Resolute Zotarolimus Stent Data Flesh Out Efficacy, Safety

Shelley Wood

April 04, 2011

April 4, 2011 (New Orleans, Louisiana) — Two newly published studies examining the performance of the Resolute zotarolimus-eluting stent (Medtronic) suggest that this "next-generation" drug-eluting stent (DES) can deliver lasting freedom from restenosis, as well as low rates of MI, death, and stent thrombosis over time [1,2]. Released for the first time at the American College of Cardiology (ACC) 2011 Scientific Sessions/i2 Summit, the single-arm RESOLUTE US study shows the new stent to yield lower rates of restenosis at one year than historical controls made up of studies testing the predecessor stent, Endeavor, also made by Medtronic. Also released at the meeting, two-year results from the European RESOLUTE "all-comers" (AC) study, first presented at last year's EuroPCR meeting, also point to durable efficacy and low rates of adverse events.

Resolute uses the same base stent and the same drug coating as the Endeavor, but a different polymer, which allows for a more protracted release of the zotarolimus (out to three months)--something the company hoped would help boost efficacy without increasing stent-thrombosis rates.

RESOLUTE US: One-Year Results

Dr Martin Leon (Columbia University, New York, NY) presented the RESOLUTE-US results during a late-breaking clinical-trial session Monday; the results were also published simultaneously in the Journal of the American College of Cardiology. RESOLUTE-US enrolled 1402 patients, all treated with the Resolute stent at 116 US sites, and compared one-year results with historical controls.

As Leon reported here, rates of the primary end point of target lesion failure (TLF) in the "main analysis" study cohort (2.5 mm to 3.5 mm stents and single lesions only) were 3.7% at one year, compared with 6.5% in historical controls, which met the prespecified definition of noninferiority. (Historical Endeavor controls came from the ENDEAVOR II, ENDEAVOR IV, ENDEAVOR PK, and ENDEAVOR II Continued Access studies.) Event rates in the different components of this end point for the main analysis group were low: just 0.4% for cardiac death, 1.3% for target vessel MI, and 2.0% for target lesion revascularization.

RESOLUTE US also enrolled patients receiving both smaller (2.25 mm) and larger stents (4 mm)--when these patients were included in the analysis, the overall TLF rate was 4.7% (TLF in the 2.25-mm-stent group was slightly higher than in the overall cohort, at 5.5%.)

One definite and one probable stent thrombosis occurred in RESOLUTE US at one year, for a rate of 0.1%.

RESOLUTE AC: Two-Year Results

Yesterday, in a separate session, Dr Patrick Serruys (Erasmus University Medical Center, Rotterdam, the Netherlands) presented the two-year results from the randomized RESOLUTE AC study; they were published simultaneously in the Lancet. As previously reported by heartwire , this trial randomized almost 2300 patients to either the Resolute or the Xience everolimus-eluting stent. At two years, rates of "patient-related outcomes" and "stent-related outcomes" were no different between groups, nor were rates of any major clinical events.

But one of the flags raised during Serruys's presentation at EuroPCR last year was the difference in stent-thrombosis rates at one year, reported in the published paper now as 1.7% for the Resolute and 0.7% for the Xience (Abbott).

Between one and two years, however, rates of stent thrombosis were identical between groups, at 0.3%, yielding overall rates of 1.9% in the Resolute group and 1.0% in the Xience group (p=0.077; one patient had two stent thromboses).

Commenting on the very different stent-thrombosis rates between RESOLUTE AC and US for heartwire , Leon acknowledged that the numbers seen in RESOLUTE AC had been "a lingering" concern. "We couldn't quite understand it. When you go over the individual cases, you get very frustrated, because on a case-by-case basis you can kind of understand how these things happen, but [they] created an impression that really taints what otherwise was a very strong study."

What the two trials speak to, says Leon, is the need for "data density" and the need to get enough trials, of enough patients, to really "get your arms around" an issue like stent thrombosis. While the "real-world" number may not be as high as that seen in RESOLUTE AC, Leon said, "I'm not sure 0.1% is the right number, either. But I'm encouraged that, in a broad population . . . this is one of the lowest numbers of probable and definite stent thrombosis that have ever been reported, so I take from that that I think this is a safe DES."

Of note, RESOLUTE US enrolled a relatively high proportion of diabetics (34%) and included patients receiving 2.25-mm stents (11%).

Others on an expert panel asked to address the difference in stent-thrombosis rates between the two studies agreed that the two together did not contain nearly large enough numbers of patients and events to draw any meaningful conclusions and noted that in both studies, these stent thromboses were very rare.

What Will Happen to Endeavor?

"No matter how you look at these data, from effectiveness or safety, they're very, very strong. They're as good as we've seen with a next-generation drug-eluting stent, and it's also a platform that physicians like using; they like using the driver platform," Leon said.

The next question will be what the future holds for the Endeavor, a stent that had been called in the past "DES-lite," due to reduced antirestenotic efficacy, compared with other DES on the market.

"The Endeavor has a track record of safety that is very impressive, but I think this stent does outperform the Endeavor from the standpoint of effectiveness. So if you want a stent for a complex situation, diabetes, or multivessel disease, the high-restenosis situations, Resolute certainly has some major advantages. We'll see in the coming years if Resolute has a similar safety profile late that Endeavor does. If it does, I think you could argue that this stent is the natural successor to Endeavor; if not you might profile the Endeavor in more safety-concern situations and Resolute in more effectiveness-concern situations."

According to Leon, RESOLUTE US, a single-arm study, fulfills a requirement from the FDA to include US patient data as part of the device submission for approval, since the "all-comers" trial was conducted in Europe, as well as new data in the 2.25-mm-stent subgroup.

RESOLUTE US was sponsored by Medtronic. Leon disclosed being an unpaid consultant for Abbott, Medtronic, and Boston Scientific.


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