Common Arthritis Drugs Can Stop Aspirin From Thinning
PA) - The ibuprofen that you take to ease arthritis
pain can counteract the aspirin that you take to protect
your heart, according to researchers at the University
of Pennsylvania School of Medicine. The researchers
studied how aspirin, taken to prevent second heart attacks,
interacts with nonsteroidal anti-inflammatory drugs
(NSAIDs), a group of drugs that includes ibuprofen,
commonly taken to treat rheumatoid arthritis. Their
findings are published in the December 20th issue of
the New England Journal of Medicine.
"Our findings have shown that multiple daily doses
of ibuprofen can undermine the cardioprotective effects
of a daily aspirin regimen," said Garret A.
FitzGerald, MD, Robinette Professor of Cardiovascular
Medicine, chair of the Penn Department of Pharmacology,
and director of the Penn Center for Experimental
Therapeutics. "NSAIDs and aspirin are two of
the most frequently consumed drugs in North America
and, since people commonly take both drugs daily, it
is important to see how they could interact."
Much of their concern rests in the fact that aspirin
and NSAIDs both inhibit two different versions of the
same enzyme, a protein called cyclooxygenase (COX).
One variant of the enzyme, COX-1, found in platelets,
is essential in creating the molecules that allow platelets
to clot blood. The other variant, COX-2, produces the
molecules responsible for the pain and inflammation
symptomatic of arthritis.
Aspirin will bind to the COX-1 enzyme irreversibly,
thereby permanently putting the enzyme - and the platelet
- out of commission. Such a sustained effect on platelets
is key to the ability of aspirin to prevent heart attack
and stroke. NSAIDs, however, bind less strongly to a
different part of the enzyme, and only impair platelets
for a short time. There is no evidence that NSAIDs prevent
heart attack or stroke, but their effects on COX-2 help
relieve pain and swelling.
"Since both NSAIDs and aspirin both bind near the
reactive site deep within the COX-1 enzyme, we thought
that NSAIDs might physically block aspirin from reaching
its target," explained Muredach Reilly, MD, a Penn
cardiologist and co-author of the study. "It would
not do you a lot of good to take one medication only
to have another wipe out its effects."
In particular, the researchers studied the over the
counter NSAIDs ibuprofen (e.g. Advil®), diclofenac
(Voltaren®) and acetaminophen (e.g. Tylenol®),
as well as the prescription NSAID refocoxib (e.g. Vioxx®),
which is part of a class of newer, COX-2 specific, NSAIDs.
To determine how the drugs might interact, the researchers
first studied how the order of dosing might influence
the effects of combinations of aspirin with the various
NSAIDs on the number of working platelets in volunteers.
As they had guessed, taking ibuprofen before aspirin
prevented aspirin's effects on platelet COX-1. If they
took aspirin 2 hours before the ibuprofen, however,
there was no problem.
They then repeated the study, giving ibuprofen three
times a day - the way people would generally take the
drug for persistent pain or inflammation. This time
they loaded the die against the interaction by giving
the aspirin two hours before the morning dose of ibuprofen
each day. To their surprise, there was still enough
ibuprofen around from the prior evening's dose to cause
the aspirin-blocking interaction.
"We know that aspirin works to protect the heart
by acting as a blood thinner, that is, it prevents clotting
by inactivating the enzyme that makes platelets stick
together," said FitzGerald. "This study tells
us that ibuprofen can prevent this from happening by
denying aspirin access to the enzyme's active site."
As expected, the researchers failed to see an interaction
with rofecoxib, an important point of distinction for
patients on aspirin who are making a choice amongst
NSAIDs. As a member of the newer COX-2 specific drugs,
rofecoxib does not bind to COX-1 in platelets. Perhaps
more surprisingly, the interaction was also absent from
combinations of aspirin with diclofenac, an older NSAID.
The interaction occurs in a narrow channel deep within
the COX-1 molecule. "There is some evidence that
diclofenac binds within the enzyme somewhat differently
than does ibuprofen, but the failure to interact may
also reflect its preference for COX-2, its turnover,
or some other factor as yet to be identified,"
The researchers also failed to see an interaction with
1000mg of acetaminophen. However, they did find out
that at this dose acetaminophen is a weak NSAID. It
remains to be seen if higher doses of acetaminophen
can exert a full NSAID effect and whether they might
effect aspirin like ibuprofen does.
"This study tells us that patients who take ibuprofen,
the most common NSAID consumed in North America, are
susceptible to an interaction that would undermine the
cardioprotective action of low dose aspirin," said
FitzGerald. "Patients taking aspirin to protect
against heart attack should seek the advice of their
doctors before commencing additional treatments for
pain or inflammation."
This study was funded, in part, by the National Institutes
of Health and the Bayer Corporation.
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Editor's Note: Neither Dr. FitzGerald nor Dr. Reilly
have any financial stake in Bayer Pharmaceuticals.
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