A rare but troubling side effect

The product is one of the biggest-selling medical devices in history. The side effect is rare and deadly. And the impact is a giant question mark hanging over Boston Scientific Corp., the region's biggest life-science company.

For a year, heart doctors have grown increasingly alarmed about the blood clots caused by a tiny device called a drug-coated stent. Implanted in millions of patients to help repair blocked arteries, stents appear to carry a long-term risk of clots in a small percentage of people. Now the US government plans to take a hard look at the safety of drug-coated stents, convening a panel of experts to sift through the growing pile of data and decide whether stents should be regulated more strictly.

The anxiety around stents shows a peril of success in the medical industry: A product may have risks that don't show up in early trials of just a few thousand people.

``You see this in drugs -- you see drugs that have been pulled from the market after tens of thousands, or millions, of patient exposures," said Dr. Richard Nesto, a cardiologist at the Lahey Clinic in Burlington who has implanted hundreds of stents.

Nesto says the benefits of drug-coated stents still far outweigh their risks, but he and his fellow cardiologists are growing more cautious about a device that looked like ``the ideal product" when it was introduced just three years ago.

``We sort of bought this drug-coated stent thing, the whole deal. And this concern about [clotting] is fueling another notion: Maybe we've gone too far with this stuff."

For the handful of people who develop a clot, it is literally a matter of life and death: A clot inside a stent can cut off the blood supply to the heart itself.

For the local economy, it could have a significant impact as well. The world's top stent maker is Boston Scientific, which employs 28,000 people -- 2,200 of them in Massachusetts -- and became the region's largest life-science firm on the strength of this one product. Stents fueled the company's growth, and last year accounted for nearly half its $6 billion in annual sales. That makes the company uniquely vulnerable if doctors lose their enthusiasm for the devices.

The idea behind a stent is simple: After doctors clear out one of the arteries that feeds the heart, they install a tiny, strong wire sleeve to keep the artery open and the blood flowing smoothly. A drug coating on the mesh prevents the artery from scarring over the stent and re-clogging. Early studies showed that drug-coated stents were extremely effective at keeping vessels open, which prevents patients from having to return to the hospital for a procedure to re-clear the artery.

On the strength of those findings, the Food and Drug Administration approved versions made by both Boston Scientific and Johnson & Johnson, which remain the only two companies to sell drug-coated stents in the United States. Most cardiologists almost immediately stopped using the older, bare-metal stents and adopted the new ones. Today about 90 percent of stents used on heart patients are drug-coated.

``People who use devices want to use the latest device, and these were the latest device," said Nesto.

But stents cannot be removed once they are implanted, making them a permanent fixture in coronary arteries. As researchers track large groups of patients over time, they have started to see a handful develop ``late thrombosis" -- clots forming more than a month, and sometimes a year or more, after the implant. With bare-metal stents, such late clotting is almost unknown.

This summer, Boston Scientific undertook an analysis of all its stent trials and found that patients with its drug-coated stent were marginally more likely to get a clot than patients with bare-metal stents. The company says a further analysis showed that the drug-coated stent patients didn't suffer more heart attacks or deaths.

``In the end, the safety profile for the patient hasn't changed," said Paul LaViolette , Boston Scientific's chief operating officer, in an interview last week.

Johnson & Johnson, which also monitors long-term effects of its stents, says that among 1,800 patients, five developed late clots. None of the bare-metal stent patients had similar clots.

``This is not a statistically significant difference, but it is an important clinical challenge that we continue to investigate," said spokesman Christopher Allman .

The matter doesn't end there, however. Both companies' studies track patients with fairly straightforward problems in their arteries. In real-life practice, cardiologists use drug-coated stents for any number of complex cases. In extreme situations doctors have implanted a dozen or more stents, or have completely lined a coronary artery with stents -- a tactic colloquially called the ``full metal jacket."

``The more metal you put in, that puts you at risk," said LaViolette.

Doctors don't know what causes the clots. Some are focusing their attention on the polymer that holds the drug coating to the metal stent. And many believe patients are more likely to clot if they stop taking Plavix, the effective but costly blood-thinning drug prescribed to all patients in the first months after their heart procedures.

After this summer's findings, Boston Scientific executives requested a meeting with the FDA to talk about clotting, and also asked the agency to call other stent companies in. Given the emerging concerns, and the wide variety of real-world practice, the Food and Drug Administration said last week it wants an expert panel to review all the data available -- not just the companies' own data, but large registries that track patients after they receive stents.

Many of the registries are European, but some American doctors are starting to track their own patients. In Washington, D.C., the Washington Hospital Center looked at 3,000 patients and found eight cases of late clotting. In California, the massive Kaiser Permanente healthcare system is now launching a review of all its patients who have received stents -- though cardiologist Calvin Weisberger , who initiated the project, says a lack of funding will make the process slow.

``We don't have Boston Scientific or Johnson & Johnson paying for this study -- they certainly won't pay for something that could show we should be buying less of their product," he said.

But will doctors buy less? For the companies that make stents, that's the crucial question. The explosive sales growth of stents had already leveled off before clotting became a hot topic, but they remain immensely profitable. Analysts estimate a profit margin between 80 and 90 percent on each stent sold. For Boston Scientific, that money is crucial to its bigger plan: paying off the debt for its $27 billion purchase of Guidant Corp. earlier this year.

Some doctors say they are seeing a switch back to bare-metal stents, which are far less expensive -- around $800 each, compared to $2,200 for a drug-coated stent. Dr. Ron Waksman , a cardiologist at Washington Hospital Center, says his hospital has scaled back from 89 percent drug-coated stents to 79 percent in the past three months, though he allows that says his hospital is ``on the conservative side."

Others, including like Weisberger, say they haven't seen a change in practice yet, and the doctors are still waiting to see if a tiny risk of blood clots outweighs the benefit of keeping numerous patients out of the hospital for another cardiac procedure.

``There hasn't been any significant shift in the country yet," he said. ``I think if you ask most doctors in the country, they're going to be implanting drug-eluting stents until they see a really good reason not to."

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