Background
Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide, with more than 1.3 million new cases reported in 2012 [
1]. Long-term (up to 20 years) follow-up of cardiovascular trials have demonstrated, in post hoc analyses, that patients randomized to daily low-dose aspirin (75–300 mg) have a reduced risk of CRC incidence and mortality after a delay of several years [
2]. The hypothesis that aspirin has a chemopreventive effect early in the adenoma sequence in CRC development is consistent with this latency period, and is supported by findings from randomized controlled trials (RCTs) showing daily low-dose aspirin (81–325 mg) reduces colorectal adenoma recurrence in average/high-risk populations [
3].
In early cardiovascular trials, the protective effect of low-dose aspirin against CRC was greatest in patients with longer scheduled duration of trial treatment [
2]. However, analyses were limited based on unknown aspirin exposure during the post-trial follow-up period, and inability to adjust for confounders. Patients who discontinued aspirin in the intervention arm or started treatment in the placebo arm after the randomized phase would have been analyzed according to exposure status at randomization, thus the protective effect of aspirin could have been mainly due to chronic aspirin exposure over the relatively short in-trial period. Recent analyses of in-trial data show that aspirin substantially reduces metastatic CRC at initial diagnosis [
4], which cannot be accounted for by an effect early in the adenoma–carcinoma sequence. Observational data suggest aspirin may reduce the risk of metastatic breast [
5] and prostate [
6] cancer at initial presentation, and reduced mortality has been reported for CRC [
7] and breast cancer [
8] with aspirin use following diagnosis. Aspirin may therefore have an inhibitory effect on the growth and spread of tumours as well as on their initial development, and this effect could be explored further in real-world patients by the evaluation of low-dose aspirin on the risk of different stage CRC in clinical practice.
Discussion
Patients starting treatment with low-dose aspirin had a significant 34% decreased risk of developing CRC compared with those not taking low-dose aspirin, in line with previous findings of a chemopreventive effect of aspirin against CRC [
2,
4,
18,
19]. The reduction in risk was apparent across all age groups, and was unrelated to dose, indication, gender, CRC location or case-fatality status. We also found an effect of low-dose aspirin among patients who started therapy after having previously undergone colonoscopy/sigmoidoscopy. The protective effect was observed in Dukes Stages B to D CRC, occurring throughout treatment duration and starting within the first year of therapy, while a suggestion of a reduced risk of Dukes Stage A CRC was observed but only after 5 years’ therapy.
To our knowledge, our study is the first to investigate the effect of low-dose aspirin on risk of CRC by stage at diagnosis among real-world patients in clinical practice. A key strength of our study is the original observational study design, which attempted to minimize bias between aspirin users and non-users at start of follow-up that are difficult to control. By obtaining incident cases of CRC for our case–control analysis from two cohorts of patients – new users of low-dose aspirin and non-users of low-dose aspirin at start of follow-up – matched by factors including a proxy for general health status, we attempted to control for this possible selection bias. This would not have been achieved from a traditional nested case–control study design in the whole THIN source population, following up the single cohort to identify cases of CRC. By then analyzing low-dose aspirin in our case-control analysis in relation to the index date (i.e. current use, never use etc), we evaluated actual use of low-dose aspirin (assuming the patient took the medication) rather than use of low-dose aspirin defined at start of follow-up, which could have changed substantially over time. Other study strengths include the representativeness of the data source to the UK population, the long study period, and the inclusion of a broad range of patients, including those with gastrointestinal disorders. Lag-time and stratified analyses showed the associations to be robust and to occur across patient groups. All incident CRC cases were identified following thorough review of EMRs, previous validation of the CRC diagnosis of nearly 20% of our cases using record linkage to hospitalization data, and through PCP questionnaires for a smaller sample, resulting in high confirmation rates [
13]. Any potential differential misclassification of CRC cases between low-dose aspirin users and non-users, for instance diagnostic bias arising from more frequent investigation and referral of aspirin users, would have underestimated the associations found. Although information on Dukes Stage was unavailable for 53% of cases, the distribution of Dukes Stage in cases with a recorded stage is largely consistent with national data [
20,
21] supporting their representativeness to cases in the general population. Furthermore, 1- and 5-year survival rates for all cases are consistent with national rates [
22]. Through sensitivity analysis restricted to CRC cases with known stage, we showed the associations to be robust. Misclassification of aspirin exposure owing to unrecorded OTC aspirin in THIN was likely to have been minimal, as shown in our previous validation study of low-dose aspirin recording in THIN [
16] and other populations [
23]. It is unlikely that our findings can be explained by healthy-user bias because we found the new users of low-dose aspirin cohort to be less healthy in terms of comorbidities and lifestyle factors than the matched (at start of follow-up) cohort. In fact, any residual lack of adjustment for the more severe co-morbidity profile of new low-dose aspirin users would have led to an underestimation of the protective effect seen. Furthermore, in another study using a similar design but where the non-user at start of follow-up cohort instead comprised new users of a ‘neutral’ drug – paracetamol – we report highly similar results [
24]. Also, in this current study, we matched our two study cohorts by number of PCP visits as a proxy for general health/comorbidity. We controlled for several confounders in our analyses, and the level of missing data for smoking and body mass index was low with risk estimates virtually similar when these variables were ascertained before the start of follow-up (data not presented). Although data on certain CRC risk factors such as red meat intake and a positive family history and were not recorded; these are unlikely to be related to aspirin exposure and confound the associations observed. Residual confounding, however, cannot be ruled out. In addition, because the mean length of low-dose aspirin use was 6 years, we were unable to investigate the effect of low-dose aspirin when used in the longer-term.
