PSA Rising, December 17, 2004. The popular Celebrex arthritis drug more than doubled the risk of heart attack in a large colon cancer-prevention trial.
Pfizer Inc. said today that the Celebrex trial involved patients taking 400-milligram and 800-milligram daily doses of the drug to prevent colorectal cancer. The anti-inflammatory drug was being tested on the theory that inflammation is a cause of cancer.
Pfizer Inc said it received new information last night about the cardiovascular risk of Celebrex (celecoxib) based on an analysis of two long-term cancer trials.
One of the studies (the APC cancer trial) showed an increased cardiovascular risk over placebo, while the other trial (the PreSAP cancer trial) revealed no greater cardiovascular risk than placebo.
Whether this difference resulted from dosing method, length of time on drug or differences in the patient population has not yet been announced.
Celebrex belongs to a class of drugs called COX-2 inhibitors.
Dr. Richard Hayes, a cardiologist at New York University, told Reuters today, "This raises my concern about Celebrex and all the COX-2 inhibitors, so I will no longer be prescribing any of them."
NCI suspends clinical trial
In the Adenoma Prevention with Celecoxib (APC) trial, patients taking 400mg and 800mg of Celebrex daily had 2.5 to 3.4 fold increased risk of major fatal or non-fatal cardiovascular event compared to patients taking placebo, according to the National Cancer Institute (NCI).
Based on these statistically significant findings, NCI, the study sponsor, has suspended the dosing of Celebrex in the study.
The APC is a study of more than 2,000 people who have had a precancerous growth (adenomatous polyp) removed. They were randomized to take either 200 mg of celecoxib twice a day, 400 mg of celecoxib twice a day, or a placebo for three years. The trial began in early 2000, had run for 33 months and was scheduled to have been completed by Spring 2005.
In a separate long-term study, the Prevention of Spontaneous Adenomatopus Polyps (PreSAP) trial, there has been no increased risk for Celebrex patients taking 400mg daily compared with those taking placebo.
These findings are based on an identical analysis conducted by the same independent safety review board. They looked at Celebrex with a view to cradiovascular effects (heart attack and stroke) after a September 2004 report that the COX-2 inhibitor rofecoxib (Vioxx Â) caused a two-fold increased risk of cardiovascular toxicities in another colon cancer prevention trial.
"These clinical trial results are new," said Hank McKinnell, Pfizer chairman and chief executive officer. "The cardiovascular findings in one of the studies (APC) are unexpected and not consistent with the reported findings in the second study (PreSAP). Pfizer is taking immediate steps to fully understand the results and rapidly communicate new information to regulators, physicians and patients around the world," McKinnell said.
Celebrex is approved for use in the United States for the treatment of arthritis and pain, at recommended doses of 100mg to 200mg daily for osteoarthritis and 200mg to 400mg a day for rheumatoid arthritis. It is also approved for a rare condition called familial adenomatous polyposis in doses up to 800mg per day.
The APC cancer trial studied Celebrex at doses of 200mg twice a day (total 400mg) or 400 twice a day (total 800mg). In the PreSAP cancer trial the dose was 400mg per day.
Pfizer opts for damage control, stresses "context"
Pfizer in a press release today stated emphatically that only the one trial showed the increase in heart attacks.
"In placing this new information in context, it is important to understand that the APC trial results differ from both the PreSAP cardiovascular results as well as the large body of data that we and others have accumulated over time, in which an increased risk of serious cardiovascular events in arthritis patients, even at higher-than-recommended doses, had not been seen," said Dr. Joseph Feczko, president of worldwide development for Pfizer.
Pfizer has not announced any plan to pull Celebrex from the market. Last month Merck withdrew its OX-2 inhibitor arthritis drug Vioxx after data showed increased risk of heart attack and stroke. On the contrary, in today's press release Pfizer executives tout Celebrex's value for arthritis patients.
"Celebrex is an important medicine that provides necessary pain relief to many patients," president of worldwide development Dr. Joseph Feczko said. "Patients being treated with Celebrex should discuss appropriate treatment options with their healthcare professionals. Physicians should factor this new information, as well as ulcer risks and gastrointestinal bleeding seen with traditional NSAIDs, into their prescribing decision."
The information from this Pfizer sponsored trial was received by Pfizer last night and, as with the APC information, was immediately shared by the company with the U.S. Food and Drug Administration.
The two studies, which are following patients over a five-year period, have enrolled a total of about 3,600 patients, some of whom have participated for more than four years. Pfizer estimates that about 2,400 patients evaluated in the cardiovascular analysis have completed two years of treatment.
A third long-term study involving Celebrex in patients at high-risk for Alzheimer's disease is also under way with about 2,000 patients enrolled, about 750 of whom are on 400mg per day of Celebrex. As with the cancer studies, this study is monitored by independent safety experts who meet regularly to assess adverse events. A review by this board as recent as December 10 did not result in any recommendations to change the conduct of this study, Pfizer said.
The COX-2 inhibitor rofecoxib (Vioxx™) was removed from the market on September 30, 2004 after a two-fold increased risk of cardiovascular toxicities was identified in people taking the drug for 18 months.
In September and October, the Data Safety and Monitoring Boards of the Pfizer APC and PreSAP Celebrex cancer trials conducted a preliminary review of all the then-available data and determined to proceed with the studies.
With the cooperation of Pfizer, the safety review boards convened a panel of cardiovascular experts to conduct additional reviews and analyis of the data from these two trials.
Last evening, Pfizer received preliminary information resulting from the reviews. The company has not yet received the full analyzes of these studies.
Pfizer has already announced plans to sponsor a major clinical study to further assess Celebrex in osteoarthritis patients at high-risk for cardiovascular disease. The company plans to continue to work with the FDA on this projected study.
Pfizer closes its press release with the standard"package insert" product warning:
Additional Information on Celebrex. Patients who have aspirin-sensitive asthma, or allergic reactions to aspirin or other arthritis medicines or certain sulfa drugs called sulfonamides, or who are in their third trimester of pregnancy should not take Celebrex. As with all NSAIDs, serious gastrointestinal tract ulcerations can occur without warning symptoms. Physicians and patients should remain alert to the signs and symptoms of GI bleeding. Celebrex does not affect platelet function and therefore should not be used for cardiovascular prophylaxis. As with all NSAIDs, Celebrex should be used with caution in patients with fluid retention, hypertension, or heart failure. In overall clinical studies the most common side effects of Celebrex were dyspepsia, diarrhea and abdominal pain, which were generally mild to moderate.
NIH Halts Use of COX-2 Inhibitor in Large Cancer Prevention Trial Friday, December 17, 2004
Edited by J. Strax,December 17, 2004
