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CIBA-GEIGY’s HIRUDIN SHOWS IMPROVED PATENCY OVER HEPARIN POST- ACUTE Ml, TIMI-5 RESEARCHER SAYS; HIRULOG UNSTABLE ANGINA DOSAGE TRIAL REPORTED TO AHA

Executive Summary

Hirudin as an adjunct to thrombolytic therapy in acute myocardial infarction patients improves the rate of patency compared to heparin, Eugene Braunwald, MD, Brigham & Women's Hospital and head of the Thrombolysis in Myocardial Infarction (TIMI) research group, said Nov. 8 at the American Heart Association's 66th Scientific Sessions in Atlanta. Hirudin, in development by Ciba-Geigy, "appears to produce improved early and sustained" patency post-acute MI, Braunwald said. His conclusions were based on the Phase II TIMI-5 trial, which examined the effects of hirudin and heparin in conjunction with front-loaded recombinant tissue plasminogen activator (Genentech's Activase rtPA). There were 162 patients enrolled in the randomized trial, which doubled as a dose-escalation study for hirudin; the maximal dose was a 0.6 mg/kg bolus followed by 0.2 mg/kg/hour I.V. infusion. After 90 minutes of treatment, more hirudin patients had complete patency (TIMI-3 on the scale), but the difference was not statistically significant. At 18 to 36 hours, however, angiograms showed a wider gap between the treatments: 84% of patients receiving hirudin had TIMI-3 patency, compared with 74% of those treated with hoparin. Hirudin patients also had lower rates of reocclusion, reinfarction, need for revascularization and death. Furthermore, there was "no increase in major hemorrhage," Braunwaid said. Another Phase II trial with front-loaded tPA, the Hirudin for the Improvement of Thrombolysis (HM study, led by Karl-Ludwig Neuhaus, NM, Kassel, Germany, showed the efficacy of hirudin by demonstrating a correlation between higher doses and better rates of patency. The maximal dose in this trial was a 0.4 mg/kg bolus followed by 0.15 mgtkg/h I.V. Neuhaus, presenting Nov. 9, mentioned three Phase III trials that will further explore hirudin. HIT-II is enrolling about 7,000 patients with AMI, GUSTO II will study about 12,000 patients with AMI and unstable angina, and TIMI-9 will look at about 3,000 acute MI patients. Braunwald said that TIMI-9 will have largely clinical endpoints including death, MI, low ejection fraction and clinical congestive heart failure. In the TIMI-6 trial, streptokinase was used as the thrombolytic agent rather than tPA. Patients received either hirudin or heparin for five days. Those treated with hirudin had a six-week rate of death or reinfarction of 7.7%, compared with 12.5% for the heparin-treated patients. Biogen's antithrombin Hirulog was tested in TIMI-7, a dosage trial with 410 unstable angina patients. Four different dosages were given and the patients given the smallest dose were compared with those in the three higher dose groups. In the lowest dose Hirulog group, the rate of death of Ml after six weeks was 10.6% compared with 3.6% in the higher-dose groups. Among those patients with ST-segment elevation, the difference was even greater, although the numbers were too small to make a valid comparison, Braunwaid said. Another study of Hirulog in unstable angina, led by Rosa-Maria Lidon, NM, Montreal Heart Institute, and presented Nov. 9, concluded that "Hirulog produces highly predictable, very stable and dosage-related prolongation of aPTTs [activated partial thromboplastin times] with no need for dose titration." Stable prolongation of APTT is thought to diminish the risk of reocclusion and reinfarction.
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