Good news and bad news about COX-2 inhibitors

The medicine decreases cancer risk while boosting cardiovascular disease risk. Researchers are hopeful about the future of chemoprevention of carcinoma.

By Victoria Stagg Elliott — Posted Sept. 25, 2006

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In September 2004, preliminary trial data were released suggesting that long-term use of COX-2 inhibitors brought an increased cardiovascular risk.

The finding made a big splash and ultimately led to the dislodging of this drug class from the bestseller list.

Now, two years later, the research question these projects were designed to answer -- whether the COX-2s offer protection from certain cancers -- has been solved. These drugs do reduce the chance of colorectal polyps in patients who have a history of them, but the price of this prevention is a dramatically increased risk of heart and vascular disease, according to a pair of studies published in the New England Journal of Medicine last month. The trials randomized just over 3,500 patients to various dosages of celecoxib (Celebrex) or placebo.

A related paper, this one published in the August online edition of Gastroenterology and expected in print in December, involved patients receiving 25 mg of rofecoxib (Vioxx) and reached similar conclusions.

"The clear message is that COX-2 inhibitors prevent colon polyps, and the effect is fairly substantial," said Curt Furberg, MD, PhD, professor of public health sciences who participated in the Food and Drug Administration advisory committee meetings regarding safety issues related to these drugs. "But that's just one effect."

An editorial, also in the August New England Journal of Medicine, concluded that the dream of using currently available COX-2 inhibitor medications for cancer prevention in the general population is effectively dead. The burden of cardiovascular disease associated with their use is too great. Also, although this regimen was proven to reduce polyps that can lead to colorectal cancer, it has yet to be shown to prevent actual cancers.

"The risk far exceeds the benefits," said Bruce Psaty, MD, PhD, the editorial's lead author and a professor of medicine and epidemiology at the University of Washington School of Medicine. "And there's no evidence that there's a clinical benefit in terms of cancer prevention. We'd like to have something that's both safe and effective. We don't have that right now."

For those who need to reduce their risk of colon cancer, it remains an option only for the very small number who are at extremely high risk but at very low risk for heart trouble. In fact, celecoxib (Celebrex), the only COX-2 still on the market, is approved for this purpose in patients who have familial adenomatous polyposis.

"For the general population at low risk of colon cancer, [taking COX-2 inhibitors] doesn't seem to be the smartest move," said Trish Palmer, MD, assistant professor in the Dept. of Family Medicine at Rush Medical College in Chicago. "For people at high risk of colon cancer, it's an effective medication, but we have to take into consideration the cardiovascular risk factors."

This drug also remains a possibility for those who need pain relief. According to statements posted on the Web site of Pfizer, the drug's manufacturer, the current labeling reflects the cardiovascular impact noted in these studies, and the company is funding research to determine how celecoxib compares with other pain relievers in this regard. The subjects of these studies also took celecoxib at higher dosages and for a longer time period than most patients who take this drug for osteoarthritis.

The possibility of chemoprevention

But the dream of someday reducing the risk of cancer by taking a pill is far from over. Those who have been working in this area are disappointed but also excited because these studies proved that chemoprevention of cancer is a possibility. The task ahead is to find something that does not exact such a high price.

"The toxicity is overriding here," said John Baron, MD, lead author on the Gastroenterology paper and professor of medicine at Dartmouth Medical School in Hanover, N.H. "But this study shows it's possible for drugs to be effective. It shows we can interfere with carcinogenesis. The next job is to do that without the toxicities."

The studies also suggest the possibility that some other formulation or regimen of a drug that inhibits COX-2 may be a possibility. For example, one of the NEJM studies found that patients who took 200 mg or 400 mg of celecoxib twice daily more than doubled their risk of cardiovascular disease, depending on the dosage. The other, which had subjects taking 400 mg daily, did not find a statistically significant increase in such adverse events.

"This may be a clue to a strategy that might be effective," said Dr. Bernard Levin, lead author on that study and vice president for cancer prevention at the University of Texas - Anderson Cancer Center in Houston.

In addition to providing possible leads for cancer prevention, this line of research also answered the long controversial question of the impact these drugs have on the heart.

"The study was very, very informative and very beneficial to the medical community," Dr. Baron said.

"I see the study as a success in scientific terms."

Researchers are continuing to pursue a variety of medical and lifestyle options for preventing this cancer. But until a better solution is found, experts advocate increased use of already proven strategies such as healthy eating, physical activity and screening.

"For the vast majority of people, some form of surveillance colonoscopy does the job," Dr. Levin said.

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The rise and fall of COX-2 Inhibitors

The Food and Drug Administration approved Celebrex (celecoxib) in 1998, Vioxx (rofecoxib) in 1999 and Bextra (valdecoxib) in 2001. With them came hopes for preventive powers. But risks, too, soon emerged. Some key dates:

Nov. 23, 2000: Vioxx GI Outcomes Research trial results published in the New England Journal of Medicine indicate that arthritis patients who take rofecoxib have fewer gastrointestinal adverse events than those who take naproxen. Cardiovascular risk appears similar.

Aug. 22, 2001: A special communication in the Journal of the American Medical Association notes a possible increased cardiovascular risk associated with use of COX-2 inhibitors.

April 11, 2002: Information about possible increased cardiovascular risk added to the label of rofecoxib.

Sept. 30, 2004: Merck & Co. withdraws rofecoxib from the market after data from trials regarding its use to prevent colorectal polyps and cancer confirm a significant increased cardiovascular disease risk.

Dec. 9, 2004: Cardiovascular risk and severe skin reaction warnings are added to the label of valdecoxib.

Dec. 17, 2004: The National Cancer Institute halts a study of celecoxib as a possible colon polyp preventive because of an increase in cardiovascular events among participants.

Dec. 8, 2005: NEJMeditors accuse those behind the VIGOR trial of withholding data about cardiovascular events associated with rofecoxib.

April 7, 2005: Valdecoxib is withdrawn from the market. Additional warnings about cardiovascular risk are added to the label of celecoxib.

Aug. 31, 2006: Two studies published in NEJM confirm that COX-2 inhibitors prevent colorectal polyps but significantly increase the risk of cardiovascular disease.

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External links

"Celecoxib for the Prevention of Sporadic Colorectal Adenomas," New England Journal of Medicine, Aug. 31 (link)

"Celecoxib for the Prevention of Colorectal Adenomatous Polyps," New England Journal of Medicine, Aug. 31 (link)

"Risks and Benefits of Celecoxib to Prevent Recurrent Adenomas," New England Journal of Medicine, Aug. 31 (link)

"Enhanced Physician Access to Food and Drug Administration Data," American Medical Association's Council on Scientific Affairs, June 2005 (link)

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