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Double-Dose Clopidogrel
(Plavix) Does Not Reduce Heart Attack or Stent Thrombosis for
Angioplasty Patients with High Platelet Reactivity
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March 15, 2011 --
When does one plus one equal one? In the case of angioplasty
or stent patients who are at high risk for adverse events, such
as stent thrombosis, a new study concludes that a double dose
of clopidogrel (Plavix) "did not reduce the incidence
of death from cardiovascular causes, nonfatal myocardial infarction,
or
stent thrombosis." The GRAVITAS study,
first presented last November at the American Heart Association's
Annual Scientific Sessions, is now published in the current Journal
of the American Medical Association (JAMA).
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Clopidogrel After Stenting
One problem that can occur after a stent
is placed in a coronary artery is stent thrombosis: the
platelets in the blood react to the foreign object and begin to form
a blood clot, or thrombosis, acutely blocking the artery. This blockage
can result in a heart attack -- fatal in almost half of
these cases. In order to prevent stent thrombosis from occurring,
stent patients are given two antiplatelet drugs, usually clopidogrel
(Plavix) and aspirin.
For bare
metal stents (BMS), the guidelines now recommend six months; for
drug-eluting stents (DES) it's a year or more, if the patient does
not suffer any bleeding complications which is a side-effect of any
antiplatelet medication.
Dual antiplatelet therapy (DAPT) has been very
successful in reducing the incidence of stent thrombosis and other
adverse events post-Percutaneous Coronary Intervention (PCI), but
the challenge has been in the group of patients who have elevated
levels
of platelet
reactivity
-- and
who, according to current thought, are therefore at higher risk
for thrombosis.
The GRAVITAS Trial
Using a platelet reactivity test, called VerifyNow (made by San Diego-based
Accumetrics), Dr. Matthew J. Price of Scripps Translational Science
Institute and
his colleagues identified 2,214 patients at 83 North
American centers between
July 2008 and April 2010 who were found to have high on-treatment
reactivity, measured 12-24 hours after PCI. (The study's acronym
GRAVITAS
stands
for
Gauging
Responsiveness with A VerifyNow assay -- Impact on Thrombosis And
Safety.) These patients were
randomized 50/50 to standard antiplatelet therapy (75 mg of clopidogrel)
and higher double-dose levels (600 mg initial dose followed by
150 mg daily). All patients also received aspirin.
The hypothesis
was that personalizing therapy, based on the VerifyNow test,
and utilizing greater levels of antiplatelet medication in certain
patients would reduce the incidence of death
from
cardiovascular
causes. However,
at
six months the rates of death were identical: 2.3% in both patient
groups. Even at 30 days, the difference in regular vs. double dose
clopidogrel was
insignificant: 1.6% vs. 1.9%. The authors concluded:
"The
results of GRAVITAS do not support
a uniform treatment strategy of high dose
clopidogrel in patients with
high on-treatment reactivity identified
by a single platelet function test
after PCI. Alternative treatment strategies
incorporating platelet function
testing merit further investigation."
Attempting to determine the optimal therapy for patients
with high platelet reactivity is an important goal, because this
patient population is not small: 41% of all the patients screened
for GRAVITAS (2,214
out of 5,429) were
in that group.
Possible Factors at Play: Low
Event Rates
In an accompanying editorial, Paul A. Gurbel, MD and Udaya S. Tantry,
PhD of Sinai Hospital in Baltimore, noted several factors that
may have contributed to the trial's failure to show any difference.
One was the possibility that the cutpoint for determining high
reactivity may have been too high (230 platelet reactivity units
or PRUs), and that a lower cutpoint would have revealed a greater
differential.
But a significant problem
in GRAVITAS was the very low event rate (only 25 events in each
cohort), making it necessary for the treatment to be "super-effective"
in order to
show
a difference
in 2,214 patients. Stent thrombosis rates alone were only 0.5%
(5 patients with double dose) and 0.7% (8 patients with standard
dose). Although this was obviously good news for the patients in
the study,
when
the trial
originally was designed,
it was
assumed
that the rates of adverse events
and
death
would be
higher.
