BB&T Washington Editor

WASHINGTON — On the eve of the two-day meeting held by the FDA in early December to discuss drug-eluting stents (DES), the American Heart Association (Dallas) released a statement essentially calling for: more care in the applications of DES, more longer-term hard data focused on the possibility of adverse events, and longer, more-targeted and consistent use of drug therapies in follow-on care after stenting.

Besides tending to put the onus on patients for failing to comply with the prescribed drug regimens with DES, the AHA noted a "second issue … less well-established at this time," referring to the increasing number of concerns — both anecdotally from physicians and clinically from new studies — that DES is associated with the risk of blood clotting and even death.

In fact, these conservative conclusions — perhaps better described as tepid — were a foreshadowing of what came out of the meetings, the agency indicating that it won't do more than tweak the current guidelines for DES use. Both days were replete with the pro and con views concerning broad DES use, and that balance served to provide a foundation supporting no large alterations in the agency's concerns about DES or to support a broad roll-back of their use in U.S. hospitals.

Giving the panel an overview on behalf of the FDA was Andrew Farb, a medical officer at the agency's interventional cardiology devices branch, focusing on the BASKET-LATE study, which pointed to significant patient non-compliance in using anti-platelet therapy and that these patients had higher rates of late major cardiac events between seven and 18 months than those on bare-metal stents (BMS). These differences were not statistically significant in the DES/BMS comparison, and he presented other data similarly equivocal. Farb concluded that "the data available to FDA indicate that the currently approved drug eluting stents, when implanted in accordance with their labeled intended use, are associated with reduced repeat procedures to treat restenosis compared to bare-metal stents and are also associated with a small but significant increase in late stent thrombosis."

But what of the longer term?

He noted also, however, the lack of data beyond three years. And Herman Gold, a professor of medicine and an interventional cardiologist at Massachusetts General Hospital (Boston) said that "although earlier pivotal studies indicate that these stents are safe, with longer follow-up, it has become clear that late stent thrombosis may impose significant risk for some patients." Gold said that "healing is not uniform within a DES and strut coverage is not uniform, either." The coating toward the middle of the stent is more subject to depletion, and he said a 37% exposure of the stent is associated with an increase in the risk of latent stent thrombosis (LST) of 11%. However, the most powerful predictor of thrombosis, Gold said, is lack of endothelial coverage on the inner lining of the blood vessel, which DES suppress inadvertently while suppressing smooth muscle proliferation.

One of the questions the agency tasked the panel to investigate was whether DES are associated with a discernible increase in the rate of LST compared to BMS.

Christopher White, MD, of the Ochsner Clinic (New Orleans), said that he was uncertain about whether the rate of thrombosis was elevated. "I'm worried, but not certain" about thrombosis, but "I think death and MRI are not" conspicuous among the DES group, he said.

An 'emotional issue'

Norman Kato, MD, of the Cardiac Care Medical Group (Encino, California), said that the evidence of increased thrombosis associated with DES had created "an emotional issue" and that the data seemed to bounce between a 1% and a one-half percent frequency producing an emotion "yes," but an "evidence-based no."

The meeting's second day produced a bit more controversy since there was considerable focus on the large percentage of DES off-label use, with those uses offering a large number of uncontrolled variables not easily measured, including uses in patients with more complex disease and more co-morbidities.

Addressing the wealth of contradictory data and its interpretation, William Maisel, MD, chairman of the panel and a staff member at Beth Israel Deaconess Hospital (Boston), noted "significant uncertainties" and as a result said he found it "difficult to make conclusive judgments regarding this issue.But the panel appeared to find considerable comfort in recommending that DES-implanted patients stay on dual antiplatelet therapy for at least a year, and suggested that stent labels inform doctors that high-risk patients do not seem to benefit as much as patients who are covered by the cleared indications.

More warnings, or no change in practice?

Steve Nissen, MD, of the Cleveland Clinic (Cleveland, Ohio), said, "I want to warn people a little more than we do now" about DES risks. On the other hand, Dr. White of the Ochsner Clinic, said he had not "heard anything today that will change my practice."

Ralph Brindis, MD, interventional cardiologist with Northern California Kaiser Permanente (San Francisco), said that his organization as a whole is "impressed with the marked reduction in clinical restenosis and improvement in quality of life" seen in patients who picked DES over bare-metal stents (BMS). Kaiser data for more than 4,200 patients over three years, ending Oct. 31, 2006, showed that more than 95% of those who underwent angioplasty chose to have a stent installed, and in that group 95% opted for DES.

Sanjay Kaul, director of the vascular physiology and thrombosis research lab at Cedars Sinai Medical Center (Los Angeles), said that DES devices offer "a quantum leap in interventional cardiology," but that they predispose patients to thrombosis. And he posed one of the key questions: Do the clinical trials reflect real-world practice in defining occurrence of restenosis?

He also asked what the duration of risk might be for various outcomes and insisted that the FDA's least-burdensome pathway would be improved by insisting on trials that are larger, of longer duration and more inclusive of "real-world" populations. "Reducing restenosis is desirable if we have ways to mitigate the risk of stent thrombosis," Kaul said, but "the optimal duration" of dual antiplatelet therapy is unknown, the data less than certain due to an information gap regarding compliance.

"With regard to the approval recommendations … we need larger and longer pre-approval randomized clinical trials" and a broader cross-section of patients and trial designs that emphasize clinical outcomes over statistical measures, " he said. "I think we will all agree that the [resulting] approval process is likely to benefit from" a more stringent standard of proof "than the current standard of least burdensome pathway." He commended the FDA for "taking the initiative" on setting up surveillance registries and insisted that "the crux of the debate here is the over-utilization of revascularization," adding that the DES vs. BMS debate can't be adequately argued until the "the root cause" for the reported adverse events is found.