October 30, 2003
Background
The
CYPHER drug eluting stent from Johnson & Johnson / Cordis
was
the
first
drug-eluting stent to receive FDA approval for
use in the United States. These devices "elute" a
medication inside the artery which slows the process of inflammation,
and
thus reduces the reclosing of the artery, normally occurring in
25-35% of all angioplasties. Obviously, expectations were high
for what was being hailed as a major advance in the treatment
of
heart
disease.
The major negative of restenosis, or recurrence, in coronary
angioplasty was shown to be greatly reduced by such devices, down to single
digits. Patients were understandably vitally interested in this
development. Many,
seeded
by
the
advance
news
surrounding
the CYPHER, were actually delaying their angioplasties until the
device was approved, resulting in the occurrence of some unfortunate
cardiac
events ("Patients
wait, risking heart attack", Bloomberg
News, April 21, 2003).
The device was given
US approval on April 24,
2003, although both it and the Taxus drug eluting stent from
Boston Scientific already had been approved for use in Europe.
In J&J's estimation, almost 450,000 of these stents have
since been implanted in 300,000 U.S. patients (some cases
require more than one stent).
Supply and Demand
The good and the bad of the FDA approval was that Cordis was now
able to sell its stent, but the FDA was concerned about the shelf-life
of the drug coating the stent, sirolimus. So they placed a restriction
on Cordis which lowered the available supply. The FDA also restricted
the stent approval to certain sizes. This created a shortfall
in the supply, which upset many cardiologists ("New
Drug-Coated Stents Exceeds Supply", Associated Press, June
27, 2003). Because
of the overwhelming popular demand for this stent (we sat in
on
a number
of angioplasty
sessions with patients who unprompted asked the cardiologist,
"So you're going to use the new medicated stent, right?")
cardiologists attempted to use the CYPHER stent whenever possible.
Problems Surface
Less than two months after approval, the FDA issued a warning to
physicians to be vigilant in reporting adverse reactions in the
use of the
CYPHER stent, since there had
been a series
of instances of blood clotting, including 5 deaths in CYPHER
cases. ("New
heart stent linked to blood clots", MSNBC News, July 8,
2003")
The concern about "stretching" the sizing of the stents
was raised. In a letter to physicians ("Dear
Colleague Letter", Cordis, July 7, 2003) the
company urged cardiologists to be careful that the
stent diameter size is optimum for the artery, and not "stretched" to
fit; to make sure that the stent is long enough for the
length of the occluded arterial area. Correct stent sizing is
crucial
in
proper
stent
placement, and variation from the optimum can sometimes give
rise to complications, specifically thrombosis or re-occlusion.
Furthermore,
because the point of a drug-eluting stent is to delay
the inflammatory response, thus avoiding reclosure, the onset
of
possible thrombosis,
or clotting, may also be delayed. This is why Cordis recommends
administering anti-clotting medications for three months
instead
of the usual two weeks. Evidently, these recommendations were
not being followed universally, so the FDA urged cardiologists
to be vigilant in their prescription of post-stent medication.
Problems Resurface
On October 29, the FDA issued a second
warning on the CYPHER stent.
The numbers of blood clotting (thrombosis) and deaths had increased. Additionally
there were also reports of allergic or hypersensitive reactions
to the stent. So the FDA issued a warning to increase vigilance
on the part of cardiologists,
increase the reporting of adverse effects, and to require Cordis
to do deep follow-up of 2,000 patients. According to John McB.
Hodgson, MD, President of The Society for Cardiovascular
Angiography and Interventions (SCAI) the subacute thrombosis rate
for the CYPHER stent is extremely low, only 0.7% ("Interventional
Cardiologists' Professional Society Supports FDA
Advisory on Drug-Eluting Stents (DES)",
SCAI, October 30, 2003). But
because
the
drug-eluting
stent is a new device, the FDA decided to exercise caution and
gather more data on how and why these complications are occurring.
A Potential Panic
In our view some of the press reaction to this FDA advisory
was relatively extreme. Suddenly there were headlines like "FDA
Warns of Deadly Complications in Highly Touted Stent" and "Deaths
prompt warning on stents". On newsgroups and
in some news articles, patients were beginning to express some
concern, several stating they were glad they didn't have
a CYPHER stent implanted (e.g. W.D.
