ACC Feature: SORTing OUT Endeavors inferiority to Cypher

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ATLANTA—The Endeavor stent was found to be inferior to the Cypher stent in routine clinical care patients at 18-month follow-up, according to the all comers SORT OUT III trial presented Monday at the late-breaking clinical trials session during the 59th American College of Cardiology (ACC) conference.

The researchers, led by Michael Maeng, PhD, from Aarhus University Hospital in Aarhus, Denmark, designed the study to “reflect daily clinical practice,” using patient driven clinical event detection by use of the Danish Civil Registration system, the National Patient Registry, and the Danish Heart Registries. Therefore, no control angiography or study-related patient contact was scheduled.

Endeavor’s manufacturer, Medtonic, has questioned whether this is truly a real-world study due to certain patient exclusions. However, the study’s discussant, Harvey White, MD, from the department of cardiology at Auckland City Hospital in Auckland, New Zealand, agreed with the study authors, when speaking with Cardiovascular Business News.

“SORT OUT is an appropriate, real-world trial because it included off-label drug-eluting stent use, which is common in clinical practice but disallowed in FDA-approved randomized, controlled trials,” White said.

The trial’s inclusionary criterion was an indication for treatment with a DES. Its exclusionary criteria was the inability to provide informed consent; life expectancy of less than one year; allergy to aspirin or clopidogrel; and participation in another trial.

The researchers enrolled 2,332 patients and completed 18-month follow-up in 2,200 (94 percent) patients with coronary artery disease to either the Endeavor zotarolimus-eluting (1,162 patients) stent or the Cypher sirolimus-eluting (1,170 patients) stent.

Meang reported that after 18 months, significantly more patients with the Endeavor stent experienced the primary composite endpoint of cardiac death, heart attack or target vessel revascularization than patients with the Cypher stent, at 9.7 percent and 4.5 percent, respectively. Also, patients with the Endeavor experienced the secondary endpoints more frequently than those with the Cypher, including heart attack (2.1 vs. 0.9 percent); target vessel revascularization (7.9 vs. 3.3 percent); and all-cause death (4.4 vs. 2.7 percent).

“Based on the Endeavor III trial findings showing that the Endeavor stent had a more uniform layer of neointimal coverage, we and many others believed it would provide strong protection against general stent thrombosis and heart attack, but we found there is a high risk of early stent thrombosis and early heart attack in the Endeavor, which may be related to the faster elution of the drug,” said Maeng. “If you have to compare the two stents, the Cypher stent is a better stent.

White attributed Endeavor’s worse comparative performance to the speed with which its drug, zotarolimus, dissolves off the stent. “It comes off over the first couple of weeks, while Cypher stays on longer. Medtronic has recognized this, and rectified it in its newer generation, Resolute drug-eluting stent,” he said. White also noted that Endeavor’s polymer is “better and more inert.”

Maeng added that based on the Endeavor III trial’s findings, many interventional cardiologists may be surprised by the 18-month outcomes of SORT OUT III, as many had expected the Endeavor to show superior performance in the long-term.

While the inferiority of the Endeavor stent for these outcomes is similar to the trial’s nine-month findings, the researchers did find two main differences between the two sets of SORT OUT III data: The outcomes for stent thrombosis and all-cause mortality. In the nine-month findings, a statistically significant difference existed for stent thrombosis between the two stents in favor of the Cypher (13 events compared with four).

However, in the 18-month findings, there was no longer any statistically significant difference (13 events vs. six), although the Cypher still recorded a lower number of stent thrombosis cases. Alternately, the all-cause mortality rates between the two stents were not statistically significant at nine months (2.2 percent compared with 1.5 percent for the Endeavor and the Cypher, respectively) but the 18-month data showed a statistically significant difference (4.4 vs. 2.7 percent, respectively).

While he called the events “disconcerting,” White commented that the event rate was not high overall even though it was an all-comers trial. Yet, he said that the data show that the Endeavor stent leads to restenosis. “One positive factor for Endeavor from the trial was that there was no stent thrombosis at nine to 18 months,” White said.

Also, Maeng pointed out that both sets of SORT OUT III data differ from the only other large, published trials to compare the two stents: The ENDEAVOR III trial and the ISAR-TEST-2 study. ENDEAVOR III and ISAR-TEST-2 did not find statistically significant differences in safety between the Endeavor and the Cypher at nine months, although the Endeavor did have significantly higher late lumen loss and binary restenosis rates.

According to Maeng, two main characteristics of the SORT OUT III trial could have caused the difference: The SORT OUT trial was an all-comer trial that accepted nearly all patients receiving a drug-eluting stent, and it was powered to assess clinical endpoints.

“If you want to assess clinically relevant differences between the various drug-eluting stents, you have to compare the stents in routine clinical care patients,” Maeng said. “The ENDEAVOR III was performed in 436 low-risk patients with a single non-complex lesion and was only powered to assess an angiographic endpoint.”

“Cypher is the preferred stent, and this trial is an indication that Endeavor should not be routinely used in clinical practice,” White said.

The trial was simultaneously published online in the Lancet and will appear in the March print edition.

SORT OUT III was supported by unrestricted grants from Cordis and Medtronic. Neither company had access to the clinical trial database.