Catherine Dubé, MD, MSc; Alaa Rostom, MD, MSc; Gabriela Lewin, MD; Alexander Tsertsvadze, MD, MSc; Nicholas Barrowman, PhD; Catherine Code, MD; Margaret Sampson, MILS; David Moher, PhD
Acknowledgments: The authors thank Mary White, ScD, Chief Epidemiology and Applied Research Branch, Centers for Disease Control and Prevention; Patrik Johansson, MD, Medical Officer (AHRQ); Therese Miller, DrPH, Task Order Officer (AHRQ); Janelle Guirguis-Blake, MD, U.S. Preventive Services Task Force (USPSTF) Program Director; and Elizabeth A. Edgerton, MD, MPH, Director of Clinical Prevention, for their contributions. Members of the USPSTF who served as leads for this project include Ned Calonge, MD, MPH; Michael LeFevre, MD, MSPH; Carol Loveland-Cherry, PhD, RN; and Al Siu, MD, MSPH. The authors thank Nav Saloojee, MD, for helping select relevant reports, Tiffany Richards for assisting with the evidence tables, Raymond Daniel for retrieving the full reports, and Chantelle Garritty for helping coordinate the process. The authors also thank Isabella Steffensen and Christine Murray, who dedicated many long hours in the editing of the report and the appendices.
Grant Support: The Evidence Synthesis upon which this article was based was funded by the Centers for Disease Control and Prevention for the Agency for Healthcare Research and Quality and the U.S. Preventive Services Task Force.
Potential Financial Conflicts of Interest:Consultancies: A. Rostom (Novartis); Honoraria: A Rostom (Novartis); Grants received: C. Dubé (Agency for Healthcare Research and Quality/U.S. Preventive Services Task Force), A. Rostom (Agency for Healthcare Research and Quality/U.S. Preventive Services Task Force).
Requests for Single Reprints: Alaa Rostom, MD, MSc (Epi), Division of Gastroenterology, University of Calgary Medical Clinic, 3330 Hospital Drive NW, #G176, Calgary, Alberta, T2N 4N1, Canada; e-mail, firstname.lastname@example.org.
Current Author Addresses: Drs. Dubé and Rostom: Division of Gastroenterology, University of Calgary Medical Clinic, 3330 Hospital Drive NW, #G176, Calgary, Alberta, Canada T2N 1N4.
Drs. Lewin, Tsertsvadze, Barrowman, Sampson, and Moher: Chalmers Research Group, CHEO Research Institute, 401 Smyth Road, Ottawa, Ontario, Canada K1H 8L1.
Dr. Code: Division of Internal Medicine, The Ottawa Hospital–Civic Site, 1053 Carling Avenue, Ottawa, Ontario, Canada K1Y 4E9.
Aspirin for prevention of colorectal cancer is controversial.
To examine the benefits and harms of aspirin chemoprevention.
MEDLINE, 1966 to December 2006; EMBASE, 1980 to April 2005; CENTRAL, Cochrane Collaboration's registry of clinical trials; Cochrane Database of Systematic Reviews.
Two independent reviewers conducted multilevel screening to identify randomized, controlled trials (RCTs), case–control studies, and cohort studies of aspirin chemoprophylaxis. For harms, systematic reviews were sought.
In duplicate, data were abstracted and checked and quality was assessed.
Regular use of aspirin reduced the incidence of colonic adenomas in RCTs (relative risk [RR], 0.82 [95% CI, 0.7 to 0.95]), case–control studies (RR, 0.87 [CI, 0.77 to 0.98]), and cohort studies (RR, 0.72 [CI, 0.61 to 0.85]). In cohort studies, regular use of aspirin was associated with RR reductions of 22% for incidence of colorectal cancer. Two RCTs of low-dose aspirin failed to show a protective effect. Data for colorectal cancer mortality were limited. Benefits from chemoprevention were more evident when aspirin was used at a high dose and for periods longer than 10 years. Aspirin use was associated with a dose-related increase in incidence of gastrointestinal complications.
