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Sun 4 Nov 2007 04:00 AM

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Opening blocked coronary arteries: new questions about the old answer

Research is helping to determine which patients will benefit from reperfusion therapy, and asking which stents are best.

Opening blocked coronary arteries: new questions about the old answer
Opening blocked coronary arteries: new questions about the old answer
Opening blocked coronary arteries: new questions about the old answer
Exercise plays an important part in staving off heart attacks and other major coronary events.

The facts are so familiar (and so depressing) that they hardly need repetition. Heart disease is the leading cause of death in the United States.

Despite all the marvellous advances in diagnosis and treatment, it's held that dubious distinction every year since the 1918 influenza pandemic. In most cases, the culprit is coronary artery disease, which is responsible for the heart attack that strikes an American every 26 seconds the year round. In all, about 650,000 Americans will die from coronary artery disease this year.

Some important studies have demonstrated that many patients don’t need reperfusion therapy.

While these facts have not changed substantially, the scientific understanding of heart disease has evolved. The disease is caused by cholesterol-laden blockages (plaques) in the arteries that carry oxygen-rich blood to the heart muscle.

It seemed obvious that big plaques, which produce the most narrowing, would be the most hazardous.

Research has challenged that view, but aggressive treatment is often aimed at clearing the most tightly blocked arteries. Remarkable technical advances have made these treatments routine, but studies show that not all patients benefit equally.

Restoring blood flow

Plumbers do it all the time. Faced with a clogged pipe, they can restore the flow of water either by clearing out the blockage or by splicing in a new pipe to carry fluid around the blockage. A blocked coronary artery is vastly more important than a clogged drainpipe, but doctors use the same strategies to restore blood flow. Their sophisticated methods have a sophisticated name: reperfusion therapy.

In the early days, reperfusion therapy required open-heart surgery. Decades later, many patients still benefit from coronary artery bypass grafting. First, cardiologists identify blockages by performing coronary angiograms. They thread a tiny catheter through an artery in the leg or arm, then advance the tip right into the coronary circulation.

Next, they inject dye through the catheter and take x-rays to identify the blockages. Patients with critical blockages may be referred to cardiac surgeons.

Bypass surgery involves removing a small segment of a vein or artery and using it to construct a new channel to detour blood around the blockage. In the right patient, this surgery can be remarkably effective, and it remains important today. But it's a big deal for every patient, so doctors began to look for a kinder, gentler form of reperfusion therapy.

The inside job

Reperfusion treatments that open blockages from the inside are called percutaneous coronary interventions (PCIs).

Several techniques are available; the most effective is balloon angioplasty. The procedure begins with a coronary angiogram that identifies critical blockages. The cardiologist then guides a catheter armed with a balloon near its tip through the angiogram catheter and gently advances it to the blockage. When it is in the right position, the doctor inflates the balloon, compressing the plaque to restore blood flow.

Balloon angioplasties were introduced in the late 1970s. The procedure was effective, but doctors soon recognised that blockages tended to recur in exactly the same places as the original narrowing, a problem called restenosis.

Starting in the 1990s, doctors solved this problem by going one step further. Instead of inserting a plain balloon, they used a catheter to insert a tiny, collapsible metal mesh, or stent, over the balloon.

When the balloon is inflated, the stent also expands. But when the balloon is deflated and withdrawn, the stent remains in place, holding the artery open.

Coronary artery disease is stubborn. Stenting improves the results of angioplasty, but the disease fights back. In time, restenosis can develop even in a stented artery. In 2003, doctors began using a new generation of stents. Instead of bare metal, the stents are coated with drugs that reduce the risk of restenosis. These coated stents have become enormously popular, but research shows that they can have problems of their own.

Second opinions

With all this progress, it's no wonder that PCIs have become enormously popular. More than one million procedures were performed in the United States in 2004 alone, and the number has continued to grow. With all the technology and manpower involved, the cost has also continued to soar, now exceeding $15 billion each year.

Many patients have benefited from angioplasties and stents, and many more will benefit in the years ahead. However, some important studies have demonstrated that many patients don't need reperfusion therapy and that the expensive drug-coated stents carry some risks.

This research evaluates reperfusion therapy in two settings, after an acute heart attack and in stable chronic coronary artery disease. Other studies compare bare metal and drug-coated stents. Taken together, these investigations should prompt a re-evaluation of reperfusion therapy based on new insights about coronary artery disease itself.
Treating heart attacks

A heart attack is the most acute and serious form of coronary artery disease. In medical lingo, heart attacks are called myocardial infarctions. They occur when a coronary artery becomes completely blocked.

Drug coated stents have become enormously popular, but research shows that they can have problems of their own.

