Long-term Celebrex Use Increases Cardiovascular Event Risk

Brigham and Women's Hospital data analysis offers details of Celebrex " related cardiovascular risk in patients participating in colorectal cancer prevention study

Boston " Clinical researchers at Brigham and Women's Hospital (BWH) found in December 2004, in a large colorectal cancer prevention study, patients who were prescribed the arthritis drug celecoxib (Celebrex) daily for an average of almost three years had an increased risk of serious cardiovascular events. Among the events reported were death due to cardiovascular causes, heart attacks, strokes and heart failure. Participants prescribed 200 mg of celecoxib twice a day had a 2.3 times greater risk of these serious cardiovascular events and those who were prescribed 400 mg of celecoxib twice a day had 3.4 times greater risk of these serious cardiovascular events when compared to study participants taking a placebo.

Details of this research are published online in the New England Journal of Medicine in advance of an FDA-led joint public meeting of the agency's Arthritis Advisory Committee and the Drug Safety and Risk Management Advisory Committee February 16, 17 and 18, 2005. The committees will discuss the overall benefit-to-risk considerations (including cardiovascular and gastrointestinal concerns) for COX-2 selective non-steroidal anti-inflammatory drugs (NSAIDs) and related medicines in various clinical settings.

The December 2004 BWH-led findings prompted the suspension of Celebrex within the Adenoma Prevention with Celecoxib (APC) Trial " a trial that is cosponsored by the National Cancer Institute (NCI), one of the National Institutes of Health (NIH) and by Pfizer, Inc., the manufacturer of celecoxib (Celebrex). The trial, led by BWH's Monica Bertagnolli, MD, included more than 2,000 people with a history of precancerous colon polyps. The study began in late 1999 and is scheduled to end in Spring 2005. Participants in the study were to take celecoxib or placebo for three years.

"These data suggest that there may be an increase in cardiovascular risk associated with the use of celecoxib. This information should be viewed in light of other studies of COX-2 inhibitors that have suggested cardiovascular risk," said Scott Solomon, MD, lead author of the data analysis study, director of Noninvasive Cardiology at BWH and associate professor of Medicine at Harvard Medical School. "The cardiovascular events were serious, but the total number of events within the trial were small. These risks will need to be weighed against any potential benefit of celecoxib in preventing colorectal cancer or in relieving pain."

The data from this trial was reviewed by additional cardiovascular experts who were added to the study's Data Safety Monitoring Board in October 2004 by the NIH after another COX-2 inhibitor, rofecoxib (Vioxx) was pulled from the market because of an increased risk of cardiovascular events in a similar polyp prevention trial. This committee consisted of Solomon, BWH's Marc Pfeffer, MD, John McMurray, MD of the University of Glasgow and Janet Wittes, MD of the Statistics Collaborative who performed the statistical analysis. The serious cardiovascular events included in the assessment were cardiovascular death, heart attack, stroke and heart failure. In the placebo group, seven of 679 people (one percent) had a serious cardiovascular event, including one death. In the group prescribed 200 mg of celecoxib twice a day, 16 of 685 people (2.3 percent) had a serious cardiovascular event, including three deaths. In participants prescribed 400 mg of celecoxib twice a day, 23 of 671 people (3.4 percent) had a serious cardiovascular event, including six deaths.

Celecoxib is one of several compounds that preferentially block COX-2, one of two cyclooxygenase (COX) enzymes, which are produced in response to inflammation and precancerous tissues. The COX enzymes also affect the production of chemicals in the wall of blood vessels and in blood cells called platelets. Other COX-2 inhibiting drugs have also been associated with an increased rate of cardiovascular events.

"Although the reason for the apparent increased risk of these serious cardiovascular events with COX-2 drugs is unclear, one hypothesis is that by blocking only COX-2, and not COX-1, an imbalance in the chemicals produced by the wall of blood vessels and platelets occurs that promotes blood clotting," Solomon said.

An analysis of the effectiveness of celecoxib in preventing the recurrence of colon adenomas in APC participants is under way. "The ability of celecoxib, or another agent that inhibits COX-2, to prevent colorectal cancer is an essential question that remains to be answered," said Ernest Hawk, MD, MPH and the NCI project officer on the APC Trial. "Cancer is a significant public health burden and the COX enzymes clearly play a role in the development of this disease."

BWH is a 735-bed nonprofit teaching affiliate of Harvard Medical School and a founding member of Partners Healthcare System, an integrated health care delivery network. Internationally recognized as a leading academic health care institution, BWH is committed to excellence in patient care, medical research and the training and education of health care professionals. The hospital's preeminence in all aspects of clinical care is coupled with its strength in medical research. A leading recipient of research grants from the National Institutes of Health, BWH conducts internationally acclaimed clinical, basic and epidemiological studies.

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