Development and Pathophysiological Basis of Thrombolytic Therapy in Acute Myocardial Infarction: Part IV

Acute and day 10 to 14 recanalization rates with intracoronary thrombolytic and/or spasmolytic therapy were determined in the First Mt. Sinai‐N.Y.U. Reperfusion Trial (1984). Recanalization of total occlusion was accelerated by intracoronary streptokinase, the first proven potentially beneficial effect of thrombolytic therapy. Intravenous administration of thrombolytic agents, including t‐PA, was less effective in accelerating recanalization than intracoronary streptokinase as assessed by 90‐minute rates of TIMI‐III flow. In clinical practice the greater ease of intravenous administration outweighed this disadvantage, but intracoronary administration was uniquely suited to analyze the pathophysiological principles of reperfusion therapy. The first randomized trial (n = 533) to establish the benefits of early reperfusion, the Netherlands Randomized Trial, achieved infarct vessel patency in 85% of patients within 200 minutes of symptom onset by administering intracoronary streptokinase alone or following a rapid intravenous infusion of streptokinase. Ejection fraction improved significantly and mortality at 28 days was reduced (6% vs 12%). The ISIS‐2 Trial (1988) showed mortality reduction with intravenous thrombolytic therapy up to 24 hours after infarct onset, but did not explain the benefit of late reperfusion. In the Second Mt. Sinai‐N.Y.U. Reperfusion Trial (1989; n = 393), intracoronary streptokinase administered 4 to 14 hours after infarct onset increased thallium uptake. Streptokinase improved ejection fraction in patients with collateralized total occlusion but not in those with noncollateralized total occlusion. Preintervention antegrade flow was associated with ejection fraction improvement regardless of treatment assignment. We concluded that thrombolytic therapy after > 4 hours of infarction salvages myocardium in patients with collateralized total coronary artery occlusion. Total coronary occlusion was associated with collateral flow in 33% at acute angiography, but in 90% at day 10 to 14 angiography, indicating a second phase of collateral growth. An angioplasty model was developed to assess appearance and disappearance of collateral flow immediately after controlled coronary occlusion and reflow in humans. Using this model we demonstrated limitation of ischemia by collateral recruitment prospectively.