Blood clots a late hazard for drug-coated stents

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Blood clots a late hazard for drug-coated stents

The benefits of drug-coated stents come with a price — long-term use of clot-preventing drugs.

When the first drug-coated stent earned FDA approval in 2003, it was hailed as a revolution in treating cholesterol-clogged arteries. These tiny, drug-releasing cages solved a problem linked with their bare-metal precursors: a vexing renarrowing of the artery. But their wide use is showing that they can create problems of their own. One that's gaining attention is the sudden appearance of blood clots that can completely block a stent months after implantation, often causing a heart attack or sudden cardiac arrest.

This problem, called late stent thrombosis, isn't common. It affects up to 3 people in 100 who get a drug-coated stent, sometimes a year or two later. Faithfully taking aspirin and clopidogrel (Plavix) is a key strategy for keeping clots at bay. But what happens if you aren't good at taking medications, or if circumstances beyond your control — like needing surgery or having a serious stomach bug — make it difficult or impossible to take these drugs? How long must you take them after getting a stent? And if you don't have a stent but some day need one, should it be a bare-metal type?

Stent evolution

These questions signal the start of Round Four in the evolution of minimally invasive ways to open a blocked or narrowed artery that feeds the heart muscle (a coronary artery). Round One started in the 1970s with the use of a balloon to open a cholesterol-clogged artery. This usually restores normal blood flow. In many people, though, the balloon-stretched artery soon recoils and shrinks back to the size and shape it was before angioplasty.

Round Two focused on fixing this problem. The ultimate solution was the use of a wire-mesh cage called a stent to prop open the newly cleared artery. This device, which is smaller than the spring inside a ballpoint pen, keeps the artery from recoiling and shrinking. But it injures the artery wall more than a balloon does. The body responds with an aggressive wound-healing response. Endothelial cells from the artery lining grow up, around, and over the stent, like honeysuckle on a trellis, eventually covering the bare metal. That's a good thing. As the stent comes to look like part of the body, platelets and blood cells sail right by.

Actual size of a stent compared with a spring from a ballpoint pen.

About one-third of the time, though, new tissue grows inside the stent. This can limit blood flow as surely as the original blockage, and sometimes even worse. Such growth is called restenosis, which means renarrowing. It's a relatively slow process, occurring over several months, and usually makes itself known by chest pain (angina) during exercise, physical activity, or stress.

The quest to conquer restenosis kicked off Round Three. After scores of failed efforts, researchers ultimately hit on drug-coated stents. Special coatings on these stents slowly release a substance that calms the wound-healing response and prevents artery-lining cells from growing and dividing. Two such stents, the Cypher and Taxus stents, are on the market in the United States. The Cypher stent releases a drug called sirolimus for about 30 days, while the Taxus stent releases a drug called paclitaxel for about 90 days.

Clinical trials of drug-coated stents showed restenosis rates of just 5% or so, a big difference from the 30% or more seen with bare-metal stents. That means far fewer trips to the doctor and fewer repeat procedures for angioplasties that didn't "take."

Real life, of course, is bigger, messier, and more complicated than clinical trials.

Delayed problem

Clinical trials are rarely large enough or last long enough to reveal uncommon problems. That's the case for drug-coated stents. As more and more people have them implanted (worldwide, 4 million and counting), doctors are starting to see more cases of late stent thrombosis.

The problem stems from the very qualities that make drug-coated stents so good at preventing restenosis — they calm inflammation and keep endothelial cells from growing and dividing. This slow growth prevents endothelial cells from covering the stent. Without this protective sheath, red blood cells and platelets interact with the stent as they might with a foreign body, sticking to it and forming blood clots.

Bare-metal vs. drug-coated stents Bare-metal stents (A) become colonized and covered with endothelial cells within a few weeks of implantation. Although this overgrowth can sometimes close off the stent, red blood cells and platelets don't stick to it. Colonization by endothelial cells occurs much more slowly with drug-coated stents (B). This prevents reclosure (restenosis), but can lead to the formation of blood clots.

For as yet unknown reasons, clots tend to form suddenly inside stents. When they do, they can completely block blood flow through the stented section of the artery, cutting off the oxygen supply to part of the heart. That's a heart attack. Sometimes the blockage causes the heart to suddenly stop beating effectively (a sudden cardiac arrest). About 70% of stent thromboses cause a heart attack or sudden cardiac arrest.

