FDA Panel Gets Set for Drug-Eluting Stent Safety Hearing

GAITHERSBURG, Md., Dec. 6 -- There are more question than answers on the eve of the start of a two-day special FDA advisory panel on drug-eluting stents, such as whether they are safe, who should get them, and who should not.

No one is even certain how many Americans are walking around with these tiny devices tucked inside a coronary artery -- maybe two million, maybe three million. The key questions involve whether they are life-savers or time bombs -- or how much of each.

The FDA will rely on an estimate from the American Heart Association to determine the number of patients with drug-eluting stents, and will lean on advice from the blue-ribbon advisory panel to assess stent safety.

That lack of precision in terms of tracking both the number and safety of drug eluting stents is endemic in coronary stenting, a world in which new technologies are adopted with lightning speed, usually far ahead of the data and well beyond the narrow parameters set forth in clinical trials that serve as the basis for FDA approval.

This week that world, where aggressive treatment strategies are usually lauded, will come under public scrutiny during the two-day meeting of a special Circulatory System Devices Panel convened by the FDA to address "issues related to stent thrombosis in coronary artery drug-eluting stents."

Drug-eluting stents have dominated precutaneous coronary interventions since 2003 when the Cypher (sirolimus-eluting) won FDA approval, followed a year later by the Taxus (paclitaxel-eluting stent).

But it is only in the past several months that the meteoric assent of these devices has slowed as serious concerns about their safety emerged.

At a press conference yesterday, Daniel Schultz., M.D., director of the FDA's Center for Devices and Radiological Health, said there was general agreement that drug-eluting stents offered an important public health benefit by dramatically reducing the rate of restenosis that was associated with bare-metal stents.

But since last March when a team of interventional cardiologists from Basel, Switzerland, reported that drug-eluting stents had a significantly higher rate of late stent thrombosis -- an event that is often fatal -- the drug-eluting stents have come under escalating scrutiny.

The debate reached a flashpoint in September at the European Society of Cardiology/World Cardiology Congress. At that meeting a pair of meta-analyses, as well as data from two registries, all pointed to an increased rate of late stent thrombosis with drug-eluting stents.

These data were bolstered by 18-month data from the same Swiss investigators who had originally raised the warning flag. The Swiss suggested that the risk increased at 12 months and continued in a linear fashion up to 18 months.

Within days of the close of the Barcelona meeting, the FDA announced plans for this week's safety hearing.

In October, the drug-eluting stent furor dominated every day of the week-long Transcathter Therapeutics meeting.

At the American Heart Association Scientific Sessions last month, the issue was again a headliner at plenary sessions as well as hot topic debates.

The findings in those reports varied widely from increased risk of stent thrombosis ranging from 0.03% to 0.06% per year to studies that reported no increased risk of stent thrombosis for drug-eluting stents.

Just this week, two studies -- one in the Journal of the American College of Cardiology and the other in the Journal of the American Medical Association -- reported that risk of events increased when treatment with Plavix was stopped.

But Dr. Schultz said the panel is not being asked to vote on any definitive guidelines for the use of drug eluting stents.

Rather, the FDA has asked the panel to offer guidance to the FDA by addressing a list of eight questions ranging from the basic question, "When used in accordance with labeled indications, are [drug-eluting stents] associated with an increased rate of stent thrombosis, death, or myocardial infarction compared to bare metal stents?"

If the panelists agree that safety is a real issue, the FDA wants to know whether they think that safety is an issue with both Cypher and Taxus stents, or does one of the two carry a higher risk?

Additionally, the panelists will be asked to weigh in on the issue of whether safety concerns outweigh the benefits of drug-eluting stents.

Other issues thorny raised by the FDA's questions:

• How long should patients be maintained on dual antiplatelet therapy with aspirin and Plavix (clopidogrel)?
• Are certain lesions more likely to carry a high risk of late stent thrombosis?
• Should drug eluting stents currently in development be required to submit long-term clinical data as part of the approval process?
• What actions should the FDA take to minimize the risk of thrombotic events associated with drug-eluting stents?

To help them answer these questions the panel members were sent three briefing books that contained 2,500 pages of printed material, which is about three time more material than is routinely included in briefing books sent to FDA advisers before a meeting.