Thursday, Sep 3, 1992

Study Shows Altepase t-PA Significantly Reduces Mortality Up to 12 Hours After Heart Attack Begins

Barcelona -- September 3, 1992 --

Results of a new international heart attack study of nearly 6,000 patients show that thrombolytic therapy with alteplase t-PA reduced mortality 27 percent in heart attack patients who were treated between six and 12 hours after their symptoms began.

The findings of the double-blind, placebo-controlled study known as LATE (Late Assessment of Thrombolytic Efficacy) were presented for the first time here today at the 14th Annual Meeting of the European Society of Cardiology. Previous thrombolytic trials, such as the recently reported EMERAS trial suggested, but were unable to prove, that there is a significant reduction in mortality when treating patients with acute myocardial infarction beyond six hours from the onset of symptoms.

"The LATE results showed a significant decrease in mortality in patients treated with alteplase t-PA between six and 12 hours after symptom onset," reported Robert G. Wilcox, MD, Reader in Medicine, University of Nottingham, and international coordinator of the LATE trial. "Although there is no question that earlier administration of a thrombolytic agent is still desirable, the data suggest that patients presenting with symptoms later may benefit from this life-saving therapy as well."

LATE Trial

The LATE trial was specifically designed to determine whether treatment with alteplase t-PA more than six and less than 24 hours after the onset of major heart attack symptoms (e.g., chest pain, nausea) reduces mortality. Patients were randomized and received infusions of either alteplase t-PA in a standard dose or placebo over three hours. All received aspirin and a majority also received intravenous heparin as anticoagulation therapy.

Although the overall mortality difference from six to 24 hours did not achieve statistical significance, a significant benefit was seen in the subgroup of patients treated between six and 12 hours after the onset of symptoms. Mortality was reduced 27 percent in patients treated with alteplase t-PA during this period as compared to placebo-treated patients; 8.7 percent vs. 11.9 percent respectively, a statistically significant difference (p=0.033) that was maintained up to one year. The LATE investigators pointed out that mortality reductions of this extent were also seen with alteplase t-PA in earlier trials (e.g., ASSET) treating patients only up to six hours from the onset of heart attack symptoms.

The difference in the incidence of overall stroke at 35 days between the two treatment groups was significant; 2.25 percent for alteplase t-PA-treated patients vs. 1.1 percent in the placebo group. While the difference in the incidence of fatal strokes was also significant at 35 days, 0.95 percent for alteplase t-PA-treated patients vs. 0.42 percent in the placebo group, the incidence of non-fatal disabling strokes was similar in the two groups (11 vs. 9 patients, respectively).

The LATE investigators pointed out that since the fatal strokes are accounted for in the mortality results, it is important to compare the non-fatal stroke rates to determine net clinical benefit. In addition, although the investigators observed a greater incidence of severe bleeding in the alteplase

t-PA-patient group versus placebo, they pointed out that this is common to all thrombolytic agents and similar to what has been seen in other large thrombolytic trials.

"In spite of these incidences, the LATE trial results suggest there is a favorable benefit-to-risk ratio for use of alteplase t-PA out to 12 hours," Dr. Wilcox said. "The safety of t-PA shown in this trial is consistent with that found in other thrombolytic trials with patients treated within only six hours from symptom onset."

Implications of Study

Although the LATE investigators pointed out that it is still crucial that heart attack patients seek treatment as early as possible, the reality is that up to 30 percent (or nearly 35,000 in the United States) do not get to a hospital within six hours of symptom onset. In addition, it is often difficult for physicians to establish the exact time when a patient's heart attack symptoms, such as chest pain, began. Based on LATE's findings, many more heart attack patients each year may benefit from life-saving alteplase t-PA therapy.

"The results of LATE again confirm that use of thrombolytic therapy with alteplase t-PA can significantly reduce heart attack death rates," Dr. Wilcox said. "And now we have a definitive trial providing a rationale for administering alteplase t-PA to patients who present between six and 12 hours from the onset of symptoms -- this may be encouraging news for a large number of potential heart attack victims."

The LATE study was independently conducted in 247 medical centers in the United States and 12 other countries with financial support from Genentech, Inc. of South San Francisco, California. Genentech markets alteplase t-PA as Activase® (Alteplase, recombinant) in the United States (NYSE: GNE).

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