Stopping Plavix Doubles
Risk of Heart Attack or Death for 90 Days, With or
Without Stents
New Study in JAMA
Suggests a "Rebound Effect" for Clopidogrel;
May
Have Major Implications for Acute Coronary Syndrome and Stent
Patients;
Study Author Gives Advice for Patients
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February 5, 2008 -- A study
appearing in tomorrow's Journal of the American Medical Association
(JAMA) reports
a two-fold increase in death and heart attack in the 90 days
after heart patients completed their prescribed course
of medical therapy with clopidogrel (Plavix). The increased
risk occurred whether or not patients had received stents and was
similar for all durations of clopidogrel therapy studied: from
less than six months to more than a year. The study itself was
generated by anecdotal reports from heart patients, similar to
those posted in Angioplasty.Org's
Patient Forums.
Titled "Incidence
of Death and Acute Myocardial Infarction Associated With Stopping
Clopidogrel After Acute Coronary Syndrome",
the study raises the possibility of a "rebound effect" with
clopidogrel which has major implications for the millions of
patients currently taking the drug. Plavix, the brand name of
clopidogrel, is
the world's second largest-selling drug, with annual sales of $5.9
billion. The study also may impact
the concerns
over late stent thrombosis that have significantly reduced the
use of drug-eluting stents over the past year.
P. Michael Ho, MD, PhD and John S. Rumsfeld,
MD, PhD of the Denver VA Medical Center in Colorado and
colleagues studied a group of 3,137 patients
with ACS
discharged from 127 Veterans Affairs hospitals with an average
follow-up of six months after cessation of clopidogrel. Approximately
half of the patients were treated with medical therapy only and half
with angioplasty/stents. 17% of those on the medical therapy group
died or had a heart attack in this period, but almost two-thirds
of those events occurred in the first 90 days. A similar pattern
was seen in the angioplasty/stent cohort. Heart attacks are caused
by sudden blood clots in the coronary artery which cut off the blood
supply to the heart.
While the authors stress this is an observational
study, the results suggest that immediately following the stopping
of clopidogrel, there may be a short period of increased platelet
activation which would in turn promote
blood clot formation. The article calls for urgent research
into possible mechanisms, which also might
lead
to strategies for safe weaning or tapering off of the drug, avoiding
this risky effect.
What Should Patients Do Now?
Concerned that the reports of their study
may confuse patients, or cause patients not to comply with their prescriptions,
for fear that there is something negative about taking clopidogrel,
co-author Dr. John
Rumsfeld
told
Angioplasty.Org that it is quite the opposite:
John
Rumsfeld, MD, PhD |
"What needs to be reinforced, number one, is
to take the full course of clopidogrel that the guidelines
recommend, which is following a heart attack twelve months,
whether or not
you got a stent. We know that clopidogrel is beneficial
in this setting.
"The result of this study is that when you get
to 12 months, we don't know what the right answer
is. Is it still the best thing to stop at 12 months because longer
courses may
not confer benefits and do come with some risk of
bleeding? Then there's obviously the cost of the drug. Is it
going to
turn out to be important to continue the medication
for a longer course or indefinitely to try to avoid this clustering
or grouping
of events? Our study can't answer that, so the
recommendation has
to be
to take the full 12 months, and after 12 months it
will
have
to be an individual decision of a patient with their
clinician.
I would anticipate at that point the clinician would
evaluate that individual patient's overall risk profile: their
severity
of their heart disease, what type of stent they received,
how many heart attacks they've had, etc., and how well
they've done
on the clopidogrel. It may be that a patient who’s
had no side effects of the clopidogrel, that the
individual clinician
and patient may decide together as a team that they'd
like to continue the medication indefinitely to avoid
this potential
rebound effect until its proven whether that is what
it is or
not."
Plavix and Stents
Clopidogrel is a major blood-thinning drug used in
heart
disease, one which is normally prescribed
after
stent
implantation
because
its antiplatelet properties help keep the blood from forming clots
around the stent
structures. Plavix is prescribed for three months or less after
bare metal stent implantation, but it is prescribed for 6-12
months or
longer
for drug-eluting stents.
In the fall of 2006, several studies raised concerns
that blood-clots, called stent thromboses, were occurring in drug-eluting
stent (DES) patients well after the 6-12 month period. Drug-eluting,
or drug-coated, stents contain a medication that prevents excess
tissue
from growing in the stented area, an advantageous property which
has lowered the rate of stent restenosis (or reblocking) by half.
While these blood clots were small in number, they were
of great concern because a clot can acutely block the artery and
cause a potentially fatal heart attack.
Theories were presented that medications in the drug-eluting stents
may inhibit tissue growth too aggressively and thus delay the
healing of the stented area, leaving it vulnerable to clotting. Late
stent thrombosis was the subject of a two-day FDA panel in December
2006 and continuing concerns have significantly impacted the use
of drug-eluting stents worldwide. In the U.S. the percentage of stent
patients receiving the drug-eluting variety has dropped from 90%
to 60% in the past year alone.
The JAMA study specifically looked at patients
who did not have a stent implanted, in order to remove the confounding
presence of the stent. Dr. Rumsfeld
told Angioplasty.Org,
"In those patients, these adverse events cannot be attributed to
a stent, because they
didn't
receive
one. It further bolsters the hypothesis of a potential rebound associated
with clopidogrel."
Whether or not a portion of the "drug-eluting stent
problem" of late stent thrombosis may be attributable to this potential
rebound effect of clopidogrel, and not the stent, will no doubt be
the subject of many studies.
The Importance of Patients' Observations
An interesting background for the Denver VA study was that it began because
of a single patient's story. Dr. Rumsfeld explains:
"A relative of one of the co-authors
made the observation that, after completing a full course
of clopidogrel and then stopping it, he had a recurrent
problem
shortly thereafter. That coupled with other anecdotes from
patients, and many of those are evident on Angioplasty.Org, the
same anecdotes
of patients taking the fully prescribed course of clopidogrel
and then right after stopping it, having a second heart attack,
these
patient-driven anecdotes actually led to us evaluating this
question in our study and, sure enough, revealed evidence that,
after
completing a course of clopidogrel, there appears to be a short-term
period
of high risk of another heart attack."
Dr. Rumsfeld continued that this type of observational
information, especially from patients, may open up a new and previously
untapped source of data:
" I think one of the lessons of this
study may be that the medical community needs to pay more attention
to patients' input on how therapies
work in the real world, and that a clustering of anecdotes, where
patients are all reporting the same thing, saying 'I found that as
well', or a family member of mine did, probably the medical community
needs a better mechanism of hearing, of getting this information
from patients. In this particular case it actually provided the hypothesis
for the study -- that's probably a model that has rarely happened
in the history of medical research but one that should be used more,
proving the value of patient partnership in our evaluation of care."
We at Angioplasty.Org could not agree more, having
presented this very concept in testimony to the FDA over a year ago.
Over a thousand
patient stories can be found on the Heart
Patients Discussion Forum at Angioplasty.Org.
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