Heart Attack Treatment : Dissolvers of Blood Clots Join Arsenal
When Robert Werner suddenly became short of breath one night last year, his wife rushed him to the hospital. And just in the nick of time. Minutes after physicians diagnosed a heart attack in progress, Werner stopped breathing and his heart stopped beating.
The doctors quickly restored Werner’s heartbeat, using electrical shocks, and then placed a breathing tube in his lungs.
Until recent years, cardiologists would have had little else to offer, although they would have stood by, ready to comfort Werner with morphine and oxygen and to treat such post-heart attack complications as irregular heartbeats or a buildup of fluids in the lungs. But they would have been powerless to prevent the inevitable heart muscle damage that often ends up killing a heart attack victim.
Advances in Cardiology
Now this is changing, thanks to some major, if little-noticed, advances in cardiology--as Werner and his wife quickly learned at Sequoia Hospital in Redwood City, Calif.
Physicians are becoming downright aggressive in combatting the leading cause of death in the United States, using new drugs and procedures to open blocked heart arteries.
After resuscitating Werner, for instance, his doctors injected a blood clot-dissolving protein called streptokinase into his bloodstream through a vein. And within 15 minutes, the 55-year-old printing salesman’s condition had stabilized, and his heart was pumping blood effectively again.
Several hours later, cardiologist Bruce J. McAuley performed a catheterization to examine the blood supply to Werner’s heart muscle, threading a thin tube through a vein in his leg into the arteries of the heart.
As dye was injected through the tube, X-ray pictures of the heart were taken. They showed that the key heart artery, which had been opened by streptokinase, was still 85% blocked--indicating that Werner was still a prime candidate for a second, perhaps fatal, heart attack.
Angioplasty Procedure
And so two days later, McAuley once again threaded a tube--this one with an deflated balloon at its tip--through Werner’s veins, in a procedure called angioplasty. When the tip reach the site of the blockage, McAuley inflated the balloon, which squeezed the blockage against the wall of the artery. The procedure fully restored the blood flow.
A week after he entered the hospital, Werner went home. And in one more week, he was back at work. “I’ve felt fine ever since,” Werner said recently. He has quit smoking and is playing golf regularly.
“This is a very dramatic case of the effectiveness of streptokinase and angioplasty,” McAuley said. “All the tests at follow-up visits have shown his heart to be completely normal.”
Throughout the country, many heart attack victims like Werner are alive and well today because of the recent advent of blood clot-dissolving drugs and procedures like angioplasty--as well as other advances, such as better success with emergency heart bypass surgery and another, highly promising, blood clot-dissolving drug known as TPA. Surgeons also are discovering that some coronary bypass patients do better in the long run if damaged heart arteries are replaced with an artery taken from the patient’s chest instead of a vein from the leg.
Yet, such gains have been largely overshadowed by the attention focused on heart transplants and the introduction of artificial hearts, which--for now at least--benefit very few people.
Instead, the little-noticed advances in cardiology are of potential--and immediate--benefit to as many as 1.5 million heart attack victims each year, especially the 250,000 who seek help within the first four to six hours after developing symptoms. About 550,000 Americans die of heart attacks each year.
Blood Clots Form
Most heart attacks occur when blood clots form in heart arteries that are already clogged by fat, cholesterol and other substances. When the blood supplied by a narrowed artery is inadequate, intermittent chest pain called angina results; when the blood flow is cut off, heart muscle cells suffer irreversible injury and die because of a lack of oxygen and other nutrients.
Animal studies in the 1970s showed that the death of heart muscle cells can be prevented if the blood supply is quickly restored, either by surgery or medication. That laid the groundwork for the eventual use of clot-dissolving agents in humans.
The efficacy of agents such as streptokinase, which stimulate the activity of other blood-clot dissolving proteins in the body, was demonstrated by an Italian study of nearly 12,000 hospital patients. The study, published in the medical journal Lancet in February, found a death rate of 10.7% in the three weeks after a heart attack among patients who received streptokinase, compared to 13% for patients who did not receive it.
