Drug-coated stents have been a bonanza since their U.S. debut in 2003. Close to 2 1/2 million of the tiny devices, which help clear blocked coronary arteries, will be implanted this year around the world. According to Citigroup (C ) analyst Matthew J. Dodds, Boston Scientific Corp. (BSX ) and Johnson & Johnson (JNJ ), which own the market, will rake in $5.5 billion in sales from the so-called drug-eluting stents this year -- a 36% gain from 2004.
But there's growing concern about these medical marvels: Do the drug-coated versions pose a higher long-term risk of life-threatening blood clots than the old-fashioned bare-metal variety did? Several papers have been published in medical journals examining cases of patients who experience blood clots more than one month after getting the stent, and in some instances a year or more after the procedure. The incidence appears to be rare -- maybe a few patients out of a thousand, according to studies by the companies. While there's no hard data to prove it, some cardiologists think the late clots more frequently occur with drug-coated stents. Dr. Mark J. Eisenberg, associate professor of medicine at McGill University, says those clots almost always cause a heart attack -- and in 20% of cases the attack will be fatal. "These are catastrophes," he says.
If drug-coated stents -- now used in nearly 9 of 10 stent procedures in the U.S. -- are proven to be more dangerous than bare-metal ones, it could be a financial blow to both J&J and Boston Scientific. Boston garners 41% of its revenues from its Taxus stent. And even widely diversified J&J said its Cypher stent drove 25% of second-quarter sales growth. Those products helped propel both companies onto the BusinessWeek 50 list of top corporate performers.
The stakes could very well go beyond lost revenues. Competitors such as Medtronic Inc. (MDT ) and Abbott Laboratories (ABT ) are developing their own stents featuring a coating made of a synthetic copy of the outside of a red blood cell that may reduce clotting risk. And, in a post-Vioxx world, companies that fail to address potential safety problems as quickly as possible face severe repercussions. In fact, plaintiffs' lawyers are already sniffing at this problem.
Blood clots have always been a risk with stents, since clotting is a natural bodily defense against a foreign object or injury. Both Boston Scientific and Johnson & Johnson say their ongoing clinical trials do not show that drug-coated stents pose a greater risk of late clots than the bare-metal versions. "We don't see anything going on with Cypher that you wouldn't see with a bare-metal stent," contends Dr. Brian G. Firth, vice-president for medical affairs and health economics with Cordis Corp., the J&J stent unit. But Dr. Joerg Koglin, senior medical director for Boston Scientific, notes: "Nobody has a definitive answer. Is there a hidden problem? We have to pay a lot of attention there."
Researchers are focused on two likely culprits: the materials that hold the drug on the stent, and the drug itself. The drugs are held on the stent by artificial materials known as polymers. Dr. Jeffrey W. Moses, director of the Center for Interventional Vascular Therapy at Columbia University Medical Center, theorizes that these polymers may cause a reaction in some patients or may flake or crack on the stent. That may cause inflammation, which sets off the body's immune responses -- and possibly a blood clot. Scientists also point to the drugs as possible causes. The drugs are designed to slow the growth of cells that cover the inside of the stent. That prevents reclogging, a common problem with bare-metal stents. But that also slows the normal healing process that walls off foreign objects like stents and fixes injured vessels. So when the blood-thinning therapy, given for a few months after stents are put in, is stopped, the body's healing response can include forming a clot.
Dr. Renu Virmani, medical director of a research service of the International Registry of Pathology, has long suspected these drugs could pose a problem. A pathologist who has received funding from Cordis, consulted for Boston, and is now doing work for Medtronic, Virmani has seen heart vessels from 40 deceased drug-coated stent patients, 14 of whom died because of a late blood clot. She says that in most of those cases she saw evidence of delayed healing in the area around the stent. Showing slides from tissue taken from one 68-year-old woman who died from a heart attack brought on by a clot on her stent, Virmani points out that "the vessel is not healed properly." Boston says there are many possible reasons for clots but says they are extremely rare. J&J says its trial data indicate healing is occurring.
Early signals from research have already had an impact on the market. One study has shown a higher overall risk of clotting with Boston's Taxus than with Cypher. But it wasn't large enough to determine with certainty that Cypher is safer. Still, while plenty of cardiologists think the stents are comparable, a perception lingers among some that Taxus is riskier. That has helped J&J gain share, says analyst Dodds. He figures that Boston, which still holds 59% of the U.S. drug-coated stent market, has lost six share points to J&J since the third quarter of last year.
Ultimately, physicians may never get a definitive answer to whether the drug-eluting stents are riskier than the bare-metal ones. Boston and J&J will spend five years following more than 5,000 patients who got either type of stent in their clinical trials. Problem is, those studies aren't large enough to give a solid answer because the later clots are so rare. Neither company is planning a massive trial to nail down the clotting risk. "We are stuck in this foggy situation," laments Dr. Eric J. Topol, chief of cardiovascular medicine at the Cleveland Clinic Foundation.
Even though doctors don't foresee a study that definitively addresses the late-clotting risk, Boston and J&J are expected to try to develop safer models. Boston's Koglin says the company's next-generation technology is aimed both at lowering the reclogging rate of arteries and reducing the risk of clotting. He says Boston is working on making polymers -- or even whole stents -- biodegradable, so they disappear over time. J&J declined to comment on its next-generation stent projects. But according to a cardiologist familiar with the project, J&J has tested a drug-eluting stent that also contained the drug Heparin in an effort to reduce clotting risk.
Of course, there's no guarantee that these technologies will pan out. In the meantime, physicians are growing frustrated. Although stent-related deaths don't appear to be numerous, "this isn't trivial," says Cleveland's Topol. With millions of these devices being implanted every year, even a relatively rare problem will be hard to ignore.
By Amy Barrett in Philadelphia, with John Carey in Gaithersburg, Md.