Abstract
Background/Aim: We investigated the effect of aspirin on colorectal cancer (CRC) risk among subgroups of women with and without risk factors for CRC. Patients and Methods: Using data from the Women’s Health Initiative, we estimated hazard ratios for CRC in association with aspirin use, with stratifications by cardiovascular disease (CVD) risk status, family history of CRC, and history of colorectal polypectomy. Results: Aspirin was associated with a lower risk of CRC among women with low/normal or high CVD-risk status; no family history of CRC; or a history of colonoscopy with polypectomy. Aspirin was not associated with CRC among women with a family history of CRC or a history of colonoscopy without polypectomy. Conclusion: Aspirin was associated with a lower risk of CRC in women at all levels of CVD-risk, in those with a history of colonoscopy with polypectomy, and in those without a family history of CRC.
Keywords: Aspirin, colorectal cancer, cardiovascular disease, polypectomy, Women’s Health Initiative, chemoprevention
Colorectal cancer (CRC) is one of the most common and fatal cancers, with approximately 1.8 million new cases and 862,000 deaths worldwide in 2018 (1). Numerous studies have established that regular aspirin use lowers the risk of CRC (2–5). However, long-term aspirin therapy is associated with several complications, including gastrointestinal and intracranial hemorrhage (6, 7). Furthermore, aspirin use among elderly patients was recently linked to an overall higher risk of cancer (8). Aspirin therapy for CRC prevention should, therefore, be limited to individuals with a favorable risk-benefit ratio.
In 2016, the U.S. Preventive Services Task Force (USPSTF) recommended aspirin use for the primary prevention of both cardiovascular disease (CVD) and CRC in adults aged 50 to 59 years who are at high risk for CVD and an average risk for bleeding (9). CRC shares several risk factors with CVD (10, 11), including older age, male sex, smoking, diabetes, and obesity (10 – 12), so individuals with high CVD-risk likely also have high CRC risk. Many of the clinical trials that have established the association between aspirin use and CRC (2, 3) were designed to investigate the cardioprotective effects of aspirin and included only high CVD-risk populations (13–18). Therefore, it is unclear if individuals with different levels of CVD risk experience the chemopreventive effects of aspirin.
An important risk factor for CRC is a prior history of a colorectal adenoma (19), as most CRC develops through the adenoma-to-carcinoma sequence (12). Adenomas are frequently identified endoscopically and managed by polypectomy. In a randomized controlled trial, regular aspirin use lowered the risk of adenomas in patients with a history of CRC (20). Similarly, a meta-analysis of randomized trials found that aspirin lowered the risk of adenomas in patients with a history of adenomas (21). A family history of CRC is another known risk factor for CRC (22).
The purpose of this study was to evaluate the potential effect modification of CRC risk factors (CVD risk status, history of colorectal polypectomy, and family history of CRC) on the association between aspirin use and CRC among post-menopausal women. We performed a stratified analysis of data from the Women’s Health Initiative (WHI), a prospective study with detailed longitudinal data on postmenopausal women (23).
Patients and Methods
The WHI is a large clinical investigation of common diseases affecting postmenopausal women, including cancer, CVD, and osteoporosis (23). The study was performed between 1995 and 2005, with two extended follow-up periods (2005–2010, 2010–2020) for some participants (24). A total of 161,808 women aged 50 to 79 years were included in an observational study (OS) or one or more clinical trials (CT) investigating hormone therapy, diet modifications, and vitamin supplementation (24). Details of the WHI study design and methods have been previously described (24).
In this analysis, we included participants from both the OS and CT. We excluded participants with a history of CVD or CRC, those who developed CVD or CRC within 3 years of study enrollment, and those missing data required for CVD risk stratification. Regular aspirin use was defined as any dose taken ≥2 times per week at study enrollment (baseline) and at the 3-year follow-up visit.
Underlying CVD risk was estimated by the non-laboratory based Framingham Risk Score, which was developed from the Framingham Heart Study (11). This risk score uses the following baseline participant characteristics: age, systolic blood pressure, hypertension treatment (yes/no), current smoking, diabetes, and body mass index (BMI). The calculator estimated the 10-year risk of a CVD event, defined as coronary heart disease, stroke, peripheral vascular disease, or heart failure (11). Participants were classified as low/normal risk (<10% ten-year risk) or high-risk (≥10% ten-year risk). Family history of CRC was defined as any first-degree relative with a history of CRC. History of colonoscopy and polypectomy were reported by the participants at study enrollment.
