November
2006 Archives:
November 30, 2006 -- 3:44pm EDT
The Catch-22 of Plavix and the FDA: Not
My Job
Everyone's worrying about drug-eluting
stents and their increased risk of thrombosis, or blood clots. Most
cardiologists know that the aspirin-Plavix combo they prescribe after
stenting is critical to keeping that risk low.
But here's something I bet you didn't know...(drum
roll, please)...
"Clopidogrel...is not approved for
PCI or stent placement outside of the setting of ACS [Acute Coronary
Syndrome]. This use is off-label."
Yes, it's true! The use of clopidogrel (Plavix)
in patients who receive stents in non-emergency situations is an off-label
and unapproved use, according to what the Center for
Drug Evaluation and Research (CDER), the FDA division that regulates
the pharmaceutical industry, told me.
And get this:
"Companies, or people acting on
the company's behalf, are not permitted to promote a drug for
an unapproved use."
This added tidbit is from another FDA sub-agency,
the Division of Drug Marketing, Advertising, and Communications (DDMAC).
So the companies that make and market clopidogrel
(Bristol-Myers, Sanofi-Aventis, even the generic-maker Apotex) will
get in trouble with the FDA if they start communicating with patients
about taking the drug after stenting -- well, non-emergency stenting
anyway, which is the vast majority of the device's use.
"This can't be correct!" said the cardiologist
who disputed my information, as we stood in the corridors of the
TCT meeting. He whipped out his BlackBerry, clicked onto his drug
info site, then looked up. "You're right!"
Well I knew I was right, because for two years,
we at Angioplasty.Org have been trying to get a small amount of funding
to underwrite a patient and professional education campaign on Plavix
compliance. We naively thought that because we are the top find on
the Net for searches like "Plavix
and aspirin" or "Plavix
and stents", we offered a worthy and ethical public service
opportunity. But we ran into a stone wall. More on this later.
• FDA: Mum's The Word
Every interventional cardiologist knows that drug-eluting stents and antiplatelet
therapy are a package deal. Putting a stent in someone creates a risk of
potentially fatal blood clots, so not prescribing anti-clotting meds would
be irresponsible. It's even in the FDA-mandated "Directions For Use" (DFU)
that the stent manufacturers must put in every box o' stents.
So what gives with the "off-label" label?
My query to the Center for Devices and Radiological
Health (CDRH), the FDA division that regulates stents, got the answer,
clear and simple:
"Clopidogrel is used in patients with drug-eluting
stents because of their continued need for antiplatelet therapy.
Since Clopidogrel is an antiplatelet drug, this is not considered
an example of the kind of off-label use of the drug that would
require re-labeling of the drug itself. Instead, the labeling for
drug-eluting stents describes the treatments that patients received
in the clinical trial but doesn't comment on whether they are on-
or off-label. In this sense, the labeling for DES is consistent
with the labeling of other approved drugs and devices in which
all other therapies received by the study patients are described."
Whaaa-huh? Got that? Was the above clipped from
a page of Joe
Heller's novel or what? Here's my short version:
Q: When is an off-label use not an off-label
use?
A: When we won't tell you one way or the other.
Okay. Cute. Enough wordplay over semantics. The
fun is over. This is actually serious business and has real implications
for patients, and especially for next week's FDA
two-day public meeting about recent concerns voiced over late
stent thrombosis in drug-eluting stents.
Well, here are my concerns.
• The Need for Patient and Professional
Education
There have been numerous studies from Milan to Missouri showing
that one of the major causes of potentially fatal blood clots in stents is
premature cessation of antiplatelet therapy. As Dr. John Spertus of the Mid-America
Heart Institute of Kansas City, Missouri told me:
"There have been no studies to date that
really examined how many patients getting these new devices are
stopping their medicines early. I think doctors didn't have much
appreciation for how often this happened. I think we need to
continue to educate patients."
Great thought, but who will pay to educate patients?
Not to mention informing the few cardiologists who don't yet know
the very latest recommendations for Plavix, and, oh yes, the surgeons,
dentists, internists, nurses, physicians' assistants, network
TV health reporters, and all the other professionals who come
into contact with patients, and who may unknowingly put a stent patient's
life at risk by telling them to stop their meds, even for a while?
• Drug Companies Off The Hook:
A Free Ride
I have talked to people at the drug companies who would like to fund a patient
education campaign, but can't because of regulatory implications. Under the
FDA rules discussed above, the drug companies that make and market clopidogrel
are barred from supporting such an effort."It's a happy coincidence, isn't
it -- they're not allowed to spend money", Dr. William O'Neill told me.
