase given in this way achieved a slightly reduced patency rate (55-75%) as compared to intracoronary streptokinase'9'20 but it was clear that if treatment was given to patients in the critical first few hours after infarction then limitation of infarct size was possible.6 The most popular regimen used for the administration of intravenous streptokinase was that developed by Schroder et al.5 based on the earlier work of Breddin21; using this regime, one and a half million units of streptokinase are given by slow intravenous infusion over 60 minutes. Following the administration of either intracoronary or intravenous streptokinase it became clear that reperfusion could be established in between 55% and 80% of cases but the next obvious question to be posed was whether this reperfusion had any impact on patient survival and ventricular function. Unfortunately all of the early studies were too small to answer these questions