In addition, the study found that patients who received streptokinase within three hours of becoming ill, such as Werner, had a death rate of only 9.2%.
One drawback of clot-dissolving medicines is that they cannot be given to patients who are at risk of developing life-threatening bleeding, such as recent stroke victims or surgery patients. They can cause bleeding from the gums, from the sites of intravenous tubes or in the lining of the stomach and intestines. Some recipients may experience blood loss serious enough to require blood transfusions.
Shortcomings Noted
Such shortcomings were underlined anew by a report in today’s issue of the New England Journal of Medicine. In a study from West Germany, which involved only 1,741 patients, the differences in death rates were small between patients treated with streptokinase and those who did not receive the drug. But four patients who received the clot-dissolving medicine developed bleeding into their brain, and two deaths were directly related to this bleeding. This bleeding in part outweighed the beneficial effects of the drug. In the Italian study, patients treated with the drug did not have an increased risk of such bleeding.
The safest and most effective approach to coronary heart disease, of course, is still preventing atherosclerotic deposits in the first place, such as by limiting intake of fatty foods and by not smoking. Such behavior modification is in part credited with a 31% drop in the age-adjusted death rate from coronary heart disease between 1972 and 1983, a decline that public health experts expect to continue.
And on the prevention front, at least one new approach may be in the offing. By the end of the decade, several biomedical companies hope to market blood tests to identify people who are predisposed to atherosclerosis, thus providing them with an early warning to adopt healthy life styles.
But for now, medical or surgical therapies are necessary for the estimated 5 million Americans who already have experienced chest pain and other symptoms from coronary heart disease.
Clot-dissolving agents such as urokinase and streptokinase have become widely used in the last decade in treating a variety of life-threatening conditions, including blood clots in the legs and lungs.
Pioneered in Soviet Union
The use of streptokinase for heart attack patients was first described in 1976 by Soviet cardiologist Eugene Chazov, who is also known for his involvement in the International Physicians for Prevention of Nuclear War, which was awarded the Nobel Peace Prize last year.
Initially, Chazov and cardiologists in the United States aimed the streptokinase directly at the blocked heart artery, by injecting it into the artery during a cardiac catheterization. But they realized that this approach was not practical for the majority of heart attack patients because, for one thing, preparation for catheterization can delay the start of treatment for up to 90 minutes or more. Another reason is that only 16% of the nation’s hospitals have cardiac catheterization facilities and cardiologists with the expertise to perform it.
To avoid these problems, many physicians now inject streptokinase directly into a vein in the patient’s arm. (The U.S. Food and Drug Administration has officially approved streptokinase only for injection into the coronary arteries for heart attack patients and not for intravenous use, but physicians have the discretion to administer the drug in this fashion, and increasingly are doing so).
But even when clot-dissolving drugs are successful in defusing the immediate crisis, an atherosclerotic heart artery may remain severely narrowed and therefore vulnerable to becoming blocked again, as physicians discovered in Robert Werner’s case.
This has led some cardiologists to advocate the use of catheterizations as a follow-up test in patients treated with these drugs. Sites of potential blockages can in turn be treated by angioplasty or surgery.
Widening Heart Arteries
The now widely used technique of using inflatable balloons to widen narrowed heart arteries was developed in the mid-1970s by the late Swiss cardiologist, Andreas R. Gruntzig.
Physicians today are testing variations of the technique to improve its success rate. For example, Dr. John B. Simpson of Sequoia Hospital, an angioplasty pioneer, is experimenting with an instrument that removes atherosclerotic deposits by shaving them into a hollow metal cylinder.
And doctors at Methodist Hospital in St. Louis Park, Minn., are testing a new laser device that can vaporize the deposits. But the laser light often also destroys the underlying blood vessel, and this problem must be solved before the technique can be widely used in humans.
