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EMINASE EFFICACY EQUALS ACTIVASE IN FIRST HEAD-TO-HEAD TEST

Executive Summary

EMINASE EFFICACY EQUALS ACTIVASE IN FIRST HEAD-TO-HEAD TEST, according to results from the French trial (ENTIM) comparing Eminase and TPA in acute myocardial infarction, presented at the annual meeting of the American College of Cardiology March 20. "In terms of efficacy, there was no difference whatever the endpoint considered: the coronary patency rate, the clinical reinfarction rate, the left ventricular systolic function preservation and the myocardial infarct size limitation," Jacques Machecourt, MD, University of Grenoble, reported. Within four hours of acute myocardial infarction, 183 patients received either a 10 mg bolus of TPA (Genentech's alteplase) followed by 90 mg TPA over three hours or 30 mg Eminase (SmithKline Beecham's anistreplase or APSAC) over five minutes. The TPA group received 5,000 IU heparin at the start of therapy. Both groups received 250 mg aspirin per day, plus 1,000 heparin per hour during the in-hospital period. Coronary angiography was performed on an average of 5.3 days following the acute myocardial infarction. Patency rate of the infarcted arteries was 76% for TPA compared to 72% for Eminase. The difference was not considered to be statistically significant. Radionucleotide ejection fraction testing of 160 patients at day 18 showed no significant difference in the pumping action of the heart between the groups (47% for TPA v. 48% for Eminase). Mortality was also similar in the two patient groups, with seven deaths in the TPA group compared to five deaths in the Eminase group. Although not statistically significant, bleeding complications were higher in the Eminase arm of the study, 11 versus 9 for TPA. Machecourt indicated that greater incidence of bleeding in the Eminase group could have been due to a greater fall in the fibrinogen level in that group. Although fibrinogen levels decreased in both groups, fibrinogen fell in the Eminase arm to 0.6 g/l compared to 2.0 g/l for the TPA arm. Based on the risk of bleeding complications in both groups, Machecourt said "we recommend delaying full heparinisation of the patients after APSAC until hour 4, and reducing the TPA dose to 1 mg/kg in very low weight patients." The ENTIM trial results dealt another blow to the assertion of superiority of TPA over other thrombolytic therapies. Results of the Italian GISSI-2 trial ("The Pink Sheet" March 12, T&G-5) and the 20,891 patient International TPA/streptokinase Mortality Trial, which demonstrated that there is a comparable mortality between streptokinase and TPA, were also presented at the meeting. Patients treated with streptokinase had an overall mortality rate of 8.5%, compared to 8.9% in the TPA group. When patients were treated with heparin, the mortality rate in the streptokinase arm of the study dropped to 7.9% but increased in the TPA group to 9.2%, for a statistically significant difference. Stroke was significantly greater in the TPA treated patients, 1.3% versus 1% percent for streptokinase treated patients. Bleeding occurred in 4.2% of the patients in the TPA group and 3.3% in the streptokinase group; however, more major bleeding occurred in the streptokinase group, 0.9% versus 0.6%. The results of the trials were discussed by a panel of cardiologists at a press conference on March 21. The experts tackled the criticisms of the GISSI-2 trial, raised in particular by Genentech and many U.S. cardiologists, that because heparin was administered at 12 hours in the study, although TPA and heparin are routinely given concomitantly in the U.S., the results are not an accurate assessment of TPA's long-term benefit. Proponents of that argument point out that early use of heparin increases TPA's ability to open clogged arteries and other trials with TPA have shown that TPA is a more potent thrombolytic agent at 90 minutes post-myocardial infarction. "At least from the American perspective, we still believe that infarct vessel patency is important and it is difficult to put the GISSI-2 in perspective if you really believe that, commented panel member Cindy Grines, MD, University of Kentucky. The question in terms of mortality, Grines said, is whether "the 90 minute patency rate is important or is it the 24 hour patency?" She added that "available data would suggest that TPA does have a higher patency at 90 minutes but at 24 hours, it is no different than streptokinase." Long-time thrombolysis researcher Sol Sherry, MD, Temple University, maintained that "what was seen [in GISSI-2] was a mortality reduction which probably relates to whether a vessel ultimately opens within a 24 hour period and that all of these agents have the same patency or reperfusion rates at 24 hours." In light of the GISSI-2 results, Sherry asserted that "the onus is now on the various TPA advocates, including the National Heart, Lung and Institute, to prove that TPA is any better than any of the other thrombolytic agents." Mortality differences between the agents may be further clarified by the ISIS-3 study, Sherry said, ISIS-3 compares Eminase, Burroughs Wellcome's double-chain TPA (duteplase) and streptokinase. Results from the study are expected soon.
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