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Colorectal cancer is an important burden on the U.S. population. The use of NSAID chemoprophylaxis, alone or in combination with a recommended screening program, is 1 strategy to reduce the incidence of colorectal adenomas, CRC, and CRC-related death.
The results of our systematic review suggest that the use of non-ASA NSAIDs for CRC chemoprevention is effective at reducing the incidence of colorectal adenomas and CRC. Cyclooxygenase-2 inhibitors seem to be effective at reducing the incidence of colorectal adenoma in patients with previous adenomatous polyps. Higher doses and longer durations of use of non-ASA NSAIDs seem to be associated with greater protection from CRC and adenomas. We found the magnitude of the relative risk reduction for CRC incidence to be approximately 30% to 40% in the pooled analyses.
We found no observational data on the effect of COX-2 inhibitors on CRC incidence or CRC-related death, although a single cohort study showed no effect of the non-ASA NSAID ibuprofen on CRC death but demonstrated a small statistically significant increase in allcause mortality.21 Further, no RCT data exist on CRC incidence with the long-term use of COX-2 inhibitors or non-ASA NSAIDs that are similar to data from the ASA-based Physicians' and Women's Health studies.9,10
The use of non-ASA NSAIDs and COX-2 inhibitors are each associated with important harms. Non-ASA NSAIDs are associated with an increased risk for ulcers and clinically important ulcer complications, such as hemorrhage, perforation, or pyloric obstruction. Cyclooxygenase-2 inhibitors are associated with fewer gastrointestinal symptoms, endoscopic ulcers, and clinically important ulcer complications than non-ASA NSAIDs. However, data from the APPROVe study18 demonstrated that over a 3-year period, COX-2 inhibitors were associated with a statistically significant increased risk for clinical ulcer complications compared with placebo.18 Although these data are in keeping with improved gastrointestinal safety of COX-2 inhibitors over non-ASA NSAIDs, the gastrointestinal safety of COX-2 inhibitors is not equivalent to that seen with placebo, as has been suggested in the past. On the other hand, COX-2 inhibitors are associated with an increased risk for adverse cardiovascular outcomes.56
During the conduct of our systematic review, rofecoxib was withdrawn from the market because of the results of the polyp prevention APPROVe study,78 which demonstrated an excess risk for cardiovascular events (16 per 1000 events) with the use of rofecoxib, confirming the suspicions reported by the VIGOR investigators.76 Subsequently, celecoxib was also found to have an excess risk for cardiovascular events (13 to 21 per 1000 events) in another polyp prevention study (Adenoma Prevention with Celecoxib [APC]).79 Valdecoxib was also withdrawn because of excess risk for cardiovascular events in 2 short-term cardiac surgery pain studies (Coronary Artery Bypass Graft [CABG] 1 and 2) and because of a rare dermatologic toxicity.80,81
A systematic review of the cardiovascular harms of rofecoxib and non-ASA NSAIDs59 suggested a small cardiovascular protective effect of naproxen, although the included studies were heterogeneous. Naproxen's relatively long half-life of 14 hours makes a twice-daily dosing schedule theoretically capable of consistently blocking COX-1 and potentially providing some degree of cardioprotection. Clinical trial data of the quality comparable to data available for the COX-2 inhibitors is not available for non-ASA NSAIDs. However, a recent meta-analysis56 using an extensive set of RCT data derived from published and unpublished studies suggests that, as a group, COX-2 inhibitors are associated with an increased risk for adverse cardiovascular outcomes (predominantly MI) when compared with placebo or naproxen but not when compared with nonnaproxen, non-ASA NSAIDs. These data, and evidence from some population-based studies,82-84 suggest that the increased risk for cardiovascular harms with COX-2 inhibitors is shared by nonnaproxen, non-ASA NSAIDs (higher doses of ibuprofen and diclofenac).56
Although it is tempting to consider adding ASA to a COX-2 inhibitor for cardioprotection, there seems to be an attenuation of the gastrointestinal safety of COX-2 inhibitors with this strategy. However, it should be noted that these observations were derived from post hoc subgroup analyses.
