Newly Released Study Shows Link Between Pfizer’s Celebrex, Cardiovascular Problems
Pfizer recently "quiet[ly]" released a previously unpublished study conducted in 1999 that found patients taking its COX-2 inhibitor Celebrex were 3.6 times as likely to have a cardiovascular event as those taking placebos, according to a Public Citizen analysis of the results, the Boston Globe reports. The 52-week study, which was never published in a medical journal, was designed to determine whether Celebrex could be used to slow the progression of Alzheimer's disease and examined the long-term effects of high doses of the medicine in the elderly (Henderson, Boston Globe, 2/1).
In the study, 285 patients were randomly selected to receive 400 milligrams of Celebrex per day, and 140 patients were given placebos. In the Celebrex group, 22 participants had heart attacks, strokes or other heart problems, compared with three in the placebo group. The study's authors wrote, "A statistically significant difference favoring placebo in adverse events was observed."
The results of the study, showing Celebrex was ineffective in treating Alzheimer's, were presented in 2000 at a conference in Sweden, according the Gail Cawkwell, Pfizer's medical team leader for Celebrex. However, she said she did not know whether safety data was presented at the conference (Berenson/Harris, New York Times, 2/1). The study's results were sent to FDA in the summer of 2001 but were not made available to an FDA panel that was reviewing the cardiovascular risks of COX-2 inhibitors earlier that year.
Pfizer recently posted the study results on a new clinical data Web site maintained by the Pharmaceutical Research and Manufacturers of America. The study initially was released last month without data on increased cardiovascular risk, but an updated study posted last week included that information (Kaufman, Washington Post, 2/1).
Public Citizen's Health Research Group Director Sidney Wolfe said he came upon the Celebrex study while on the PhRMA Web site for another reason, and he then publicized the study, the Globe reports.
The study's disclosure apparently "contradict[s] recent statements by the company" about the safety of Celebrex, according to the Globe (Boston Globe, 2/1). In December 2004, a National Cancer Institute study found that high doses of Celebrex tripled patient risk for cardiovascular events compared with a placebo. At that time, Pfizer Chair and CEO Hank McKinnell said in a statement that the results were "unexpected and not consistent with the reported findings in" other Celebrex studies (California Healthline, 12/20/04).
Pfizer maintains that although participants in the recently released study were randomly selected, patients in the Celebrex group already were at an increased risk of having cardiovascular problems. Cawkwell said, "The patients had very different cardiovascular histories" (New York Times, 2/1).
On Monday, the company released a statement saying, "Celebrex patients were up to four times more likely to have key cardiovascular risk factors compared to patients who received placebo. These risk factors include hypertension, diabetes, aspirin use and previous bypass surgery. Because of this marked imbalance in the health of the participating patients, definitive conclusions about cardiovascular risk cannot be drawn from this study" (Boston Globe, 2/1).
Cawkwell added that the study's results should not be overstated, noting that other trials have shown Celebrex to be safe and effective in treating arthritis (New York Times, 2/1).
On Monday, Public Citizen renewed its request to FDA to immediately ban Celebrex and Bextra, Pfizer's other COX-2 inhibitor. FDA said it would "review the petition carefully" (Boston Globe, 2/1). Wolfe called the newly released study a "smoking gun." He said, "This was the first randomized and placebo-controlled study to show these cardiovascular problems as statistically significant, and Pfizer had a responsibility to inform the public about it." He added, "If Pfizer sent this information to the FDA like they say and the agency sat on it, then the FDA had been incredibly irresponsible as well."
In Wolfe's assessment of the study results, he grouped together all cardiovascular events, rather than leaving them in distinct categories as the study did. He said grouping the events together made the results statistically significant, while Pfizer's analysis of the results did not. Wolfe's analysis was reviewed by Bruce Psaty, co-director of the University of Washington's Cardiovascular Research Center and an expert on cardiac medication safety. Psaty indicated that Pfizer apparently presented the cardiovascular data in a manner that minimized the evidence of risks, the Post reports. Additionally, Psaty said the company should have published the results sooner (Washington Post, 2/1).
Wolfe said he was skeptical of Pfizer's claim that patients in the Celebrex group already were at an increased risk for cardiovascular problem since the nature of a random sample seeks to eliminate patient differences that could skew the results (Rubin, USA Today, 1/31).
Psaty said, "This study was completed in 2000, but we're just learning about it in 2005, and that's just unacceptable. How can physicians be expected to responsibly prescribe drugs to their patients if we don't know the true risks and benefits?" (Washington Post, 2/1). He added, "This just speaks to the need to have clinical trials registered and reported publicly in a prompt and complete way."
This month, European and U.S. regulators will meet to discuss the risks and benefits of COX-2 inhibitors (Boston Globe, 2/1).
Kaiser Permanente, the nation's largest not-for-profit HMO, last week ordered its pharmacies to stop dispensing Pfizer's COX-2 inhibitor Bextra because of evidence that it might increase the risk of heart attack (California Healthline, 1/31). Additionally, Kaiser is asking doctors to refrain from prescribing high doses of Celebrex "until information is available to reassure our physicians that the drug is safe," according to David Campen, Kaiser's head of pharmacy operations.
Also this month, Sen. Chuck Grassley (R-Iowa) plans to introduce legislation that would encourage pharmaceutical companies to publish trial data (Boston Globe, 2/1).
Two newspapers on Tuesday published articles addressing the risks of painkillers, particularly Naproxen and COX-2 inhibitors. Headlines appear below.
Wall Street Journal: "Treating Pain Without a Prescription: With Vioxx Off the Market, Herbs and Yoga Gain Favor, But Caution Is Necessary" (Petersen, Wall Street Journal, 2/1).
- Washington Post: "Healthy Skepticism: Where the Naproxen Story Went Wrong" (Woloshin et al., Washington Post, 2/1).