For the past year drug-eluting stents (DES) have raised concerns about blood clots, damaging sales of FDA-approved DES devices — in the U.S., the Taxus from Boston Scientific (Natick, Massachusetts) and the Cypher from Cordis (Miami Lakes, Florida), a Johnson & Johnson (J&J; New Brunswick, New Jersey) business.

But long before this now-controversial class of products began making headlines, Medtronic (Minneapolis) was preparing for what it says is the largest randomized trial to focus on the safety of DES, a company spokesman told Medical Device Daily.

Medtronic yesterday said it has enrolled the first patient in Patient Related OuTcomes with Endeavor versus Cypher stenting Trial (PROTECT), an 8,800-patient study that will pit Medtronic's Endeavor zotarolimus-eluting coronary stent system against the Cypher sirolimus DES, using key safety endpoints and other clinically relevant outcomes.

Medtronic said the first patient enrolled in PROTECT was implanted in Germany, by Johannes Brachmann, MD, of Klinikum Coburg (Coburg, Germany) and Christoph Bode, MD, of Universitätsklinikum (Freiburg, Germany).

The Endeavor DES received CE Mark in 2005 and it is now available in more than 100 countries, the company said. In the U.S. Endeavor is an investigational device under review by the FDA.

Scott Papillon, a senior public relations manager for Medtronic, told MDD that the trial was designed to enroll 8,800 patients in order to create broad statistical significance.

"It's a first-of-its kind study," he said, "the first to go head-to-head with safety as a primary endpoint" — differentiating it from the many studies comparing rates of restenosis.

PROTECT is a response to the call for more long-term safety data, Papillon said, not necessarily a reaction to the controversy the products have sparked over the past year. "Doctors have been looking for long-term safety data for quite a while," Papillon said.

The primary endpoint for PROTECT will be overall stent thrombosis at three years, defined as definite and probable, according to the new Academic Research Consortium criteria. Secondary endpoints include a composite of death and non-fatal myocardial infarction, as well as numerous additional safety and clinical efficacy endpoints, the company said. The study will enroll patients at 200 clinical centers worldwide. The patients will represent the people typically seen by doctors on an everyday basis.

"We think no matter what definition you use, the Endeavor stent is exhibiting an excellent safety profile, and we think that will continue," Papillon said.

"PROTECT is a very important clinical trial for the interventional industry, as it is well-designed and adequately powered to provide the type of long-term safety data physicians have been seeking," said William Wijns, MD, co-director of the Cardiovascular Center, OLV Ziekenhuis (Aalst, Belgium) and co-principal investigator of PROTECT. "This trial should help offer greater clarity around the safety issues that have become part of the drug-eluting stent landscape. Patients and physicians are interested in the safety and efficacy performance of drug-eluting stents. This trial will provide the data which will be most relevant to daily clinical practice."

"We are encouraged by the safety results achieved with Endeavor in our clinical trials thus far," said Sean Salmon, VP and general manager of Medtronic's Coronary and Peripheral business (Santa Rosa, California). "We've consistently seen very low rates of repeat procedures and stent thrombosis in a large number of patients who have been monitored for at least two years and many for three years. Our observed rates of stent thrombosis are extremely low and this strong safety profile has come without a tradeoff in efficacy.

"This trial will generate valuable information for the industry and we have confidence that PROTECT will deliver the data physicians need to make the best possible decisions about treating their patients with coronary artery disease."

In addition to Wijns, other co-principal investigators for PROTECT are Patrick Serruys, MD, PhD, Thoraxcenter, Erasmus University (Rotterdam, Netherlands); Philippe Gabriel Steg, MD, H pital Bichat-Claude (Bernad, Paris); and Edoardo Camenzind, MD, Division of Cardiology, University Hospital Geneva. An independent clinical events committee will be engaged for adjudication of events related to the primary endpoint and an independent statistical organization will be used for data analysis, Medtronic said.

The company also reported positive nine-month results from its Endeavor RESOLUTE trial Tuesday at the EuroPCR meeting in Barcelona.

The company said the Endeavor Resolute DES system with BioLinx polymer is designed to address the needs of patients with complex medical conditions and is engineered to match the duration of drug delivery with the longer healing duration often required by those patients.

In clinical results at nine months, RESOLUTE showed no Target Lesion Revascularization, no Target Vessel Revascularization and a Major Adverse Cardiac Event rate of 7%. Of the trial's 130 patients, 129 (99.2%) received clinical follow-up, and 95 had angiographic follow-up. In-stent late lumen loss, the study's primary endpoint, was 0.22 mm, while in-segment late loss was 0.12 mm. In-stent Angiographic Binary Restenosis was 1% and in-segment ABR was 2.1%.

Medtronic said its Endeavor Resolute leverages the strengths of the Endeavor stent and introduces BioLinx, a biocompatible polymer designed by Medtronic scientists. According to the company, BioLinx is different from other polymers in that its outer surface is hydrophilic (water friendly), which leads to high biocompatibility with the body. At the same time, the interior of the polymer is hydrophobic, which helps to control the drug release.

Medtronic said data from the Endeavor RESOLUTE clinical trial will be used to support the CE mark application. The Endeavor Resolute stent is not yet approved in any country.