October 11, 2002
by Clinton Colmenares
A new study by Vanderbilt researchers shows that some people who take
high doses of the non-steroidal anti-inflammatory drug (NSAID) rofecoxib,
commonly called Vioxx, are at almost twice the risk of developing heart
disease, including heart attack.
The research, published in the Oct. 5 issue of the British medical
journal Lancet, reinforces findings from a previous clinical trial of the
drug that suggested a link between Vioxx and heart disease. By reviewing
medical data of close to 300,000 people for two and a half years,
researchers were able to compare people on a variety of NSAIDS to patients
not taking those drugs. One group in the study took 25 mg of Vioxx and
another took a higher dose, 50 mg. It’s the last group that, compared to all
the others, had a higher rate of heart disease and heart attack, even though
they were not at greater baseline risk for developing heart problems.
“All the data taken together suggest there’s no increased benefit from
taking the higher dose (50 mg), but there are increased risks,” said Dr.
Wayne Ray, professor of Preventive Medicine who led the study.
The higher dose is recommended only for short-term use against acute
pain; for example, for up to five days following surgery. The higher dose is
not indicated for treatment of chronic pain associated with arthritis.
However, both doctors and patients seem to be confused about this, according
to Dr. Marie Griffin, professor of Preventive Medicine and a co-author in
the study.
Fifteen percent to 20 percent of the people in the study population who
were prescribed 50 mg of rofecoxib received more than a five-day supply,
most commonly, a 30-day supply, Griffin said.
A large clinical trial called VIGOR studied Vioxx, which blocks only the
cox-2 enzyme associated with pain, in 50 mg doses to show that the drug did
not cause gastrointestinal side effects seen with older NSAIDS that block
both cox-2 and the enzyme cox-1, which protects the stomach lining. “From
that study, people inferred that 50 mg was the right dose, but it’s not,”
Ray said.
But many people are not aware that all NSAIDS, including rofecoxib, have
other side effects, including increased blood pressure, increased risk of
kidney problems and edema, or swelling, Griffin said. These effects are
likely to be most pronounced for high doses, such as the 50 mg dose of Vioxx.
The VIGOR trial tested rofecoxib against another NSAID, naproxen, and
found a five-fold increase in heart disease. But the trial was in patients
with rheumatoid arthritis who had to receive some kind of NSAID, and
therefore was unable to include an “untreated” control group.
"This is an important study from a respected group with a long history of
investigation of the side effects of anti-inflammatory drugs. The study
provides critical information lacking from the initial study linking Vioxx
to an increased risk of cardiovascular disease," said Dr. Larry Marnett,
Mary Geddes Stahlman Chair in Cancer Research. "Specifically, the present
work demonstrates that other NSAIDS beside Vioxx do not confer the same risk
of cardiovascular side effects at clinical doses and that the effects seen
with Vioxx depend upon the dose taken.
"It is particularly important to note that cardiovascular side effects
were not seen with the other COX-2 inhibitor, Celebrex, or with Vioxx itself
at the doses recommended for treatment of inflammation. COX-2 inhibitors are
enormously popular and currently account for more than 40 percent of the
anti-inflammatory market. The Ray and Griffin study provides a much stronger
basis for physicians to make recommendations to patients regarding the use
of COX-2 inhibitors."
The study compared current users of the drugs ibuprofen, naproxen,
celecoxib, rofecoxib (25 mg) and rofecoxib (50 mg). The number of heart
disease events (heart attack, coronary heart disease death) in people on
other NSAIDS, no NSAIDS or 25 mg of rofecoxib was about 12 in 1,000 per
year. In people taking 50 mg of rofecoxib the number was 21 in 1,000.
Others participating in the Lancet study were Dr. C. Michael Stein,
associate professor of Medicine and Pharmacology, Dr. Patrick Arbogast,
assistant professor of Preventive Medicine, and James Daugherty and Kathi
Hall, analysts in Preventive Medicine.
Therapeutic
Dosage
