December 28, 2006 -- 10:30pm ET
DES'ed and Confused: What the FDA Stent
Safety Panel Means for Patients
If you had been worrying about that
drug-eluting stent (DES) implanted in your coronary artery,
your concerns were no doubt greatly reduced by the extensive
news coverage following the much-anticipated FDA stent safety
panel held on December 7-8. Here's a small sample:
Stents Don't Boost Death Risk, U.S. Advisers Say (HealthDay)
says wide use of drug-coated stents risky (Reuters)
Drug-Coated Stents Are Safe (CBS / AP)
Urges Caution on Coated Stents (New York Times)
Stents Do Not Increase Risk of Heart Attack or Death, Benefits
Outweigh Increased Blood Clot Risk, FDA Advisory Panel States (Kaiser
Advisory Panel Recommends More Warnings About Drug-Eluting
Stents (Kaiser Network - 3 days later)
Confused? Of course you are. And if you are the
recipient of a drug-eluting stent, you're probably confused and scared
-- because the stakes are high, and this device can't be taken out!
So, let's take a breath of fresh air: inhale...and
now slowly exhale.
The clinical trials for both the Taxus (Boston
Scientific) and the Cypher (Cordis / Johnson & Johnson) drug-eluting
stents were done in simple uncomplicated patients: those with a previously
untreated ("de novo") blockage in a single vessel in a
straight-forward location. The stents were approved by the FDA for
those situations, because they showed a clear and significant benefit
over bare metal stents: much lower chance of reblockage.
In order to get their devices approved, companies
tend to design their clinical trials for this straight-forward type
of patient population (one that will show a clear benefit). But in
the "real world", almost two-thirds of the time, interventional
cardiologists use these devices outside of these strict and limiting
definitions. There is nothing illegal about this.
Physicians have studied these additional uses and
shared this data with other doctors at the major heart meetings.
They use these devices in many "off-label" indications
(multiple stents, multiple vessels, in-stent restenosis) because
they feel that the patient is better served by the newer device that
shows less restenosis. More restenosis means more repeat procedures
and more complications; studies have shown that restenosis is not
benign -- it increases the incidence of heart attack and hospitalization.
Furthermore, prior to drug-eluting stents, physicians often used
bare metal stents in these same off-label indications -- they did
not perform as well as drug-eluting stents do.
But over the past year, concerns about the tendency
of drug-eluting stent patients to experience stent thrombosis (not
a reblockage, per se, but an acute gathering of platelets, a.k.a.
a blood clot) six months or more after implantation has prompted
a new look at the use of these devices. The incidence seems very
small, but the data about this population, as evidenced at the FDA
hearing, are incomplete, not very robust, in the words of one panelist
to me, "We've got lots of data -- it's just that it's lousy
The FDA panel clearly stated that, when used
within the confines of the approved uses of the original clinical
trial population, there is no increased risk with drug-eluting
stents -- and there is a considerable benefit: freedom from restenosis.
But the data for "off-label" uses is
not clear: these are more complex blockages, in sicker patients,
with more Plavix and aspirin -- in the words of panelist Dr. Eric
Topol, there are "a lot of moving parts -- it's a big grey area,
and the risk may be considerable".
And there lies the problem with "off-label" use
-- it's not that this use is dangerous; it's that the FDA doesn't
regulate "off-label" use and therefore doesn't require
long-term studies of patients in these situations before approval.
So the data is not so clear. The FDA did require Cordis to do a followup
post-market study after approval of the Cypher stent in 2003. But
Cordis stopped collecting data after one year, and they were taken
to task by the panel chairman Dr. William Maisel for not following
up longer. However, the FDA agreed with Cordis that they only requested
a one-year follow-up -- and added that in retrospect, it should have
been longer, and probably will be for future devices.
As to how this affects patients, we wrote a "Patient
Advisory" right after the European Congress of Cardiology
four months ago, and nothing discussed at the FDA panel has changed
what's in that Advisory. Most cardiologists have been recommending
longer-term Plavix and aspirin for quite a while now. I suggest
patients with questions read that Advisory and discuss it with
your doctor. For many patients drug-eluting stents work great;
for some not necessarily, especially those who have a risk of bleeding,
making long-term Plavix therapy not a good option.
What has changed this month is something I discussed
in my last
entry: two days of panel discussions by the FDA have given these
problems a public airing, providing instant and widespread "patient
education". The message was that there is something to be concerned
about after all. And this message prompted an all-out defense by
the two drug-eluting stent manufacturers: Boston Scientific immediately
ran full-page ads in all the major U.S. newspapers, Cordis issued
press releases about "educational programs", and both manufacturers
mass-emailed the professional cardiology community with copies of
the PowerPoint presentations they made to the FDA.
And, of course, their stocks went down a bit as
analysts saw the extremely lucrative market for drug-eluting stents
begin to shrink. Can you say "a 20% reduction in a $6 billion
annual market equals $1.2 billion"?
