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Adenoma recurrence is already widely accepted as a surrogate end point for colorectal cancer. However, our data on initial adenoma, taken together with our earlier findings in this cohort, which demonstrated an inverse relationship between use of aspirin and colorectal cancer, provide additional evidence to substantiate the protective effect of aspirin on colorectal neoplasia. In our previous study, the relative risk for cancer after 20 years of consistent aspirin use was 0.56 (CI, 0.36 to 0.90). The influence of duration on risk for colorectal cancer (but not adenoma risk) seems plausible because there may be a dwell period of a decade or longer within which an adenomatous polyp becomes invasive cancer. Our results also demonstrate that optimal chemoprevention requires substantially higher doses of aspirin than those previously considered. These findings may have clinical implications related to potential adverse events associated with prolonged use of aspirin. Gastrointestinal bleeding, the most common major toxicity of aspirin, occurs in approximately 1 in 100 people taking aspirin over at least 2 years, and considerable evidence suggests that this toxicity, as well the severity of bleeding, is strongly dependent on increasing dose. In a large, randomized trial of aspirin in the secondary prevention of cerebrovascular events, the annual rate of upper gastrointestinal bleeding was 0.6% in patients taking 1200 mg/d, 0.3% for those assigned to 300 mg/d, and 0.1% for those taking placebo. Another rare but potentially devastating adverse consequence of aspirin use, intracerebral bleeding, may also be related to increasing dose. In our cohort, participants tak ing the highest dose of aspirin (_2 tablets/d) had a 2-fold higher risk for subarachnoid hemorrhage. Treatment of large numbers of healthy persons to prevent colorectal cancer in a small percentage requires a high standard of safety as well as efficacy. For example, the U.S. Preventive Services Task Force presently recommends routine use of low-dose aspirin as primary prophylaxis against myocardial infarction only in those at high risk for coronary heart disease. Thus, it has been suggested that any agent requires a safety profile that meets or exceeds that of low-dose aspirin before it can be recommended for widespread use in colorectal cancer prevention.

Moreover, 2 cost-effectiveness analyses concluded that present colorectal cancer screening strategies were generally superior to daily use of 325 mg of aspirin. Although the overall cost-effectiveness of aspirin improves if cardiovascular benefits are incorporated, our findings suggest that the optimal doses for cardiovascular and neoplasia prevention differ considerably. Because our study is observational, the results are not as definitive as an intervention trial designed to directly examine the effects of daily administration of low-dose, standard-dose, or 2 standard-dose aspirin tablets on subsequent risk for initial adenoma, as well as adverse outcomes in a healthy population. However, such a trial is probably not feasible given the need for a large number of patients to examine relatively rare outcomes and even more infrequent toxicities. Moreover, the cost of surveillance colonoscopy would be prohibitive, and ethical concerns about adverse consequences related to high doses of aspirin may be considerable. In summary, our results demonstrate that both shortand long-term aspirin use reduces the risk for adenoma in an average-risk population. However, chemoprevention efforts using aspirin may require substantially greater doses of aspirin than those currently recommended for the prevention of cardiovascular disease. The potential of regular use of moderate aspirin doses to prevent colorectal neoplasia necessitates further evaluation. The risk–benefit profile must be thoroughly considered, especially when compared with other potential strategies.