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November
17,
2009 -- 11:30pm EST
PPIs and Plavix -- Confusion Reigns Supreme
Patients
taking Plavix (a.k.a. clopidogrel) -- and that would be all
stent patients -- sometimes experience
a side effect of gastric upset, heartburn or even bleeding. So
they are given a Proton Pump Inhibitor
(PPI)
with
a brand name
of Prilosec,
Nexium, Prevacid or Protonix to alleviate these symptoms.
In the past a number of observational studies (namely
from Medco and
the Veterans Administration) have shown that patients who take
PPIs and Plavix experience an increased risk of adverse
events, such as heart attacks.
However,
other
studies
have shown no clinical effect. In fact it
was only a short while ago that a panel of cardiologists, commented
during this year's TCT meeting on
the
COGENT
trial (COGENT
examined
the clinical results of taking Plavix with PPIs). The panel
exclaimed quite pointedly that the COGENT study, a randomized
clinical trial (not a retrospective observational study)
was THE study
that revealed the truth -- and that truth was that there was
NO increase in adverse clinical
events when
PPIs were taken with Plavix. They even did a Colbert-like "wag
of the finger" to the medical news outlets that published inflammatory
headlines about the non-existent danger.
So it was a bit of a shock to these and other cardiologists assembled
at the American Heart Association Annual Scientific Sessions in Orlando
to read today's warning
from the FDA:
The concomitant use of omeprazole [Prilosec]
and clopidogrel should be avoided because of the effect on
clopidogrel's
active metabolite levels and anti-clotting activity. Patients
at risk for heart attacks or strokes, who are given clopidogrel
to prevent blood clots, may not get the full protective anti-clotting
effect if they also take prescription omeprazole or the OTC
form (Prilosec OTC)....
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This warning also mentioned other drugs to be avoided
when taking clopidogrel, such as esomeprazole (Nexium),
cimetidine (Tagamet) and so on.
In addition, yet another observational study about PPIs
and Plavix was presented yesterday at the AHA meeting. This retrospective
study, which looked at patient records from Mt. Sinai in New York,
showed an increase in adverse events. These two provided a double
whammy to the results of the COGENT trial.
So
earlier today I asked Dr. Christopher Cannon about this new study
(two months ago he stated in no uncertain terms that the COGENT study
proved that there was no increased risk for patients when
taking Plavix
and PPIs). Dr. Cannon is the senior investigator of the Thrombolysis
in Myocardial Infarction (TIMI) Study Group, and has led some of
the most well-known practice-changing guidelines in the treatment
of heart disease He replied:
These new studies are observational ones
-- with exactly the same flaws as the prior Medco and VA database
studies -- [and] they get the same wrong answer...
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The
difference between a randomized clinical trial (RCT) and a retrospective
observational
study is an
important one here in understanding the
different results. An RCT is a carefully-designed scientific test
of a hypothesis -- patients are randomized to two different treatments
in a way that negates differences in ages, states of health,
and other "confounding" data. An observational study looks at
patient data that already exists. Attempts can be made to normalize
the patient groups for comparison's sake, but the results are not
necessarily accurate when measuring two treatments, for example.
This is why
the FDA normally requires that an RCT be done before a new treatment
is approved. Observational studies, however, can point to possible
problems, or can generate hypotheses for future randomized scientific
trials. They can show associations, but not necessarily prove cause
and effect.
This is, in effect, what happened with PPIs and Plavix,
and why the COGENT trial was done: to answer the questions raised
by the early observational studies.
Dr. Chet Rihal, director of the catheterization
lab at Mayo Clinic put it another way (as quoted in HealthDay):
All this shows is that people taking PPIs
have a worse outcome than those not taking PPIs. This
does not prove there's causation. That would be like saying
that carrying matches is associated with lung cancer. It is
associated, but it doesn't mean it causes lung cancer.
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Indeed, one explanation for these different results is
that patients who are having gastric distress and require Prilosec
may be sicker or older patients, thus skewing the results of any
observational study against the group taking PPIs -- they may have
worse outcomes because they started off sicker or older -- and the
worse outcomes are not "caused" by the PPIs.
As for the FDA
warning, which involves a label change to the drug clopidogrel,
Dr.
Cannon noted to me
that it was more carefully worded, and did not claim that PPIs
caused more adverse events,
only that PPIs have been shown to
reduce the antiplatelet effect, something that was
shown in a small study last year, titled OCLA
(Omeprazole CLopidogrel Aspirin) -- a study conducted by Dr. Deepak
L. Bhatt, Cannon's colleague at Brigham and Women's in Boston.
Dr. Cannon continues:
But, as we know from COGENT, there
is not a difference in clinical events when combining omeprazole
[Prilosec] and clopidogrel. Thus, as we have seen before,
often small changes in the level of platelet inhibition don't
translate into a clinical effect. The label is careful to
stick to the platelet data.
It is reasonable to know of the platelet data, but the FDA needs to see the COGENT
data -- and, of course, we all need to give much more weight
to the randomized trials, not the confounded observational
studies.
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So should you stop taking your Prilosec or Nexium with
your clopidogrel? Most doctors say no -- in fact suddenly stopping either
medication could cause serious problems. However, you should call
or see your cardiologist and ask him or her about these
studies.
Meanwhile the FDA has placed this issue on the agenda
for the November
meeting of its Drug
Safety Oversight Board and HealthDay reports that new AHA/ACC recommendations
on the use of PPIs with Plavix will be announced tomorrow (Wednesday)
during the American Heart meeting.
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