Important clinical and methodological heterogeneity in the definitions of regular use, dose, and duration of use of aspirin necessitated careful grouping for analysis.
Aspirin appears to be effective at reducing the incidence of colonic adenoma and colorectal cancer, especially if used in high doses for more than 10 years. However, the possible harms of such a practice require careful consideration. Further evaluation of the cost-effectiveness of chemoprevention compared with, and in combination with, a screening strategy is required.
Study selection, inclusion, and exclusion at each screening phase for the efficacy end points.
ASA = aspirin; CRA = colorectal adenoma; CRC = colorectal cancer; RCT = randomized, controlled trial.
Table 2. Cardiovascular Outcomes with Aspirin Use*
Table 1. Effects of Regular Use of Aspirin on Colorectal Cancer Incidence and Mortality and on Adenoma Incidence*
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Brigham and Women's Hospital, Harvard Medical School
March 23, 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.
Mary B. Barton
Agency for Healthcare Research and Quality
June 14, 2007
Re: Aspirin and NSAIDs for the primary prevention of colorectal cancer - weighting the evidence
Editor Annals of Internal Medicine
To the Editor:
We want to respond to the complaint expressed by Dr. Til Sturmer and colleagues, regarding the posting on the AHRQ Web site of the report, "The Use of Aspirin to Prevent Colorectal Cancer: A Systematic Review." The appendixes were inadvertently omitted from the Web posting. The mistake has been corrected, and the full systematic review is now available on the Web site at http://www.ahrq.gov/clinic/uspstf07/aspcolo/aspcoloes.pdf. We regret the frustration this error has caused.
Mary B. Barton, M.D., M.P.P. Scientific Director U.S. Preventive Services Task Force
Marion M. Torchia Manuscript Coordinator Agency for Healthcare Research and Quality
Dr Shamsul A Bhuiyan
Mount Sinai School of Medicine(Cabrini)
November 13, 2007
ASA versus Sigmoidoscopy/Colonoscopy as primary prevention of CRC
Colorectal cancer (CRC) is the third most common cancer in USA and 2nd leading cause of death overall with ninety percent occurring after the age of fifty. Twenty-five percent of patients have family history, and the question is, how effective would ASA be in this population as a preventive measure? Also people who have mutation in APC tumour suppressor gene, 100s to 1000s of polyps at young age, are 100% life time risk of developing colorectal cancer. Will this group of people get benefits if we use ASA as preventive measure? Same thing can be thought for HNPCC (hereditary non polyposis colorectal cancer"”mutation in DNA mismatch repair genes).
On the other hand, in the case of inflammatory bowel disease, ASA is shown to increase risk with increase extent and duration of disease. Since an ulcerative colitis patient has a chance to develop cancer, will this group benefit from ASA?
No doubt that many peoples are on ASA because of their medical condition like CAD, S/P stent placements, TIA, atherosclerosis, headache, arthritis,and fever. These groups will get benefits as a protective measure for CRC somehow. The question is how beneficial would it would if ASA being used only as prophylaxis for CRC in general population considering all those disadvantages of ASA. Which would be better? Doing a colonoscopy in a patient that has risk factors or using ASA for long time only for preventive measure for CRC.
In consideration of recurrence of adenoma, will it be really great to use rather than colonoscopy? Even if we use ASA for prevention and recurrence, ultimately we have to do sigmoidoscopy and colonoscopy that are diagnostic and therapeutic. There is no doubts that evidence pointing to an association between aspirin and reduced cancer risk is largely derived from epidemiologic studies, although laboratory experiments and a few clinical trials have provided support for this idea.
Dubé C, Rostom A, Lewin G, Tsertsvadze A, Barrowman N, Code C, et al. 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;146:365–375. doi: 10.7326/0003-4819-146-5-200703060-00009
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Published: Ann Intern Med. 2007;146(5):365-375.
Colorectal Cancer, Gastroenterology/Hepatology, Gastrointestinal Cancer, Guidelines, Hematology/Oncology.
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