Sunday, Mar 3, 1991

ISIS-3 Results Controversial and Inconclusive for U.S. Practice; T-PA Used in ISIS-3 Study Not Genentech's Product

South San Francisco, Calif. -- March 3, 1991 --

The most widely used thrombolytic agent in the United States, Activase®, t-PA (alteplase) was not included in the third International Study of Infarct Survival (ISIS-3, which compared the life-saving effects of clot-dissolving drugs in the treatment of heart attacks.

In addition, the trial did not employ the intravenous administration of heparin, an anticoagulant, in the manner used by more than 95 percent of the cardiologists in the United States, and as recommended by the American College of Cardiology and American Heart Association. In fact, half of the patients in ISIS-3 did not receive any heparin at all, and the other half received heparin by route of injection under the skin, later than is typically given in conjunction with thrombolytic therapy in the United States.

The overall mortality rate in ISIS-3 for patients receiving any thrombolytic agent was 10.3 percent. In data pooled from 6,375 patients treated in clinical trials using the U.S. regimen of heparin, Activase® (alteplase) had a mortality rate of 5.8 percent.

Recently reported results reveal relative equivalence of the mortality rate among the three thrombolytic agents studied in ISIS-3, including the currently marketed versions of APSAC (Eminase, SmithKline Beecham) and streptokinase (SK, Astra) and duteplase, an experimental variant of t-PA, produced by Burroughs Wellcome.

"Since the t-PA used in the trial is not the same as that used to treat heart attack patients in the United States, the ISIS-3 results with t-PA should not be directly applied to U.S. medical practice," said Ray Bahr, M.D., director of the Cardiac Care Unit at St. Agnes Hospital, Baltimore.

In addition to the distinctions between the two t-PAs, Bahr, a leading U.S. investigator in the study, cites the discrepancies between this predominately European trial and treatment of heart attack patients in this country.

"In considering the ISIS-3 results, U.S. physicians need to note the lack of adequate heparinization, and the unspecified patient selection and diagnostic criteria, both of which vary from U.S. standards," he added.

Different t-PAs

The ISIS-3 study used Burroughs Wellcome's duteplase, which is not approved for sale anywhere in the world and is no longer under development.

Although no head-to-head clinical studies comparing duteplase with Activase have been conducted, the data that exist about the two t-PAs indicate that the two do not necessarily confer the same clinical benefit.

"The duteplase dose used in the ISIS-3 trial cannot be equated to the standard dose of Activase," said Desire Collen, M.D., professor of medicine, University of Leuven, Belgium, and an expert on t-PA.

"In terms of patency rates, the only published paper with a dose of duteplase similar to the ISIS-3 dose (Koster, European Heart Journal, 1990) shows a patency rate of 53 percent at 90 minutes. Another study reported, but not published (Grines, et al) found the patency rate of 68 percent at 90 minutes. In aggregate, the available clinical data suggest that the 90 minute patency rates with duteplase are considerably lower than the 70 percent to 77 percent rates observed with Genentech's t-PA. "Therefore," Collen added, "it would be scientifically inappropriate to extrapolate the results obtained in ISIS-3 for duteplase to Activase."

David C. Stump, M.D., director of clinical research for Genentech, Inc., said, "We are not able to address questions raised about the duteplase safety profile, since Genentech did not develop, manufacture or study duteplase. The clinical comparability of the two t-PAs has never been established."

He added, "As far as Genentech and Activase, t-PA are concerned, ISIS-3 is pertinent only for the comparison of SK and Eminase, although it may provide some useful insight into overall patient eligibility criteria for thrombolytic therapy use in general."

Comparison of the Streptokinase-Based Agents

ISIS-3's primary endpoint was mortality (death-rate, at 35 days). The results showed that 10.6 percent of the 13,328 patients treated with Eminase died after 35 days, compared with 10.5 percent of the 13,295 patients treated with SK.

The overall rate of stroke for Eminase was 1.4 percent and for SK, 1.1 percent. The rate of intracranial bleeding was 0.6 percent vs. 0.3 percent, respectively.

In addition, a higher rate of allergic reactions, hypotension and bleeding was seen with APSAC compared with SK.

Further Study Needed

The ongoing U.S.-based GUSTO study (Global Utilization of Streptokinase and t-PA in Occluded Coronary Arteries) was designed to address the question that neither GISSI-2 nor ISIS-3 addressed. That question relates to the value of opening arteries quickly and keeping them open with appropriate conjunctive therapies, such as IV heparin and aspirin. In GUSTO, this issue will be addressed in a way that is consistent with the treatment of heart attack patients in the United States. All GUSTO patients will receive immediate, intravenous heparin in conjunction with thrombolytic therapy, as recommended by the American College of Cardiology and American Heart Association.

Furthermore, the mortality rate in nine published studies with Activase and IV heparin involving 6,375 patients showed a 5.8 percent mortality rate, which is lower than the 10.3 percent rate reported in ISIS-3 for duteplase, although the study designs are not identical.

This use of continuously administered intravenous heparin with Activase has been demonstrated to be safe and effective in treating thousands of heart attack patients to date. In the largest U.S.-based thrombolytic study conducted thus far, (TIMI-2), the intracranial bleed rate for 3,016 patients who received 100 mg. of t-PA, immediate IV heparin, and oral aspirin, was 0.4 percent. Additionally, a compilation of all Activase studies with the standard dose of intravenous heparin given with the standard dose of Activase shows an intracranial bleed rate of 0.5 percent in 6,375 patients. This is the intracranial bleed rate which appears in the FDA-required labeling for the product.

Additionally, in a new 421 patient study, the t-PA and APSAC Patency Study (TAPS), t-PA (alteplase), when used in an accelerated dose, was shown to open significantly more coronary arteries early and to provide significant differences in mortality compared with Eminase (mortality reported at 1.8 percent for t-PA (alteplase) vs. 7.8 percent for Eminase). TAPS data was initially reported at a symposium prior to the American Heart Association meeting last fall, and will be presented at scientific session at the American College of Cardiology meeting on March 5.

"Based on the TAPS results, Genentech feels confident that GUSTO will definitively address the hypothesis that opening more arteries early and keeping them open, will save more heart attack patients' lives," Stump noted.

"I am confident that the GUSTO results will not only help determine the thrombolytic regimen of choice, but will also help to increase the expanded use of this vital life-saving type of therapy," Stump added.

"Toward this goal, we have conducted extensive educational efforts during the past four years. A vast majority of heart attack victims who are eligible under current applicable treatment criteria, such as age and time of arrival at the hospital, are being treated with one of the drugs. We are sponsoring research to expand the use of this therapy to all those who can benefit from it," he said.

Stump added, "Genentech strongly believes that no patient should go untreated because of the cost of a drug. Genentech's Uninsured Patients program allows hospitals to immediately treat patients without insurance, or who cannot afford to pay, and then the hospital is reimbursed by Genentech."

Genentech, Inc., is a leading biotechnology company focusing on the development, manufacture and marketing of pharmaceuticals produced by recombinant DNA technology.

NOTE TO EDITORS: Stories on ISIS-3 results would be better balanced if they included comments of cardiologists who represent the majority view of thrombolytic treatment in the United States. Upon request, Genentech will attempt to assist in locating expert cardiologists attending the ACC.

# # #