US study estimates excess heart disease events caused by Vioxx
Use of rofecoxib (Vioxx) in the US between 1999 and 2004 could have been responsible for between 80,000 and 140,000 cases of serious coronary heart disease, a study reveals.
David Graham, from the office of drug safety at the US Food and Drug
Administration, and colleagues used data collected from 1.4 million patients
treated under a Kaiser Permanente managed care system in California.
Patients had received various non-steroidal anti-inflammatory drugs (NSAIDs),
including celecoxib (Celebrex, around 40,000 users), ibuprofen (just
under a million users), naproxen (around 435,000 users) and rofecoxib
(around 27,000 users).
The researchers identified 8,143 cases of serious coronary heart disease,
2,210 of which were fatal, and matched each case with four controls.
By comparing the incidence of coronary events among users of the cyclo-oxygenase-2
(COX-2) inhibitors rofecoxib and celecoxib and among users of other NSAIDs
the researchers found evidence that rofecoxib increased risk of serious
coronary heart disease (see Panel).
Risk of serious coronary heart disease
Patients treated with rofecoxib (all doses)
were found to have a 34 per cent higher risk of coronary heart
disease compared
with
patients who had previously been treated with other NSAIDs (adjusted
odds ratio 1.34, 95 per cent confidence interval 0.98–1.82,
P=0.066). For patients treated with rofecoxib at a dose higher
than 25mg daily the risk increased (3.00, 1.09–8.31, P=0.03).
Risk was amplified with recent use of any NSAID, current use of
naproxen, and current use of other NSAIDs (attributable to the
effects of diclofenac).
In current users of celecoxib, a slightly reduced risk was noted
(0.84, 0.67–1.04, P=0.12). |
The researchers estimate that 88,000–140,000
excess cases of serious coronary heart disease probably occurred in the
US over the market life
of rofecoxib. “In the future, when
trials show that a new treatment confers a greater risk of serious adverse
effect than a standard treatment, we must be much more careful about
allowing its unrestrained use,” they conclude (published online
in The Lancet on
25 January).
In an accompanying editorial, Simon Maxwell and David Webb, of the University
of Edinburgh, remark that increased attention will now be directed towards
the cardiovascular safety of other COX-2 inhibitors. “It now falls
to the manufacturers, under the careful review of the regulatory authorities,
to provide all the evidence that this class of drugs is safe, if necessary
including studies that directly address cardiovascular morbidity as a
primary outcome.”
A spokeswoman for Merck, Sharp & Dohme, the company that manufactured
Vioxx, said Dr Graham’s estimates were speculation based on observational
studies. “In
addition, Dr Graham’s conclusion is based on the assumption that
the relative risks he identified applied equally to patients who took
Vioxx for two days as it did to patients taking Vioxx for two years.”
Merck estimates that there were 105 million US prescriptions written
for Vioxx from May 1999 through to August 2004 and that the number of
patients who have taken Vioxx in the US since its launch is approximately
20 million.
The company was unable to provide similar figures for the UK but estimates
that approximately 400,000 patients were prescribed Vioxx in the three
months before the end of August 2004.
The Lancet study coincides with others published this week that
add to the growing body of evidence on the cardiovascular risks associated
with
COX-2 inhibitors (Archives of Internal Medicine 2005;165:161 and 181).
EMEA review In response to an ongoing review
of COX-2 inhibitors by the European Medicines Agency, Pfizer has agreed not to launch
its celecoxib product Onsenal in Europe until the EMEA has finalised
its assessment.
Onsenal has orphan status for the treatment of adenomatous intestinal polyps
in familial adenomatous polyposis.
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