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Sun 1 Apr 2007 12:51 PM

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Late blood clots tarnish drug-coated stents

Uncommon complication raises questions about who really needs a drug-coated stent and how long to continue drug therapy after getting one.

Medicine is both science and art. It's also a balancing act, teetering between the benefits of therapies for treating and preventing illness and their hazards. When it comes to new drugs, devices, and operations, healing powers are usually seen first, with harms trickling in over time. That's been the case for drug-coated stents. They were hailed as a huge innovation when introduced in 2003 and almost universally adopted for holding open cleared coronary arteries. Now, with more than four million drug-coated stents implanted in the U.S. alone, an uncommon but hazardous side effect known as late stent thrombosis is giving some cardiologists pause about using them.

How stents help

Stents are flexible wire-mesh cages slightly smaller than the spring inside a ballpoint pen. The early ones were made of bare metal. They are placed inside an artery immediately after balloon angioplasty has cleared it of cholesterol-filled plaque. Cells lining the artery underneath the stent gradually grow over and around the metal struts, embedding the stent in place and covering it with healthy living tissue.

About one-third of the time, though, the healing response goes overboard. The cell growth doesn't stop once the stent struts are covered, but continues into the open space in the middle of the stent. This overgrowth, called restenosis, narrows the space available for blood flow, sometimes even more than the initial blockage, and leads to the return of chest pain. Getting rid of it requires another round of angioplasty and placement of another stent.

Drug-coated stents lick restenosis through chemistry. In these devices, the metal struts are coated with a drug-infused polymer. As the drug oozes into the surrounding tissue, it calms the wild wound-healing response and slows the growth of smooth muscle cells, the cells mainly responsible for restenosis. Clinical trials of drug-coated stents showed a return of symptoms with stent closure in just 5% or so of recipients, a big reduction from the 15% or higher with bare-metal stents. That means fewer trips to the doctor and fewer repeat procedures for angioplasties to unblock the stent. The trials also showed that drug-coated stents were as safe as bare-metal ones.

Cardiologists quickly embraced drug-coated stents. Glowing media reports even prompted people with heart disease to ask their doctors for them. Within a year, drug-coated stents accounted for a whopping 70% of all stents placed. Today it's closer to 85%. That extraordinarily fast adoption was based on short-term benefits, with little knowledge of long-term effects.

Paying the piper

Not long after doctors started using drug-coated stents, reports began trickling in from emergency room doctors and cardiologists who were seeing heart attacks and sudden deaths caused by blood clots that suddenly formed on or inside drug-coated stents months after the stent was placed. This came to be known as late stent thrombosis.

It turns out that there's a downside to suppressing cell growth around a stent. Without a protective sheath of living tissue, the stent looks like the foreign body that it is. Instead of sailing right past the stent, platelets and blood cells may stick to it. This forms the nucleus of a clot. If that clot completely blocks blood flow to part of the heart, it triggers a heart attack. Sometimes the blockage causes the heart to suddenly stop beating effectively (a sudden cardiac arrest).

At cardiology meetings and in the pages of medical journals, doctors began debating whether drug-coated stents were more hospitable to clot formation than their bare-metal precursors.

The FDA took up the issue in December 2006. It convened a panel of experts to review the safety of drug-coated stents and recommend how long people with them should take the anticlotting combination of aspirin plus clopidogrel (Plavix).

Expert opinion

Data presented to the panel show that drug-coated stents aren't the miracle everyone was hoping for. They don't improve survival more than bare-metal stents. But they do cause less restenosis. That's a good thing. Restenosis and the return of symptoms is worrisome, and fixing it requires a repeat angioplasty with its small but real risk of complications. What's more, people affected by restenosis have poorer survival following stent placement than those untouched by it.

Results reviewed by the panel suggest that late stent thrombosis may afflict up to 0.5% of people per year who get a drug-coated stent. It doesn't seem to be limited to the first few months after getting a stent, but can appear two or three years later.

The FDA approved drug-coated stents for use in a specific group of people: those with a new and relatively short narrowing in an artery with a diameter between 2.5 and 3.75 millimeters. Yet most people who need a stent fall outside of this definition. That's why more than two-thirds of stents have been placed for so-called off label uses.

For people who get a drug-coated stent for an approved reason, the chance of stent thrombosis is relatively low. It occurs more often in those who get one for an off-label use, and far more often in people who stop taking clot-preventing drugs.

The FDA panel was split on how long stent recipients should take aspirin plus Plavix. Some panelists thought that recipients of drug-coated stents should take the combination for two years or more. Others worried that the potential for stomach problems and serious bleeding from this combination would outweigh the reduction in late stent thrombosis. As a compromise, the panel stuck with the existing recommendations for people who get a stent for an approved use - aspirin plus Plavix for one month after getting a bare-metal stent, three months with a Cypher drug-coated stent, and six months with a Taxus drug-coated stent. Those who get a drug-coated stent for an off-label use should take the combination for up to a year.

In a special advisory published in mid-January, the American Heart Association offered a simpler recommendation: Everyone with a drug-coated stent should take aspirin plus Plavix for a year. The AHA also recommended the use of bare-metal stents in people who would not or could not take the combination, or in those likely to need surgery for some other problem in the year after stent placement.

Future direction

Although we were hoping the FDA panel would offer crystal clear recommendations, it didn't really have enough solid information to do that. So we'll have to be satisfied with its hazier forecast until the science of drug-coated stents catches up with the technology.

In the meantime, here are a few recommendations we can give right now:

• Patients who have received a stent in the last year or two should know whether it is a bare-metal or a drug-coated type.

• If it is a drug-coated stent, tell them to relax. The odds are very high that they will be fine. Still, they should be advised to take their prescribed anticlotting medicine, and inform you if they need to stop taking it temporarily due to illness.

• Keep an open line of communication with your patients. This field is moving rapidly, and recommendations can change faster than their annual appointment schedule.

Rethinking stenting

Stents offer a quick fix for chest pain. The ease and effectiveness of drug-coated stents lulled many into thinking these devices were a nearly no-risk proposition. That's not the case. What's more, they do nothing to fight atherosclerosis, the disease that causes arteries to narrow. That's reflected in the fact that drug-coated stents don't prevent future heart attacks or prolong life.

In comparison, a battery of drugs (aspirin, cholesterol-lowering statins, beta blockers, and ACE inhibitors) combined with healthful lifestyle changes can stall atherosclerosis and even reverse it, while gradually quelling chest pain and other symptoms.

In other words, angioplasty plus stenting shouldn't be the automatic response to the discovery of a narrowed coronary artery. Nor is it necessarily the first and best solution for stable, uncomplicated chest pain.

The lure of the new

The promise of new drugs and devices often far outstrips their reality. Either they aren't as effective as hoped, or side effects that weren't seen during the testing needed for FDA approval chip away at - or negate - their benefits.

The removal of Vioxx from the market due to an increased risk of heart attack is just one recent example of this tension between promise and reality.

Most clinical trials are relatively small and short. Those for drug-coated stents were no exception. They were adequate for determining if these devices limited restenosis. But they weren't enough to see how they would perform over the long haul, or in the real world. Such long-term, widespread use is bound to reveal unexpected problems that never cropped up during the trials.

Standard advice for car buyers is to avoid the first year of a new model. By the second or third year, its long-term potential and hidden bugs are revealed (and sometimes fixed). Similar patience pays off when it comes to new drugs or devices, even though it can be hard to resist the excitement and hype surrounding them.

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


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