Doctors study risk of clots in new stents

WASHINGTON -- With drug-eluting coronary stents implanted in more than 2 million people worldwide, some doctors and researchers are now concerned about a long-term problem they see in a small number of patients who have received stents: blood clots inside the stents themselves.

Although the rate of serious clotting is extremely low, with manufacturers reporting just a handful of clots in more than 1,500 patients they are following, the cases concern doctors because clots nearly always cause heart attacks or death.

At the top national conference for interventional cardiologists here this week, more than a dozen presentations and lectures in the first two days alone focused on the issue of clotting in and around the new stents.

''It's not a huge epidemic," said Dr. Mark Eisenberg, a cardiologist at McGill University in Montreal who is preparing a research article that reviews all reported cases of late clotting in drug-eluting stents. ''It's a small but very important problem."

The companies that make stents disagree, saying the differences between the coated and uncoated versions are not statistically significant.

In the two years since they have been approved for sale in the United States, drug-eluting coronary stents have quickly become the fastest-selling medical device in history. Sales this year could pass $6 billion total at the only two companies that sell them in the United States, Boston Scientific Corp. of Natick and Johnson & Johnson of New Jersey.

A stent is a tiny wire mesh sleeve threaded into an artery to prop it open after it has been cleared of blockages. For many patients, a stent procedure offers an alternative to more dangerous and costly open heart surgery.

The new generation of stents is coated with a drug that helps prevent re-narrowing of blocked arteries around the heart, a problem encountered with older, uncoated stents. Because stents become sealed to the artery wall, they are permanent, and the long-term effects of the drug-eluting variety are only beginning to be assessed.

The largest studies of stents are those run by the manufacturers themselves. According to data provided by Johnson & Johnson on its Cypher stent, clots were reported in nine of 878 patients within three years of getting a drug-coated stent, compared with five of 870 patients who got uncoated metal stents. Four of the Cypher clots happened in the second and third years after the procedure, a period when the bare-metal stents did not cause any clots.

Similarly, Boston Scientific said it saw five cases of clotting in 754 patients with its drug-coated Taxus stent between one and two years, compared to none in the group with the bare-metal stents. None of the Taxus or bare-metal stent patients had clots in their third year.

Executives from both companies yesterday said their analysis of the data found clotting was not a greater hazard in drug-coated stents.

''We do not see a problem" said Paul LaViolette, Boston Scientific's chief operating officer.

''We would like 100 percent success over time with these patients," he said, but said the risk of late clotting appeared ''equivalent" to that with bare-metal stents.

''We don't see anything at this point that suggest there's a problem here, but we're going to track this out," said Dennis Donohoe, vice president for clinical and regulatory affairs for the stent-making division of Johnson & Johnson.

Officials at both companies said they were sending updates on the safety of their stents, including clotting reports, to regulators at the Food and Drug Administration.

In an e-mailed statement, an FDA spokeswoman said the agency is monitoring stents ''for long-term adverse events."

However, Gregg Stone, a Columbia University cardiologist, said that both companies' data show a small but almost identical increase in clotting compared to uncoated stents. Stone presented his findings at several sessions at this week's Washington meeting, the Transcatheter Cardiovascular Therapeutics conference.

''If all I saw was one stent, then I would probably downplay it too," Stone said in an interview yesterday. ''But seeing it exactly the same with two different stents makes me think that it's a class effect."

Some research suggests that rates of blood clots for patients in normal clinical practice may be higher than indicated by company numbers, which are based on tightly controlled trials. A European study published earlier this year in the Journal of the American Medical Association found that clots ''remain the primary cause of death" after interventional cardiology procedures, and found that about 1.3 percent of patients had clots within 9 months of treatment. Many of the clot victims, the study found, had prematurely stopped taking the anticlotting drugs that are recommended after stent implants.

Researchers disagree on what might cause blood clots a year or more after a stent is implanted. Some speculate that the drug that coats the stent, designed to prevent scarring inside the artery, also impedes the normal healing that helps blood flow smoothly. Others say that the synthetic coating that binds the drug to the metal may trigger irritation and clotting.

Renu Virmani, a pathologist who specializes in analyzing hearts and blood vessels, says she was initially intrigued when she examined pigs and rabbits that had received experimentally implanted stents, and noticed their blood vessels had trouble healing around the drug-coated version. Since then, she has performed autopsies on 40 human patients with drug-eluting stents.

''What we're discovering is exactly what you'd predict from animals," she said. ''You get delayed healing. Eventually they're going to heal, but it takes a long time."

Virmani presented data earlier this week from her autopsy work. She found signs of late-developing clots -- defined as clots that develop 30 days or more after implantation -- in about one-third of the cases, compared with 13 percent in a published study of patients with bare-metal stents. She has submitted her data to medical journals for publication.

Many doctors interviewed for this story said that the clotting risk doesn't change their preference for drug-coated stents over the bare-metal versions, but does suggest that patients should be vigilant about taking their anticlotting drugs, possibly for longer than manufacturers currently recommend.

Eisenberg, the Canadian doctor, said the question mark around stents' long-term effects is similar to that with any new product.

''Look, medicine is scary," he said. ''That's the way it is -- you just never know until you put it into millions of people and have long-term follow-up."

Stephen Heuser can be reached at sheuser@globe.com.