Schroder et al. (50) tested a strategy of short-term (1 h), high-dose (0.5-1.5 million units [MU]) infusions of SK given to patients at an early time (within 12 h) of symptom onset. In their initial clinical trial, a baseline angiographic study was followed by a 0.5 MU SK infusion. After 1 h, occluded coronary arteries from 11 of 21 patients (52%) had opened, and total patency rate (adding those with initial subtotal occlusions) was 62%. In a subsequent study, 93 patients were treated with 1.5 MU over 1 h. Early angiography was not performed, but an 84% later patency rate (in the fourth wk) was shown. Serum CK-MB concentrations peaked early (within 10-12 h after therapy), consistent with the pattern seen with angiographically demonstrated recanalization, and myocardial salvage was suggested by improved function in the infarct zone. A successful recanalization pattern was more frequently observed for patients treated within 3 h than later. The safety profile of IV SK in these doses, including bleeding rates, was acceptable.
Several small to intermediate-sized randomized trials of IV vs IC SK followed these feasibility studies (35,51-54). These trials generally supported "equivalence" between the two routes of administration with little difference in coronary patency at 24 h and no significant difference in clinical outcome by route of administration.
The potential utility of IV SK in the modern era of investigation was further supported by a larger randomized trial (Intravenous Streptokinase in Acute Myocardial Infarction, n = 1741 patients), which observed an 11% mortality reduction with IV SK, from 7.1% to 6.3% (55). This favorable trend did not achieve statistical significance, however.
In parallel with these, other studies investigated effects on ventricular function. An overview of results suggested functional improvement (myocardial salvage) when therapy was begun early (within 3 to 4 h). Results were inconsistent or negative for later therapy (41) as predicted by animal models (17,18). In 12 studies, SK was begun within 4 h of symptom onset. An increase in infarct-zone ventricular function was observed in each study, and an increase in global function (ejection fraction) was noted in 9 of these studies (41,56). By contrast, if therapy was begun more than 4 h after symptom onset (6 studies), regional wall motion rarely improved (in only one study) and global ejection fraction was unchanged (41,56). When functional improvement occurred in patients given later therapy, it appeared to be based on collateral or residual antegrade blood flow and other factors slowing the rate of necrosis (57,58). Consistent improvement in function was observed when reperfusion interventions occurred within 2 h (58-60). Given the variability in functional response and the potential importance of other mechanisms (such as remodeling), the focus shifted to large mortality trials for the assessment of clinical thrombolytic benefit.
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