A 63-year-old man walked into the emergency department of St. Michael’s Hospital in Toronto last week complaining of indigestion. But doctors soon discovered that the man’s real problem was a blood clot in his coronary artery: he was suffering a major heart attack. Ordinarily, that diagnosis would have temporarily halted treatment because, apart from keeping the patient comfortable, there is little doctors can do to intervene while a heart attack is actually in progress.
But this man, whom doctors would not identify, had better luck than most victims. One week earlier the hospital’s chief cardiologist, Dr.
Paul Armstrong, had received supplies of an experimental new drug which many researchers say could be the most important development in the treatment of heart attacks in decades. Armstrong obtained the man’s permission to administer tissue-type plasminogen activator, and at week’s end the first heart-attack victim in Canada to receive t-PA had made a strong recovery. Said Armstrong:
“This could be the magic bullet we’ve all been waiting for.”
Despite his apparent improvement, the man’s actual prognosis —the long-term state of his health—is still unknown.
Armstrong will be studying his case as part of hundreds of clinical trials now being conducted around the world to determine the effectiveness and safety of t-PA, a drug manufactured from human protein and one that speedily dissolves clots. Still, t-PA’s dramatic performance in early tests has strained the cool objectivity that researchers and scientists usually display toward unproven drugs. For one thing, the normally cautious New England Journal of Medicine broke its own policy and reported the results of U.S. t-PA trials before their completion last year. And an editorial in the periodical also predicted that the drug “might be of immense clinical value.”
Indeed, Armstrong demonstrated his
confidence in t-PA by administering it to a second patient barely 48 hours after he first used it. The recipient on that occasion was a 60-year-old woman who was in the hospital’s coronary care unit with unstable angina—a disease characterized by intense chest pain. In their efforts to avert a full-blown heart attack, her doctors had first administered nitroglycerin in order to dilate the clogged arteries supplying her heart
with blood. Then, when that treatment failed to stabilize her condition, they turned to more sophisticated chemicals, some of which lowered the amount of oxygen needed for the heart to function. But her condition continued to worsen, forcing the team to turn to t-PA in a desperate attempt to prevent major damage to the patient’s heart. The result: by week’s end, the woman was comfortable and her heart functions were more stable.
Researchers say that further tests are needed to gauge t-PA’s full effectiveness. But they acknowledge that a powerful new weapon may soon be deployed in the battle against heart attacks—from which 50,000 people die in Canada every
year. Said Armstrong: “If t-PA is in fact as good as it looks now, it will certainly be the single most important advance in the management of heart attacks in my lifetime.” Added Dr. David Waters, director of research at the Montreal Heart Institute, who will conduct another set of trials next year: “I think t-PA will save a significant number of lives. A patient who might have had a large heart attack will instead have a small or
moderate-sized one and will probably live a longer and better life as a result of this drug.”
At the centre of this unusual excitement is a drug that Belgian doctor Désiré Collen first isolated in 1979 from a line of cells taken from a cancer tumor. In fact, t-PA is a drug derived from a protein which the body produces naturally in minute quantities, and early tests soon revealed its powerful ability to dissolve blood clots.
But researchers were unable to use the substance in human trials until the San Francisco-based company Genentech Inc. took up the challenge of synthesizing the substance with genesplicing technology. The company’s researchers first isolated the genes in the cancer cells that were responsible for producing the t-PA protein. Then they implanted them in another line of quickly reproducing mammalian “host cells,” which in turn began generating the substance. Said Waters: “Everybody has a little t-PA in their bodies. We’re just giving patients a lot more of it.”
Beginning in 1984, Genentech began supplying researchers at the U.S. National Heart, Lung and Blood Institute in Bethesda, Md., with sufficient t-PA to compare its effectiveness with streptokinase. That drug, which also dissolves clots, is derived from streptococcus bacteria and has been used to treat heart-attack victims in Canada for more than six years. During the yearlong duration of the tests, researchers at 13 clinical sites administered t-PA to 143 patients in the first stages of heart attack and streptokinase to another 147 in similar circumstances. They found that blocked coronary arteries reopened in 66 per cent of the subjects who received t-PA. By contrast, only 36 per cent of those who received streptokinase experienced a similar improvement. Indeed, t-PA’s clear superiority prompted Dr. Eugene Passamani to stop the trial before its scheduled conclusion and report his findings to the Journal of Medicine. “I feel very optimistic,” he told Maclean's last week. “There is no question this is going to be the topic of very intensive discussion.”