Ascertainment and adjudication methods of cancer outcomes in the WHI have been previously described (25). Participants or next-of-kin reported cancer diagnoses on questionnaires annually in the OS or semiannually in the CT through 2005 and annually in both studies thereafter. Reported cancer events were verified by centrally trained physician adjudicators via review of medical records and pathology reports.
Multivariable Cox proportional hazards regression models were used to estimate hazard ratios (HR), 95% confidence intervals (CI), and p-values for the associations between aspirin use and CRC incidence, with stratification by CVD risk status, family history of CRC, and history of polypectomy. We were investigating aspirin use for primary prevention, so observations were censored at stroke, myocardial infarction, and death. All analyses were performed using Stata 14.2 (College Station, TX, USA).
Results
Patient characteristics.
Among the 161,808 participants in the WHI, 33,296 met exclusion criteria, leaving 128,512 participants for analysis (Figure 1). Of these, 47% (n=60,912) had high CVD-risk, 15% (n=19,133) had a family history of CRC, and 47% (n=60,532) had a history of a colonoscopy (Table I). Among women with a history of colonoscopy, 16% (n=9,896) also had a history of a polypectomy. Participant selection and stratification is described in Figure 1.
Figure 1.
Consort. A) Stratification by CVD risk status. B) Stratification by family history of colorectal cancer. C) Stratification by history of colorectal polypectomy. WHI: Women’s Health Initiative; MI: myocardial infarction; CVD: cardiovascular disease; CRC: colorectal cancer.
Table I.
Baseline patient demographics and characteristics, by aspirin use status.
| All participants (n=128,512) | Aspirin non-users (n=115,749) | Aspirin users (n=12,763) | |
|---|---|---|---|
| Age, n (%) | |||
| <60 | 45,993 (36) | 43,014 (37) | 2,979 (23) |
| 60–69 | 57,417 (45) | 51,096 (44) | 6,321 (50) |
| ≥70 | 25,102 (20) | 21,639 (19) | 3,463 (27) |
| Race/Ethnicity, n (%) | |||
| White/Other | 117,365 (91) | 105,163 (91) | 12,202 (96) |
| Black/African American | 11,147 (9) | 10,586 (9) | 561 (4) |
| BMI, median (IQR) | 27 (24, 31) | 27 (24, 31) | 27 (24, 31) |
| Systolic blood pressure, median (IQR) | 125 (114, 138) | 125 (114, 137) | 128 (117, 140) |
| Treatment for hypertension, n (%) | 27,896 (22) | 24,143 (21) | 3,753 (29) |
| Diabetes mellitus, n (%) | 6,179 (5) | 5,486 (5) | 693 (5) |
| Current smoking, n (%) | 8,759 (7) | 8,063 (7) | 696 (6) |
| CVD risk (%), median (IQR) | 10 (6, 15) | 9 (6, 15) | 11 (8, 17) |
| CVD risk, n (%) | |||
| Low/normal | 67,600 (53) | 62,239 (54) | 5,361 (42) |
| High | 60,912 (47) | 53,510 (46) | 7,402 (58) |
| Family history of CRC, n (%) | 19,133 (15) | 17,113 (15) | 2,020 (16) |
| History of colonoscopy, n (%) | 60,532 (47) | 53,691 (46) | 6,841 (54) |
| History of polypectomy, n (%) | 9,896 (8) | 8,754 (8) | 1,142 (9) |
BMI: Body mass index; IQR: interquartile range; CVD: cardiovascular disease; CRC: colorectal cancer.
Of all the included participants, 12,763 (10%) used aspirin. There were 1,820 (1.4%) incident cases of CRC over a median follow-up of 17 years. Patient demographics and characteristics at study enrollment are described in Table I.
Risk factors for CRC.
In multivariable Cox-proportional hazards regression, age, high CVD-risk status, and family history of CRC were independently associated with higher risk of CRC ( p<0.001) (Table II). Among the entire cohort, a history of polypectomy was not associated with CRC (HRadj=1.07; 95%CI=0.91–1.26; p=0.414) (Table II), however among women who had undergone a colonoscopy it was associated with an approximately 27% higher risk of CRC (HRadj=1.27; 95%CI=1.06–1.50; p= 0.008). In the entire cohort, aspirin use was associated with an approximately 23% lower risk of CRC (HRadj=0.77, 95%CI=0.65–0.90, p=0.001) (Table III).
