FDA Safety Official Testifies COX-2 Inhibitor Cardiovascular Risks Comparable to Those of Smoking
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. 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.
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 (California Healthline, 2/17).
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Graham based his testimony on an unpublished five-year study that he conducted with Gurkirpal Singh of Stanford University School of Medicine.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).
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 (California Healthline, 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).
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."
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."
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.
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).
- 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 whistleblower 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, 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.