O'Neill, a high-profile interventional cardiologist
and Professor and Executive Dean for Clinical Affairs at the University
of Miami's Miller School of Medicine expressed other strong thoughts
on Plavix and the drug companies who make and market it:
"They haven't put a dime into clinical trials
on the use of their drug in stents. They've piggy-backed onto the
device makers and they haven't really needed to do the science.
Like there's a real concern about Plavix resistance or hypo-responsiveness
-- they haven't done squat on that.... They haven't had to act
responsibly toward the use of their drug, the length of the time,
and the potential premature termination. They could get it past
a labeled indication if they did the proper trial, but they don't
want to do it because they figure that they'll just make all the
money with doctors using the drug off-label.
"You know all these trials done with clopidogrel
were done as physician-sponsored or device-sponsored trials. So...they're
fat and happy because they're making a fortune off of the use of
Plavix for non-approved indications. Now what about that as
a scandal?"
Bad drug companies; good device
companies. Or is it?
• Device Companies: Laying Low
Over a year ago, on my mission to raise patient education funds, I was speaking
to "the man" in charge of drug-eluting stents at one of the two
approved device manufacturers (you flip the coin -- it'll take a large donation for
me to tell which one). Since Angioplasty.Org gets almost 80,000 visits monthly,
we hear from a lot of patients, so I challenged him with this question:
"A lot of patients seem to not be really
aware, and physicians, like their doctors and dentists, don't understand
the implications of stopping Plavix even for a short time. Don't
you think that the device companies have a responsibility to educate
patients and their physicians and corollary physicians more than
seems to be the case. I mean just so many patients write in and
are not aware of this."
His answer put my worries to rest:
"Well that's new news to me, Burt. And I've
just made a note, and [to his assistant], I want you to
also. That's something that we can definitely dial up to our patient
education channels.
"It is obviously a part of all of our in-servicing
with the interventional cardiology physicians. But I think the
physicians you're talking about are the referring physicians, in
particular, that refer into the interventionalists. So we will
definitely put some more emphasis on that, if that's a common question
that you are getting from your audience."
Ah yes. Dial up the Patient Education channel.
I don't think I get that on my cable. Let's see, Episode One might
be titled -- "That stent you're thinking of getting means you
will have to take a $4 pill every day for a year or more that might
cause bleeding and means you can't ever have surgery without stopping
it." That will certainly sell a lot of stents, especially to
the channel's main demographic: the over-60 crowd.
• Patient Education: Stonewalled
So you've got the drug companies who aren't allowed to fund patient education,
and don't seem anxious to change that situation. And then you've got the
device manufacturers who, until very recently, were not so interested in
publicizing the fact that the Ferrari in your heart performs great but needs
a lot of maintenance.
In summary (ahem!) there's a crack at the FDA and
patients are falling through it. There's a problem (compliance) and
a solution (education). But who will assume responsibility? Whose
job is it anyway?
* * * * *
Well...doctors always like to end their PowerPoint
lectures with a funny cartoon or photo, so since "I'm not a
doctor, but I play one on the Web", here's my finish: the results
of a Google image search for "Not
My Job".
(Note: Patients who are trying
to figure out what this means for them should read Angioplasty.Org's Patient
Advisory.)
November 21, 2006 -- 2:45pm ET
Eentsy Weentsy Time Bombs -- or -- The
Pen is Mightier Than the Clot
Just when I was thinking that the popular
press coverage of the late stent thrombosis issue with drug-eluting
stents (DES) had been relatively balanced, along comes this
bizarre piece out of NBC News this morning from highly-regarded "chief
science and health reporter", Robert Bazell.
There are so many things wrong with
this article that it's hard to know where to begin discussing it.
So for now I'll just quickly give Mr. Bazell a few suggestions on
how to improve his report.
Tip #1: Know Your Audience
When you're writing to people who have weak coronaries, you might not want
to lead with:
"Millions of Americans could
be walking around with tiny time bombs in their hearts."
At least not without a roller-coaster warning
at the top. I'll wager more stent patients will experience health
problems just from reading this sentence than from their drug-eluting
stents.
When the news headlines mis-reported the
CHARISMA trial back in March, stent patients got very scared and
some immediately and incorrectly stopped taking their Plavix and
aspirin. As a result, a few of them had heart attacks (Dr. Tim Henry
of Abbott Northwestern in Minneapolis related to me at least one
of his patients where this occurred -- we're sure there were others.)
It is not a public service to misreport and mischaracterize
health issues, especially when the incomplete information might lead
patients to panic and harm themselves.
