The urokinase-pulmonary embolism trial.

ON October 16, 1968, a nationwide cooperative study was officially begun to assess the therapeutic efficacy of urokinase in acute pulmonary thromboembolism. The beginning of the "Urokinase-Pulmonary Em-bolism Trial" was the culmination of the efforts of many individuals* during the course of several years. The fact that the study is now in progress is in large part a result of extensive cooperation between the academic medical community, the pharmaceutical industryt and the National Heart Institute, the sponsoring agency. Following the first observation of the in vitro fibrinolytic activity of human urine by MacFarlane and Pilling' in 1947, this activity was identified as due to urokinase, a plasminogen (profibrinolysin) activator with a molecular weight of 53,000. In addition to its availability, human urokinase possesses certain properties which made it a promising thrombolytic agent; for unlike the strep-tococcal plasminogen activator, streptokinase, urokinase is nonantigenic in man and less likely to be toxic. Early clinical experience indicated that intravenous administration into humans was both safe2 and effective in dissolving experimental intravascular clots.3 The identification of certain problems relative to the orderly development of urokinase as a therapeutic agent prompted the establishment of the Committee on Thrombolytic Agents of the National Heart Institute in February 1963. Sufficient quantities of the material for clinical trials then became available under contract to the National Heart Institute according to rigid specifications; for example, it was free from thromboplastic contamination, possessed high specific activity , was heat treated at 60 C for 10 hours for virus inactivation, and was shown to be nontoxic and nonpyrogenic in animals. A CTA (Committee on Thrombolytic Agents) unit was established and reproducible assay methods were developed. Finally, the material was demonstrated to be effective in lysing de novo intravascular human thrombi and for inducing and sustaining a predictable and reproducible thrombolytic state in man without the necessity of rigid laboratory monitoring.4 For several reasons, acute pulmonary em-bolism was chosen as the most suitable clinical entity and experimental model for the initial evaluation of urokinase: First, pulmonary embolism is a relatively common and important disease and restoration of blood flow could provide a significant clinical benefit. Second, lung scanning, pulmonary angiography, and assessment of hemo-dynamic data provide objective methods for diagnosing and following the course of pulmonary embolism. Third, a relatively fresh 153 1969 NO. 2 EDITORIAL clot, composed primarily of fibrin, is generally lodged in an otherwise normal pulmonary vessel which is …