Alaa Rostom, MD, MSc; Catherine Dubé, MD, MSc; Gabriela Lewin, MD; Alexander Tsertsvadze, MD, MSc; Nicholas Barrowman, PhD; Catherine Code, MD; Margaret Sampson, MLIS; David Moher, PhD, for the U.S. Preventive Services Task Force
Rostom A, Dubé C, Lewin G, Tsertsvadze A, Barrowman N, Code C, et al. Nonsteroidal Anti-inflammatory Drugs and Cyclooxygenase-2 Inhibitors for Primary Prevention of Colorectal Cancer: A Systematic Review Prepared for the U.S. Preventive Services Task Force. Ann Intern Med. 2007;146:376-389. doi: 10.7326/0003-4819-146-5-200703060-00010
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Published: Ann Intern Med. 2007;146(5):376-389.
To examine the benefits and harms of nonaspirin (non-ASA) nonsteroidal anti-inflammatory drugs (NSAIDs) and cyclooxygenase (COX-2) inhibitors for the prevention of colorectal cancer (CRC) and adenoma.
MEDLINE (1966 to 2006), EMBASE (1980 to 2006), Cochrane Central Register of Controlled Trials, Cochrane Collaboration's registry of clinical trials, Cochrane Database of Systematic Reviews.
Randomized, controlled trials and caseâ€“control and cohort studies of the effectiveness of NSAIDs for the prevention of CRC and colorectal adenoma were identified by multilevel screening by 2 independent reviewers. Systematic reviews of harms were sought.
Data abstraction, checking, and quality assessment were completed in duplicate.
A single cohort study showed no effect of non-ASA NSAIDs on death due to CRC. Colorectal cancer incidence was reduced with non-ASA NSAIDs in cohort studies (relative risk, 0.61 [95% CI, 0.48 to 0.77]) and caseâ€“control studies (relative risk, 0.70 [CI, 0.63 to 0.78]). Colorectal adenoma incidence was also reduced with non-ASA NSAID use in cohort studies (relative risk, 0.64 [CI, 0.48 to 0.85]) and caseâ€“control studies (relative risk, 0.54 [CI, 0.4 to 0.74]) and by COX-2 inhibitors in randomized, controlled trials (relative risk, 0.72 [CI, 0.68 to 0.77]). The ulcer complication rate associated with non-ASA NSAIDs is 1.5% per year. Compared with non-ASA NSAIDs, COX-2 inhibitors reduce this risk but, in multiyear use, have a higher ulcer complication rate than placebo. Cyclooxygenase-2 inhibitors and nonnaproxen NSAIDs increase the risk for serious cardiovascular events (relative risk, 1.86 [CI, 1.33 to 2.59] for COX-2 inhibitors vs. placebo).
Heterogeneity in the dose, duration and frequency of use necessitated careful grouping for analysis.
Cyclooxygenase-2 inhibitors and NSAIDs reduce the incidence of colonic adenomas. Nonsteroidal anti-inflammatory drugs also reduce the incidence of CRC. However, these agents are associated with important cardiovascular events and gastrointestinal harms. The balance of benefits to risk does not favor chemoprevention in average-risk individuals.
Appendix Table 1.
Appendix Table 2.
Studies not shown but included were acetylsalicylic acid (ASA) studies or studies that considered more than 1 intervention, outcome, or both. The Nurses' Health Study (NHS) represents an initial publication (46) and a follow-up publication (34) for colorectal cancer (CRC) and a separate publication for colorectal adenoma (CRA) (47). Three cyclooxygenase (COX)-2 inhibitor polyp studies and a systematic review were added after we submitted our report to the U.S. Preventive Services Task Force and the Agency for Health Research and Quality. *11 of these considered harms of ASA. CV = cardiovascular; NSAID = nonsteroidal anti-inflammatory drug; RCT = randomized, controlled trial.
Appendix Table 3.
Appendix Table 4.
Appendix Table 5.
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Brigham and Women's Hospital, Harvard Medical School
April 5, 2007
Aspirin and NSAIDs for the primary prevention of colorectal cancer - weighting the evidence
The authors of the review papers on aspirin (1) and nonsteroidal anti -inflammatory drugs (NSAIDs) (2) for the primary prevention of colorectal cancer (CRC) ignore important limitations of observational studies, raise concerns unlikely to be valid (1), and fail to include the analysis on NSAIDs from the Physicians' Health Study (PHS) that was published in the time period covered (3). The authors correctly discuss shortcomings of randomized trials showing no protection in men and women, i.e. low dose and short duration (1). They fail, however, to address shortcomings of observational studies on regular long-term drug use, i.e. unmeasured confounding, as an alternative explanation for the reduced risk of CRC observed in most of these studies.
Specifically, regular long-term drug use is associated with difficult to measure healthy characteristics. These healthy characteristics of long- term adherers may be associated with reduced risks independent of drug effects as evinced by reduced risks for many adverse outcomes in adherers to placebo. This can lead to paradoxical relations in observational studies (4). To reduce the magnitude of this problem, we excluded regular users of aspirin and NSAIDs from the PHS, thus studying only new regular users, and observed no reduction of CRC risk with aspirin (5) and NSAIDs (3).
Unfortunately, the referenced detailed assessment of the quality of each of the studies (1,2) was not available from AHRQ or the authors. However, the authors mentioned concerns about our aspirin analysis in the PHS because of contamination by intervention and a reduced standardized mortality ratio for CRC compared with the U.S. population (1). Randomized aspirin treatment does not threaten the validity of our post-trial study of self-selected aspirin use. Any carry-over of putative aspirin effects would bias the results towards observing a reduced CRC risk in post-trial aspirin users. Reduced standardized morbidity ratios (5) are ubiquitous in volunteer studies and generally do not bias measures of relative risk.
Finally, since only three cohort studies of NSAIDs and CRC are included in their analysis (2), the failure to include our observational study on NSAIDs and CRC in the PHS (3) largely reduces the value of the summary estimates. Taken together, we believe that the authors overstate the overall benefits from aspirin (1) and NSAIDs (2) on CRC. Putting greater weight on randomized evidence and observational studies with new- user designs would tip the harm to benefit balance even more towards harm for individuals at average risk for CRC.
1. Dube C, Rostom A, Lewin G, Tsertsvadze A, Barrowman N, Code C, Sampson M, Moher D. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the u.s. Preventive services task force. Ann Intern Med 2007;146:365-75.
2. Rostom A, Dube 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: A Systematic Review Prepared for the U.S. Preventive Services Task Force. Ann Intern Med 2007;146:376-89.
3. StÃƒÂ¼rmer T, Buring JE, Lee IM, Kurth T, Gaziano JM, Glynn RJ. Colorectal cancer after start of nonsteroidal anti-inflammatory drug use. Am J Med 2006;119:494-502.
4. Glynn RJ, Knight EL, Levin R, Avorn J. Paradoxical relations of drug treatment with mortality in older persons. Epidemiology 2001;12:682- 9.
5. StÃƒÂ¼rmer T, Glynn RJ, Lee IM, Manson JE, Buring JE, Hennekens CH. Aspirin use and colorectal cancer: post-trial follow-up data from the Physicians' Health Study. Ann Intern Med 1998;128:713-20.
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