"No One Wanted To Hear"
Two years ago, at a meeting of top heart doctors in Paris, Dr. Renu Virmani tried to dampen the raging enthusiasm for drug-eluting stents--new devices that prop open narrowed blood vessels and exude chemicals to keep them open. The stents were having a glorious sunrise, she said, because they prevented blood vessels from renarrowing. But inevitably "the sun would set," she warned, as patients with the stents ran into deadly problems.
Based on her years of experience and studies, the Indian-born Virmani was troubled by the devices, but at the time "no one wanted to hear what I was saying," she recalls. For one thing, the message threatened products from Boston Scientific Corp. and Johnson & Johnson viewed as breakthrough treatments with multibillion-dollar potential. And as a pathologist with a flair for the dramatic, Virmani was seen as both an alarmist and an outsider in the elitist world of interventional cardiology. "There was hostility," says Dr. Steven Nissen, chair of cardiovascular medicine at the Cleveland Clinic. "No one likes someone who is saying what you are doing is not the right thing."
They're listening now. Over the past two years, doctors have noticed that patients with the new stents sometimes suffer fatal heart attacks months or years after the devices were inserted. At her nonprofit laboratory, the cvpath Institute in Gaithersburg, Md., Virmani, 64, has vivid microscope slides showing why: The victims' stents are totally blocked by clots. New analyses of the data from clinical trials, reported at a meeting last month in Barcelona, show that such late-occurring clots form more often with the new stents than with old bare-metal ones. In its own trials with its Cypher drug-eluting stent, J&J's Cordis division said in a written response that five patients have had late clots, compared with zero for bare-metal stents. The company says the difference is not statistically significant, but that "it is an important clinical challenge."
Prominent cardiologists like Nissen are calling for a large, long-term trial to figure out the size of this problem. The Food & Drug Administration terms it "a small but significant increase in the rate of death" and is convening a panel to examine the risks. Cardiologists estimate that the drug-coated stents may be causing 5 to 15 more clots per 1,000 people than the bare-metal stents. That's not a big number, but such a clot "is a catastrophe," explains Dr. Robert S. Schwartz of the Minneapolis Heart Institute; "100% of patients will have an infarction, and 20% to 40% will actually die. With millions of stents, that's a lot of catastrophes--10,000 to 30,000 patients per year."
The clotting problem is catching the attention of trial lawyers, who are exploring the potential for litigation. Virmani is among the researchers who have already fielded calls from attorneys. So far, trial lawyers say that the grounds for mass torts are uncertain because the late- occurring clots appear to be a side effect rather than the result of a product defect. The analysis of the issue at the personal-injury firm Parker & Waichman is "really preliminary," says lawyer David B. Krangle. But, ever provocative, Virmani suggests that drug-eluting stents could be another Vioxx, the Merck & Co. painkiller whose link to heart disease sparked many lawsuits.
The function of the small metal tubes known as stents is to prop open narrow arteries. Once a stent is inserted, the blood vessel grows new layers of cells over the metal as part of the healing process. That's a good thing, but problems arise when the healing is too vigorous and the resulting layer of cells is too thick. The vessel narrows, causing symptoms like chest pain. Current thinking is that 15% to 30% of patients who get first-generation bare stents will have this problem, called restenosis, although one new study suggests that the rate could be as low as 8%.
That's why researchers have been seeking ways to tame the over-exuberant healing process. The first promising approach, embraced by cardiologists in the 1990s, was zapping blood vessels with radioactive seeds for a short time after stents were inserted. Virmani, then head of cardiovascular research at the Armed Forces Institute of Pathology, was skeptical. The radiation would only delay restenosis, she warned, while damaging the vessel and leading to other ills, like clots. After being a lonely voice of caution for years, "I was proven right," she says.
Now doctors typically use drug-coated stents instead of radiation. Millennium Research Group estimates 920,000 patients in the U.S. will get them this year. The drugs--an anti-cancer agent in Boston Scientific's Taxus and a potent immune-system suppressant in Cypher--are secreted by a plastic polymer in the stent to slow healing.
The problem is that "delaying healing is a double-edged sword," Virmani explains. Examining stents under the microscope months after they were implanted, Virmani often finds that no new protective layer of cells has formed. As a result, the body still views the site of the stent as an unhealed wound, so it sends in a clotting protein to speed the healing. That, in turn, can lead to a deadly clot, called a thrombus. What's more, work by Virmani and others shows that the polymer itself can trigger an inflammatory response, compounding the problem.
Virmani was leery of such stents even before the first one was approved in 2003. Her doubts were soon strengthened. A European doctor involved in trials had a patient who died 16 months after getting a Cypher stent, and sent samples to Virmani. She showed that there was little healing at the site of the stent--and sure enough, there was a clot. She also saw a hypersensitivity reaction in another patient. The cases were "a revelation that we were on the right track," she says. "But J&J didn't want to believe it."
J&J's Cordis division says the company convened a panel of experts to review Virmani's work and concluded the clot was an anomaly. "Hypersensitivity to the Cypher stent or its components, if it were observed, would result in restenosis and not thrombosis," the J&J spokesman said. Boston Scientific notes that bare-metal stents can also cause cardiac problems. The flamboyant Virmani, who went through basic training in her 40s and served as a lieutenant colonel in the U.S. Army Reserve, doesn't buy these arguments. "I would never take a drug-eluting stent," she says. "The chances of thrombosis are so high."
While doctors are just starting to figure out the actual incidence of harm from the new stents, the work of Virmani and others points to safer ways of using the devices. Doctors understand now that ending treatment with the anti-clotting drug Plavix is dangerous. Again and again they see stent patients who go in for additional surgery months later, and stop taking Plavix to avoid excessive bleeding during the procedure, only to suffer a heart attack. "I don't feel comfortable telling my patients with stents to stop Plavix, ever," says Schwartz.
Some cardiologists are already switching back to bare-metal stents, causing Boston Scientific to lower its revenue projection. And companies and researchers are redoubling their efforts to come up with less risky, next-generation eluting stents, some with lower levels of drugs or a more biocompatible polymer.
Doctors, meanwhile, have learned to take Virmani's warnings more seriously. At the Paris meeting this year, she was given a major award for contributions to interventional cardiology. "She has been somewhat prophetic," says Nissen.
By John Carey