In March, the the American
College of Cardiology held its 54th Scientific
Session in Orlando, Florida. This annual event is considered
one of the most important
meetings
for cardiologists (the ACC represents most board-certified U.S. cardiovascular
physicians) so the results from the various
clinical trials of the newest addition to the interventional cardiologist's
toolbox, namely the drug-eluting
stent, were much anticipated.
The most publicized trial was REALITY.
Sponsored by Johnson & Johnson / Cordis, makers of the Cypher
Sirolimus
drug eluting
stent, this "stent wars" trial randomized 1,386 patients
from 90 international centers to either the Cypher or the
Taxus
Paclitaxel
drug-eluting
stent, manufactured by rival Boston Scientific. J&J's stated
goal was "to compare performance
differences between the two drug-eluting stents, particularly
in high-risk patient group subsets, such as diabetics and
patients with long lesions and small-diameter vessels. Diabetics
represent 32% of the study's population." The results
were originally scheduled to be reported during the October
TCT 2004 meeting, but were postponed until the ACC.
|
|
The 2005
Annual Scientific Session of the American College of Cardiology
was held in Orlando,
Florida |
Reality Trial Results
With a $5 billion market at stake, the results were crucial to both
companies. So what happened? Well, that depends on who you listened
to -- it
truly was a Rashomon event.
Here's just a sampling of the news headlines about the trial:
The reality of "Reality" was
that it basically was a draw -- as defined by the study's endpoints.
Across the board, there was no significant difference in
the restenosis
rate for
either stent
and no significant difference in the clinical outcomes either.
And this applied to all the subgroups: diabetics, complex lesions,
etc. There was, and has been in every trial conducted of the two
stents, more
"late
lumen
loss"
with
the Taxus
stent,
as
measured
by followup
angiography. But that loss has not translated into any clinical
difference in
the
two
stents. While there is some controversy as to whether late lumen
loss may foretell a clinical difference farther down the line,
it hasn't as of yet.
"You might
do a different trial and find a different result...",
Spencer B. King III |
|
The bottom line of the trial, in the words
of Dr. Marie-Claude Morice, chief investigator for REALITY: "There
are not enough data to select one DES over the other. They
are both very durable and very efficient to prevent restenosis....
There is no one good and one bad, one ugly and one marvelous.
The
reality's
not
there.
We are in small differences and I think we need much
more data to dramatically change the practice."
Or take angioplasty pioneer Dr. Spencer
King's comment: "You might
do a different trial and find a different result.
The (stents) are largely
interchangeable...we've used both stents a lot."
|
The Safety Issue
There was one
"significant" difference in numbers, as touted by a
couple of the headlines above,
one that caused Boston Scientific to move to a strong defensive
posture -- Cypher showed less blood clot formation,
or thrombosis
(0.4%), than the Taxus (1.8%). REALITY is the only trial that
showed such a large difference -- most previous trials (which were
not head-to-head) showed SAT (Sub-Acute Thrombosis) rates for
all stents
somewhere under 1%. Thrombosis is a very serious complication of
stenting
--
it can
cause
a heart attack
or death and there has been much concern that drug-eluting stents,
as a class, are more thrombogenic (more likely to cause thrombus)
than
bare metal stents.
Note: There was a scare with the Cypher stent
in the fall
of 2003,
when headlines shouted, "FDA
Warns of Deadly Complications in Highly Touted [Cypher] Stent".
Calmer heads prevailed and it was noted that the complication rate
did not differ significantly from that of bare metal stents. Now
the headlines were targeting the Taxus as being "less safe" than
the Cypher.
But, here's the story-behind-the-story.
This "significant
difference" had to do with one single patient who had actually
been randomized for Cypher, but his/her anatomy was too tortuous
and the cardiologist was unsuccessful in delivering
the Cypher to the lesion -- in fact reports were that the artery
was dissected or injured -- so they switched to the Taxus stent,
which they were able
to deliver ("deliverability" is
a characteristic that Boston Scientific has touted as one of Taxus'
advantages). Unfortunately, the artery had already been injured
and the patient developed blood-clotting. The way the REALITY
study
was measured, this failure of the Cypher stent wound
up being counted against the Taxus. If this patient's
thrombosis had been counted against the Cypher instead, the results
would
have been brought into the statistical realm labeled a "not
significant" difference
between the two stents (i.e. a "p-value" > 0.05) and the claims
that the Cypher was "safer" than
the Taxus would not be scientifically valid.
