Medical Device Daily Washington Editor

GAITHERSBURG, Maryland – The first day of the FDA’s circulatory devices panel seemed replete with the academic and clinical disagreements that ordinarily pepper such gatherings, but even with a Harvard-trained biostatistician on board, the cluster of MDs and PhDs could find little reason to make drug-eluting stents (DES) the whipping boy of the day, regardless of their treatment in the mainstream press.

However, much of the first day’s discussion centered on approved uses of DES, and as the second day began (which will be covered in Tuesday’s issue of Medical Device Daily), the question of off-label use provided more of the fireworks that are typical of such gatherings.

Giving the panel an overview on behalf of the agency, Andrew Farb, a medical officer at the agency’s interventional cardiology devices branch, reminded the panel that off-label use is not directly under the agency’s purview. “FDA does not regulate the practice of medicine,” he said, despite the fact that the agency “is responsible for any use of a device that raises a public health concern.” Farb added that data suggested that “at least 60% of current use is off-label.”

One of the imperatives mentioned by Farb is the use of the definitions of stent thrombosis published by the Academic Research Consortium (ARC) (see Sidebar) in October. Farb said that “FDA finds the ARC definitions acceptable” and asked that all the sponsors at the meeting employ those definitions in presenting their information.

The BASKET-LATE study, according to Farb, enrolled 746 patients whose surgeries were at least six months prior to enrollment and did not exhibit signs of major adverse cardiac events (MACE). These patients dropped off dual therapy after three months and while the patients who had coated stents exhibited higher rates of late major cardiac events between seven and 18 months than those on bare stents, “these differences were not statistically significant,” Farb said. Other data presented by Farb were similarly equivocal in terms of statistical significance.

Farb concluded by remarking 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.” Farb said that available data do not show that these events are associated with death and infarction, but data from beyond three years is relatively small and it is not clear whether a longer follow-up will change the picture.

During the public comment session, 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.

Alan Michelson, MD, a professor of medicine at the University of Massachusetts Memorial Hospital , is credited with having authored the definitive, eponymously titled book on platelets. He informed the panel that LST “is associated with discontinuation of anti-platelet therapy in some patients, but not all,” and that in some patients, pharmacological resistance is the culprit rather than discontinued therapy.

Michelson argued that “a clinically meaningful definition of aspirin resistance needs to be developed,” and that the science behind this use of aspirin is not very robust due to lack of studies. He did not recommend trying to test aspirin resistance pursuant to its use in an anti-platelet setting “other than research trials, which I strongly encourage.” He added that a similar examination of clopidogrel [Plavix] is also in order. Nonetheless, he recommended that clopidogrel doses be boosted from 75 mg to 150 mg a day in patients for whom sub-acute thrombosis could lead to disastrous outcomes.

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 bare metal stents. Christopher White, MD, of the Ochsner Clinic (New Orleans) said that where rates of thrombosis are concerned, “the number spoke for itself,” but he is nonetheless uncertain that the rate of thrombosis is elevated. “I’m worried, but not certain” about thrombosis, but “I think death and MRI are not” conspicuous among the DES group.

Sharon-Lise Normand, a professor of public healthcare policy and a biostatistician at the Harvard School of Public Health said that “I really don’t think I see a strong signal of thrombosis.” Norman Kato, MD, of the Cardiac Care Medical Group (Encino, California) said that “I’ve been torn with some of what I see as an emotional issue.” He said that the data seem to bounce around from a one percent to a half a percent frequency, and if he had to answer the question “emotionally, yes, evidence-based, no.”

Speaking in dissent, Steve Nissen, MD, the chairman of the department of cardiovascular medicine at the ClevelandClinic said that“[w]e know there’s an early advantage ... but we have less than four year’s of experience. If the risk continues unabated for a long time, those event curves will cross and late events will overwhelm early benefits.” The consensus was essentially that the data do not argue forcefully for an increased risk of thromboses for the coated stent vs. the bare metal stent.

With regard to anti-platelet therapy, Maisel said that he was reluctant to recommend continued use beyond the period recommended by the stent manufacturers without a concomitant statement as to the risks of such a course.

Another panelist said that the label could include a reference to guidelines recently published in the American Journal of Cardiology that recommend one year of therapy (mean time to LST for the DES in question were 18 months or less), but Normand replied that “I don’t think that data from the observational studies should be in the label” because the more solid data are from the clinical trials.