OBJECTIVES A multicenter pilot study was instituted to assess the role of intracoronary thrombolytic therapy during angioplasty for ischemic rest angina. BACKGROUND Acute thrombotic coronary occlusion is increased during angioplasty for unstable angina, and intracoronary thrombolytic agents have been used to maintain patency. Prophylactic use of intracoronary thrombolytic agents has been advocated in certain high risk subgroups, although no studies have randomized therapy. METHODS Ninety-three patients with either unstable angina and pain at rest (trial A, 66 patients) or postinfarction pain at rest (trial B, 27 patients) were randomized in double-blind fashion to administration of either intracoronary urokinase, 150,000 U, or saline solution placebo given immediately before angioplasty. Cineangiograms of the culprit lesion were recorded and analyzed in blinded fashion by a core laboratory for definite or possible (haziness) filling defects 15 min after angioplasty or after acute closure. RESULTS Urokinase decreased filling defects at 15 min after angioplasty in comparison with placebo (14% vs. 29%, respectively, p = 0.08). Four patients in each treatment group developed acute vessel closure. However, although urokinase significantly reduced the incidence of filling defects in trial A (3% vs. 23%, p = 0.03), the drug had no effect at the selected dose in trial B (42% vs. 43%, respectively). Acute vessel closure occurred significantly more frequently in trial B than in trial A, and urokinase at the selected dose also had no effect. Ischemic events after angioplasty appeared to be related more to dissection than to thrombosis, although redilation, which was more frequent after placebo administration, may have reduced their incidence as well as that of acute closure. CONCLUSIONS These data suggest a possible role for intracoronary urokinase during angioplasty for unstable angina. The lack of effect after infarction may represent a greater thrombus burden or degree of plaque disruption. A trial utilizing higher doses of urokinase in a larger patient group is in progress.