The other important point
was that Sub-Acute Thrombosis (SAT) was not set up as an end-point
for the REALITY
Trial and that to show a difference the study needed to be much
larger. As Dr. Eberhard
Grube of Siegberg,
Germany,
the official "discussant" on the REALITY study, said
to the audience at the ACC:
In order to demonstrate a 100% increase in
stent thrombosis from Cypher to Taxus, from 0.5% to 1.0%, more
than 10,000 patients for 80% power would have been necessary...Thus,
given the possibility of an alpha error in a trial underpowered
for this end point, no firm conclusions regarding relative
stent thrombosis rates should be drawn.
Also, late stent thrombosis
data, beyond 30 days, was not reported. Dr. Grube said "I
would have liked to have seen the 8-month results".
Two other studies which compared the
two stents were also presented: ISAR-DIABETES
and SIRTAX.
ISAR-DIABETES
This was a relatively small trial, only 250 patients -- and
atypical: all diabetics. Dr. Adnan Kastrati of The Deutsches Herzzentrum
in Munich, the primary investigator for the study, explained that they wanted
to look only at diabetic patients who were at the highest risk for restenosis,
in order to give the two drug-eluting stents a real workout -- he referred
to it at a "stent stress test". His team, not funded by any device
company, thought this would be a way to "unmask" differences
in the two stents because he didn't think diabetics were "different
animals" -- he stated that, while the vascular disease process is accelerated
in diabetics, it is not substantially different.
The primary end point of the study was Late Lumen
Loss (LLL) which is the amount that the lumen (open channel of
the artery) has closed between the immediate post-stenting measurement
and the measurement at the 9-month angiographic follow up. The
Cypher definitely scored better on that. This was no surprise because,
as stated above, in every study done to date, in many thousands
of patients, the Cypher stent has shown less Late Lumen Loss than
the Taxus.
The question is what does that mean for the patient? A secondary
end point was binary angiographic restenosis. If the artery treated
showed a reblockage of 50% or more at 9 months, it has officially
restenosed. On this, the Cypher again did almost 2 1/2 times better,
showing a 6.9% restenosis, as opposed to the Taxus at 16.5%. But
then, there's the other secondary end point, TLR -- Total Lesion
Revascularization -- did the lesion (blockage) need to be reopened?
Even if there was restenosis, did it cause symptoms or clinical
events that required a repeat procedure or bypass surgery? In this
measure, although the Taxus was higher (12.2% to Cypher's 6.4%)
it was not considered statistically significant due to the small
numbers in the trial.
So what measures
are important?
Dr. Gregg Stone of Columbia University Hospital
in New York, and principal
investigator on several Taxus studies, commented, when speaking
about the REALITY trial: "...no
patient cares about his acute gain, no patient cares about
his (late)
loss, the patient
doesn't even care about his binary angiographic restenosis
rate. He only cares if he dies, has an MI or needs a repeat
revascularization procedure or has recurrent angina, etc.
And that's why the most important endpoint in REALITY is
the TLR rate.... All of these trials are underpowered and
unfortunately we are going to get a lot of confusion when we
look at these small underpowered studies showing big differences." |
|
Gregg W.
Stone, MD
Columbia University
|
His point is that the TLR (do you
need a repeat procedure?) rate is what's important, and in ISAR
DIABETES, the
difference in TLR rates was statistically insignificant -- and
the MI and death rates for both stents were similar. Another very
important fact, an example of Dr. Spencer King's "different trial,
different result" comment, is that the number of diabetic
patients enrolled in the REALITY
trial
was
378 -- that's
50%
more
diabetics
than
were in the
entire ISAR-DIABETES
trial, yet the REALITY trial showed no significant differences
in outcomes (the TLRs in REALITY were 5.4% for Taxus to 5.0% for
Cypher). Moreover, an analysis of the diabetic subgroup in REALITY
actually showed that the Taxus stent performed slightly better
than Cypher in
diabetics, but still statistically not
significant.
