New Medtronic Stent Begins Process for FDA for Approval

New Medtronic Resolute Stent Begins Process for FDA Approval
RESOLUTE US Trial Results Completes Submission of Data
Boston Scientific Also Aiming at 2012 for New Version of Promus

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Medtronic's Resolute Integrity Stent

April 9, 2011 -- By this time next year, the first new drug-eluting stent in four years may be hitting the U.S. market: the Resolute® zotarolimus-eluting stent, manufactured by Medtronic.

The RESOLUTE clinical program has studied more than 5,000 patients around the world and results from the final study, the RESOLUTE US trial of 1,402 patients, were presented by Dr. Martin B. Leon last Monday to the 60th Annual Scientific Session of the American College of Cardiology (ACC). In the U.S. trial, only 3 out of 100 patients needed to have a repeat procedure and only 2 patients out of the total had a stent thrombosis (0.1%) -- one of the lowest rates in any trial to date.

The Resolute stent has been available in Europe for over three years; a version of the stent on Medtronic's latest Integrity platform received the CE Mark last summer (the Integrity bare metal stent was approved by the FDA in September). A Medtronic spokesperson told Angioplasty.Org that the company has submitted its complete package to the FDA and is hoping for approval in the first half of 2012 (there is a mandatory six month waiting period from the time of submission).

During the same session at the ACC, Dr. Gregg W. Stone (Dr. Leon's colleague at Columbia University Medical Center/New York-Presbyterian Hospital) presented the results from Boston Scientific's PLATINUM Trial, which randomized 1,530 patients to either the current Promus stent (same as XIENCE V) or the new Promus Element™. The results were that the new Promus was "non-inferior" to the current version. The data from this trial were also sent to the FDA for approval which, according to Boston Scientific, they expect mid-2012.

Current and Future Landscape for Drug-Eluting Stents in the U.S.
There are currently somewhere between four to six drug-eluting stents (DES) available in the U.S., depending on how one counts. Here is the list, in order of FDA approval, starting in April 2003 with the Cypher and ending in October 2008 with the Taxus Liberte:

Cypher sirolimus-eluting stent (Cordis/Johnson & Johnson)
Taxus Express2 paclitaxel-eluting stent (Boston Scientific)
Endeavor zotarolimus-eluting stent (Medtronic)
XIENCE V everolimus-eluting stent (Abbott Vascular),
Promus (a "private brand" of the XIENCE, marketed by Boston Scientific)
Taxus Liberte paclitaxel-eluting stent (Boston Scientific)

anticipated approvals for 2012
Resolute zotarolimus-eluting stent (Medtronic) -- anticipated first-half of 2012
Promus Element everolimus-eluting stent (Boston Scientific) -- anticipated mid-2012

The reason for the "range" of four to six DES is that the XIENCE V and the Promus are the same stent, manufactured by Abbott and marketed under two names, XIENCE V and Promus. This shared marketing was part of an agreement between Abbott and Boston Scientific, dating back to Boston Scientific's 2006 acquisition of Guidant, the original creator of the Xience V. Currently Boston Scientific pays Abbott 40% of its Promus revenues, but that agreement ends in June 2012. So, in order to compete in the second/third generation DES stent market, Boston Scientific needed to develop a new stent that could be approved in 2012. And they did. Called the Promus Element, the stent itself is made with an alloy made of Platinum Chromium, as opposed to the Cobalt Chromium alloy of the XIENCE V. But the Promus Element has the same polymer and the same drug (everolimus) as the current XIENCE V/Promus. And in its trial, created specifically for an FDA approval, the new Promus was judged "non-inferior" to the current Promus.

Boston's other two stents, the Taxus Express2 and the Taxus Liberte, are also very similar to each other. The same drug, the same polymer, the same alloy, but slightly different metal stent platform design. Unfortunately, in some comparison trials, the newer Liberte has performed less well than the original Taxus, so again, many consider them to be essentially the same stent.

New Alloy / New Polymer
While Boston Scientific's new stent is the same as the Promus, but with a different stent alloy, Medtronic's new stent, the Resolute, is the same as its Endeavor, but with a different polymer and a much longer rate of drug elution -- and that, says Dr. Alan Yeung, a principal investigator of RESOLUTE US, makes all the difference:

"Because the stent is the same, the drug is the same, but the polymer is different -- what we're trying to compare in using this study design is asking the question, 'If we use the polymers somewhat different to achieve a different elution profile, what do we get?'"

"And that's really the scientific reason that the Resolute stent was designed, to see if we can improve on the performance of the Endeavor stent that can allow us to treat more complex patients and have hopefully better results."

Dr. Alan C. Yeung
Stanford Medical Center

And the results of lengthening the drug-elution period from 28 days with the Endeavor to 180 days with the Resolute were most definitely better, especially in diabetic patients, who tend to have higher-than-normal event rates. In the RESOLUTE US trial, 34% of the patients were diabetic (by comparison, Boston Scientific's PLATINUM trial has 23.5% diabetic patients). And the event rates were all below 5%.

Narrower Stents / Low Stent Thrombosis Rates
RESOLUTE US also included a narrower version of the stent: 2.25mm. Most trials only include stent diameters down to 2.5mm, because it is known that event rates and especially stent thrombosis rates are higher with narrower (and longer) stents. Yet in the RESOLUTE US trial, only two patients out of the total 1,402, were judged to have had a stent thrombosis (ST) -- and both of them occurred in the narrow 2.25mm stent. Additionally one of those patients, according to Dr. Yeung, never even took the requisite dual antiplatelet medicines (Plavix and aspirin) which increased his risk for ST in any diameter stent.

The low ST rate in the U.S. trial was of comfort to clinicians, because the RESOLUTE All Comers trial, done in Europe and Israel, had a slightly higher-than-normal ST rate. Dr. Yeung offered an explanation for what he considered to be an aberration:

"In the All Comers study from Europe, there were issues in a few patients that were treated with the Resolute stent early on. Five of them were on day zero [the day of the procedure]. If you look at this in detail, it's really related to how the patient was treated with antithrombotic drugs. So it's really that the patients were not treated well in my opinion: all in the same center, all on day zero. Sometimes the definition of stent thrombosis on the procedural day has no meaning...sometimes you attribute it to stent thrombosis when there's clot still present -- so it's very difficult to use that definition for the procedural day.... To me, to see whether a stent is safe or not, you really need to look at the data at least 5 days, if not 30 days, out. Then you can get a better sense of how the stent performs."

So changing the polymer and the elution rate seemed to cause a significant increase in efficacy for the new Medtronic stent, one that the company hopes will make significant inroads in the U.S. interventional cardiology market next year. The company pointed to two other items regarding the Resolute stent. New data will be presented at the upcoming EuroPCR meeting in May as a review of 2,000 diabetic patients from the total RESOLUTE program, which may serve to differentiate Medtronic's new stent from the rest of the field. The company also has approval in Europe for the Resolute on its very flexible and conformable "Integrity" platform, which has achieved a high rate of adoption. Since the bare metal version of the Integrity has already been approved in the U.S., it's hoped that the Resolute may be approved on that platform as well.

While the earlier drug-eluting stents will no doubt be used less and less, by mid-2012 there will be hopefully be three new generation DES for clinicians to choose from: the current XIENCE V and, if approved, the Resolute and Promus Element -- all of which have shown event rates in the low single digits and very very low risks for stent thrombosis.

Reported by Burt Cohen, April 9, 2011