Prevention of coronary artery reocclusion and reduction in late coronary artery stenosis after thrombolytic therapy in patients with acute myocardial infarction. A randomized study of maintenance infusion of recombinant human tissue-type plasminogen activator.

Abstract

Sixty-eight patients with acute "transmural" myocardial infarction presenting within 6 hours (range, 1.3-5.8 hours) of onset of chest pain were given intravenous recombinant tissue-type plasminogen activator (rt-PA) at a dosage of 1 mg/kg during 90 minutes. Coronary angiography at 90 minutes revealed a patent infarct-related coronary artery in 52 patients (76%). These patients were randomized either to treatment by continuous infusion of heparin alone (27 patients) or to treatment by heparin and a maintenance infusion of rt-PA at a dosage of 0.8 mg/kg during 4 hours (25 patients). Coronary angiography was repeated 60 minutes after the start of the maintenance infusion and again after 8-14 days. Acute symptomatic reocclusion of the infarct-related artery occurred during the 1-hour observation period in five (19%) patients treated with heparin alone but in none of the patients treated with rt-PA (p = 0.05). The measured residual stenosis of the patent infarct-related coronary artery was similar in the heparin-treated and the rt-PA-treated groups at 90 minutes infusion: 66±14% versus 68±13% diameter stenosis, respectively (mean ± SD) and 1.1 ± 1.1 mm2 versus 0.82 ± 0.7 mm2 area (p = 0.35). At 8-14 days after infusion, residual stenosis was unchanged in the heparin-treated group, but it improved to 55 ± 17% (p = 0.001) and 1.6 ± 1.2 mm2 (p = 0.003) in the rt-PA-treated group. At 90 minutes of infusion, residual intraluminal thrombus was observed in 29 of the 52 patients (56%) with a comparably measured distribution in the two groups (p= 0.43). At 150 minutes, however, the extent of intraluminal thrombus was significantly reduced in the rt-PA-treated group as compared with the heparin-treated group (p= 0.03). In-hospital ischemic events (symptomatic reocclusion, unstable angina, or cardiovascular death) occurred in 12 patients of the heparin-treated group but only in three patients of the rt-PA-treated group (p = 0.03). Fibrinogen levels decreased to 65 ± 21% of baseline at 90 minutes of rt-PA infusion. During the rt-PA maintenance infusion, fibrinogen fell slightly from 63 ± 26 to 57 ± 28% (p = 0.18). This study shows that after successful reperfusion with 1 mg/kg rt-PA during 90 minutes, a maintenance infusion of 0.8 mglkg rt-PA during 4 hours prevents acute symptomatic coronary artery reocclusion, and it reduces the frequency of ischemic events and the severity of residual coronary artery stenosis at hospital discharge. (Circulaton 1988;78:546-556) S uccessful thrombolytic therapy of acute myoin-hospital reocclusion rate after reperfusion with cardial infarction does not always produce intravenous streptokinase has ranged from 10% to stable coronary artery patency. The reported

Relative efficacy of antithrombin compared with antiplatelet agents in accelerating coronary thrombolysis and preventing early reocclusion.

“…[4][5][6]7,10,13,25,26,[37][38][39] Prolongation of fibrinolysis appears to reduce the incidence of reocclusion but may predispose to bleeding.6,39 Although aspirin improves the outcome of thrombolysis,8 the mechanism responsible is uncertain. The efficacy of antiplatelet agents may be limited when they are administered in doses that perturb hemostatic function only moderately because reocclusion appears to involve deposition of both fibrin and platelets, perhaps reflecting effects of thrombin both on the coagulation system itself and on local activation of platelets.…”

“…[6][7][8][9] Early reocclusion may result, in part, from activation of platelets, as has been demonstrated clinically. '0,11 Augmentation of thrombin activity has been shown also to accompany thrombolysis,1213 possibly reflecting a paradoxical prothrombotic effect of plasminogen activators attributable to elaborated plasmin that may contribute to reocclusion.14 Because the relative contribution to reocclusion of activated platelets and of thrombin activity per se has not been delineated, it is not yet clear whether thrombolysis can Haskel et al Adjunctive Agents for Coronary Thrombolysis 1049 be best facilitated with powerful antiplatelet agents, powerful antithrombin agents, or both.…”

Cilostazol, a novel cyclic AMP phosphodiesterase inhibitor, prevents reocclusion after coronary arterial thrombolysis with recombinant tissue-type plasminogen activator.

“…In particular, this complication occurs frequently in cases of severe stenosis, thus causing further myocardial damage. 29 Thus, to further improve the management of acute myocardial infarction, treatment of the coronary thrombosis and protection against reocclusion must be performed simultaneously.…”

Recurrent ischemic events after successful thrombolysis in acute myocardial infarction. The Achilles' heel of thrombolytic therapy.

“…Gold et a15 reported that, combined with a large initial dose, a maintenance infusion of rt-PA could greatly reduce the reocclusion rate.5 Subsequently, however, these investigators reported that a reduceddose rt-PA infusion was associated with a reocclusion rate of more than 40%. 40 Although increased doses of nonfibrin-selective agents might decrease the incidence of rethrombosis, rt-PA doses of more than 100 mg are contraindicated because of a lhigher incidence of intracerebral bleeding. New genetic engineering approaches to create rt-PAs with longer intrinsic thrombolytic activity appear to be a promising avenue for further investigation.41…”