Deprived of their blood supply and oxygen, some heart muscle cells die. The dying cells leak enzymes into the bloodstream, enabling doctors to diagnose myocardial infarctions with great precision.

A heart attack is a medical emergency. Nearly all are triggered by a blood clot that forms on an atherosclerotic plaque, completely blocking a narrowed artery. If you develop chest pain, sweating, nausea, shortness of breath, weakness, or another symptom of a heart attack, chew an aspirin tablet to fight additional clot formation. Then call emergency services.

Heart attacks come in two basic varieties. Full-thickness attacks produce a characteristic change in the EKG pattern called ST-segment elevation. As a result, doctors describe these as ST-segment elevation myocardial infarctions (STEMIs). Because partial-thickness attacks don't produce the same EKG pattern, they are known as non-ST-segment elevation myocardial infarctions (non-STEMIs).

An ongoing series of studies has demonstrated that reperfusion therapy deserves to be the standard of care for STEMIs.

Two methods can be used in the acute setting, clot-busting drugs (thrombolysis) and balloon angioplasty. In head-to-head trials, angioplasty is the clear winner, but if this high-risk treatment is not available, thrombolysis is a valuable alternative.

Different results for different attacks

Angioplasty has become such an important treatment for STEMIs that it's often used for non-STEMIs as well. However, a 2007 study from the Netherlands adds to the body of evidence that argues against this practice as a matter of routine.

The ICTUS Trial randomly assigned 1,200 patients with non-STEMIs to receive either an early invasive strategy (routine angiography followed by angioplasty when appropriate) or a selective invasive strategy that reserved angioplasty for patients whose ongoing symptoms did not respond to medical therapy. At the end of three to four years, the two groups did not differ in their rates of rehospitalisations for coronary events, heart attacks, or death.

Non-STEMI patients who respond well to medical therapy do not require routine reperfusion therapy, but unstable patients still benefit. In contrast, nearly all patients with STEMIs can benefit - if the timing is right.

Timing is everything

Speed is essential. Current standards call for STEMI patients to undergo angioplasty and stenting within 90 minutes of their arrival in the emergency ward. Cardiologists say that time is muscle: To preserve and protect as much heart muscle as possible, reperfusion should be completed within 12 hours of a full-thickness heart attack.

It's a very demanding standard. And since early reperfusion is so beneficial, many doctors believed that delayed reperfusion would also help. Small studies provided tentative support, but a major multinational 2006 study did not.

This study evaluated 2,166 patients with acute heart attacks. All the patients had angiograms showing that a complete coronary artery blockage was responsible for the heart attack. About 86% had EKG evidence of full-thickness damage, and all the patients met the criteria for high risk, though all were clinically stable when they entered the trial three to 28 days after their heart attacks.

Everyone in the study received the best available medical therapy. In addition, half of them were randomly assigned to receive angioplasty and stenting. Scientists tracked the patients for an average of 2.9 years. At the end of that time, the groups did not differ in the rate of recurrent heart attacks, congestive heart failure, or death. If treatment is delayed even a few days, routine angioplasties and stents do not help heart attack patients who are clinically stable.

Preventive reperfusion therapy

Before the recent round of studies, scientists had proven that early angioplasty with stenting has important benefits for patients with full-thickness heart attacks. Those benefits remain unchallenged. But these earlier good results generated the open artery hypothesis, which argued that most patients with significant coronary artery disease could benefit from reperfusion therapy.

The 2006 and 2007 studies cited above found that opening blocked arteries does not improve on modern medical therapy for patients with partial-thickness heart attacks or for victims of full-thickness attacks whose reperfusion is delayed, providing that the patients are responding well to non-invasive therapy. But how about the much larger number of people with heart disease and angina who have not suffered recent heart attacks?

A major 2007 study addressed this important question. Between 1999 and 2004, doctors at 50 centres in the United States and Canada evaluated 2287 patients with significant but stable coronary heart disease. All the patients received optimal medical therapy. Half were randomly assigned to undergo angioplasty and stenting.

Researchers tracked these patients for 2.5 to 7 years. At the end of the study, the patients in the two groups did not differ in their rate of heart attacks, other major cardiovascular events, or death.
A much smaller 2004 German study provides additional information. Only 101 patients were enrolled, and all were men below the age of 70, but like the patients in the newer, larger North American study, all the subjects had stable coronary artery disease with significant blockages shown by angiograms. Half the patients received full medical therapy plus angioplasty and stenting.

The other half received full medical therapy plus 12 months of supervised exercise training. At the end of four years, 88% of the exercise group enjoyed freedom from heart attacks and other major coronary events, while 70% of the reperfusion group had similar benefits.

Medical care must be tailored to individual patients.

