Cardiologists shocked by new FDA alert on

clopidogrel-PPI interaction
November 17, 2009 Sue Hughes

Orlando, FL - The FDA has today issued a new public-health warning on the possible
interaction between clopidogrel (Plavix, Bristol-Myers Squibb/Sanofi-Aventis) and the
proton-pump inhibitor (PPI) omeprazole (Prilosec, Procter & Gamble) [1,2]. The alert states:
"New data show that when clopidogrel and omeprazole are taken together, the effectiveness
of clopidogrel is reduced. Patients at risk for heart attacks or strokes who use clopidogrel to
prevent blood clots will not get the full effect of this medicine if they are also taking
omeprazole."
But the timing of the this alert appears peculiar, given that just a few weeks ago, what was
said to be the definitive answer to this issuethe only randomized clinical trial on the
interactionwas reported, showing absolutely no hint of any reduction in effect of
clopidogrel in patients taking omeprazole.
Cardiologists contacted by heartwirewere surprised at the new FDA announcement.
Dr Peter Berger (Geisinger Medical Center, Danville, PA) said: "I was shocked by the
strengthened warning. Proper subgroup analyses from randomized trials, including CREDO,
TRITON, PRINCIPLE, and preliminarily from PLATO and CURRENT, all indicate that
no interaction exists. And as shown by the registries, all these trials indicate just how
different patients on and not on a PPI are from one another. And then a preliminary analysis
of data from the COGENT trial, a trial dedicated to specifically examining clopidogrel with
a PPI vs placebo, fails to suggest even the slightest signal of a negative interaction. For the
FDA to then strengthen the warning of a interaction is baffling, to say the least."
Dr Christopher Cannon (Brigham and Women's Hospital, Boston, MA) had similar
concerns: "It is certainly reasonable for the FDA to inform clinicians of the platelet-function
data, but their interpretation of the clinical action oversteps the evidence, I believe. As we
know from COGENT, there is not a difference in clinical events when combining clopidogrel
with omeprazole. Recommendations on clinical care should be based on randomized trials
with clinical end points. For clinical effects of this pharmacologic interaction, what we see
are no adverse cardiac effects. We need to see how the final published data lookbut I don't
think the 'info sheet's' recommendation to avoid these medications is the correct advice based
on the clinical data."
Cannon added: "I wonder just what vetting of these clinical recommendations FDA has done.
Have they consulted with the relevant specialty societies? The [American
Gastroenterological Association] AGA, AHA, or ACC? Hopefully the ACC/AHA/AGA
expert panel, cochaired by Drs Deepak Bhatt and Robert Harrington, can meet urgently to
review the data and make an updated recommendation (or reaffirm their current standing
recommendationwhich I think is actually correct as written) that for patients at high risk of
GI bleeding on aspirin and clopidogrel we should use PPIs."
The FDA says it is aware of the COGENT study and that "it might provide information about
the effect of this interaction on clinical outcome." It adds: "Although the FDA has not fully
reviewed the study results, the applicability of these data is limited because of the study
design and follow-up."

New studies from sponsor
The FDA alert says the new information on which its warning is based comes from new
studies conducted by the sponsor that compared the amount of clopidogrel's active metabolite
in the blood and its effect on platelets in people who took clopidogrel plus omeprazole vs
those who took clopidogrel alone. A reduction in active metabolite levels of about 45% was
found in people who received clopidogrel with omeprazole compared with those taking
clopidogrel alone. The effect of clopidogrel on platelets was reduced by as much as 47% in
people receiving clopidogrel and omeprazole together. These reductions were seen whether
the drugs were given at the same time or 12 hours apart, the statement adds.
Based on the current scientific information, the clopidogrel label has been updated with new
warnings on omeprazole and other drugs that inhibit the CYP2C19 enzyme that could interact
with clopidogrel in the same way. In addition, the manufacturer of clopidogrel is conducting
follow-up studies to explore this and other drug interactions.
The agency advises patients using clopidogrel to consult with their healthcare provider if they
are currently taking or considering taking omeprazole. It adds that patients who use
clopidogrel and need a medication to reduce stomach acid can use antacids or H2 antagonists
such as ranitidine, famotidine, or nizatidine, because the FDA does not believe that these
medicines will interfere with the anti-clotting activity of clopidogrel. However, cimetidine
should not be used, it says.
The FDA adds that the manufacturers of clopidogrel have agreed to look at other possible
drug interactions with clopidogrel.
It also says that other drugs that are potent inhibitors of the CYP2C19 enzyme would be
expected to have a similar effect and should be avoided in combination with clopidogrel.
These include: cimetidine, fluconazole, ketoconazole, voriconazole, etravirine, felbamate,
fluoxetine, fluvoxamine, and ticlopidine. "Since the level of inhibition among other PPIs
varies, it is unknown to what amount other PPIs may interfere with clopidogrel. However,
esomeprazole, a PPI that is a component of omeprazole, inhibits CYP2C19 and should also
be avoided in combination with clopidogrel," it adds.
The FDA says it is continuing to investigate other drug interactions with clopidogrel and
plans to present on this issue at the next meeting of FDA's Drug Safety Oversight Board in
November.
http://www.theheart.org/article/1025121.do