It begins with a crushing pain, like an elephant sitting on your chest. The pain travels to your arm and shoulder, back and jaw. You sweat. You struggle to breathe. You feel nauseated and dizzy. The problem: your heart isn’t getting enough oxygen. The medical term is angina, from the Greek for “strangling.”
The heart pumps oxygen-containing blood to every organ of the body, including itself. The two main arteries that provide blood to the heart (called coronary arteries) originate from the base of the aorta as it leaves the left ventricle. If these arteries or their branches are blocked, they can’t effectively supply oxygen to the heart. If patients have chest pain, they are said to have angina. If the heart muscle is damaged, they are said to have had a heart attack. If the damage is overwhelming, they die.
Heart disease is the leading cause of death worldwide, including in low- and middle-income countries.1 More people suffer from heart disease than from tuberculosis, AIDS, and malaria combined. By 2030, the worldwide death rate from heart disease will reach 23 million.2
In the United States, 17 million people suffer from heart disease, 10 million have angina, and 8 million have heart attacks every year. Indeed, one out of every four deaths in the United States, about 600,000 people, is caused by heart disease—the single most common cause of death in American men and women.3
Because of the enormity of this problem, many researchers and clinicians have devoted their professional lives to solving it. Some of the lessons have come at a high price. Some remain unlearned.
The first description of angina appeared in 1772. One hundred years passed before anyone had any idea what caused it. Ludvig Hektoen, an American pathologist, was the first to understand what was happening. Hektoen found that people who died from heart attacks had clogged coronary arteries at autopsy. At the time, no specific therapies for unclogging arteries existed. Rather, those suffering from angina were treated with bloodletting, opium, and bed rest, which weren’t particularly helpful.4 Bloodletting deprived patients of oxygen-carrying red blood cells, and opium launched a generation of opium addicts.
Bed rest, probably the most dangerous of the three, was the only therapy that survived into the twentieth century. From the late 1800s until the early 1960s, patients admitted to hospitals following heart attacks were placed in beds far from nurses’ stations so that they wouldn’t be disturbed. Removed from constant supervision, many of these patients were found dead in their beds, most from a fatal arrhythmia (a disturbance of electrical impulses in the heart). The mortality rate in people admitted to the hospital following a heart attack was 30 percent. This grim statistic gave birth to coronary care units, where patients’ heart rhythms could be monitored constantly with an EKG machine. As a result, the mortality rate dropped by half.5
In the 1960s, two events ushered in the modern era of heart care. Now doctors realized that they could not only treat heart disease but also prevent it.
The National Heart Institute, which was renamed the National Heart, Lung, and Blood Institute, precipitated the first major discovery. In 1948, the institute commissioned experts in the fields of epidemiology, biostatistics, and cardiology to study the lifestyles and habits of five thousand people living in Framingham, Massachusetts. Experts were charged with answering one question: Who was at risk of heart disease? Two decades later, researchers found that those at greatest risk had high blood pressure (hypertension). Clinicians now realized that drugs such as spironolactone (introduced in 1959), propranolol (introduced in 1964), and captopril (introduced in 1980) not only treated hypertension, but also lessened the incidence of heart disease.6
The Framingham Heart Study also found something else. Those at risk for severe heart disease had high cholesterol levels. Researchers later learned that not all cholesterols were the same. There was good cholesterol (called high-density lipoprotein cholesterol, or HDL) and bad cholesterol (called very low-density lipoprotein cholesterol, or LDL). At the time that these different cholesterols were being defined, Ancel Keys introduced the concept of the “heart healthy diet.” Keys, who chaired the International Society of Cardiology for the World Health Organization, had written several bestselling books on diet and disease. He argued that saturated fats (such as animal fats) were bad and that unsaturated fats (such as those contained in partially hydrogenated vegetable oils) were good. Researchers later found that partially hydrogenated vegetable oils, such as those contained in margarine, were loaded with trans fats, a substance that not only increased the level of bad cholesterol but also decreased the level of good cholesterol. By telling Americans that they were better off eating margarine than butter, Keys had inadvertently driven them into the waiting arms of one of the most dangerous food substances ever ingested. Researchers at Harvard Medical School later estimated that trans fats had caused about 250,000 serious or fatal heart attacks every year.7
The finding that high cholesterol levels increased the risk of heart disease gave birth to another class of drugs, statins, the first of which, lovastatin, was introduced in 1987. Like the antihypertension drugs, statins dramatically lowered the incidence of heart disease.
