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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. |
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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 |
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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.
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