Medical Device Daily Associate

In the wake of recent concerns about the safety of drug-eluting stents (DES) — concerns likely to generate much debate at the Transcatheter Cardiovascular Therapeutics (TCT) meeting this week in Washington — Medtronic (Minneapolis) is set to initiate a new, large-scale clinical trial focusing on DES safety.

The company said that the PROTECT (Patient Related OuTcomes with Endeavor versus Cypher stenting Trial) will be the largest randomized trial ever conducted to assess key safety measures of two DES devices. The trial will compare the Medtronic’s Endeavor zotarolimus-eluting DES and the Cypher DES made by Cordis (Miami, Florida), a unit of Johnson & Johnson (J&J; New Brunswick, New Jersey).

Primary endpoint for the PROTECT study will be stent thrombosis, the focus of recent safety concerns, with secondary endpoints that include death and non-fatal myocardial infarction and other customary clinical efficacy end points, Medtronic said.

The study will enroll 8,000 “real world” patients at 200 clinical centers in Europe and other international markets and follow patients for an additional two years. Real world patients, the company said, refers to patients seen by physicians in everyday clinical practice, including those with complex medical conditions — a designation clearly meant to differentiate vs. more carefully selected trial patients.

“That’s all comers,” company spokesperson Scott Papillon told Medical Device Daily, “the patients who would typically come into a physician’s clinic on an everyday basis.”

While the timing of the trial may appear calculated as piggy-backing on current DES debate, Papillon insists that it is only coincidental.

“More than a year ago, we started talking to physicians about it,” he said. “It’s in response to the call for more [long-term] safety [data] but not necessarily tied to the recent activity that everyone is hearing about.”

That activity includes reports at last month’s European Society of Cardiology (Sophia, Antipolis, France) annual meeting in Barcelona, where researchers issued reports indicating the risk of increased blood clots up to several years after DES implantation.

Eduardo Camenzind of University Hospital Geneva (Switzerland), said that a review of BASKET-LATE (Basel Stent Cost-effectiveness Trial — Late Thrombotic Events) data suggests that the rates of cardiac death and non-fatal myocardial infarction were higher in patients with DES than those with their bare-metal cousins. Camenzind insisted: “The problem is likely to be significantly underreported since if people die on the street, they don’t fulfill the angiographic criteria to be classified as in-stent thrombosis.”

Camenzind’s meta-analysis pointed to a 2.4% increase in the incidence of death or infarction in Cypher-implanted patients vs. those implanted with bare-metal stents (BMS).

Up to 6 million patients worldwide have received DES devices since they were first launched in 2002, creating a $5 billion-a-year business for market leaders Boston Scientific (Natick, Massachusetts) and J&J.

Asked if Medtronic had concerns that the DES market has peaked and is now in correction mode due to real-life concerns, Papillon acknowledged these as valid issues, but stressed that the problems are with the first-generation stents.

“We think that Endeavor as the next-generation stent offers some answers to that,” he said.

Improvements that he cited for the Endeavor over its older brethren include a polymer/drug combination with excellent safety data thus far.

The Endeavor failed to meets its primary endpoint in a study with Cordis last year. In that trial — ENDEAVOR III — Endeavor failed to exhibit non-inferiority to Cypher in a comparison of late-lumen loss. Specifically, the 282 patients treated with Endeavor had an average in-segment late loss of 0.34 mm at eight months compared to 0.13 mm among the 94 Cypher-treated patients. That 0.21 mm difference, however, was just 0.01 mm more than the trial’s predetermined non-inferiority margin of difference (MDD, Oct. 18, 2005).

Papillon said, however, that the late-loss data was determined as not applicable and that late loss has not been shown to lead to adverse clinical outcomes. He noted that Endeavor was “as least as good as the Cypher” in the secondary endpoints and that safety was never an issue in ENDEAVOR III.

At TCT last yeat, Patrick Serruys, MD, PhD, of the Thoraxcenter (Rotterdam, the Netherlands), in reviewing the ENDEAVOR III data noted that among high-risk patients, in-segment late loss is commonly associated with increased risk of target lesion revascularization. He therefore postulated that the study’s failure to meet such an endpoint could “become even more evident in a high-risk patient cohort.”

The company noted that the Endeavor stent has demonstrated a favorable safety profile throughout its multi-phased clinical program, with about 1,000 Endeavor patients studied beyond two years.

Data published recently in Circulation magazine from the ENDEAVOR II clinical trial showed no documented stent thrombosis beyond 30 days up to two years after implantation. Endeavor’s overall stent thrombosis rate in all clinical trials is just 0.3%. Endeavor’s efficacy data also has been excellent, with a target lesion revascularization rate at two years of 6.5% in the ENDEAVOR II trial — meaning that approximately 94% of the patients receiving Endeavor did not require a repeat procedure.

“Safety has become a growing concern among physicians, and this trial is carefully designed and powered to provide an extremely thorough, long-term assessment of Endeavor and Cypher safety in real world practice,” said William Wijns, MD, co-director of the Cardiovascular Center of OLV Ziekenhuis (Aalst, Belgium), co-principal investigator of the PROTECT trial. “This safety data will serve as a complement to the extensive clinical data already available on these two devices and will provide physicians with a clearer picture on the balance between safety and efficacy of drug-eluting stents.”