Medtronic’s Endeavor Hits a Bump

Medtronic Inc. (Minneapolis) was expected to make a big splash at this month’s Transcatheter Cardiovascular Therapeutics (TCT) scientific symposium in Washington, DC, where the company presented results from its Endeavor III U.S. clinical trial. Favorable results were expected to help speed U.S. market entry for Endeavor, the company’s first drug-eluting coronary stent.

Instead, results presented at TCT indicated that Endeavor had failed to meet Medtronic’s primary goal, which was to demonstrate in-segment late loss that was “noninferior” to the performance of the Cypher drug-eluting stent by Cordis Corp. (Miami Lakes, FL), a Johnson & Johnson company. Late loss refers to the difference in the width of a vessel immediately following stenting versus that found six to nine months later. In the study presented at TCT, the Endeavor stent missed its goal by just 0.01 mm.

Medtronic’s Ward: A near miss.

“We narrowly missed,” said Scott Ward, president of Medtronic Vascular (Santa Rosa, CA). Endeavor’s in-segment late loss after eight months was 0.34 mm compared to 0.13 mm for the Cypher stent. To demonstrate noninferiority, Endeavor’s late-loss figure had to be no more than 0.20 mm greater than Cypher’s, or 0.33 mm.

However, Ward noted that in some other categories of the study, such as poststenting lesion revascularization and adverse cardiac events, Endeavor was clinically equivalent to Cypher. Adverse cardiac events include the need for repeat procedures, heart attack, and death.

In the latest clinical trial, the rates of poststenting lesion revascularization and adverse cardiac events for Endeavor were 6.3% and 7.6%, respectively, compared to 3.5% and 7.1% for Cypher. The differences are not considered statistically significant. However, a significant difference was found in the success rate for stent implantation, with Endeavor at 98.1% compared to 91.2% for Cypher.

David E. Kandzari, MD, coprincipal investigator of the Endeavor III clinical trial and assistant professor of interventional cardiology at Duke University Medical Center (Durham, NC), downplayed the significance of the late-loss results. He noted that rates of poststenting lesion revascularization and adverse cardiac events are typically considered more important variables to clinicians. “We don’t routinely bring patients back to the cath lab because of concerns over late loss,” Kandzari said. “Instead, we bring them back due to recurrent symptoms related to the development of restenosis. What is very interesting is that the observed difference in late loss did not translate into differences in any of the clinical results.”

Leon: Strong evidence for safety.

According to Martin B. Leon, MD, of New York’s Columbia University Hospital and chair of the Cardiovascular Research Foundation (New York City), Endeavor’s clinical trials “continue to provide strong evidence that this stent is safe for patients and effective at reducing target lesion revascularization.” Leon was also a coprincipal investigator on the Endeavor III trial.

Speaking to industry analysts, Ward said Medtronic considers late loss as a measure of healing and that a balanced amount is indicative of both stent efficacy and long-term safety. “Too little late loss and you could have safety issues like thrombosis,” he said.

Ward also noted that “the clinical performance of the Endeavor drug-eluting stent has been remarkably consistent in all three of our major clinical trials completed to date.” The trials found that 95.1% of the 1300 patients receiving the Endeavor stent did not need poststenting lesion revascularization in the nine months following the procedure, which Ward said was clinically equivalent with both Cypher and the Taxus drug-eluting stent from Boston Scientific Corp. (Natick, MA). He also said that no stent thrombosis occurred beyond 10 days after the procedure.

Despite these findings, analysts noted that the stent exhibited a clinically acceptable but higher rate of restenosis than Cypher. However, the relative simplicity of the lesions and the short timeframe of the study were cited as reasons for caution in interpreting the results.

The Endeavor stent is made of a cobalt alloy and has what Medtronic describes as a “unique modular architecture designed to enhance deliverability over standard bare-metal stents.” Endeavor’s drug is a proprietary compound known as ABT-578, and the stent is also coated with phosphorylcholine, a polymer that the company says “simulates the outside surface of a red blood cell and mimics the structure of the natural cell membrane.”

Medtronic’s next clinical trial will compare the Endeavor stent with Taxus. Endeavor IV will include more than 1500 patients in North America. Enrollment is expected to be completed early in 2006.

Endeavor was granted the CE mark last July, clearing the way for market distribution in 40 countries. Medtronic submitted the first module of the product’s premarket approval application to FDA in early October.

In spite of Medtronic’s narrow miss on its goals in Endeavor III, the company says that there were no “statistical differences in clinical outcomes between Endeavor and Cypher.” The company reports the stent is still on track for U.S. market entry in 2007.

© 2005 Canon Communications LLC

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