Prescription Pharmacy Rx News
Coxib cardio risks: Class effect?
EU health regulators reviewing long-term data for all COX-2 inhibitors; U.S. researchers cite evidence for class risk, blast inaction on rofecoxib.
The European Medicines Agency (EMEA) announced yesterday that
it will spend the next 2 weeks reviewing the available long-term
data on cardiovascular safety for all licensed COX-2) inhibitors.
The results of the review will be discussed during meetings of
the agency’s Committee for Medicinal Products for Human
Use and its Pharmacovigilance Working Party later in October.
EMEA plans to assess studies of celecoxib (Celebrex—Pfizer),
valdecoxib (Bextra—Pfizer), etoricoxib (Arcoxia—Merck),
and parecoxib (Dynastat—Pfizer), as well as those of rofecoxib
(Vioxx—Merck). Parecoxib is not approved by FDA for sale
in the United States, and Merck is currently pursuing an NDA
for etoricoxib.
The move was prompted by Merck’s worldwide market withdrawal
of rofecoxib after evidence from a study of its use for preventing
colon cancer showed that long-term (more than 18 months) use
of the COX-2 inhibitor significantly raised a patient’s
risk for myocardial infarction (MI) and stroke. EMEA investigators
conducted a comprehensive review of coxib safety in late 2003
and noted that while use of the drugs posed some cardiovascular
risks, the benefits outweighed those risks.
Merck has halted the manufacturing and marketing of rofecoxib
and has made arrangement with the National Notification Center
(800-805-9542) to coordinate returns of the product. The company
is promising to reimburse patients for their unused doses of
Vioxx.
Pfizer is denying that either of its COX-2 agents has associated
risks similar to those of rofecoxib. In an article posted early
to the New England Journal of Medicine (NEJM) Web site, however,
Garrett A. Fitzgerald, MD, of the University of Pennsylvania,
argues that increased risk for adverse cardiovascular events
is common to all coxibs.
FitzGerald, whose article will also be published in the October
21 issue of NEJM, cites evidence he and colleagues found as early
1999 that all COX-2 inhibitors suppress formation of prostaglandin
I2. Suppression of this hormone can potentially raise users’ risk
for MI and thrombotic stroke by leading to elevations in their
blood pressure and by speeding atherosclerosis.
In light of this evidence, FitzGerald advises that coxib therapy
be avoided in patients with or at risk for cardiovascular disease.
He also notes that FDA and the makers of COX-2 inhibitors have
been remiss in issuing appropriate warnings and usage guidelines,
writing: “The rofecoxib story … reflects poorly on
the process that leads to drug approval. The rational basis for
addressing the cardiovascular effects of these drugs has been
clear for the past five years, yet even the most fundamental
questions have not been addressed directly.” He concludes
his article with a call for long-term follow-up with rofecoxib
users to determine long-range risks and for more studies to determine “whether
the cardiovascular risk is or is not a class effect.”
Eric J. Topol, MD, of the Cleveland Clinic Foundation, is much
more direct and forceful in his criticism in “Failing the
Public Health—Rofecoxib, Merck, and the FDA,” another
October 21 article that has been released early on the Web site
of NEJM. Topol describes how he and colleagues analyzed risk
data made public by FDA in 2001, found that patients using rofecoxib
experienced more MIs than did patients taking placebo, and called
for a study specifically designed to determine the level of risk.
He then takes the company to task for failing to conduct that
study, and the U.S. drug agency to task for failing to require
it. Rather than conduct the safety study, Topol writes, Merck
sponsored journal articles, symposia, and continuing medical
education sessions on the theme spelled out in the title of a
May 21, 2001 company news release, “Merck Reconfirms Favorable
Cardiovascular Safety of Vioxx.”
After noting that 80 million patients have taken Vioxx since
its 1999 approval by FDA and that in the study that led Merck
to withdraw rofecoxib 3.5% of active treatment patients experienced
an MI as opposed to 1.9% of patients who received a placebo,
Topol asks for a congressional investigation of Merck and FDA. “The
senior executives at Merck and the leadership at the FDA,” he
writes, “share responsibility for not having taken appropriate
action and not recognizing that they are accountable for the
public health.”
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