Non-ASA NSAIDs and COX-2 inhibitors are used for longer durations for a variety of arthritic and inflammatory conditions.12 Although their use for these conditions is more easily justified, it is much more difficult to make a case for their use for the chemoprevention of adenomas and CRC in average-risk individuals or even in individuals with a history of polyps. In light of the cardiovascular and gastrointestinal toxicity of these agents when used in a multiyear setting, the demonstration of the chemopreventive efficacy may be a "pyrrhic victory" as stated by Lynch85 in his editorial on the APPROVe trial. Furthermore, considering the newly identified risks for cardiovascular events associated with these agents, the cost-effectiveness of a chemopreventive strategy for CRC needs to be fully evaluated, particularly because a screening strategy alone appears to be effective.4 In a simplified risk-benefit analysis, assuming that CRC incidence can be reduced by 50% with COX-2 inhibitor use, Psaty and Potter86 suggested that significantly more cardiovascular events would occur than cases of CRC prevented. However, the balance of benefits and risks in high-risk patients, such as those with familial adenomatous polyposis and nonpolyposis syndromes and those with a history of CRC, may be quite different from that detailed here for average- to higher-risk individuals. A role for COX-2 inhibitors continues to be evaluated in the setting of these high-risk patients.86
Although ASA seems to be an attractive candidate for CRC chemoprophylaxis, the apparent need for doses higher than that used for cardiovascular protection represents a crucial drawback.48 Likewise, the improved gastrointestinal safety profile of COX-2 inhibitors over non-ASA NSAIDs made COX-2 inhibitors an attractive candidate until their cardiovascular toxicity came to light. Nonnaproxen, non-ASA NSAIDs seem to be the least attractive option because they are associated with both gastrointestinal and cardiovascular toxicity.
In conclusion, non-ASA NSAIDs seem to be effective at reducing the incidence of colorectal adenomas and CRC in observational studies. Good-quality RCT data suggest that COX-2 inhibitors are effective at reducing the incidence of colorectal adenomas in patients with previous adenomas. However, positive data on the reduction of death is lacking for both non-ASA NSAIDs and COX-2 inhibitors.
No quantitative data exist on the risk for gastrointestinal or cardiovascular harms associated with daily, multiyear use of non-ASA NSAIDs. Available data on COX-2 inhibitors suggest that absolute risk increases of over 1% for cardiovascular events and for clinically important gastrointestinal complications can be anticipated after only 2 to 3 years of use, and higher risks may accrue over longer periods. Furthermore, the cost-effectiveness of chemoprevention needs to be considered carefully and compared with other strategies, such as colorectal cancer screening alone. Therefore, the balance of benefits and risks does not appear to favor chemoprevention with non-ASA NSAIDs or COX-2 inhibitors in average-risk individuals or in those with a history of colorectal adenomas.
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The investigators thank Mary White, Sc.D., Chief Epidemiology and Applied Research Branch (CDC); Patrik Johansson, M.D., Medical Officer (AHRQ); Therese Miller, Dr.P.H., Task Order Officer (AHRQ); Janelle Guirguis-Blake, M.D., USPSTF Program Director; and Elizabeth A. Edgerton, M.D., M.P.H., Director of Clinical Prevention. They also thank members of the USPSTF who served as leads for the project: Ned Calonge, M.D., M.P.H.; Michael LeFevre, M.D., M.S.P.H.; Carol Loveland-Cherry, Ph.D., R.N.; and Al Siu, M.D., M.S.P.H. They thank Nav Saloojee, M.D., for helping in the selection of relevant reports; Tiffany Richards for assisting with the evidence tables; Raymond Daniel for retrieving the full reports; Chantelle Garritty for helping to coordinate the process; and Isabella Steffensen and Christine Murray for dedicating many long hours to editing the report and its appendix tables.
a. Drs. Dubé and Rostom: Division of Gastroenterology, University of Calgary Medical Clinic, Calgary, Alberta, Canada.
b. Drs. Lewin, Tsertsvadze, Barrowman, Sampson, and Moher: Chalmers Research Group, CHEO Research Institute, Ottawa, Ontario Canada.
c. Dr. Code: Division of Internal Medicine, The Ottawa Hospital—Civic Site, Ottawa, Ontario Canada.
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Source: Rostom A, Dubé C, Lewin G, Tsertsvadze A, Barrowman N, Code C, Sampson M, Moher D. Nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 inhibitors for primary prevention of colorectal cancer: Systematic review for the U.S. Preventive Services Task Force. Ann Intern Med 2007;146:376-89.
Current as of March 2007
Rostom A, Dubé C, Lewin G, Tsertsvadze A, Barrowman N, Code C, Sampson M, Moher D. Nonsteroidal Anti-inflammatory Drugs and Cyclooxygenase-2 Inhibitors for Primary Prevention of Colorectal Cancer: Systematic Review for the U.S. Preventive Services Task Force. Originally published in Ann Intern Med 2007;146:376-89. March 2007. http://www.uspreventiveservicestaskforce.org/uspstf07/aspcolo/nsaidsrev.htm