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QUESTION: In persons at risk (recent history of histologically documented adenomas), is chemoprophylaxis with aspirin more effective than placebo for reducing the incidence of colorectal adenomas?
9 clinical centres in Canada and the US.
1121 patients (mean age 57 y, 64% men) who had ≥1 of the following: ≥1 histologically confirmed colorectal adenoma removed <3 months before recruitment; ≥1 histologically confirmed adenoma removed ≤16 months before recruitment and a lifetime history of ≥2 confirmed adenomas; or a histologically confirmed adenoma ≥1 cm in diameter removed <16 months before recruitment. Exclusion criteria included a history of a familial colorectal cancer syndrome, invasive colorectal cancer, and malabsorption syndromes. Follow up was 97%.
Patients were allocated to aspirin, 325 mg/day (n=372) or 81 mg/day (n=377), or placebo (n=372).
Main outcome measure
Number of patients in whom ≥1 colorectal adenoma was detected at ≥1 year of follow up.
At ≥1 year, ≥1 colorectal adenoma was detected in fewer patients who received aspirin, 81 mg, than in those who received placebo (table). The 325 mg aspirin and placebo groups did not differ for incidence of colorectal adenomas.
In persons at risk (with a recent history of colorectal adenomas), chemoprophylaxis with aspirin (81 mg daily) was more effective than placebo for reducing the incidence of new colorectal adenomas.
A series of animal experiments as well as epidemiological studies dating back to the early 1980s have supported the protective effects of non-steroidal anti-inflammatory drugs against the development of colorectal adenomas. Over time, these studies have been consistent and positive, and now, with the studies by Baron and colleagues and Sandler et al, we can add 2 well designed, randomised, placebo controlled trials to this body of evidence.
In the study by Baron et al, 2 doses of aspirin, 81 mg and 325 mg daily, were compared with placebo. A modest 19% reduction in the relative risk of any adenoma was found in patients who received aspirin, 81 mg/day, but no significant protection was found in those who received aspirin, 325 mg/day, when compared with placebo. In the study by Sandler et al, only 1 dose of aspirin (325 mg/d) was evaluated. A 36% reduction in the relative risk for ≥1 polyp was found. The greater benefit observed in the study by Sandler et al may be attributed to differences in the populations of the 2 studies. Both recruited patients at “high risk” for polyps, but Sandler et al selected patients with a history of colorectal cancer, whereas Baron et al selected those with a history of polyps. The side effects from regular use of aspirin were similar to placebo in the study by Sandler et al. However, in the study by Baron et al, the incidence of stroke was of concern: there were none among those who received placebo, 2 among those who received aspirin, 81 mg/day, and 5 among those who received aspirin, 325 mg/day (p=0.06).
The results from these studies raise several important questions: Firstly, how does aspirin protect against adenoma formation? In a separate study, it has been proposed that aspirin might increase the catabolism of carcinogenic polyamines.1 The most commonly proposed mechanism of action is inhibition of cyclooxygenase enzymes and subsequent inhibition of prostaglandin synthesis. Prostaglandin E2 is the most abundant prostaglandin in colorectal tumours and can block apoptosis.2 It has also been reported that the doses of aspirin from 81 mg to 650 mg daily are equally effective at inhibiting the production of prostaglandin E2 in the rectal mucosa.3 Similarly, no dose effect is evident for aspirin used in cardiovascular prophylaxis.4 Therefore, if a physician were to recommend aspirin to prevent colorectal polyps, the smaller dose would seem justifiable and may minimise rates of such other adverse events as gastrointestinal bleeding.
In the study by Sandler et al, aspirin protected against the development of new adenomas overall but had no effect on larger (>1 cm) polyps or polyps with villous features. This differs from the Baron et al study, where the only significant effect was a reduced incidence of advanced adenomas among patients randomised to receive aspirin, 81 mg/day. How can this be? Whether this observation is because of differences in the colonic milieu of persons who have had colon cancer compared with those who have had previous adenomas, other undisclosed factors, or chance is yet undetermined. Other curious findings were noted in the subgroup analyses of the study by Baron et al. Patients who were younger than the median age of 57 years and women seemed to be more likely to benefit. Explanations for these findings are elusive at present and will require further study before our understanding of the association between aspirin and colorectal adenomas is complete.
Aspirin should not replace endoscopic surveillance or be recommended for everyone. However, for persons at high risk of developing adenomas, low dose aspirin can be added with assurance that it is reasonably effective and safe.