Crotty, Fool.com, October 30, 2003).
Reality Check
The reality is that any stent has a complication rate, about 1-2%
for standard bare metal stents, according to Cordis spokesperson
Martin Schildhouse
("FDA
issues advisory notice about SAT/hypersensitivity reactions with
Cypher stent", theHeart.org,
October 29. 2003 -- registered users only).
There will be a certain number of thromboses, there will be some
failures, complications and
even
deaths
with
any device or medical intervention. This is measured
against the great number
of patients who have no complications, and whose lives are
enhanced by these devices. Nevertheless, a new device needs to
be examined
ruthlessly and "best practice" guidelines must be followed by
physicians. And that is exactly what the FDA is requiring.
It is highly possible
that what will emerge from the CYPHER follow-up study is a stricter
post-procedure drug regimen. But much may be learned. Dr. Eric
Topol, chairman of cardiovascular medicine at the Cleveland Clinic,
and
who is
continuing to use the CYPHER stent, said he was surprised at the
high number of hypersensitivity or allergic
reactions reported. "This
was thought to be extremely rare, if not unheard of," Dr.
Topol said. " It deserves a lot of attention," ("Some
Doctors to Use J&J's Cypher Stent Despite Advisory",
DowJones Business News, October 30, 2003).
The FDA approval came about after extensive clinical
trials were conducted in a number of centers by highly-experienced
interventional cardiologists. Now that the device is interfacing
with an expanded user-base and hands-on work in the cath labs,
new data is being revealed. Regimens, procedures, protocols will
no doubt need to be adjusted.
As for the incidence of sub-acute thrombosis
in drug-eluting stents, Dr. Gregg Stone in his exclusive
interview with Angioplasty.org, states, "...the
rate that events were occurring were deemed initially to be excessive,
but then when cooler heads prevailed, and actually scientifically
tried to collect the [Cypher] data and numbers...we did in fact
find that the rates were very similar to the bare metal stent thrombosis
experience."
A Look Back
Angioplasty itself is less
than 30 years old, and it took a decade for the
procedure
to
gain
the maturity it needed to become a major therapy in the treatment
of heart disease.Andreas
Gruentzig, the inventor of coronary angioplasty, always put the
discovery
of knowledge before any marketing or financial concerns. In
fact, he refused to allow newspapers to carry the story of the
first
angioplasty in 1977 until he had reached a higher level of
perfection with the procedure -- he knew the danger of "over-hyping" and
unrealistically raising expectations, because then
the early problems could hinder the progress of the procedure.
We hope
that
the data
produced
by
the
FDA-ordered
follow-up will
only make the future of drug-eluting stents even more promising.
Update
On October 18, 2004, the FDA issued an update titled, FDA
Public Health Web Notification:
Final Update of Information for Physicians on Sub-acute Thromboses
(SAT) and Hypersensitivity Reactions with Use of the Cordis CYPHER™ Sirolimus-eluting
Coronary Stent . This update basically confirms the views expressed
above that the rate of SAT for the Cypher is no greater than that
for bare metal stents.
Update 2
As a result of the early experience with drug-eluting stents, detailed
in this editorial, cardiologists realized that patient compliance
with dual antiplatelet therapy, consisting of aspirin plus either
clopidogrel
(Plavix)
or ticlopidine (Ticlid), was crucial for lowering the risk of
stent thrombosis. Recommendations for a minimum of 6 months of
these medications became the standard. The incidence of late
or very late stent thormbosis (afer a year) is still an issue
with drug-eluting stents, prompting many physicians to recommend
12 months or more of antiplatelet therapy, assuming there are
no complications from the medicines, such as bleeding. Most studies
have shown that total stent thrombosis is similar between bare
metal and drug-eluting stents, but this percentage is still very
small. See our StentCenter for the latest news and information.
We welcome your
comments on this editorial.
Source: Angioplasty.org, posted October 30, 2003
-- revised October 18, 2004 and April 12, 2009)
CONTACT: Burt
Cohen, Producer of Angioplasty.org
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