Most Popular Angioplasty Web Site
Stent Center Stent Center
with support from Medtronic Cardiovascular
Alan C. Yeung, MD, FACC
Email Bookmark and Share

Alan C. Yeung, MD, is the Li Ka Shing Professor of Cardiology at the Stanford School of Medicine, director of the Cardiac Catheterization and Coronary Intervention Laboratories, and chief of the Division of Cardiovascular Medicine. His clinical focus is on cardiology, cardiovascular disease, coronary artery disease, chronic total occlusions and complex coronary angioplasty..

Dr. Yeung has published extensively and has received numerous awards, including the Merck American College of Cardiology European Society of Cardiology Exchange Fellowship and the Clinician Investigator Development Award from the National Heart, Lung and Blood Institute. He sits on the editorial boards of several major cardiovascular journals and is chairman of the Interventional Cardiology Board of the American Board of Internal Medicine.

Dr. Yeung served as a principal investigator for the RESOLUTE US clinical study, the pivotal trial for Medtronic's drug-eluting stent submission to the F.D.A.

    Alan C. Yeung, MD, FACC
Alan C. Yeung, MD, FACC

Q: The RESOLUTE US trial is different, in that it's not a randomized clinical trial where you're pitting one stent against another. It's a single arm, but historically you’re looking at it in comparison to the Endeavor stent.
Dr. Yeung: This is somewhat unique in the sense that you can do this trial with Resolute against Endeavor 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?” So you really cannot compare the Resolute stent to a different stent to answer that question. And because we want to compare, if we move from Endeavor to Resolute, so we have to use historical data.

Resolute Stent
Resolute Stent

Number two, obviously it's difficult to do randomized studies, to put stent against stent. They have their own issues. And we have done that in a sense data-wise. We did the Resolute All Comers which is in Europe: a big study comparing one to the other [Xience vs. Resolute].

So we thought it would be helpful to add a different dimension -- and we designed this trial to ask, "When we change a component of the DES, 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.

Q: And the results from RESOLUTE US are very good. So what have you learned from this?
Dr. Yeung: First is that the RESOLUTE US study has a very high incidence of diabetic patients. I think it's a bad time for the U.S., meaning that, compared to Europe, we now have 34-35% diabetic patients in these trials -- in Europe it's about 20-21%. So that's one important subset: how is this stent performing in diabetic patients. In terms of the primary endpoint, it showed that they had significant improvement in terms of its performance in terms of TLF and TLR, as compared to the Endeavor stent. And that gives us the validation that by changing the elution profile, it really has improved the TLR rates in these patients. The TLF and TLR are in the single digit range, so that really gives you a good sense that by increasing the elution profile which was designed to treat these very difficult patients that always have this proliferative response going on, that they can be inhibited by using this stent.

Also it had extremely low stent thrombosis rates in the first year, almost non-existent. In all the stents, except the 2.25mm -- the two stent thromboses happened there – so we have not sacrificed the safety profile by giving more drug over longer period of time for example in these situations. So that's reassuring in the finding as well.

Q: There is a larger percentage of diabetics in the U.S. trial than in the European trial because the populations are different?
Dr. Yeung: Yeah. We have a higher incidence of diabetic patients in the U.S. And we have increased substantially in the last five to six years. Hopefully we can reverse that; otherwise it will really be a heavy burden to the system.

Q: The TLR in diabetics, while higher than in non-diabetic patients, was only incrementally higher in the RESOLUTE US study, a bit like the TAXUS in that respect. For example, in the SPIRIT IV trial, the difference between diabetic and non-diabetic populations was significant with the XIENCE stent, not so much with the TAXUS.
Dr. Yeung: In RESOLUTE US, it's running in the range of 3% in non-diabetic, in the diabetic patients approximately 4%, so it's slightly higher, but still it's in the same range. And if you look at the Resolute's International data, that's actually very similar. That's kind of the encouraging sign that, hey, maybe if we give this drug longer, we could actually help make the diabetic patients behavior, at least from the stent assessment, similar to the non-diabetic. Obviously the data numbers are still relatively small, about 480 patients or so, but still that gives us the thought that maybe there's something here. As you pointed out, XIENCE behaved differently [between diabetic and non-diabetic patients]; TAXUS was very similar, except that both were kind of high.

Q: Quick question about the MIs in the total cohort. The rate was 1.4% in the data, but most of those were non-Q-wave MIs. Were those periprocedural MIs?
Dr. Yeung: Yes, most were periprocedural, because after the first 30 days or so, you usually don’t have MIs unless you have stent thrombosis and our stent thrombosis was very low. So most were periprocedural and most were pretty small, really an enzyme leak.

Q: Out of 1,400 patients you had only two stent thromboses?
Dr. Yeung: Right. Both were in the 2.25mm stent. One was in an 83-year-old on day 5, and was put in a very distal part of the right coronary and the LAD and had been treated on clopidogrel and warfarin and basically that was an issue and they thought it was stent thrombosis. And the other one was a 51-year-old patient that had a second OM branch done and he didn't take any antiplatelet therapy at all, for whatever reason! And so probably he had some thrombosis of that second obtuse marginal branch later on. So one is kind of uncertain, but since he was taking warfarin as well, so it was counted as probable, and the other one was a documented stent thrombosis in a small stent in a person that didn't take any dual antiplatelet drugs.

Q: There were more stent thromboses in the Resolute All Comers study and much less in the US trial.
Dr. Yeung: 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, as well. Sometimes the definition of stent thrombosis on the procedural day has no meaning, because if you don’t treat it well -- you know 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. So that's an ARC definition issue. 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.

Q: Do you think the Resolute retains the safety profile and the rapid and homogenous healing of the endothelium over the stent struts that has been seen in the Endeavor stent, for example under OCT imaging?
Dr. Yeung: The Resolute stent has been tested in pre-clinical studies quite extensively, as well. The Biolinx polymer is specially designed to be safe. You never know for sure until you test it clinically. But it sort of has the characteristics of the PC [Phosphorylcholine polymer] but allows it to be more stable and elute the drug longer, which was sort of the weakness of the PC coating is that it just tends to elute quicker. So the preclinical data show that, if you compare to Endeavor, you are pretty similar in terms of endothelialization over time. At 14 days, in an atherosclerotic model measured by electron microscopy, it seemed to endothelialize pretty quickly as well. It seems like the cells covering those stents are functioning pretty well.

This interview was conducted in April 2011 by Burt Cohen of Angioplasty.Org.