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Analysis: Drug-coated stents' downside?

By ED SUSMAN

BARCELONA, Spain, Sept. 5 (UPI) -- It's been five years since drug-eluting stents -- tiny, drug-coated coils that prevent unwanted cell growth in the heart's arteries -- became the darlings of interventional cardiologists with the use of the $3,000 devices implanted into 800,000 chests a year in the United States.

But, now, a stunning series of reports at the World Congress of Cardiology in Barcelona, Spain, appears to have turned those little darlings into the "black sheep" of the family.

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Controversial reports indicate that compared to bare metal stents, patients implanted with the newer, drug-eluting stents have up to a 38-percent greater risk of death three years following their procedures.

"This is madness," said Salim Yusuf, professor of medicine at McMaster University, Hamilton, Ontario, Canada, a longtime critic of overuse of the angioplasty and stenting. "We have been chasing our tails trying to fix one problem after another. We have lost our clinical judgment. We have let the cowboys decide who gets these devices."

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When angioplasty was first developed 30 years ago, doctors were enraptured by the technique that allowed for relief of angina -- chest pain -- without requiring open-heart surgery.

In angioplasty, an incision is made in the groin, allowing doctors to insert a balloon-tipped catheter into the femoral artery in the leg. Under X-ray guidance, the catheter can be advanced through the arteries to a point where a blockage is situated in the heart arteries.

The balloon is then inflated, which in turn crushes the clogging plaque to the sides of the artery, allowing for greater blood flow and relief of pain. More importantly, the patient -- now pain free -- can go home after one or two days in the hospital, and almost immediately return to regular work or play. In contrast, open-heart surgery requires a week of hospitalization and months of recuperation.

Angioplasty had two drawbacks. One, it relieved pain but did nothing to change the course of atherosclerosis, the progressive disease that causes most heart attacks and strokes.

Second, in about 30 percent of cases, the artery that had been opened, closes up again -- a condition known as restenosis -- which sometimes restricts the blood flow even further.

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Responding to this phenomenon, scientists devised coil-like structures made of stainless-steel mesh to prop open the arteries. Once introduced, stents almost overnight were used in nearly every angioplasty, including in a procedure done on Vice President Richard Cheney's ailing heart in 2001.

The stents reduced the failure rate of angioplasty by almost 50 percent, but came with their own problems. Cells would migrate through the stent walls and in some cases would keep on growing, creating a man-made disease known as "in-stent restenosis."

Scientists went back to the bench and came up with the drug-eluting stents, designed to stop this growth. The drug-eluting stents were hailed as the panacea to in-stent restenosis.

The rejoicing stopped abruptly this week in Barcelona. With more than 25,000 cardiologists on hand, doctors began throwing cold water on the stent bonfire.

The conference was rocked first by a study from researchers in Switzerland and the Netherlands that showed that thrombosis -- a potentially lethal blood clot -- appeared to occur continually after implantation of the drug-eluting stents.

Thrombosis is known to occur in many conditions when foreign elements are implanted in the body -- such as stents or heart valves. With bare metal stents, the thrombosis stops when the metal gets covered by cells. The thrombosis occurrence reaches a plateau and stops.

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The study reported by Peter Wenaweser, an interventional cardiologist at the Swiss Cardiovascular Center, Bern, said that with the drug-eluting stents, thrombosis keeps on coming at the rate of about 0.6 percent a year with no signs of a plateau effect. More than half of the events -- deaths or heart attacks -- occurred more than a year after implantation at a time when medication to prevent thrombosis is discontinued.

Aspirin and clopidogrel -- sold as Plavix -- are prescribed for up to a year after the original implantation, yet these deadly events occurred long after the anti-thrombin agents were stopped, Wenaweser said.

In a second study, Edoardo Camenzind, associate professor of cardiology at the University of Geneva, Switzerland, said late-stent thrombosis was the likely cause of the adverse events he saw in a meta-analysis of all available data from published and present randomized trials of Cypher -- the sirolimus-eluting stent made by Cordis -- and Taxus -- the paclitaxel-eluting stent made by Boston Scientific.

Camenzind said he found a significant 2.4-percent increase in the incidence of death or heat attack in patients who received Cypher stents, compared with patients treated with bare metal stents; a relative risk increase of 38 percent.

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He also reported that patients receiving Taxus stents had a 16-percent increased risk of death or heart attack.

In yet another blow, researchers said that drug-eluting stents appear to be best suited to prop open smaller coronary arteries, but when used in the larger arteries they were no better than bare metal stents, and might even cause harm.

Christoph Kaiser, a cardiologist at the University Hospital in Basel, Switzerland, said that overall the rate of death or heart attack was 8.4 percent for patients treated with drug-eluting stents and 7.5 percent for bare metal stents.

Dennis Donohoe, vice president of worldwide regulatory and clinical affairs at Johnson & Johnson's Cordis unit, told United Press International, "We looked at total mortality over four years in our studies. Of the 870 patients getting bare metal stents, there were 44 deaths, or 5.1 percent. Of the 878 patients getting Cypher stents there were 57 deaths or 6.5 percent. That's an absolute difference of 1.4 percent, and is not significantly different."

Donohoe also said that 53 patients on bare metal stents in his studies had heart attacks, compared with 55 patients getting Cypher.

"I'm not satisfied with the information surrounding the meta-analyses," said Christian Spaulding, professor of cardiology at Cochin Hospital in Paris, France.

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He told UPI he wanted to see how the meta-analysis was performed. "I want to see that study peer reviewed and published, I want to know how they resolved cases in which the patients dropped out of the study. I want to know more about how they determined which incidents were heart attacks and which were caused by thrombosis. There are a lot of questions with that study."

In fact, questions abound regarding stenting and the studies on stenting. Yusuf asked for a blue-ribbon panel to investigate not only what he calls an overuse of stents but an overuse of angioplasty in general and to clear the air about the safety of the devices.

About 1 million procedures are done each year in the United States.

Raymond Gibbons, president of the American Heart Association, who held off on calling for any new recommendations, wanted to know why, as one study pointed out, as many as one-quarter of people who had angioplasty and stent implantation were no longer taking even aspirin, a drug known to prevent second heart attacks.

Sid Smith, professor of medicine at the University of North Carolina at Chapel Hill and a spokesperson for the World Heart Federation, wanted to know why it was that patients seemed to think that undergoing angioplasty was curative of heart disease. "Do the patients not listen? Do doctors not tell them?" he said.

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In the midst of the roiling controversy, researchers presented data Tuesday on a new drug-eluting stent using everolimus, a sister drug to sirolimus. The results -- had they been announced 10 days ago -- would have likely been greeted with applause. This drug-eluting stent appears to prevent cell re-growth better than other stents.

Instead the response was muted, with doctors suggesting that just being able to prevent re-growth of tissue was not sufficient to get excited about it. Some researchers demanded a longer approval process until the Abbott Laboratories product can show it's not just another -- in the words of Yusuf -- "expensive placebo or worse, a Trojan horse."

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