Thursday, Sep 20, 1990
Stockholm -- September 20, 1990 --Presenting at the XII session of the European Congress of Cardiology, Phase 6 of the European Cooperative Study Group (ECSG-6) for recombinant tissue plasminogen activator (t-PA), reported that use of effective concurrent anti-coagulation is critical to sustaining the high early patency rates seen with t-PA.
"Our trial, which was specifically designed to examine the effect of early intravenous heparin when used with t-PA, confirms that adjunctive therapy is important to maintain infarcted artery patency in the post-thrombolytic period of hospitalization," stated Dr. David P. De Bono, Professor and Chief of Cardiology, University Leicester School of Medicine, England.
In the ECSG-6 Trial, all 652 patients received t-PA and aspirin. Patients were randomized to receive intravenous heparin simultaneously with the initiation of thrombolytic therapy or placebo. Heparin was continued until the time of angiography which was performed at two to five days (average 81 hours) to evaluate coronary artery patency. Infarct artery patency in patients receiving heparin was 83%, whereas patency fell significantly to 75% when heparin was not administered. With intravenous heparin, patients were two-thirds as likely to have an occluded infarct artery at the time of angiography as compared to patients who received aspirin only (relative risk .66, p0.05).
In addition to the important patency data, ECSG-6 results also showed trends in a number of other clinical endpoints. The results show that there were fewer left ventricular thrombi at the time of angiography with 3.7% in the heparin arm and 6.8% with no heparin. Likewise, patients who received heparin experienced less recurrent ischemia (9.3% versus 11.6%) in the period before angiography. In regard to reduction of infarct size, there was a difference of 4% in cumulative enzyme release.
There were no statistically significant safety differences between the two arms of the study. In both arms, the incidence of intracranial bleeding and stroke were low, with an overall stroke rate of 0.45% in all patients.
The current findings support other heparin trials including two U.S. studies reported last year by Allan Ross from George Washington Unversity Medical Center and Stanley D. Bleich from Tulane University. These trials also showed that without effective early anti-coagulation, the high initial patency rates seen with t-PA were not sustained.
The role of adjunctive heparin has been central to the debate over the large GISSI-2 and International t-PA/SK Mortality Trials whose results were released earlier this year (Lancet July 14, 1990). These trials compared the two most commonly used thrombolytics, t-PA and streptokinase.
"Based on our results, as well as those previously reported, it now appears that the heparin regimen used in these trials--only initiated subcutaneously 12 hours after the completion of thrombolytic therapy or not at all--did not confer optimal anti-coagulation to sustain patency with t-PA. Hence a maximum clinical outcome was not achieved, " remarked Professor Verstraete (Center for Thrombosis and Vascular Research, University of Leuven). "The results of the ECSG-6 Trial limit the interpretation of any comparative findings between t-PA and streptokinase in these trials or in any trial not using early intravenous heparin".
ISIS-3 is another large scale international trial which is now in progress. It will compare Burrough Wellcome's double-chained t-PA (duteplase) to streptokinase and the most recently introduced thrombolytic agent, APSAC.
"ISIS-3 suffers the same inherent limitations as did GISSI-2 and the International t-PA/SK Mortality Trials in which patients received late subcutaneous or no heparin," Pr. Verstraete explained. In ISIS3, heparin is given subcutaneously 4 hours after the initiation of duteplase and is consequently 8 hours earlier when compared with the GISSI-2 and International t-PA/SK Mortality Trials."
"When given in this manner, " continues Pr. Verstraete, "patients reached a level of anti-coagulation hours after the initiation of subcutaneous heparin. Even when the maximum effect of this mode of administration is obtained, it may not be optimal in all patients. This may be adequate for drugs such as streptokinase and APSAC. They directly produce a prolonged systemic lytic effect with a significant decrease in fibrinogen and subsequent increase in fibrinogen degradation products which provide anti-thrombotic protection. This appears to be insufficient for more clot specific drugs like t-PA and pro-urokinase which do not have such profound systemic effects".
Pr. Verstraete noted that, based on the ECSG-6 results confirming the role of immediate intravenous heparin t-PA, ISIS-3 may not resolve the issue of which thrombolytic agent is superior. Nevertheless, it is expected that ISIS-3 will still yield valuable information about which patients should be treated.
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