The Framingham Heart Study had taught doctors that lowering blood pressure and lowering bad cholesterol could prevent heart disease. But it was another event that occurred in the 1960s that had the greatest impact. In 1964, the Surgeon General of the United States concluded that cigarette smoking, in addition to causing lung cancer and bronchitis, also caused heart disease. Cigarette smoking can cause high blood pressure, damage the lining of blood vessels, and increase the tendency of blood to clot, all of which can lead to clogged arteries. By 1973, when consumption of cigarettes started to fall in earnest, the incidence of heart disease fell with it. During the past four decades, choosing not to smoke cigarettes has, more than any other medical intervention, been responsible for the 60 percent reduction in the incidence of heart disease.8
At this point, researchers knew that coronary arteries could be clogged with cholesterol-containing fatty deposits surrounded by platelets, small cells in the bloodstream that cause clotting. This realization gave rise to another medical treatment: aspirin, an antiplatelet drug that had been around since 1899. Some cardiologists, however, were tired of dancing around the problem. They wanted to open up clogged arteries directly, surgically. On its surface, this idea made a lot of sense. Most people with heart attacks had a greater than 70 percent blockage of only one coronary artery. And the heart muscle that was damaged invariably received its blood supply from that artery. The question at this point was how could doctors get into the artery and what could they do once they got there?
The first person to thread a small catheter into a coronary artery was Werner Forssmann. He did it in 1929. Most impressively, he did it on himself.9 Forssmann had opened a door. Now cardiologists could theoretically inject a dye into coronary arteries to determine the amount of blockage. Beginning in 1958, they have done exactly that.10
The next step was to figure out how to relieve the blockage. The first approach, which was invented in 1976, was to inject a clot-busting enzyme called streptokinase into the blocked artery, which worked. A trial of more than ten thousand people found that streptokinase prolonged the lives of patients who had suffered a heart attack.11 In 1977, one year after streptokinase was introduced, cardiologists invented balloon dilatation, which involved taking a catheter with a tiny, uninflated balloon at the end of it, threading it into the blocked artery, and inflating the balloon, which opened up the artery.
Nine years later, in 1986, scientists developed bare metal stents. Now cardiologists could place a small meshed metal tube in the blocked coronary artery and leave it there. By 1999, stenting had largely replaced balloon dilatation.
In 2002, another intervention, called drug-eluting stents, was born. This time, the stents weren’t made of bare metal only. Rather, they were soaked in drugs that either had an anti-inflammatory effect (sirolimus) or decreased unwanted cell growth around the stent (paclitaxel).
The discovery of risk factors for coronary artery disease, such as high blood pressure, high cholesterol, and cigarette smoking, caused people to suffer less angina, experience fewer heart attacks, and live longer. The same was true for the antihypertension drugs, cholesterol-lowering agents, and streptokinase. The results from these interventions were clear, consistent, reproducible, and compelling. But what about balloon dilatation and stents? Were the results from these surgical procedures also clear? Because threading a catheter into a coronary artery could cause a heart attack or death, both recognized complications of the procedure, they had better be, especially given that tens of thousands of people in the United States and hundreds of thousands in the world were undergoing these procedures every year.
Early studies showed promise. In 1992, researchers from the Veterans Affairs Medical Centers in Massachusetts and Connecticut randomly assigned two hundred patients to receive either medical treatment (such as antihypertension medicines or cholesterol-lowering agents) or balloon dilatation. All the patients suffered from angina, and all had one coronary artery with at least a 70 percent blockage. Six months later, 64 percent of the patients in the balloon group and 46 percent in the medical treatment–only group were free of angina. Patients in the balloon group were also able to increase their time on a treadmill without experiencing chest pain. Two patients in the balloon group, however, had to undergo emergency coronary bypass surgery following a complication from the procedure. The authors of the study concluded, “For patients with single-vessel coronary artery disease, [balloon dilatation] offers earlier and more complete relief of angina than medical therapy and is associated with better performance on the exercise test. However, [balloon dilatation] initially costs more than medical treatment and is associated with a higher frequency of complications.”12
This study gave birth to the notion that surgical treatment of clogged coronary arteries lessened the frequency of angina, a notion that has been hard to put to rest despite the parade of contradictory studies that followed.
