Aspirin and cancer: trials and observational studies.

Aspirin recently celebrated its commercial centenary, but the exciting news has been a series of articles by rothwell et al. (1–6) that report on the follow-up of cardiovascular trials begun in the late 1970s and afterward. those data suggest striking efficacy of aspirin in reducing cancer mortality. one of the recent reports (2) analyzed short-term, in-trial incidence and mortality data from 51 trials. It showed that aspirin conferred a 31% reduction in cancer mortality 5–10 years after subjects were randomized to study treatment, though there was essentially no reduction during the first 5 years. motivated by these striking findings, in this issue of the Journal, Jacobs et al. (7) report on the association of aspirin use with cancer mortality in the large American Cancer Society (ACS) cohort. taking advantage of the study’s repeated assessment of aspirin use, they attempted to replicate the trial findings by evaluating the association of 5 or more years of reported daily aspirin use with subsequent cancer mortality. unfortunately, they found only 8% or 16% lower cancer mortality, depending on the analytic approach used. In apparent contrast to the trials, associations were similar among those using daily aspirin for less than 5 years and for those using for 5 or more years. An observational study such as the ACS cohort describes the association of aspirin use with cancer mortality in real life. Did the trials lead us to an overoptimistic assessment, or is the report by Jacobs et al. off the mark? the answer is important, as it clearly will affect an important clinical decision: whether to recommend aspirin for primary prevention of cancer. An earlier analysis from the ACS cohort assessed cancer incidence in relation to aspirin use (8). As in the report from Jacobs et al., it showed more modest associations than the corresponding ones in the trials’ meta-analysis (2), though the differences were less marked than those reported for mortality. the ACS analysis of cancer incidence (8)—like the trials’ meta-analysis (2,3), but unlike the ACS mortality analysis (7)—saw reduced cancer risks only with longer aspirin use and follow-up. two other sizeable cohort studies have reported on aspirin use and cancer mortality (9,10). Both report stronger associations for ever users of aspirin than Jacobs et al. report, suggesting that the ACS estimates may be conservative. Several factors probably do not explain the difference between the short-term trials’ meta-analysis (2) and the ACS mortality study (7). In both reports, age and sex were not related to the observed effects of aspirin on cancer mortality. Primary prevention studies dominated the clinical trials’ analysis, but in the ACS cohort the findings were similar in subjects with, and without, cardiovascular disease. there was no material impact of dose on the aspirin effects in either analysis. Differences in the assignment of causes of death seem unlikely to account for the studies’ findings. rothwell et al. have argued persuasively that various biases in disease ascertainment are not likely explanations for their findings (2,6), and many of their arguments apply equally as well to the study by Jacobs et al. It has to be acknowledged that there are fundamental differences between the observational ACS data and those from the randomized trials. the trials’ intention-to-treat analysis isolates the study factor but ignores compliance: individuals who stop using aspirin (or placebo subjects who use it on their own) are retained in the originally assigned treatment groups for the analysis, even though they have become former users (or new users, in the placebo group). Because there was a high rate of treatment dropout in the trials (1,3), there is a corresponding disconnect between the trials’ analysis and the reality of the actual aspirin use. In contrast, as in all observational studies, the ACS investigators simply recorded whether or not a subject used aspirin. this is potentially important, because most observational analyses (11) [including the ACS study (7,8)] have found little association with cancer mortality or incidence in former users of aspirin. how all this relates to the ACS and trials’ analyses is not clear: neither report considered continued vs discontinued use after the time of the study baseline (or updated baseline for the ACS updated analysis). Nonetheless, the ACS analysis is likely less affected by former users than the trials, and so it would be expected to show more pronounced effects, not less. Neither the trials nor the ACS study analyzed the actual duration of aspirin use. Subjects in either analysis may have used aspirin before study baseline; clearly a proportion of the longer-term daily aspirin users in the ACS cohort did so. A true comparison of the findings about duration of use is therefore difficult. Nonetheless, primary prevention trials dominated the trials’ data, and these were conducted largely in europe in the 1980s and 1990s when use of cardioprotective aspirin was less common than more recently in the united States. It is likely that the ACS aspirin users had been taking the drug longer than the trial subjects who were randomly assigned to aspirin. thus, a shorter duration of use is also unlikely to contribute to the lower efficacy of aspirin in the ACS cohort. Details of the ACS analysis do provide some possible clues about the differences with the aspirin trials. the ACS “updated” analysis suggested stronger aspirin effects than the baseline analysis, entirely because of the findings for the years 2004 through 2008, when there were marked reductions among aspirin users in mortality from luminal gastrointestinal cancers and borderline statistically significant reductions for other malignancies. In that subanalysis, cancer deaths were included only if the malignancy was diagnosed after January 1, 2004: the only cancers included were those that were fatal within 5 years of diagnosis. this resembles the trials’ analysis because individuals with a cancer diagnosis are unlikely to enter trials and so accounted for only 3% of the cancer deaths in the short-term cancer mortality analysis (2). thus, the sort