COX 2 Inhibitors for Colorectal Adenoma Prevention Increase Serious Cardiovascular Events
Mar 26, 2005 - 2:47:38 PM
Researchers affiliated with the Adenoma Prevention with Celecoxib (APC) study have reported that Celebrex® (celecoxib) increased serious cardiovascular events. Similar conclusions were reached by the Adenomatous Polyp Prevention on Vioxx (APPROVe) Trial. Both studies were reported in the March 17, 2005 issue of the New England Journal of Medicine.
Cyclooxygenase (COX) is an enzyme that catalyses the synthesis of prostaglandins. COX-1 and COX-2 are the two isoforms, inhibited by nonsteroidal anti-inflamatory drugs (NSAIDs). COX-1 is constitutively expressed in a number of cell types, whereas COX-2 is an inducible enzyme whose expression and activity are up-regulated in response to a variety of cytokines, growth factors, and tumor promoters. Cyclooxygenase 2 (COX-2) is overexpressed in 71% to 85% of CRCs.
Two potent COX-2 inhibitors, Celebrex® and Vioxxx®, are undergoing intense testing in different types of cancers, including colorectal cancer. Current phase II data suggests that COX-2 inhibitors enhance the effects of chemotherapy in patients with metastatic colorectal cancer.
Cox-2 inhibitors have also shown promise in phase II studies for the prevention of recurrent polyps in individuals who had surgical removal of colorectal polyps.
The Celebrex® trial compared a 200mg with a 400mg dose versus placebo in 2,035 patients with a history of colorectal neoplasia. Individuals received drug or placebo for 2.8-3.1 years. Death from cardiovascular causes occurred in 7 of 679 patients on placebo, 16 of 685 receiving 200 mg of Celebrex® and 23 of 671 receiving the 400 mg dose of Celebrex®. Deaths from cardiovascular causes increased from 0.5% in the placebo group to 2.2% in individuals receiving the higher dose of Celebrex®. The effects of Celebrex® appeared dose-related for most endpoints of the study. The hazard of dying was greatest for those with increased risk factors for cardiovascular disease. These findings prompted early discontinuation of this study.
The Vioxx® trial compared 25 mg of Vioxx® to placebo for three years in 2,586 individuals with a history of colorectal adenomas. This study was terminated after an average of 2.4 years. The investigators observed an increased incidence of confirmed thrombotic events, congestive heart failure, pulmonary embolus and cardiac failure in patients receiving Vioxx®. There were 6 deaths in the Vioxx® group and 4 in the placebo group.
Comments: Both studies reported an increased incidence of cardiovascular events, which were in excess of what is tolerable for a prevention trial. Whether or not COX-2 inhibitors will have a role in the treatment of cancer remains to be determined.
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