Alteplase

Clot-Busting Drugs To Turn Off Heat Attacks

Every year, about 1.5 million Americans suffer a heart attack. Of that number, one-third die within one year, 100,000 before they can be hospitalized. Typically, a blood clot develops in one of the arteries to the heart, preventing oxygen-rich blood from that part of the heart muscle. The greater the blockage and the longer it continues, the more of the heart muscle that is lost. Substantial loss of heart muscle can lead to heart failure and death.

But over the past several years, researchers have developed drugs called thrombolytic agents that can help dissolve the clots. Blood can then again flow through the artery, preventing further damage to the heart. last fall, FDA approved alteplase (trade name Activase), one of a new class of thrombolytic agents known as tissue plasminogen activators (TPA). In addition, FDA approved the expanded use of another thrombolytic agent, streptokinase (trade names Kabikinase and Streptase). These approvals mean that heart attack victims have greater reason for hope than ever before that they will successfully recover from their attacks.

Alteplase is a genetically engineered copy of a protein produced naturally by the body. In 1979, scientists in Belgium first purified TPA and showed that it could dissolve clots in laboratory animals. But the amount produced in the body, or from most human cells in culture, is so minute that large-scale production would be impractical. So, in 1981, Genentech Inc., of South San Francisco, Calif., began using recombinant DNA technology to produce enough alteplase to be tested in heart attack victims.

Genetically engineered alteplase is made by introducing the human gene that holds the instructions for producing the protein into cells originally derived from the ovaries of Chinese hamsters. The inserted gene programs the cells to consistently produce large quantities of alteplase.

Clinical trials of alteplase began in 1984. In all, Genentech's alteplase has been tested in more than 4,000 patients. It has been shown in controlled clinical trials to dissolve clots in 71 percent of heart attack patients when injected within six hours after symptoms occur. In separate trials, the drug significantly improved heart function when given within four hours.

One of the largest studies, sponsored by the National Heart, Lung, and Blood Institute, was known as the Thrombolysis in Myocardial Infarction Trial. This study included alteplase and streptokinase. Streptokinase -- made by Behringwerke AG, a German firm represented in the United States by Hoechst-Roussel Pharmaceuticals Inc. of Somerville, N.J., and KabiVitrum AB of Stockholm, Sweden, which has offices in Alameda, Calif. -- has been licensed for use in treating heart attacks since 1982. Until last fall, however, the use of streptokinase, which is derived from Streptococci bacteria, was limited because it could be administered only by inserting a catheter directly into the coronary artery. This procedure could only be done in hospitals that have special coronary care units.

But recent data from clinical trials, including one involving more than 11,000 patients, have shown that streptokinase given intravenously -- by a needle inserted into a vein -- reduces the death rate among recipients by 20 percent to 25 percent when given within six hours after a heart attack. "The most dramatic result -- a 47 percent reduction in mortality," said FDA Commissioner Frank E. Young, M.D., Ph.D., "was observed when streptokinase was administered within one hour of the onset of symptoms." In separate studies, it was shown to improve heart function.

Alteplase and streptokinase can be used to treat the vast majority of heart attack victims, but should not be given to patients at high risk of hemorrhaging. This includes patients with internal bleeding; a recent stroke, surgery or major injury; long-standing, uncontrolled high blood pressure; or a bleeding disorder. Both drugs also should be used with caution in people over 75, in pregnant women, and where bleeding is a significant hazard.

Bleeding within the brain was one of several issues that concerned the Cardiovascular and Renal Drugs Advisory Committee -- an advisory committee made up of nongovernment experts -- on May 29, 1987. This committee advised FDA to obtain more data on safety and effectiveness before approving alteplase.

Data submitted later showed that the bleeding problem occurred more frequently at higher doses, but at the recommended dose of 100 milligrams it occurred only in 0.4 percent of patients. Bleeding occurred at about the same rate with streptokinase when given at recommended dosages.

The committee also recommended FDA find out whether a change in manufacturing procedures at Genentech made any difference in alteplase's safety and effectiveness. Data submitted by the manufacturer showed that it did not. In addition, the committee questioned whether alteplase's ability to dissolve clots actually, as theorized, limited heart damage. Subsequent data showed that it did.

Robert E. Windom, M.D., assistant secretary for health, observed that although changes in diet, anti-smoking campaigns, and other factors have helped reduce deaths from heart disease, coronary heart disease "remains America's number one killer, responsible for about 768,000 deaths each year -- or about a third of all deaths," he said. "At some point in their lives," Dr. Windom added, "one out of every four or five people will feel the pain and constriction of a heart attack -- pressure or pain in their chest or pain in their left arm." When that happens, he advised, "Don't waste time hoping against hope that the pain will go away . . . get help quickly."

COPYRIGHT 1988 U.S. Government Printing Office
COPYRIGHT 2004 Gale Group