Medical Device Daily Washington Editor

GAITHERSBURG, Maryland — The second day of the FDA devices panel looking at drug-eluting stents (DES) was the scene of a variety of scorching remarks aimed at the companies making the devices.

But seeming to carry more weight were registry data and testimony by administrators at two locations in the Kaiser Permanente network, with the panel opting for a set of recommendations to the agency that were less than dramatic.

The first day’s material covered indicated usage of DES devices (Medical Device Daily, Dec. 11, 2006), but second-day proceedings were bound to be more controversial as the panel tackled off-label use, such as for patients at higher risk for poor outcomes.

Still, the data were too equivocal to push the panel to push for anything more drastic than that DES labels recommend dual antiplatelet therapy continue for a year, and more cautious recommendations to surgeons for their use.

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.

David Magid, MD, director of the Colorado Permanente Clinical Research Unit (Denver), noted that data on patient risk characteristics showed that 74% of Kaiser patients who chose a DES “were receiving stents in the setting of non-FDA-approved indications.”

Magid said that among the predictors of post-surgical infarction, diabetes mellitus correlated with the strongest hazard ratio at a rate of 3.2, with previous graft surgery coming in second at 2.6. Lesion length of greater than 30 mm exhibited a hazard ratio of 1.9, followed by congestive heart failure (CHF) at 1.8.

As for the predictors for all-cause death, the hazard ratio for CHF led all groups at 3.8, and bifurcated lesions followed at 1.8. Age and diabetes were the third and fourth most powerful predictors at 1.7 and 1.6.

On the use of clopidogrel beyond the recommended term, Magid said that the in-house nature of the organization’s prescription drug benefit “allows us to carefully track” compliance. The data show that “we have seen a protective effect of Plavix in that three month period beyond the recommended period of time, and there is also a trend toward protection in the second three-month period, but there were no differences” after that.

“There is no evidence of any protective effect associated with clopidogrel use beyond a six-month addition to the recommended duration of use for either type of stent among the Kaiser patient population,” he said.

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. He added that clopidogrel use for this is an off-label use of the drug.

“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.

Kaul also suggested that DES use is part of the trend toward defensive medicine and the “need [for] tort reform. “All of this is going to take a lot of willpower,” he added.

Jeffrey Moses, MD, an interventional cardiologist at Columbia Presbyterian Physician Network (New York), said “the negative characteristics [of DES] portrayed in the press have really frightened patients,” thus compromising the interventionist’s ability to advise patients.

“Let’s not lose perspective on what restenosis is all about,” Moses said, arguing that abandoning off-label DES in favor of BMS would induce 300,000 clinical events a year and hundreds of thousands of bypass surgeries each year. The resulting “burden in the [U.S.] healthcare system would be $1 billion” a year, he said, citing Medicare data.

Moses said that in-stent restenosis, more commonly associated with BMS, “is not a benign entity.”

Remarking that the quality of the restenosis is as important as frequency, he said that the majority of restenosis associated with BMS was diffuse” and that the recurrence rate ranges from 35% to 80%, resulting in major cardiac event rates of more than 50% over two years.

“Unfortunately, all we’re going to have for the foreseeable future are these nine randomized trials” for deciding which stent is better. As for the discussion of real-world and non-real-world data, he said the registry data provide four-year follow-up and clinical measures have improved as a result of widespread adoption of DES, including “profound reductions in restenosis.”

The off-label data provided by the ARTS II follow-up of the Cypher stent indicated that after three years, the composite rate of death, stroke, heart attack and revascularization compared to coronary bypass was better for the stent, although the difference was apparently not statistically significant. However, significant differences were seen between the Cypher and BMS devices for this grouping of events as well as for the incidence of stroke and heart attack.

DES “are unquestionably the standard of care,” Moses averred, noting that in intent-to-treat trials, “overall thrombosis rates are not very different and term-to-thrombosis is narrowed.” He added that events secondary to thrombosis are eliminated from most studies, but that such an exclusion tilts the numbers toward BMS.

Panel chairman William Maisel, MD, of Beth Israel Deaconess Hospital (Boston), noted that the panel saw “significant uncertainties” and as a result, found it “difficult to make conclusive judgments regarding this issue.” On the other hand, the panel felt comfortable in recommending that 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.

Steve Nissen, MD, of the ClevelandClinic (Cleveland), said, “I want to warn people a little more than we do now.”

On the other hand, Christopher White, MD, of the Ochsner Clinic (New Orleans), said he had not “heard anything today that will change my practice.”