In 2005, researchers from the Netherlands randomly assigned 1,200 patients with stable heart disease to receive either medical therapy or balloon dilatation. Investigators found no differences in the frequency of angina, the rate of hospitalization, or the likelihood of death from heart disease.13
Also in 2005, researchers in Greece published a review of eleven studies with a total of 2,900 patients who received either balloon dilatation or medical treatment and found that surgery “does not offer any benefit in terms of death, myocardial infarction [heart attack], or the need for subsequent [surgery] compared with conservative medical treatment.”14
From this point forward, clinical trials changed in two important ways. Balloon dilatation was replaced by stents, and patients were randomly assigned to receive medical therapy plus stents or medical therapy alone. The results didn’t change. Surgery, whether it was balloon dilatation, bare metal stents, or drug-eluting stents, was an unnecessary, expensive, and potentially dangerous procedure.
In 2006, researchers from New York University School of Medicine, in collaboration with researchers from around the world, randomly assigned 2,200 patients to receive bare metal stents plus medical therapy or medical therapy alone. They found that stents “did not reduce the occurrence of death, myocardial infarctions, or heart failure.”15
In 2007, researchers from fifty U.S. and Canadian medical centers randomly assigned 2,300 patients to receive stents plus medical therapy or medical therapy alone, finding that stents “did not reduce the risk of death, myocardial infarctions, or other major cardiovascular events.” At the time of this study, more than one million stents had been placed in the United States.16 A follow-up of this study showed that while those in the stent group were more likely to be free of angina three months after surgery, three years later the benefit disappeared.17
In 2009, researchers from Tufts Medical Center, in Boston, reviewed twenty years of studies that initially evaluated balloon dilatation and later bare metal and drug-eluting stents to see if surgery was better than medical therapy alone. It wasn’t.18
A casual observer at this point would have reasonably assumed that the twenty-year review would have put an end to stenting. It didn’t.
In 2014, researchers from the State University of New York Stony Brook School of Medicine reviewed yet another five studies, which involved 5,300 more patients. They found that stents plus medical therapy were “not associated with a reduction in death, non-fatal myocardial infarction . . . or angina compared with medical therapy alone.”19
Similar to the 2009 review, the 2014 review also didn’t eliminate the medical profession’s desire to put stents into patients with angina. There would be one more study—a study that should have ended all studies. For years, cardiologists had argued that while stents might not prolong lives or lessen the risk of heart attack, they did seem to lessen the frequency of angina, even if only for a short while and even if only in a few studies. The problem with angina, however, is that it’s subjective. People perceive pain differently. Those who opposed stenting argued that following a procedure that is supposed to reduce pain, patients would be more likely to believe that they were experiencing less pain—even if they weren’t. In other words, the placebo effect. But how could cardiologists perform a placebo-controlled trial of stenting? As it turned out, Rasha Al-Lamee and colleagues at Imperial College London found a way. In 2017, they published the results of their groundbreaking and controversial study.
To control for the placebo effect, the researchers in the United Kingdom randomly assigned patients who had single-vessel coronary artery disease with at least 70 percent blockage to receive a stent or to undergo a procedure where a catheter was threaded up into a coronary artery, but no stent was placed. None of the patients knew whether they had actually received a stent. Patients were then tested on a treadmill to see how long they could exercise before experiencing pain. Researchers found that both groups had improved exercise tolerance, even those with the fake stent procedure.20
Heart stents had seemed to make a lot of sense for patients who had previously suffered angina or heart attack. All these patients had single-vessel disease with blockages greater than 70 percent, some as great as 99 percent. After the stent was placed, the blockage was reduced. For patients, the concept of stenting was easy to understand. For doctors, it was easy to explain. So why didn’t it work?
The most likely explanation is that a blockage in one large coronary artery was merely indicative of a much bigger problem. Large arteries supply smaller arteries. As it turned out, a blockage in a large artery invariably accompanied blockages in smaller arteries downstream. This explained why relieving the blockage in one large artery didn’t solve the problem.21
In the end, patients have to ask themselves this question: Should I undergo a procedure that has been shown to be no better than medical therapy alone (after studies involving tens of thousands of patients), is expensive (about $67,000 per procedure), and is potentially dangerous (occasionally causing heart attack and the need for emergency surgery)? Harry Krumholz, a Yale cardiologist, in response to the placebo-controlled study by Al-Lamee and his team, said, “This should make us step back and ask questions about what we are accomplishing with this procedure.”22
Nonetheless, despite overwhelming evidence to the contrary, every year tens of thousands of Americans with angina receive a stent.