Our findings support an effect of low-dose aspirin on at least two phases of the natural history of CRC. The early and large reduction in risk seen among patients presenting with Dukes Stage D CRC is consistent with previous clinical trial data [
4]. Experimental evidence exists to suggest that platelets play an important role in metastasis [
25,
26]. Pharmacological inhibition of thromboxane synthase in animal models has been shown to significantly inhibit tumour cell growth, invasion, metastasis and angiogenesis [
27]. The short-term effect of aspirin on advanced stage CRC seen in our study supports the hypothesis that aspirin has an effect on the progression of established tumours – a clinically important finding because of the poor prognosis of patients presenting with advanced stage disease. Five-year survival for Dukes Stage D CRC cases in our study was 9%, in line with previous reports [
20]. At least 5 years’ therapy with low-dose aspirin was necessary to observe a reduction in risk of Dukes A CRC, a latency period consistent with the average time for an early stage carcinoma to evolve from an adenomatous polyp [
28]. This adds supports for an effect of aspirin early in the adenoma–carcinoma sequence [
3]. Biologically plausible mechanisms that could mediate an effect of aspirin against CRC development have been postulated, also involving platelet inhibition [
29]. Co-incubation of activated human platelets with CRC cells has been shown to upregulate cyclooxygenase-2 (COX-2) expression and induce epithelial-mesenchymal transition [
30]. Induction of COX-2 expression in adjacent nucleated cells could thereby trigger a chain of downstream events affecting cell proliferation, apoptosis and angiogenesis. At low-doses (75–100 mg daily), aspirin permanently inactivates the enzyme cyclooxygenase 1 in platelets, leading to long-lasting suppression of thromboxane A2 production.
For Dukes Stages B to D CRC, we did not observe the latency period for an effect of low-dose aspirin as seen in post-hoc analyses of trial data [
2,
18]. And interestingly, in a recent analysis of data from the Women’s Health Initiative [
31] use of statins – medication also reported as having anti-cancer properties [
32] – was found to be associated with a significant reduction in CRC mortality. There are several possible reasons why we were able to identify cases earlier during follow-up than previous aspirin trials. Firstly, our study was designed to investigate CRC as the clinical endpoint, and information on low-dose aspirin use throughout the whole follow-up was ascertained and analyzed. Secondly, our study did not screen-out patients with peptic ulcer disorders or other disease-related eligibility criteria, and some of these patients may have had preclinical CRC, already along the lengthy adenoma–carcinoma sequence at start of follow-up. Thirdly, our study population included real-world patients, which included those with multiple comorbidities; the average age of patients at start of follow-up was 64 years in our study compared with 61 in four previous low-dose aspirin trials [
2]. Fourthly, follow-up began between 2000 and 2009, considerably later than the start of several trials that began in early/mid 1980s. Irrespective of the age and health of the study population, there have been temporal changes in the management of CRC, including the availability of better diagnostic techniques, the introduction of multidisciplinary teams in secondary care, the national bowel cancer screening programme, bowel cancer awareness initiatives/increased media attention, and accessibility to information.
In line with trial data [
2], we found an aspirin dose of 75 mg/day to be effective in reducing CRC. No increased benefit was seen with up to four-fold higher aspirin doses, although our study was underpowered to reliably evaluate these exposures with around 90% of current low-dose aspirin use at 75 mg/day. Nevertheless, this is an important finding considering that doses of less than 100 mg are sufficient to reduce the risk of thrombotic cardiovascular events, and the dose-dependent increased risk of gastrointestinal bleeding [
33]. The benefits of low-dose aspirin in reducing ischaemic vascular events [
34] must be weighed against the risk of gastrointestinal bleeding, which increases with age and when aspirin is prescribed alongside other gastrotoxic agents [
33]. Prevention strategies to minimize aspirin-associated gastrointestinal problems, such as use of proton pump inhibitors, have conferred an acceptable safety profile for low-dose aspirin use in the general population and thereby the potential for use in CRC prophylaxis. Recently, the U.S. Preventive Services Task Force issued a draft recommendation statement advocating long-term use of low-dose aspirin for primary prevention of CRC and CVD among adults aged 50 to 59 years who have a 10% or greater 10-year CVD risk and who are not at increased risk of bleeding [
35]. For comparable adults aged 60 to 69 years, the Task Force recommends the decision to take low-dose aspirin for primary CRC and CVD prevention should be made on an individual basis. A quantification of the gastrointestinal safety profile of low-dose aspirin in our patient population is warranted to make a valid benefit/risk evaluation in CRC prevention. There is also a need for our results for CRC stage to be verified in other large, population-based, observational studies. The potential for low-dose aspirin to be used post-diagnosis as adjuvant treatment to prevent recurrence and prolong survival is another promising research question and is currently being assessed in the ongoing placebo-controlled ADD-Aspirin trial [
36].