However, all's good now....
Today's New York Times announced, "Street
Expresses New Confidence in Drug-Coated Stents". The "Street",
of course, is not the one you live on, but where stock analysts
dwell, and where they now are feeling optimistic that drug-coated
devices will still account for 75-80% of the stent market.
What does this mean for patients? Well, the article
is not in the Health section, but in the Business section. Interestingly
enough, the article ends with:
It seems farfetched that drug-coated stents
could fall that far [to 40%]. Unless, of course, there is more
bad news about clotting risks.
Perhaps not so farfetched if patients who are about
to have an intervention and have read the news today oboy and don't
particularly want to risk a stent thrombosis in two years and don't
like the idea of taking Plavix for a year or two or life, if those
patients spend a few extra minutes in their cardiologist's office
discussing this, and their cardiologist determines that maybe after
all this patient is at low risk for restenosis, or won't be compliant
with the Plavix/aspirin combo, so why not just go with a bare metal
stent. Maybe that might have an effect on "the Street".
After all, at its worst, the restenosis rate with
bare metal stents was 20%. The closer cardiologists come to predicting
who that 20% might be, the less important the drug-coated stent will
become. Dr. John Spertus of the Mid-America Heart Institute in Kansas
City told me a few weeks ago that probably 60% of patients would
benefit from drug-eluting stents. Dr. Sanjay Kaul of Cedars-Sinai
in L.A. thinks it's more like 40%.
We welcome your opinion. After all, when the data
are lacking, your guess is as good as anyone's.
December 12, 2006 -- 2:45pm EDT
The FDA Stent Panel: A Catalytic Converter
I'm reflecting on last week's FDA panel,
convened to discuss the issue of drug-eluting stent safety
and late stent thrombosis. I plan to write over the next couple
days about what happened there, but the important thing is
that something DID happen there.
There were over 25 presentations given by industry
representatives, cardiologists, surgeons, the three major professional
cardiology groups, me and
a patient who
visits our Forum --
and for two days from 8:00am on, the panelists listened and asked
questions, sometimes probing, sometimes challenging, and they debated
among themselves whether to recommend that the FDA attach stronger
warnings, change the labels, lengthen the recommended duration of
Plavix or Ticlid and aspirin.
Even though the panel wound up disagreeing on several
key issues and did not recommend many of the label changes that they
might have (indeed, it is ultimately the FDA's decision as to what
to do officially; the panel is only advisory) the bottom line is
that these issues, which are complicated and unfortunately not easy
to judge due to lack of sufficient and "good" data, these
issues were aired in public, in a room of 500, many of whom were
reporters, seated against the walls, close to power outlets, tapping
away non-stop on their laptops and condensing the proceedings into
stories instantly filed with the home office.
Regardless of the final recommendations, the current
state of knowledge about these devices, the pluses and minuses, saw
the light of day -- actually two days. And as they went on, one heard
the constant refrain of the panel -- how does this translate into
clinical benefit for our patients? I've observed lots of professional
meetings where interventionalists debate p-values, relative risk
assessment, which device is better, etc. But here you had a broader
spectrum of active participants: clinical cardiologists, surgeons,
statisticians, regulators, me,
Patient (who truly moved the meeting with his story and plea
for more support).
The FDA may or may not take any regulatory action
right now. But the real action was the meeting itself. The cats were
all let out of their bags. This time the FDA used its power as a
catalyst: something that enables a reaction without becoming part
of it. And that reaction, both professional and private, will certainly
result in some self-imposed limitations on use of these devices in
certain patients, because physicians will be weighing the risk/benefit
more -- even though the risk is very very low (I'll be talking more
about this later).
Hopefully what will happen is that, given more
appropriate patient selection and compliance strategies (more on
this later, as well), patients who are best served by drug-eluting
stents, and there are many, will get them with confidence, and that
those who may not do as well, won't.
The FDA has come under much criticism in recent
days, some from yours truly. There is no question that the agency
needs to profoundly improve post-market monitoring and clarify for
the public the meaning of "off-label" use of drugs and
devices. But this event was impressive in its scope -- and the ability
for the public to speak and influence decisions in a very direct
way was not unlike some Board meetings I have attended in the little
village where I live. My thoughts were echoed by Daniel G. Schultz,
MD, the Director of FDA's Center for Devices and Radiological Health,
who concluded the panel:
"This meeting needed to happen... In the
past I think sometimes we shied away from bringing these kinds
of controversial issues. But to me what these last two days have
demonstrated is that this is the best way, maybe the only way,
to get some moving forward, if not resolution, of this kind of
In coming posts, I'll be exploring some of the
technical issues and specific concerns about these devices, the media
reporting of the meeting, and the post-panel ad campaign to win the
(yes) hearts and minds of patients and physicians.