Tip #2: Know Your Facts
The following statements made in this article are totally incorrect (my commentary
follows each statement in italics):
"They [drug-eluting stents] may be doing
more harm than good."
(Even doctors who are critical of drug-eluting stents
agree that late stent thrombosis is a very low frequency
problem -- and many interventional cardiologists, like
Dr. Jeffrey Moses of Columbia-Presbyterian Medical Center
in New York, feel that the lower restenosis rates of DES
have prevented heart attacks, as well as repeat interventions,
which carry their own complication rates.)
"many top doctors...admit they are in
uncharted waters with a frightening problem that was largely
unanticipated."
(Concerns about increased risk of stent thrombosis
were raised
immediately upon approval of the first DES in the fall
of 2003 -- studies at that time showed a rate equal to
that of bare metal stents.)
"the DES's end up as a piece of metal
sticking out in the artery."
(A disturbingly unhealthy visual -- not only incorrect
but this would be different than a bare metal stent in
what way?)
"The FDA panel may well recommend they
not be used at all."
(In the words of Dr. Jeffrey Moses to me earlier today,
this article "...is doing a disservice. To suggest
that the FDA is going to withdraw these stents is preposterous!
That's not what this panel is about.")
"The origin of this terrifying problem
is that medical devices...get tested for a few months in a few
hundred or at most a few thousand of people before the FDA approves
them."
(The various Cypher and Taxus trials involved thousands
of patients over a minimum 12-month period -- the Cypher
approval in April 2003 came after two-year followup in
the initial RAVEL trial.)
Tip #3: Know Your Controversies
I'm not by any means saying that drug-eluting stents are without flaws and
should be given to everyone. Most cardiologists agree that patients who aren't
going to be able to maintain the required antiplatelet therapy (Plavix and
aspirin for 6 or more months) might be better off with a bare metal stent
in certain situations. Even DES evangelists like Dr. Moses have told us they
would consider using a bare metal stent in certain straight-forward cases
(a single blockage in a very wide artery).
But many U.S. cardiologists take issue with the
data presented in the European studies, which they say incorrectly
portrayed bare metal stents as having far less clotting issues. The
recent TCT meeting reported data that came to different conclusions
and also redefined what should be considered a "stent thrombosis" --
the controversy, to some extent, has taken the form of a USA
vs. Europe dispute.
Hopefully the FDA open-to-the-public hearings,
set for December 7-8, will help clarify some of these issues. We
posted a "Patient
Advisory" on the issue of late stent thrombosis, most recently
revised over a month ago, and see nothing that would change its recommendations
(based on those of leading cardiologists).
We agree with Dr. Moses. To use the terms "frightening", "terrifying", "lethal
devices" and "time bombs" in an article read by millions
of heart patients is irresponsible fear-mongering. Patients are able
to discern some of the finer points of these issues, something Angioplasty.Org
strives to deliver. In fact, Dr. Sanjay Kaul, author of the American
College of Cardiology editorial cited in the MSNBC article, recently
complimented Angioplasty.Org:
"...a wonderful website. Very accurate,
very balanced, and clearly having the best interest for the patients
and for the professional community in mind. I want to commend
you for that. Even critics like me enjoy your website!"
Does more need to be done to ensure the safety
of these devices? Of course. No one disputes that. And while perspective
is necessary, so is caring for the individual patient.
Next year marks the 30th anniversary of the first
balloon angioplasty -- a procedure that has revolutionized the treatment
of coronary artery disease. And the technology has advanced tremendously.
But as Andreas Gruentzig, the inventor of coronary angioplasty, told
me back in 1985:
"I am speaking all the time about complications.
You may wonder and will say, 'Well he's talking about complications
from the beginning to the end. Why is he doing dilatation [angioplasty]?'
Well fortunately those complications are rather minor in percentage.
And that's the reason I speak up about complications. It is not
because it is such a major problem, but it is always my major
concern in selecting patients or treating patients."
By the way, the photo (reproduced
above) that illustrated the MSNBC story, depicts an open surgical
procedure, not an angioplasty....
November 16, 2006 -- 10:06pm ET
Called It! J&J to Acquire Conor
On October 4, Angioplasty.Org ran a news
feature about Conor Medsystems and its innovative CoStar stent,
called "Conor
CoStar: New Stents May Be Solution to New Stent Problems".
We ended the article by noting that in May of this year Cordis
/ J&J had announced the establishment of a new "Innovative
Research Center" in Silicon Valley. We also noted that Conor Medsystems
is located in Menlo Park, the epicenter of Silicon Valley.
Today J&J announced it
is going to acquire Conor.
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