Several things seem to influence late stent thrombosis. These include stents that are too long, stents that don't perfectly fit an artery, hypersensitivity or an allergic reaction to the coating or the drug, and stopping clot-preventing medications. The last one seems to be the most important. It's also the one you can control.

Everyone who has a stent placed should take aspirin plus Plavix. How long to take the combination depends on the type of stent:

• Bare-metal stent: at least1 month

• Cypher (sirolimus) or Taxus (paclitaxel) stent: at least one year

This dual therapy isn't without its own drawbacks. It is more likely to cause bleeding problems than aspirin alone, especially in older people. It is pricey, since Plavix costs around $100 a month. And surgeons hate it. People taking aspirin plus Plavix bleed more easily, and their blood clots less readily. This can interfere with an operation, increase the need for a blood transfusion, and pose higher risks of bleeding complications during and after surgery. That's why most surgeons automatically tell their patients to stop taking aspirin and Plavix a few days before an operation. This can be a problem if one or more of your coronary arteries is propped open with a drug-coated stent.

Surgery isn't the only hurdle. Getting the flu, food poisoning, or a gastrointestinal bug that makes it impossible to keep food or medications down for a few days can increase the chances of having stent thrombosis.

Protecting yourself

Round Four of the stent saga is as contentious as the earlier ones. Some researchers say that late stent thrombosis occurs as often with bare-metal stents as it does with the drug-coated variety. Others believe that drug-coated stents are a special hazard.

As the different sides slug it out, here are some things to think about, and to talk with your doctor about, if you have a stent or need one in the near future.

First off, some reassurance. Late stent thrombosis isn't common — it doesn't happen to 97% or more of people with drug-coated stents. The longer you've had your stent without a problem, the smaller the chances of it happening.

Taking aspirin plus Plavix indefinitely can help you be one of the 97%. Stopping it early can tip you toward the 3% camp. In a small, early study from Harvard's Beth Israel Deaconess Medical Center, people who stopped taking aspirin plus Plavix too soon after getting a Cypher stent were 30 times more likely to develop a blood clot inside a stent than those who kept taking the combination. In a larger European study published in 2005 in the Journal of the American Medical Association, stopping aspirin plus Plavix early was associated with a 90-fold increase in the chances of late stent thrombosis.

But long-term use of aspirin and Plavix can pose problems. If you need surgery, whether it's an elective procedure like a hip replacement or an emergency one like removal of a tumor, your surgeon will want you to stop taking these clot-preventing medications. No matter what the reason, make sure that your surgeon talks with your cardiologist before you stop taking aspirin and Plavix. They should be able to work out an approach that's good for your heart and your surgery.

If a stomach bug or something else keeps you from taking these medications for more than a couple of days, that's a medical emergency. Call your cardiologist and tell him or her what's been going on.

What if you are facing the prospect of getting a stent to ease chest pain? "Have a very frank discussion with your cardiologist about the risks and benefits of each kind of stent," says Dr. Aloke V. Finn, a cardiologist at Harvard-affiliated Massachusetts General Hospital. He and others at Mass General are among a small but growing number of doctors who think that preventing the aggravation of restenosis from a bare-metal stent isn't worth the small but real risk of having a heart attack or cardiac arrest with a drug-eluting stent. They hope that newer stents (see "The next generation(s) of stents") will solve both problems.

If you have stable coronary artery disease, you should also ask whether angioplasty with stenting is truly necessary in the first place. A large, well-done study presented at the American College of Cardiology meeting held in March 2007 found that in people with stable coronary disease—that is, people who have chest pain with exertion but not at rest—angioplasty with stenting was no better than taking medication and modifying their lifestyle.

If you do need angioplasty with stenting, make sure your cardiologist knows about other health issues — like a bad hip that needs replacing, an inflamed gallbladder, or recurrent stomach ulcers — that might get in the way of taking anti-clotting medications. At the same time, make sure your other doctors know what your cardiologist is planning.

Long-term studies should eventually lead to clearer recommendations on how long to take aspirin plus Plavix, even as testing begins on the next generation of stents and therapies. In the meantime, if you have a drug-coated stent, stick with the anti-clotting medications your cardiologist prescribed. Equally important, make sure all your doctors know you have a stent and are taking these medications.

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Last updated:	May 15, 2007