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By David Brown
The popular painkillers Celebrex and Vioxx
may slightly increase a person's risk of having a heart attack,
according to an analysis of clinical studies of the "super
aspirin" drugs.
The drugs, while extremely popular, appear
to carry a small risk of
heart attack, somewhere in the range of 0.3% to
0.5%. This translates to about 1 in 300 patients.
COX-2 inhibitors, like older drugs such
as ibuprofen are nonsteroidal anti-inflammatory drugs, or
NSAIDs. Older NSAIDs reduce inflammation by blocking an enzyme
called COX-2, but they also block another enzyme called COX-1.
This enzyme helps protect the lining of the stomach, so blocking
COX-2 can cause stomach
irritation. COX-2 inhibitors only block COX-2,
leaving the stomach-protecting COX-1 alone.
The analysis, which was strongly contested
by the makers of the drugs, does not say the drugs unquestionably
increase cardiovascular risk. It says only that it's possible.
Since their introduction in 1999, the
drugs, which are known technically as COX-2 inhibitors, have
been among the nation's best-selling prescription pharmaceuticals.
One of them, celecoxib, sold as Celebrex, was the sixth-leading
prescription drug in sales dollars last year and
has been used by 14 million
people. The other COX-2 inhibitor is rofecoxib,
sold as Vioxx.
The drugs are popular because they provide
the same pain-killing
effects as aspirin and non-steroidal anti-inflammatory
drugs (NSAIDs) such as ibuprofen, but with less chance of
causing ulcers and intestinal bleeding. Aspirin inhibits two
closely related enzymes, COX-1 and COX-2. The new drugs specifically
inhibit only the second (which is involved in pain and inflammation)
while not affecting the first (which, among other things,
is involved in protecting the lining of the stomach).
COX-2 inhibitors illustrate the pharmaceutical
industry's ability to tailor-make a drug with the same benefits
as its predecessors, but with fewer hazards. However, the
analysis suggests that even such highly specific compounds
may have unexpected hazards.
In one trial, about 8,000 people with
rheumatoid arthritis were randomly assigned to get either
Vioxx or naproxen, an NSAID. There were more than twice as
many cardiovascular events in the Vioxx group as in the naproxen
group -- 46 vs. 20, this was more than two
times higher in the Vioxx group than in the Naprosyn
group.
The researchers then looked at the small
number of people who had a history of heart disease going
into the study. These people were supposed to be excluded
from the trial, because most people with heart disease take
daily aspirin, and aspirin use was not permitted in the study.
As is usually the case in large studies,
however, a retrospective review uncovered a small number of
people -- 321 in this case -- who should have been excluded
but weren't. Among them, those taking Vioxx were four times
as likely to have a cardiovascular event as the ones taking
naproxen.
There are two explanations for those observations.
Vioxx may have increased the risk of cardiovascular events.
Alternatively, naproxen may have lowered it.
The second study the Cleveland Clinic
researchers looked at involved Celebrex. About 8,000 arthritis
patients were randomly assigned to get either Celebrex or
one of two NSAIDs, ibuprofen or diclofenac. There was no difference
in cardiovascular events among the groups.
However, the annual
rates of heart attack in both the Celebrex and Vioxx studies
were increased compared to a review of studies
containing a total of more than 48,000 patients. In those
studies, 0.5% of patients taking an inactive placebo pill
had a heart attack each year. The annual rate of heart attack
was 0.74% for patients taking Celebrex and 0.80% for those
taking Vioxx.
In the Vioxx trial, however, people were
allowed to take low-dose aspirin for heart disease, and about
20 percent did. Topol and his colleagues theorized that aspirin
use may have counterbalanced Vioxx's possible risk to heart
patients.
Data from the studies were presented to
an advisory committee of the Food and Drug Administration
in February. Two FDA officials said yesterday that the agency
is continuing to review the cardiovascular safety of COX-2
inhibitors to determine whether new information needs to be
added to the drugs' labels, which is the information that
accompanies each prescription.
Testing COX-2 inhibitors' potential hazards
in heart patients directly will be difficult, however. Aspirin
is known to help heart patients, but there is unlikely to
be a benefit from COX-2 inhibitors alone. Testing it in heart
patients to see only if it is a hazard would not be ethical.
It's possible that COX-2 inhibitors plus
aspirin might be better than aspirin alone. That's
because in some people with heart disease, there seems to
be inflammation in the coronary arteries, which supply blood
to the heart muscle. COX-2 inhibitors might help suppress
the inflammation.
Washington
Post August 22, 2001; Page A04
JAMA August
22/29 2001;286:954-959
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