The two treatments were equally effective at relieving chest pain, but the members of the exercise group had superior exercise capacities, and they required only about half as many health care dollars. Best of all, perhaps, it took only 20 minutes of stationary biking a day to achieve these benefits.

Which stent?

Research is helping to determine which patients will benefit from reperfusion therapy, and research is also asking which stents are best. Bare metal stents were the only choice until 2003. Since then, drug-coated stents have gained steadily and are now used in about 80% of procedures in the United States. But a series of studies published in 2007 reveals that drug-coated stents carry a higher than anticipated risk of blood clot formation, which can lead to heart attacks.

Studies are under way to learn if prolonged anti-clotting therapy can overcome this problem. It's a work in progress, but like the other studies we've been discussing, it shows the critical importance of research that questions widespread assumptions. It also shows the need for making individual clinical decisions.

Which blockages?

At first glance, the value of reperfusion therapy seems obvious. If a significant blockage in a vital coronary artery can be opened safely, it should help. The research shows it's not necessarily so. But why? There are three major reasons why one could question the need for reperfusion therapy.

Firstly, this therapy targets the most tightly blocked coronary arteries. The older mechanical ("clogged pipe") theory of coronary artery disease suggests that these blockages are the most troublesome.

Indeed, they are responsible for the chest pain of angina, a very important problem. But these blockages are caused in large atherosclerotic plaques that have enlarged slowly. Most often, a sturdy cap of fibrous tissue, something like scar tissue, covers up such plaques.

Because of these caps, large plaques tend to be stable. In contrast, younger, smaller plaques are the site of active inflammation triggered by fresh deposits of oxidised LDL (‘bad') cholesterol. These plaques don't have dense fibrous caps, so they are unstable and can rupture. When that happens, tiny blood cells called platelets stick to the ruptured plaque and trigger the formation of a blood clot that blocks the artery.

That's how relatively small plaques trigger heart attacks. Reperfusion therapy targets large plaques, effectively relieving angina, but it may not prevent heart attacks caused by small, unstable plaques.

Second, this therapy targets only tiny segments of the coronary artery tree, the parts with the largest blockages. But other parts of the coronary tree often have atherosclerosis as well. Reperfusion therapy can correct old blockages, but it never prevents new ones.

Third, medical therapy continues to improve. The studies discussed here do not refute the benefits of reperfusion therapy. Instead, they suggest that for many patients, angioplasty and stenting do not add to aggressive modern medical therapy.

Drugs that improve cholesterol, control blood pressure, stabilise the heart rhythm, fight blood clots, reduce the work of the heart muscle, relax tight arteries, stabilise vulnerable plaques, manage diabetes, and address other risk factors have enormous benefits. When these medications are added to lifestyle therapy that includes smoking cessation, diet, exercise, and stress reduction, they produce results that are hard to beat, even with reperfusion therapy.


Reperfusion therapy is here to stay. Nearly all patients with full-thickness heart attacks should have their blocked arteries opened with balloon angioplasty and stenting, provided it can be done promptly.

Later is too late for patients who are doing well on medications, but patients with ongoing problems should have angiograms to find out if angioplasties might help. Similarly, patients with partial-thickness heart attacks don't benefit from reperfusion therapy if they respond well to medications, but if problems continue, they should go the angiogram-angioplasty route.

About 85% of the angioplasties in the United States are performed not for acute heart attacks but for chronic coronary artery disease. All patients deserve aggressive therapy with medications and lifestyle modification. Patients who respond well are unlikely to gain further benefit from angioplasty and stenting, but patients who have ongoing chest pain or other complications may benefit enormously.

Perhaps the most important lesson of these studies is that medical care must be tailored to individual patients, particularly when it involves complex decisions about invasive procedures. For example, although the average patient with stable coronary artery disease may not need an angioplasty, a 2007 trial reports that it may benefit certain heart attack patients who have silent ischemia (a lack of blood flow to the heart muscle that does not trigger the warning pain of angina).

That's why cardiologists must work with primary care doctors and patients to select the best treatment for each case.

Every form of medical treatment has just two goals: to help patients live better and to help them live longer. Medication and lifestyle changes can achieve these goals for many patients with coronary artery disease, but when they fall short, it's important to have reperfusion therapy at the ready.

Balloon angioplastyTo open an artery narrowed by plaque, the cardiologist feeds a catheter to the site of the blockage and threads a thin, flexible guide wire through the narrowing (A). The balloon catheter advances along the guide wire until it's positioned directly inside the narrowed area (B). As the balloon inflates, the plaque stretches and cracks, allowing freer passage of blood through the now-reopened artery (C).

This article is provided courtesy of Harvard Medical International. © 2007 President and Fellows of Harvard College.

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