More evidence of how painkillers
called COX-2 inhibitors can raise the risk of heart disease
was published Monday, showing Pfizer Inc.'s Bextra can
triple the risk of heart attack and stroke in certain
A second study shows how
older drugs such as aspirin work to prevent heart disease.
Both appear in this week's issue of the American Heart
Association journal Circulation.
The COX-2 inhibitors were
designed to help treat arthritis pain and similar long-term
conditions without the serious stomach side-effects of
aspirin and related drugs such as ibuprofen, and other
non-steroidal anti-inflammatory drugs or NSAIDS.
But in September Merck
& Co. Inc. pulled its COX-2 inhibitor Vioxx from the market
after clear evidence its use could raise the risk of heart
attacks. And in December, the National Institutes of Health
halted a study involving Pfizer's COX-2 inhibitor Celebrex.
The U.S. Food and Drug
Administration cautioned patients and doctors to limit
their use of such drugs and will hold a meeting next month
to discuss them. The European Medicines Agency is holding
a similar meeting this week.
Dr. Garret FitzGerald of
the University of Pennsylvania School of Medicine and
colleagues used a statistical approach called meta-analysis
to combine the findings of two trials to estimate the
risk of heart attack and stroke in people taking Bextra,
another COX-2 inhibitor made by Pfizer.
Their analysis, first presented
at a Heart Association meeting last November and published
this week in Circulation, suggests Bextra tripled the
combined incidence of heart attack and stroke in heart
bypass surgery patients.
NSAIDS work by suppressing
two enzymes called COX-1 and COX-2. But they can cause
gastrointestinal bleeding, and research had suggested
that suppressing COX-1 caused this damage.
So drug companies worked
to make drugs that only affect COX-2, the enzyme associated
with pain and inflammation.
But in the second study,
the researchers studied mice genetically prone to hardening
of the arteries or atherosclerosis and found that a compound
called thromboxane or TxA2, produced by COX-1, accelerates
"This is of particular
interest, as low-dose aspirin prevents heart attack and
stroke by blocking COX-1 formation of TxA2 in blood cells
called platelets," FitzGerald said in a statement.
When a COX-2 inhibitor
was added, something happened that may help explain why
the COX-2 inhibitors raise the risk of a heart attack,
said FitzGerald's colleague, Karine Egan.
"Addition of the COX-2
inhibitor caused changes that, if they occurred in humans,
would result in a loss of stability of the plaque, making
it more likely to rupture and activate clotting, causing
heart attack or stroke," she said.
"These results would have
disturbing implications for patients at high cardiovascular
risk treated with aspirin and a coxib (COX-2 inhibitor),"