Summary Robert Roberts, MD

D ata from the Heparin-Aspirin Reperfusion Trial, Bleich and Sixth European Cooperative Study Group trials confirmed the benefits of early in-

travenous heparin as an adjunct to thrombolytic therapy with tissue plasminogen activator (t-PA). The second Gruppo Italian0 per lo Studio della Soprawivenza nell’Infarto Miocardico (GISSI-2) suggested that strep- tokinase and t-PA were equally effective in reducing mor- tality associated with acute myocardial infarction; how- ever, critics noted that the heparin regimen used in GISSI-2 was delivered subcutaneously and was therefore suboptimal in conjunction with t-PA. Investigators con- cluded that the need for heparin administered early and in high doses is greater in patients treated with t-PA than in those treated with streptokinase, because t-PA has less systemic anticoagulant effects than does streptokinase.

Results of 2 large international trials will be forthcom- ing and hopefully will shed more light on the role of adjunctive agents in thrombolysis. The third Internation- al Study of Infarct Survival (ISIS-3) will compare dute- plase (a Burroughs Wellcome t-PA formulation), strep- tokinase and anisoylated plasminogen activator complex in >30,000 patients. However, in this trial, the heparin regimen is also suboptimal for use with t-PA, because heparin will be administered subcutaneously 4 hours af-

From the Department of Cardiology, Baylor College of Medicine, Houston, Texas.

Address for reprints: Robert Roberts, MD, Baylor College of Me&- tine, 6535 Fannin, MS F-905, Houston, Texas 77030.

ter initiation of therapy. Also, the t-PA that will be used in ISIS-3 appears to be underdosed, compared to the alteplase regimen currently used in the United States. Recent reports suggest that duteplase will not be market- ed in the United States. Thus, ISIS-3 will not be a true comparison of the 3 agents. Such a comparison would necessitate use of early intravenous heparin with ade- quate dosing in the t-PA arm.

In response to questions raised by GISSI-2, a new trial is planned to evaluate t-PA and streptokinase with an appropriate heparin regimen. The Global Utilization of Streptokinase and t-PA for Occluded Arteries (GUSTO) trial will be conducted outside the United States and will include >30,000 patients. At present, the protocol is planned to include 3 arms: a rapid infusion dose of up to 100 mg of t-PA administered over 90 minutes; a standard dose of 1.5 million U streptokinase administered over 60 minutes; and a combination arm of 1 mg/kg (maximum, 90 mg) t-PA administered over 60 minutes (with 10% as a bolus), plus 1 million U streptokinase over 60 minutes. The rationale for the combined arm is to use t-PA to open the artery, and then streptokinase as a “super heparin” to maintain patency over the first 24 hours. The primary end point will be mortality at 30 days. GUSTO should begin enrolling patients shortly.

Overall, the studies to date suggest that heparin and aspirin are important adjuncts to thrombolytic therapy, and that newer adjunctive strategies will be useful in shortening the time to thrombolysis and maintaining pa- tency by preventing reocclusion/rethrombosis.

32A THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 67