FDA advisory panel recommends conditional approval for new zotarolimus-eluting stent

The Endeavor coronary stent system demonstrated adequate safety, deliverability but limited efficacy.

The FDA Circulatory Systems Advisory Panel has recommended a premarket approval for a zotarolimus-eluting stent, based upon data presented at a recent meeting.

The stent (Endeavor, Medtronic) is poised to become the first drug-eluting stent introduced in the United States since 2004. The panel unanimously voted that the FDA should approve it but did so with several clearly-defined conditions.

Medtronic would be required to alter the product label to reflect professional societal guidelines recommending the use of dual antiplatelet therapy; the company must also institute a postmarket, single-arm registry of at least 5,000 patients to be followed up for a minimum of five years. The postmarket study would contain primary end points of late stent thrombosis and secondary endpoints of cardiac death and MI.

Trials demonstrated safety

According to Medtronic, the zotarolimus-eluting stent is designed to improve coronary luminal diameter in patients with ischemic heart disease due to de novo lesions <27 mm in coronary arteries and in native coronary arteries between 2.25 mm and 3.5 mm in diameter. The stent is coated with a phosphorycholine polymer and a layer of the immunosuppressant zotarolimus, originally designed to prevent rheumatoid arthritis and later developed to prevent inflammation and lumen loss.

The FDA was particularly interested in the zotarolimus-eluting stent’s ability to meet its primary clinical endpoints, which were set according to each trial design. Medtronic conducted six total trials; three of the six were prospective clinical trials to test the safety, efficacy and deliverability of the stent. The clinical studies examined by the panel, due to their larger sample sizes and randomized designs, were the ENDEAVOR II (n=1,197), ENDEAVOR III (n=436) and ENDEAVOR IV (n=1,548) trials. ENDEAVOR II, which compared the zotarolimus-eluting stent with a cobalt-based bare metal stent (Driver, Medtronic), was a prospective, multicenter, randomized, double blind trial. ENDEAVOR III and IV compared the zotarolimus-eluting stent with a sirolimus-eluting stent (Cypher, Cordis) and a paclitaxel-eluting stent (Taxus, Boston Scientific), respectively. Both were prospective multicenter, randomized, single blind trials.

The totality of the ENDEAVOR clinical program, which included three substudies and three randomized clinical trials, enrolled 2,133 total patients and assigned 1,287 patients to receive zotarolimus-eluting stents; follow-up was 24 months. ENDEAVOR II met its primary endpoint of reduction in nine-month target vessel failure vs. the Driver stent. ENDEAVOR III failed to meet its primary angiographic endpoint of eight-month in-segment late lumen loss vs. the Cypher stent, although the trial was underpowered to evaluate clinical endpoints for TVF or major adverse cardiac events. This endpoint failure was of primary concern to the panel, as it portended potential increases in restenosis rates. ENDEAVOR IV met its primary endpoint of demonstrating noninferiority to the paclitaxel-eluting stent with a reduced TVF rate of 6.8% vs. 7.4% with the paclitaxel-eluting stent. According to the FDA executive summary of the safety data for the ENDEAVOR II, III and IV clinical trials, no increased rate of death, MI, noncardiac death or stent thrombosis was observed.

Approval with caveats

Upon extensive review of the data of the ENDEAVOR program, the panel unanimously decided that the zotarolimus-eluting stent demonstrated a reasonable level of safety and effectiveness to continue in the approval process but also that rigorous postmarket studies needed to be submitted to ensure the clinical data were consistent over longer follow-up periods and in larger patient populations. Some panel members were enthusiastic about the stent, given the strong safety data shown in the trials.

“I was intrigued and somewhat surprised to find that the efficacy appeared to be in the same ballpark with the other drug-eluting stents,” John Hirshfeld, MD, professor of medicine at the Hospital of the University of Pennsylvania, said at the meeting. “In terms of how to apply this in practice, we all still need to do some serious thinking about what the role of this stent is going to be vis-a-vis the other stents that are available. I think that this judgment will require a lot more data and experience.”

Other panel members voted in the affirmative but also expressed their desires to see more complete and higher-powered data sets. Most of the panel members echoed each other’s concerns regarding study size and follow-up studies.

“I still have some reservations regarding the total number of patients found,” Norman S. Kato, MD, cardiovascular surgeon at the Cardiac Care Medical Group, Encino, Calif., said at the meeting. “The numbers, particularly when we’re looking at a very small frequency of adverse events, do require 5,000, 6,000 or 10,000 patients to look at. I’m cautiously optimistic that Medtronic and the FDA will continue on this course of getting that data so we can increase our confidence as to the use of this new product.” – by Eric Raible

For more information:

• To access meeting information online: http://www.accessdata.fda.gov