When angioplasty is not successful or severe coronary artery disease is discovered, emergency heart bypass surgery is often necessary. In this operation, surgeons relieve blockages in the arteries that supply blood to the heart by replacing sections of these arteries with undamaged blood vessels from elsewhere in the body.
Physicians at the Cleveland Clinic Foundation reported earlier this year that long-term survival after bypass surgery was improved when arteries from the patient’s chest were used as the replacement blood vessels. In their patients, only 4% of these internal mammary arteries were blocked after 10 years, compared to 25% of veins from the patient’s legs.
Initially, many doctors had thought that angioplasty would reduce the need for some heart bypass surgeries. But the number of bypass surgeries has continued to increase gradually, while the number of catheterizations and angioplasties has skyrocketed--perhaps reflecting indiscriminate use, some say. Another explanation may be that patients whose lives are saved by these techniques later require repeat procedures.
Procedures Expected to Rise
U.S. surgeons this year will perform about 185,000 bypass surgeries, 112,000 angioplasties and 900,000 cardiac catheterizations, according to the newsletter Biomedical Business International. By 1990, 204,000 bypass surgeries, 208,000 angioplasties and 1.25 million catheterizations are predicted.
Second-generation clot-dissolving drugs, which appear to be much more effective than streptokinase, are being extensively tested. The greatest attention has focused on tissue-type plasminogen activator, or TPA, a human protein that is involved in the normal regulation of blood clotting.
TPA, which is mass produced through recombinant DNA technology, is more selective than streptokinase in dissolving blood clots and causes fewer allergic reactions.
According to a 1985 study published in the New England Journal of Medicine, TPA injected into a vein promptly relieved blockages in 66% of 118 patients with obstructed heart vessels, while streptokinase relieved only 36% of similar blockages in 122 patients.
The preliminary results of this National Heart, Lung and Blood Institute trial were considered so conclusive that, in a rare action, the first phase of the study was halted after only six months and all 4,000 patients in the $31-million study were given TPA, according to Dr. Eugene Braunwald of the Harvard Medical School, the study’s chairman.
A course of treatment with TPA is expected to cost $1,000 to $2,000, compared to under $200 for streptokinase.
Competing versions of the TPA drug are being developed by Genentech of South San Francisco and G. D. Searle & Co. of Skokie, Ill. In May, Genentech asked the U.S. Food and Drug Administration for marketing approval, a process that could take six months to several years.
Some researchers also are investigating the feasibility of a self-injectable form of TPA for heart attack patients to use at home on a physician’s orders, if symptoms of a second attack were to develop. Others are investigating whether it is safe for paramedics to give such medicines in ambulances on the way to hospitals.
Nationwide Trial
Dozens of cardiologists throughout the country are participating in the National Heart, Lung and Blood Institute trial and other studies to define the best ways to use blood-clot dissolving medicines, particularly TPA, and to determine which patients need other therapies as well.
One such pilot program is being coordinated by the University of Michigan Medical Center. Patients at participating hospitals throughout that state receive TPA in emergency rooms and are then transported, usually by helicopter, to the university hospital for immediate heart catheterization and further therapies.
“We don’t know if every heart attack patient should have a catheterization and possibly angioplasty,” said Dr. Eric J. Topol, a principal investigator for some of the University of Michigan studies. “We also don’t know if these procedures are best done right away or several days later.”
Learning when such therapies are necessary is crucial for both medical and economic reasons. Billions of dollars may be added to the cost of medical care if these procedures are widely recommended for heart attack patients. Heart catheterization costs from $2,000 to $3,000; angioplasty from $6,000 to $8,000, and bypass surgery more than $30,000.
Yet the combination of blood-clot dissolving therapies and angioplasties may save lives, shorten hospital stays and help patients return to work sooner, according to Topol.
That, indeed, is what happened in Werner’s case.
“I am glad to be here and hear the stories of how (my heart stopped) twice,” he said. “The doctors came in and shook my hand the next day because they never thought I would make it.”
