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RAPID PATENCY RESULTS IN LOWER MORTALITY AND IMPROVED VENTRICULAR FUNCTION

Executive Summary

RAPID PATENCY RESULTS IN LOWER MORTALITY AND IMPROVED VENTRICULAR FUNCTION and may be the mechanism by which accelerated t-PA therapy (Genentech's Activase, alteplase) produced better survival rates than streptokinase in the GUSTO trial, an angiographic substudy of GUSTO suggests. The substudy was published in the Nov. 25 New England Journal of Medicine. "This study points to important associations between early patency of the infarct-related artery, better preservation of ventricular function, and improved survival after thrombolytic therapy for acute myocardial infarction," substudy authors Allan Ross, MD, George Washington University, et al. wrote. "We propose that our findings explain the survival advantage of patients in the GUSTO trial who received accelerated t-PA therapy." In GUSTO, the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries trial, 30-day mortality rates in patients treated with streptokinase and subcutaneous heparin; streptokinase and I.V. heparin; accelerated t-PA and I.V. heparin; and both thrombolytics with I.V. heparin, were 7.2%, 7.4%, 6.3% and 7%, respectively, a 14% survival advantage for the t-PA arm over the two streptokinase arms ("The Pink Sheet" May 3, T&G-3). The results of two previous megatrials, GISSI-2 and ISIS-3, did not show survival differences between t-PA and streptokinase. The substudy authors noted that there is controversy surrounding "the open-artery theory" because of the results of the two earlier trials. Those trials, they said, "provided no information on coronary-artery patency, reocclusion or ventricular function." In a Nov. 24 release, Genentech said it filed an amendment on Oct. 15 to the Activase product license application for approval of the accelerated dosing regimen used in GUSTO ("The Pink Sheet" Sept. 6, 1993, T&G-8). Current labeling recommends dosing over three hours. The GUSTO angiography substudy enrolled 2,431 patients, "of whom 94% had at least one analyzable angiogram." Patients were randomly assigned to one of the four treatment groups and to cardiac angiography at one of four times after therapy: 90 minutes, 180 minutes, 24 hours, or 5 to 7 days. The substudy results show that "the rate of patency of the infarct-related artery at 90 minutes was highest in the group given accelerated-dose t-PA and heparin (81%), as compared with the group given streptokinase and subcutaneous heparin (54%, p < 0.001), the group given streptokinase and [I.V.] heparin (60%, p. < 0.001), and the group given combination therapy (73%, p = 0.032)." "Flow through the infarct-related artery at 90 minutes was normal in 54% of the group given t-PA and heparin but in less than 40% of the three other groups (p < 0.001)," the study adds. "Angiograms obtained 180 minutes after the start of therapy showed no residual differences in patency among the treatment groups." As for ventricular function evaluation, "the group given t-PA with heparin and the group given the combination treatment had significantly less depression of regional wall motion in the ischemic zone than either group given streptokinase." In addition, "the group given t-PA with heparin had fewer patients with abnormal chords and more patients with preserved wall motion than any of the other three groups." Mortality rates at 30 days were: 6.5% among patients given streptokinase with subcutaneous heparin, 7.5% among those given streptokinase with intravenous heparin, 5.3% among those given t- PA with heparin, and 7.8% among those given the combination treatment." Patency grades regardless of treatment were analyzed. "A lack of patency at 90 minutes (TIMI grade 0 or 1) was associated with mortality of 8.9%, and patency (TIMI grade 2 or 3) with mortality of 5.7% (p = 0.04)." In an accompanying editorial, Eugene Braunwald, MD, Brigham and Women's Hospital, said that "the demonstrated correlation between early coronary-artery patency, better left ventricular function, and improved survival should allow the conduct of much smaller trials in which patency and left ventricular function are used as endpoints, thereby accelerating progress in this important field." While the substudy reemphasizes "the importance of early reperfusion," Braunwald pointed out that it "also emphasizes that there is still considerable room for improvement in thrombolytic therapy." He noted that 46% of the patients receiving accelerated t-PA, intravenous heparin and aspirin, "did not have full patency at 90 minutes." Braunwaid is head of the Thrombolysis in Myocardial Infarction (TIMI) research group.
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