New concerns over choice of artery stents

Data suggesting that, when compared with bare-metal stents, drug-eluting stents may increase the risk of some adverse events have begun to shift the focus of conversations between some doctors and patients.

Philadelphia-based cardiologist Howard Weitz, MD, says his discussions with patients in need of this intervention are no longer just about which stent is right for the blocked artery. Now a range of additional issues come into play.

For a drug-coated stent to be chosen, for instance, the patient should be aware of the need to take blood-thinning medication for a full year, the current recommendation. It is also important to consider possible cost, compliance or logistical barriers that could prevent such a commitment. Also, does the patient have an impending surgery that would require these drugs to be discontinued? And what if the patient's situation changes?

"If I cannot be assured that they have a year, we're now using the bare-metal stents," said Dr. Weitz, co-director of the Jefferson Heart Institute. "But who has a crystal ball? We have really been thrown into a dilemma with the broad spectrum of patients who come in needing coronary revascularization."

Drug-eluting stents came onto the market in 2003 and 2004 and dramatically decreased the risk of patients developing restenosis, a problem commonly associated with the bare-metal versions. By the end of 2004, 80% of implanted stents were drug-coated.

"Patients have a tremendous improvement in quality of life," said Gregg W. Stone, MD, an interventional cardiologist and professor of medicine at Columbia University Medical Center in New York. "They're not having a re-narrowing of the artery. They're not undergoing bypass surgery. They can live easier with heart disease."

This enthusiasm, however, has been dampened slightly because of rising concerns that the risk of late stent thrombosis may be higher than with bare-metal stents. This possibility first came up in 2003 when the Food and Drug Administration issued and withdrew a warning about an increased risk of this adverse event.

The subject was then resurrected last year at the American College of Cardiology meeting in Atlanta and the World Congress of Cardiology in Barcelona, Spain, where some researchers suggested that thrombosis was more common in patients implanted with drug-eluting stents after stopping anti-platelet therapy. These patients also seemed to have a higher risk of death and heart attack than did patients with the bare-metal stents.

The FDA then convened an advisory panel to consider the issue in December 2006.

Last month, the New England Journal of Medicine published online much of the data considered at that meeting. These papers appear in the March 8 print edition.

Among them, one utilizing data from the Swedish Coronary Angiography and Angioplasty Registry found that drug-eluting stents were associated with an increased risk of death after six months. Another, by Dr. Stone, pooled four double-blind trials and found an increase in stent thrombosis at one year but no increase in the risk of death or heart attack at the four-year mark. Three papers, also analyzing various pools of studies, found no increased risk of stent thrombosis and no differences in death rates.

"It's disappointing that millions of patients have received these devices, and we still have so many questions about their safety and which patients they should be used in," said William Maisel, MD, MPH, the FDA panel chair and author of a perspective piece accompanying these studies.

More data needed

Sorting through the data has been complicated by the fact that a single definition of stent thrombosis has been lacking. The characteristics of patients and their disease also varies widely, and some study protocols may have biased the results in favor of bare-metal stents.

"The studies are not ideal for assessing the relative risk of stent thrombosis," said Dr. Maisel, also an assistant professor of cardiology at Beth Israel Deaconess Medical Center and Harvard Medical School in Boston.

The FDA advisory panel concluded a slight increase in the risk of late stent thrombosis exists, but the risks of these devices did not outweigh the benefits when used for the specific purpose for which they gained approval -- treating small, newly diagnosed coronary lesions.

The safety of these devices for the many patients who don't fit this definition, such as those with more complicated cardiovascular problems and other comorbidities, remains an open question.

Many physicians say this point is where the results of clinical trials set up for approval can diverge from real-world practice. About 60% of patients who receive a drug-eluting stent do not fit the profile of those included in the initial trials.

"We don't have adequate data at this point whether drug-eluting stents are better or worse than bare-metal stents or surgery in those patients," Dr. Maisel said. "There could be an overuse of drug-eluting stents in the off-label population."

Recognizing that stent thrombosis in those who receive drug-eluting stents seems to occur later than in those who receive bare-metal ones, the FDA panel also called for patients to stay on Plavix (clopidogrel) for at least a year and on aspirin for a lifetime. This timeline is far longer than the label for these devices previously indicated.

"Early on, the Plavix matters a lot." said Christopher White, MD, an FDA panel member and chair of the Cardiology Dept. at the Ochsner Clinic Foundation in New Orleans. "If I had a drug-eluting stent, I would take Plavix for the rest of my life."

Meanwhile, in the wake of these developments, both manufacturers, Cordis Corp. and Boston Scientific Corp., reaffirmed the safety of their devices and took action to build a stronger evidence base to support that assertion.

Cordis Corp. increased patient education on the need for anti-platelet regimens, expanded their patient registry and increased the length of follow-up of their clinical trials from five to eight years.

Boston Scientific Corp. is also backing three large trials into the use of their device in more complicated patients.