Dr. Gurbel pointed out that the elimination of periprocedural MI
as an adverse
event
may
have
contributed
to
this low event, but he also opined that:
"It
also may just be that interventionalists are better than
they were years ago. The procedures are faster, flow is
maintained fairly well in each procedure, and the concomitant
therapies
that these patients get, statins, good blood pressure control
and, if you look at the frequency of patients who were stable,
there
was like 60% of the patients had
stable angina -- it was in general a fairly low risk group
of patients."
Dr.
Price also told Angioplasty.Org that another reason might have
been that 73% of the patients were treated with the newer second
generation
drug-eluting stents (XIENCE/PROMUS and Endeavor) which probably
contributed to better outcomes, as well. So the excellence in procedural
skills
and the improvement in the stents themselves may have been a factor
in GRAVITAS not showing a difference.
A further factor may be that clopidogrel has
a "threshold effect": that more concentration of the drug
doesn't have any impact. However, platelet reactivity, as measured
by the
VerifyNow assay, was significantly reduced at six months in many
of the patients who received the double-dose, yet there was no change
in
the clinical
outcomes -- which might offer a hypothesis that, as Dr. Gurbel noted
in his editorial:
"...would suggest that high on-treatment
platelet reactivity identified early after stenting is
only a marker of risk
and that the level of
risk cannot be modified by intensification
of antiplatelet therapy."
Indeed, even in the patients who were found to
have normal platelet reactivity, the event rates, while numerically lower,
did not achieve statistical significance over the highly reactive
patients.
Take-Away Message for Clinical Practice
Left with the message that increasing clopidogrel in this population
of "low responders" is not effective, cardiologists are
left with many questions. Some feel, as does Dr. Gurbel, that an
alternative
antiplatelet agent like prasugrel (Effient) should be utilized
in those patients at high risk for thrombosis. And there are several
trials now underway or in the near future that will test prasugrel
in highly reactive patients.
Further analyses of the GRAVITAS patient cohorts
are ongoing; one such substudy of patients who had genotype
testing, in addition to the VerifyNow phenotype test, will be presented
at the upcoming American College of Cardiology meeting as a late-breaking
trial. (For more information on genotype testing, read our
exclusive interview with Dr. Eric Topol, also of Scripps.)
When asked by Angioplasty.Org how they currently
manage their patients, in light of the results from GRAVITAS, Drs.
Price and Gurbel responded, as follows:
"One
takeaway from GRAVITAS is that patients with low reactivity
do really well. I think, if you have a patient, either elective
or ACS, if the PRUs are low, then the likelihood of them having
an event is very small.
"But I look at the whole patient. Platelet
reactivity does not exist in a vacuum. So I look at other risk
factors for thrombotic events, be it stent length or diabetes,
and then decide how best to treat that patient. I think that
platelet reactivity can help guide how aggressive we should
be with antiplatelet therapy." |
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Matthew J.
Price, MD
Scripps Translational
Science Institute |
Paul A. Gurbel,
MD
Sinal Hospital of Baltimore |
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"High platelet
reactivity entails a risk. Particularly those patients in the
highest quartile for on-treatment platelet reactivity. Particularly
if they have high predictors of stent thrombosis, such as implantation
of multiple stents, overlapping stents, long vessel segments
stented, bifurcation stenting, poor left ventricular function
-- all those anatomic features would make me want to personalize
the therapy in those patients. And also co-morbid factors such
as diabetes, history of congestive heart failure, prior stent
thrombosis,
prior myocardial infarction -- any patient who's proven that
they can form a thrombus would be a high risk patient. And I
don't think any clinical trial result's going to really alter
my thinking
about that. |
When asked, what his treatment strategy in these
high risk patients would be, Dr. Gurbel answered, "Prasugrel."
Reported by Burt Cohen, March 15, 2011
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