The Protective Effect of Low-Dose Aspirin against Colorectal Cancer Is Unlikely Explained by Selection Bias: Results from Three Different Study Designs in Clinical Practice

Background We conducted three differently designed nested case-control studies to evaluate whether the protective effect of low-dose aspirin against colorectal cancer (CRC) is explained by selection bias. Methods Using a large validated UK primary care database, we followed different cohorts of patients, who varied in their demographic and clinical characteristics, to identify first ever cases of CRC. In Studies 1 and 2, two cohorts were followed, i) new users of low-dose aspirin at start of follow-up (N = 170,336 in Study 1, N = 171,527 in Study 2) and either ii) non-users of low-dose aspirin (Study 1, N = 170,336) or new users of paracetamol (Study 2, N = 149,597) at start of follow-up. In Study 3 a single cohort of individuals naive to low-dose aspirin at the start of observation was followed. Controls were selected using incidence sampling and logistic regression used to obtain an unbiased estimate of the incidence rate ratio (RR) with 95% confidence intervals (CIs). Low-dose aspirin exposure was analyzed 'as-treated' before the index date (CRC date for cases, random date for controls). Results In the three studies, median (maximum) follow-up was 5.1 (12), 5.8 (12) and 7.5 (13) years, respectively. 3033 incident CRC cases were identified in Study 1, 3174 in Study 2, and 12,333 in Study 3. Current use of low-dose aspirin was associated with a significantly reduced risk of 34%, 29% and 31% in the three studies, respectively; corresponding RRs (95% CIs) were 0.66 (0.60-0.73), 0.71 (0.63-0.80) and 0.69 (0.64-0.74). In each study, significantly reduced risks of CRC were seen when low-dose aspirin was used for primary or secondary cardiovascular disease prevention, in both sexes, and across all age groups evaluated. Conclusion Low-dose aspirin is associated with a significantly reduced risk of CRC. The consistency of our findings across different studies makes selection bias an unlikely explanation.