Celecoxib, Rofecoxib Associated With Risk of Cardiovascular Events

Key Words

Colorectal cancer, adenoma, polyp, COX-2 inhibitors, cardiovascular disease, celecoxib (Celebrex), rofecoxib (Vioxx). (Definitions of many terms related to cancer can be found in the Cancer.gov Dictionary.)

Summary

Participants in clinical trials who took rofecoxib (Vioxx®) and celecoxib (Celebrex®) to learn if the drugs would reduce their risk of colorectal cancer had more serious cardiovascular events, including death, than patients who took a placebo (a dummy pill), two new studies show.

Although the absolute number of patients who experienced serious cardiovascular events while taking these drugs was small, the increased risk still needs to be balanced against the drugs’ potential for reducing the risk of colorectal cancer in people with a very high likelihood of developing that disease.

Source

New England Journal of Medicine, early online publication, February 15, 2005.

Background

Observational studies have shown that people who regularly take non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, to treat conditions like arthritis have lower rates of colorectal cancer and colorectal polyps (precancerous growths, also called adenomas) and are less likely to die from colorectal cancer.

NSAIDs block enzymes known as COX-1 and COX-2 that the body produces in response to inflammation and that are also produced by precancerous tissues. However, the blocking of COX-1 may cause certain medical problems, like stomach bleeding, when NSAIDS are taken regularly for long periods of time.

In the late 1990s, new NSAIDs that block COX-2, but not COX-1, enzymes came on the market in the United States. In addition to their not causing the stomach-related side-effects seen with NSAIDs that block both COX-1 and COX-2, scientific work suggested that these “selective COX-2 inhibitors” had the potential to prevent and treat cancer.

Numerous studies have been designed to test this potential against cancers of the bladder, breast, cervix, colorectum, esophagus, head and neck, skin, lung, oral and prostate, as well as multiple myeloma. The people enrolled in the two studies discussed here are at high risk for colorectal cancer because of a strong family history of the disease or because they have already had surgery to remove precancerous colon polyps.

Some earlier studies had suggested that taking certain COX-2 inhibitors might increase patients’ risk for heart attacks and strokes, while other studies had found no increased risk.

Study 1 (Merck Research Laboratories)

This study’s primary aim was to find out whether three years of treatment with the COX-2 inhibitor rofecoxib (Vioxx) would reduce the risk of recurrent colon polyps in patients who had already had surgery to remove at least one of these precancerous growths. Starting in 2000, a total of 2,586 patients in 29 countries were assigned at random to take either 25 mg rofecoxib or a placebo daily.

Because recently released data from another trial raised questions about the drug’s potential for causing heart and stroke problems remained unanswered, the study’s sponsor, Merck Research Laboratories (the maker of rofecoxib), set up an independent committee to evaluate the risk of heart and stroke problems for patients enrolled on the cancer prevention study.

This study was formally known as the Adenomatous Polyp Prevention on Vioxx (APPROVe) trial. It was led by Robert S. Bresalier, M.D., of the University of Texas M.D. Anderson Cancer Center in Houston.

Study 1 Results

After an average of two-and-a-half years of treatment, 46 out of 1,287 patients taking rofecoxib (3.5 percent) had had a “thrombotic event” (that is, a blood clot, unstable chest pain, a heart attack, a stroke or transient ischemic attack, or sudden cardiac death). By contrast, 26 out of 1,299 patients taking a placebo (2 percent) had had such an event. The risk of heart and stroke problems appeared to increase after patients had been taking rofecoxib for 18 months.

As a result of these findings, the APPROVe study was halted on September 30, 2004, about two months ahead of schedule. On the same day, Merck announced that it was voluntarily withdrawing rofecoxib from the market worldwide.

Study 2 (National Cancer Institute and Pfizer Corporation)

Like Study 1, this study’s primary aim was to test whether a COX-2 inhibitor - in this case, celecoxib (Celebrex) - was effective in reducing the recurrence of colorectal polyps in people who had already had polyps surgically removed and were thus at high risk for colorectal cancer. A total of 2,035 patients in the United States, Canada, Australia, and the United Kingdom were randomly assigned to take either 200 mg or 400 mg of celecoxib or a placebo twice a day for three years.

This study, known as the Adenoma Prevention with Celecoxib (APC) study, was sponsored by the National Cancer Institute (NCI) and co-sponsored by Pfizer Corporation, the maker of celecoxib.

When the findings of the APPROVe study were announced, NCI set up an independent committee to more carefully analyze the occurrence of heart and stroke problems in the APC study. This committee was chaired by Scott D. Solomon, M.D., of Harvard Medical School in Boston, who is the lead author of the current report.

Study 2 Results

After a minimum of 2.8 years of follow-up, 16 out of 685 patients taking the lower dose of celecoxib (2.3 percent) had died of a cardiovascular event or had experienced a heart attack, stroke, or heart failure. Among those taking the higher dose of celecoxib, 23 out of 671 patients (3.4 percent) had one of these outcomes. By contrast, seven out of 679 patients in the placebo group (1 percent) had died from a heart or vascular problem or had a heart attack, stroke, or heart failure.

NCI suspended the use of celecoxib for patients remaining in the APC study on December 17, 2004, when these findings were announced publicly. Follow-up is continuing to determine whether the drug reduced the recurrence of colorectal polyps. However, initial results presented on April 3, 2006, at the annual meeting of the American Association for Cancer Research showed that those participants taking celecoxib had fewer new adenomas and fewer new advanced adenomas than those on placebo. For more details, see The Adenoma Prevention with Celecoxib Trial: Questions and Answers ¹.

In the United States, celecoxib remains on the market for the treatment of arthritis and other chronic pain conditions, as well as an adjunct to usual care for people with Familial Adenomatous Polyposis (in which it may reduce the number of colon polyps).

Comments

"Our results heighten concern that this class of drug may be associated with increased cardiovascular risk," write the APC study authors. These risks "will need to be weighed against any potential benefits of celecoxib in preventing colorectal [cancer]." The APPROVe study authors draw similar conclusions.

Although the risk of heart and vascular problems was higher among patients in the APC study who took celecoxib compared with those who took a placebo, it is important to keep in mind that this risk may be offset by the potential benefits of the drug in certain clinical settings, says Jaye Viner, M.D., M.P.H., of NCI’s Division of Cancer Prevention.

If final results from the APC trial show celecoxib to be effective at preventing the recurrence of colorectal polyps, some patients with an extremely high risk of colorectal cancer may be willing to accept a low degree of increased risk for heart problems and stroke in exchange for better odds of remaining cancer-free, says Viner. "The risks of any drug must be balanced against its potential benefits," she adds.

Because heart and vascular problems are common in Americans, it is not a simple matter to show that a drug is responsible for an increase in the risk of these conditions, notes Viner. The heart and stroke risks associated with the use of celecoxib in the APC trial, she says, came to light in part because of the high degree of scrutiny to which the trial was subjected by the investigators.

NCI is continuing to support a number of studies examining the potential benefits and risks of using COX-2 inhibitors to prevent and treat various cancers.