For pain reliever,
questions of risk remain
By: Gina Kolata
New York Times, October 9, 2001
The prescription pain relievers Vioxx and Celebrex
surged onto the scene two years ago with an unprecedented marketing effort
by their makers and an avalanche of sales. Patients demanded the drugs.
And doctors took out their prescription pads, often not even trying to
dissuade people who would have done just as well with a cheap alternative,
like acetaminophen or aspirin.
Tens of millions of
prescriptions have been written, and the drugs remain wildly popular. But
now there are troubling questions about whether Vioxx may have an
unexpected side effect — a very slight increase in the risk of heart
attack.
The risk is hypothesized,
not proved; it was suggested in a single Vioxx study and not in studies of
Celebrex. And even one of the researchers who is most worried, Dr. Eric
Topol, a heart disease expert at the Cleveland Clinic, said, "We are
not talking about big risks here." He added that his analysis showed
that both Vioxx and Celebrex might increase the risk of heart attacks by
0.3 percent to 0.5 percent a year. That number may seem small, but with
millions of people taking the drugs, even a small increase means
"you've got a lot of heart attacks on your hands," he said.
In interviews, leading
arthritis specialists who have no financial ties to Merck, the maker of
Vioxx, or Pharmacia, which makes Celebrex, say that they are not concerned
and that they prescribe the drugs for patients who may have heart disease.
But the Food and Drug
Administration recently sent Merck a warning letter, telling the company
that its marketing campaigns had to discuss the possibility that Vioxx
might increase the risk of heart attacks. And some heart specialists say
they are now telling patients that they may want to consider taking other
drugs for pain.
At issue is the subtle
question of what counts as evidence. The new drugs, known as cox-2
inhibitors, were developed because scientists had discovered a way to make
a drug that could alleviate pain and inflammation like aspirin, ibuprofen
and naproxen, but without their tendency to cause stomach pain, bleeding
or ulcers in a small percentage of people.
Huge clinical trials
involving thousands of arthritis patients — the principal intended users
of the new drugs — showed that the drugs performed as expected. They
were as effective in relieving inflammation as aspirin and the other
nonsteroidal anti-inflammmatory drugs available over the counter. And the
incidence of stomach ulcers and their complications plummeted.
But a few years ago, Dr.
Garret FitzGerald, a University of Pennsylvania scientist, raised a
theoretical question: can cox-2 inhibitors shift a biochemical balance so
that blood will be more likely to clot? If so, patients taking cox-2
inhibitors may be at greater risk for heart attacks and strokes.
As a consequence, said Dr.
Edward Scolnick, the president of Merck Research Laboratories, the company
decided to look specifically for excess heart attacks and strokes in a new
study it was designing.
The study, known as Vigor,
involved 8,000 rheumatoid arthritis patients who were randomly assigned to
take Vioxx or naproxen. Its main objective was to look for
gastrointestinal side effects. It found that patients taking Vioxx had
less than half the incidence of these disorders — 2.09 percent had the
complications, compared with 4.49 percent of patients taking naproxen.
But the study also found
that the patients taking naproxen had just one quarter the number of heart
attacks of those taking Vioxx. Twenty Vioxx patients, 0.5 percent, had
heart attacks, compared with four, or 0.1 percent who took naproxen.
"There are two
possible interpretations," Dr. Scolnick said. "Naproxen lowers
the heart attack rate, or Vioxx raises it." Either cox-2 inhibitors
shift the clotting balance, or naproxen, which can impede blood clotting,
has a protective effect.
And so, while the company
announced the heart attack findings to doctors and the public, it looked
back at its data from studies using different drugs or dummy pills in
comparison to Vioxx. It found no evidence that Vioxx increased the risk of
heart attacks, Dr. Scolnick said.
He said the company
decided that "the likeliest interpretation of the data is that
naproxen lowered lowered the thrombotic event rate," meaning that it
protected patients from heart attacks. He added that without the
theoretical question raised by Dr. Fitzgerald, "no one would have a
question remaining in their mind that their might be an additional
interpretation."
On the other hand, Dr.
Scolnick said, now that the clotting question has been raised, none of the
findings to date are enough to prove that the issue is fully resolved.
That lack of proof is why the F.D.A. demanded that Merck explain both
sides of the hypothesis, telling doctors and patients that it is not known
whether naproxen protects against heart attacks or Vioxx makes them more
likely.
In the meantime, Dr. Geis,
the group vice president for clinical research of Pharmacia, said his
company's drug, Celebrex, was getting tarred with the same brush.
Pharmacia's studies never showed any increase in heart attacks or strokes
in patients taking Celebrex, he said.
"We say, you must
look at the data with the individual drugs and not make a sweeping
statement about all cox-2 inhibitors," Dr. Geis said. He added that
the company constantly heard from doctors and patients who were worried
that Celebrex caused heart disease. And, he said, every time he addresses
a medical meeting, he is asked about it. In question-and-answer sessions
after his talks, he said, someone always says, "Tell us about the
cardiovascular effects."
Usually, Dr. Geis said, he
has already discussed the data in his talk, but he does so again.
"We systematically go
through our data," he said, and he carefully explains again that the
Celebrex studies found no such effect.
Dr. Topol, the heart
disease researcher, said his analyses of the data on Celebrex and Vioxx
indicated that the drugs might be making blood more likely to clot and so
might slightly increase the risk for a heart attack.
All of his patients
already have heart disease, he said. And, he added, "We don't have a
clue to what we should be doing in patients with heart disease." He
tells them to take other drugs for pain if they can tolerate them. And, he
said, someone — Merck or Pharmacia or the federal government — should
conduct a study in patients with heart disease to find out conclusively if
the cox-2 inhibitors increase heart disease risk.
Some leading doctors who
treat arthritis patients are less concerned. "By and large, the drugs
are very helpful," said Dr. Michael Lockshin, who directs the Barbara
Volcker Center for Women and Rheumatic Disease at the Weill Medical
College of Cornell University. Dr. Lockshin does not consult for and is
not on the speaker's bureau of Merck or Pharmacia.
While most patients can
safely take drugs like aspirin, he added, it is impossible to predict
ahead of time who will have problems with gastrointestinal bleeding, and
so the cox-2 inhibitors are useful because, he said, they give doctors and
patients, "a freedom from that concern."
Dr. John Sergent, an
arthritis expert who is chief medical officer at Vanderbilt medical
school, also continues to prescribe Vioxx and Celebrex and, like Dr.
Lockshin, has not even suggested to Vioxx patients that they switch to
Celebrex. He too is neither a consultant nor a member of the speaker's
board for Merck or Pharmacia.
Doctors say that even
though some patients worry about cox-2 inhibitors, many people continue to
ask for the drugs. And doctors tend to comply, even when they suspect that
the patients would do just as well with a cheap, over-the-counter pain
reliever. Dr. Lockshin, for example, said about half of his arthritis
patients who took nonsteroidal anti-inflammatory drugs took cox-2
inhibitors. "That's as much due to public pressure as to my
desires," he said. "They come in all the time and ask for
them," he said.
Dr. Sergent has the same
experience. "We have a lot of people who don't have contraindications
to the standard drugs and who get cox-2 inhibitors," he said.
"If someone comes in and says, `My friend is on Vioxx and I took some
of it and it made me feel great,' I may not go to the trouble of
suggesting they take naproxen first," he said.
And, Dr. Sergent added,
doctors and patients tend to expect that an office visit will lead to a
prescription. "To go to a doctor, pay for a consultation, get X-rays,
and then have the doctor say, `What you need are six acetaminophen a day,'
is sort of a downer for both the doctor and the patient," Dr. Sergent
said.
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