FDA Safety Official Testifies COX-2 Inhibitors Have Cardiovascular Risks Similar to Smoking at Advisory Committee Meeting

COX-2 inhibitors increase risk for cardiovascular events at about the same rate as cigarette smoking, hypertension and diabetes, FDA Office of Drug Safety Officer David Graham told an agency advisory committee on Thursday, the Washington Post reports (Kaufman,
Washington Post, 2/18). The committee, which began three days of meetings on Wednesday to examine the safety of COX-2 inhibitors,
includes members of the FDA arthritis and drug safety and risk management advisory committees. The committee decided to meet amid increased
scrutiny of FDA and questions about the safety of COX-2 inhibitors after Merck in September 2004
withdrew from the market the COX-2 inhibitor Vioxx over safety concerns. In addition, FDA recently announced that Bextra -- a COX-2 inhibitor
manufactured by Pfizer -- could increase risk for heart attack and stroke, and recent studies have
found that similar risks could apply to all COX-2 inhibitors (Kaiser Daily Health Policy Report, 2/17). Pfizer officials in January also agreed to an FDA request to end all direct-to-
consumer advertisements for the COX-2 inhibitor Celebrex after a national study found that high doses of the medication tripled patient risk for
cardiovascular events (Kaiser Daily
Health Policy Report, 1/13). The committee will advise FDA on whether to remove COX-2 inhibitors from the market, reduce the dose or
duration of use, require more explicit warning labels or limit use of the medications to individuals who have a low risk for heart problems. The committee
also could request additional studies to examine whether COX-2 inhibitors increase risk for cardiovascular events (Kaiser Daily Health Policy
Report, 2/17).

Graham Testimony
At the meeting, Graham testified that all COX-2 inhibitors can increase risk for heart attacks
and strokes and might not provide more benefits than older pain medications, such as aspirin, ibuprofen and naproxen. In addition, Graham said that the
nonsteroidal anti-inflammatory drug Mobic -- a COX-2 inhibitor substitute manufactured by Boehringer Ingelheim and distributed by Abbott Laboratories
-- might have the same safety risks as Vioxx and other COX-2 inhibitors. Mobic became the most popular prescription pain medication for arthritis in the
United States after the Vioxx withdrawal (Washington Post, 2/18). Graham based his testimony on an unpublished five-year study that he
conducted with Gurkirpal Singh of Stanford University School of Medicine. The study examined
data from about 650,000 California Medicaid beneficiaries who received either Vioxx or Celebrex. The study found that participants who took Vioxx were
more likely to experience heart attacks than those who took Celebrex. In addition, the study found that participants who took as much as 200 milligrams of
Celebrex did not have a higher risk for cardiovascular events than those who did not take COX-2 inhibitors. However, participants who took more than 200
milligrams of Celebrex were 24% more likely to experience cardiovascular events than those who did not take COX-2 inhibitors (Alonso-Zaldivar/Gellene,
Los Angeles Times, 2/17).

Study Concerns
In the weeks prior to the committee meetings, Graham said that FDA
officials instructed him not to present the results of his study because they were not adequately reviewed. FDA officials said that they advised Graham to
"rely on published literature in his talk" and that he could decide whether to include data from the unpublished study (Kaiser Daily Health Policy Report, 2/14). Acting FDA
Commissioner Lester Crawford on Thursday told Graham that he could include the unpublished study results (Silverman, Newark Star-Ledger, 2/18). According
to the Post, "It is unusual for such research to be presented publicly before it has been peer-reviewed" and published (Washington
Post, 2/18). Some committee members said that the criticisms Graham made about all COX-2 inhibitors were not supported by his data,
according to CQ HealthBeat. In response, Graham said, "Maybe a better thing to say in the end is that you do need to look at it drug by drug."
He added, "I would submit to the committee that you actually know very little about the population benefit of any of these products" (CQ
HealthBeat, 2/17). "I believe there is a COX-2 effect, and that it is dose dependent," he said (Baer, Baltimore Sun, 2/18). Graham also said that "no safe level" exists for Vioxx. He
said, "The bottom line is, there really doesn't appear to be a need for COX-2" inhibitors (Los Angeles Times, 2/18).

Pharmaceutical
Industry Response
Merck spokesperson Casey Stavropoulos said that the company could not comment on the Graham presentation because
he used data from the unpublished study, which Merck officials have not reviewed (Baltimore Sun, 2/18). Boehringer Ingelheim
spokesperson John Yonsky called the Graham presentation "a surprise to us and to many people." He added, "This was preliminary and unpublished data
that was presented, and we have no way to address it. All I can say is that more than 10 million people have taken Mobic in 100 countries, and we've seen
no trends towards excess risk of cardiovascular events."

Additional Response
Arthritis Foundation President John Klippel said, "I don't think showing slides of data and having a person present their opinion is equivalent to a
scientific vetting of a study. The public and interested parties have to scrutinize this data before people start acting on it." He added, "We've lost touch
with the benefits of these drugs, which are considerable" (Washington Post, 2/18). Committee Chair Alastair Wood said that committee
members were not concerned about the data from the unpublished study. He said, "We're all big boys and girls. It would probably be much worse if data
popped up later that someone said they had but were prevented from presenting." He added, "I see a very clear cardiovascular signal from all of these
drugs that is of a substantial magnitude. That would seem to necessitate some clear action to safeguard patients going forward."

Other
Testimony
Committee members also heard testimony from a National Cancer Institute
physician who said that COX-2 inhibitors might help prevent colon cancer. Womack Army
Medical Center physician Capt. Christopher Grubb also testified that COX-2 inhibitors are "essential in the global war on terrorism" because they help
relieve pain for U.S. troops and do not cause bleeding, as aspirin can (Los Angeles Times, 2/18). The committee on Friday likely will make
recommendations to FDA on COX-2 inhibitors.

European Union Officials Restrict COX-2 Inhibitors
In related news, public health
officials in the European Union on Thursday, after four days of meetings, said that physicians should not prescribe the COX-2 inhibitors Celebrex, Bextra
or Arcoxia, which is manufactured by Merck, to patients who have a history of heart disease or stroke. They also recommended that physicians not
prescribe Arcoxia for patients with hypertension and prescribe other patients the lowest possible doses of all COX-2 inhibitors for the most limited period
of time (Baltimore Sun, 2/18).

Broadcast coverage
CBS's "Evening News": The program includes coverage of the FDA meetings (Kaledin "
Evening News," CBS, 2/17). A video excerpt is available online in RealPlayer. CNN's "Live From": The program includes comments from CNN medical correspondent Elizabeth Cohen (Cohen, "Live From," CNN, 2/17).
The complete transcript is available online. CNN's "Live From": The program includes
comments from Dr. Chris Pappas of St. Luke's Episcopal Hospital,
pharmaceutical industry whistle-blower David Franklin and U.S. Attorney Mike Sullivan. (Griffin, "Live From," CNN, 2/17). The complete transcript is
available online. CNN's "Newsnight with Aaron Brown": The program includes comments
from rheumatologist Stephen Paget, a Celebrex user David Pollinger and Elizabeth Tindall of the American College of Rheumatology. (Brown, "Newsnight with Aaron Brown," CNN, 2/17). The complete transcript is available online. NPR's "Day to Day": The segment includes comments from Byron Cryer of
the University of Texas Southwestern Medical School, University of Pennsylvania researcher Garret FitzGerald and Steven Galson, acting director of the of
the FDA Center for Drug Evaluation and Research (Silberner, "Day to Day," NPR, 2/17). The complete segment is available online in
RealPlayer.















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View drug information on Bextra; Mobic; Vioxx.