SIRTAX
Like ISAR-DIABETES, this trial also was not funded by any company,
but was supported by the University Hospital of Bern and Zurich, Switzerland.
(An
aside: University
Hospital
in Zurich is where coronary angioplasty was invented by Andreas
Gruentzig; and a co-author of the SIRTAX study, Bernhard Meier, was the
first angioplasty patient's physician -- see a video
clip about this -- RealPlayer required.) The SIRTAX study also was not
blinded (doctors knew which stent they were using) and was done at two centers,
not 90 like the REALITY trial. There were over a thousand patients, however.
And the patient population was, by and large, sicker and more complex than
the REALITY trial. The results were not favorable to the Taxus which showed
a significantly higher cardiac death rate as well as a higher TLR rate (over
50% higher than the Taxus TLR in the REALITY trial). Interestingly enough,
the incidence of stent thrombosis, the big "red flag" in REALITY,
was pretty much the same for Taxus, but five times higher for the
Cypher. The Taxus actually had a lower thrombosis rate than the
Cypher in the SIRTAX trial. However, the endpoint of SIRTAX was the MACE
rate (Major Adverse Cardiac Event, defined as death, myocardial infarction
or target lesion revascularization -- a repeat procedure -- and in that
endpoint Taxus was shown to be inferior to the Cypher -- this has not been
the case
in other
trials and physicians are waiting for the trial results to become available
in manuscript form so they can be further analyzed.
TAXUS V
This was a trial of the Taxus stent only in very difficult and
complex patients and situations so, while there is no direct
comparison data with the
Cypher stent, there was a lot of data to show that drug-eluting
stents are a paradigm shift from bare-metal stents for the treatment
of coronary artery disease. The statistics and outcomes of this
trial will be the subject of a separate, more detailed feature,
but suffice to say, the results showed that drug-eluting stents
may make treatment of multivessel, left main, very narrow arteries
and very large arteries far more successful than it has been,
with less chance of restenosis -- a result that will further
erode the role played by coronary artery bypass surgery.
ENDEAVOR II
Medtronic's entry into the drug-eluting stent arena passed its
first test at the ACC. The trial met its end points and clinical
trials will continue to go forward, with the Endeavor III results
to be presented at the 2005 TCT in the fall. While Medtronic's
stent will not be available in the U.S. in the next 18 or so
months, it may become a significant player in the ongoing "Stent
Wars".
What Does This Mean If You Are A
Patient?
When you are told by your cardiologist that you need a catheterization
and that, if he/she finds a blockage, you may wind up with a balloon
angioplasty and probably a stent, you definitely should ask
if it will be a drug-eluting (a.k.a. "coated" or "medicated")
stent, because the restenosis rates have been shown to
be so much lower (it is, of course, more expensive). If your cardiologist
is planning to use a bare metal stent, he/she may have good reason
-- but you should know what it is. Gregg W. Stone MD has said that
in his cath lab, they treat almost 99% of their patients with
stents and about 95% of those get drug-eluting stents.
The results of the ACC head-to-head stent trials
showed that drug-eluting stent technology is durable and has significantly
increased the success of interventional treatments for coronary
narrowing. Whether your cardiologist plans to use a Cypher or a
Taxus most likely will be a personal preference. It's even possible
that the decision will be made based on what sizes are in stock
(the size can't be known until your angiogram is performed). Both
stents have been shown to be excellent and as we have often said
on Angioplasty.Org, in all of these trials, there is one clear
winner -- and that's the patient.
(By way of full disclosure, Angioplasty.Org,
an independent educational site, has received funding from Boston
Scientific,
manufacturer of the Taxus
stent.)
For the latest
news about developments in the field, go to our Drug-Eluting
Stent NewsCenter. We welcome your
comments on this article.
Source: Angioplasty.Org, April 19, 2005
CONTACT: Burt
Cohen, Producer of Angioplasty.org
|