The impressive performance is significant because streptokinase itself is a powerful drug. According to Armstrong, widespread publicity about its effectiveness has led many U.S. patients with heart problems to deluge cardiologists with requests for the drug. But streptokinase use is often accompanied by unwelcome side-effects. For one thing, it can prompt severe allergic reactions if administered a second time.
Researchers have discovered no signs of allergic reaction to t-PA. But it has at least one drawback: like streptokinase, it can cause hemorrhaging, and some patients in the U.S. t-PA trials bled spontaneously from the nose or vomited blood. U.S. and European researchers have administered doses of between 80 mg and 150 mg of the drug to patients, and the Toronto trials will attempt to determine a dosage level that will dissolve clots with a minimum of bleeding.
As well, doctors now know that they can swiftly treat patients by injecting t-PA directly into veins in their arms. It is possible to achieve comparable results with streptokinase only by administering it through a catheter—a hollow tube threaded through blood vessels to the heart. But heart catheterization is a difficult, painful and time-consuming process. Indeed, the ability of either drug to prevent damage to the heart muscle depends directly on how quickly it is administered after the attack begins. Said Armstrong: “There are only a few cardiologists who can do it. And they sure don’t have cath labs in Thunder Bay or Timmins.”
Armstrong says that he hopes current t-PA research will produce a therapy that can be used easily by nurses or emergency crews treating the earli-
est stages of heart attacks. And Waters is currently negotiating to supply the drug to Quebec’s Urgences-Santé (emergency care)—a system that provides doctors to go out on emergency calls requiring medical expertise that ambulance crews do not possess. He said that those doctors could be administering t-PA in the field as early as this spring. Added Waters: “By the time people finally decide they are sick, go to the hospital and see a doctor, the average delay will make it too late for at least half the patients.” Armstrong is cautious about predict-
ing quick licensing and widespread use of the drug. And despite the drama of t-PA’s debut at St. Michael’s, he is following a deliberate and cautious course in it use. “I am not a cowboy,” he declared. “As a clinical scientist, I have been planning this for over a year. It is clearly, effectively planned.” Indeed, last week’s treatments were merely the first stages of a pilot study to determine the dosing strategy that will be followed in a clinical trial set to begin early next year. There will be 11 Toronto institutions participating in the trial, which over the course of one year will include 300 patients. As principal investigator, Armstrong will coordinate the Toronto trial with t-PA provided by London-based Burroughs Wellcome International Ltd., a company that is competing with Genentech. Similar trials will be conducted in nine U.S. centres. Armstrong said that determining the still-unknown long-term effects of t-PA will be a key to the trials. He added: “We have to ask ourselves, are we creating a new disease? You cannot just dissolve a clot. There is more you have to do about it.”
The immediate goal of doctors involved in t-PA therapy is to reduce the amount of heart-muscle damage, called myocardial infarction, that occurs as a result of clots in the coronary artery. Dissolving the clots will restore blood flow in the short term, but experience with anticoagulants has shown that in 15 per cent of patients the clots re-form in the same locations —sometimes as soon as three days after administration of the drug. Waters said that administering t-PA a second time can increase the danger of hemorrhaging. And Armstrong noted that in cases where a threatened heart attack is accompanied by hardening of the arteries, the effectiveness of t-PA therapy is limited. “It will dissolve the clot,” he said, “but it won’t take away the hardening of the arteries. It is not a magic drug for all forms of heart disease.” Researchers say that surgery may still be necessary for patients who respond well in the short term to treatment with t-PA. For Genentech Inc., however, such careful qualifications do not obscure the fact that t-PA will likely generate huge amounts of revenue. And Wall Street observers estimate that with individual treatments likely to cost between $1,400 and $4,000, the substance could produce revenue of $1.4 billion annually for the company. But for doctors—and their patients— the significance of t-PA lies in the imminent arrival of a powerful new tool which can save lives.
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