Medical Device Daily

Was the FDA too hasty in approving what has become a blockbuster medical product? Do drug-eluting stents (DES) provide any benefits beyond the avoidance of redundant procedures to open clogged arteries? Have all of the questions been answered concerning the appropriate uses of these devices in the appropriate patients? And the appropriate doses? And what are the proper dosages of follow-on drugs? Do DES devices provide added benefit in terms of increased mortality?

Are DES devices safe?

To this last question the Center for Device and Radiology Health of the FDA seems to be saying: Yes . . . well, at least we think so . . . so we'll have to look again. While supporting the safety of DES technology in a statement issued last week, the agency said it is continuing a close study of new data concerning the devices and that it will convene a meeting of its cardiovascular advisory panel later this year to consider the issue more, and consider the need for labeling changes.

This raises more questions. Is the agency itself convinced of DES safety – or is it planning to “reposition” itself on the issue?

The agency's statement came in response it said, to a variety of inquiries concerning the devices, and emphasizing that the statement is no different than its previous position concerning the technology's safety and efficacy.

But it also stated an important caveat: That it is continuing to study the issue.

And in a summary statement that appeared to be its most definitive position, the agency said that there are still “important questions” concerning the devices . . . for example, what causes drug-eluting stent thrombosis, how often it occurs, under what circumstances it occurs, or what the risk of occurrence is in a given patient?

The agency said that it is “aware” of new research that has recently emerged to suggest that DES devices may not be the vastly superior technology – superior especially to bare-metal stents – than originally thought. That research focused on adverse events and indications of no additional benefit in terms of life expectancy for those implanted with DES devices.

“We are aware of recent data suggesting a small but significant increase in the rate of death and myocardial infarction (heart attack) possibly due to stent thrombosis (a blood clot in the stent) in patients treated with DES,” the statement said. “The specific studies that have prompted recent media inquiries are the BASKET-LATE study (presented at the March 2006 American College of Cardiology Scientific Sessions in Atlanta, Georgia) and more recently, the Camenzind meta-analysis presented at the September 2006 European Society of Cardiology Annual Meeting/World Congress of Cardiology Meeting in Barcelona, Spain.”

It goes on to say that in these studies, targeting patients following 18 months to three years after stent implantation, there was found a “small but significant increase in the rate of death and myocardial infarction.”

These research results “have raised important questions,” the statement says, while adding that “the data we currently have do not allow us to fully characterize the mechanism, risks, and incidence of DES thrombosis.”

It said that a “more formal evaluation of the data in these studies is necessary, and any conclusions are dependent upon a thorough peer review.”

It said it intends to study the data presented at the Atlanta and Barcelona meetings with “a more formal evaluation.”

The statement notes the importance of stent thrombosis related to stent implantation, saying that while it occurs “at low rates” it is still quite serious. And it goes on to say that the agency has met with the manufacturers of the two FDA-approved DES devices – Boston Scientific (Natick, Massachusetts), maker of the Taxus DES, and Cordis (Miami Lakes, Florida), maker of the Cypher DES – “to discuss any information and perspectives they have that may be pertinent to this issue.”

It noted that it has been monitoring the devices since their approval for commercialization and acknowledges that the studies presented in Atlanta and Barcelona have raised “important questions [but that] the data we currently have do not allow us to fully characterize the mechanism, risks, and incidence of DES thrombosis. A more formal evaluation of the data in these studies is necessary, and any conclusions are dependent upon a thorough peer review.”

In terms of regulatory concerns, it said the agency is “keenly interested in the long-term follow-up of patients enrolled in the original pivotal DES randomized trials, as well as those in the more complex patient and lesion subsets (for example, patients with diabetes; acute myocardial infarction or multiple vessel disease; or lesions involving arterial bifurcations, the left main coronary artery, and long arterial segments) who are currently being treated in “real world” randomized and registry studies.

It also said it continues to evaluate information related to treatment using the drug clopidogrel (Plavix), in combination with aspirin, to reduce or prevent restenosis in DES patients.

“Although the duration of clopidogrel appeared to be adequate for the selected patients in the original clinical trials conducted to support FDA approval,” the statement says, “the agency recognizes that the optimal duration of clopidogrel in more complex patients has not been defined. The recommended duration of clopidogrel administration and patient compliance with the prescribed regimen are likely interrelated with patient and anatomical factors that are associated with DES thrombosis.”

It adds: “Additional clinical data are likely needed to reach conclusions regarding the optimal antiplatelet therapy regimen for DES patients.”

The incidence and timing of stent thrombosis related to DES and the appropriate duration of the use of clopidogrel in patients implanted with DES devices, it said, will be two important topics of the advisory panel meeting that it said will be scheduled “by the end of the year.”

The advisory panel of “outside experts,” it said, “will assist the agency in the review and analysis of the available scientific data and provide recommendations for appropriate actions to address this issue, such as possible changes to device labeling or the need for additional clinical studies.

Boston Scientific issued a press release saying that it welcomed the FDA's statement supporting DES safety “when used for the FDA-approved indications.”

The company's Taxus Express Paclitaxel-Eluting DES is indicated for improving luminal diameter for the treatment of de novo lesions <28 mm in length in native coronary arteries >2.5 to <3.75 mm in diameter.

The Cypher Sirolimus-eluting DES from Cordis is indicated for improving coronary luminal diameter in patients with symptomatic ischemic disease due to discrete de novo lesions of length <30 mm in native coronary arteries with reference vessel diameter of >2.5 mm to <3.5 mm.

Boston Scientific said it is conducting additional studies of its own, “involving more than 10,000 patients with long-term follow up to evaluate the TAXUS stent in an even broader range of patients and lesions.”