Table II.
Hazard ratios for colorectal cancer. Multivariable Cox proportional hazards regression with colorectal cancer as the outcome.
| HRadj (95%CI) | p-Value | |
|---|---|---|
| Age | ||
| <60 | Reference | |
| 60–69 | 1.71 (1.51, 1.93) | <0.001 |
| ≥70 | 2.36 (2.03, 2.74) | <0.001 |
| CVD risk | ||
| Low/normal | Reference | |
| High | 1.37 (1.23, 1.52) | <0.001 |
| Family history of CRC | ||
| No | Reference | |
| Yes | 1.24 (1.10, 1.40) | <0.001 |
| History of colorectal polypectomy | ||
| No | Reference | |
| Yes | 1.07 (0.91, 1.26) | 0.414 |
HR: Hazard ratio; CI: confidence interval; CVD: cardiovascular disease; CRC: colorectal cancer.
Table III.
Hazard ratios for colorectal cancer according to aspirin use status, stratified by colorectal cancer risk factors.
| Risk strata | Aspirin use | HRadj (95%CI) | p-Value |
|---|---|---|---|
| All participants | No | Reference* | -- |
| Yes | 0.77 (0.65, 0.90) | 0.001 | |
| Low/normal CVD-risk | No | Reference† | -- |
| Yes | 0.72 (0.54, 0.96) | 0.025 | |
| High CVD-risk | No | Reference† | -- |
| Yes | 0.79 (0.65, 0.96) | 0.017 | |
| No family history of CRC | No | Reference‡ | -- |
| Yes | 0.72 (0.60, 0.86) | <0.001 | |
| Family history of CRC | No | Reference‡ | -- |
| Yes | 0.97 (0.70, 1.36) | 0.882 | |
| History of colonoscopy without polypectomy | No | Reference# | -- |
| Yes | 0.90 (0.70, 1.15) | 0.398 | |
| History of colonoscopy with polypectomy | No | Reference# | -- |
| Yes | 0.52 (0.29, 0.93) | 0.028 |
HR: Hazard ratio; CI: confidence Interval; CVD: cardiovascular disease; CRC: colorectal cancer.
Adjusted for age, CVD risk, family history of CRC, and history of polypectomy
Adjusted for age, family history, and history of polypectomy
Adjusted for age, CVD risk, and history of polypectomy
Adjusted for age, CVD risk, and family history of CRC.
Stratified analyses.
CVD-RISK. Approximately 8% (n=5,361) of women in the low/normal CVD-risk cohort and 12% (n=7,402) of women in the high CVD-risk cohort used aspirin. In multivariable Cox-proportional hazards regression, aspirin use was associated with an approximately 28% lower risk of CRC in the low/normal CVD-risk cohort (HRadj=0.72; 95%CI=0.54–0.96; p=0.025) and an approximately 21% lower risk of CRC in the high CVD-risk cohort (HRadj=0.79, 95%CI=0.65–0.96; p=0.017) (Table III).
Family history of CRC.
Approximately 10% (n=10,743) of women without a family history of CRC and 11% (n=2,020) of women with a family history of CRC used aspirin. Of the 1,820 participants who developed CRC, 23% (n=338) had a family history of CRC. In multivariable Cox-proportional hazards regression, aspirin use was associated with an approximately 28% lower risk of CRC among women without a family history of CRC (HRadj=0.72; 95%CI=0.60–0.86; p< 0.001) (Table III). Aspirin use was not associated with risk of CRC in women who had a family history of CRC (HRadj=0.97; 95%CI=0.70–1.36; p=0.882) (Table III).
History of polpyectomy.
In the subgroup of 60,532 women with a history of a colonoscopy, 11% (n=5,699) of those who did not have a polypectomy and 12% (n=1,142) of those who did have a polypectomy used aspirin. In multivariable Cox-proportional hazards regression, aspirin use was not associated with the risk of CRC among women who did not have a polypectomy (HRadj =0.90; 95%CI=0.70–1.15, p=0.398), however it was associated with approximately 48% lower risk of CRC among women who had a polypectomy (HRadj =0.52; 95%CI=0.29–0.93; p=0.028) (Table III).
Discussion
Meta-analyses of observational and clinical trials have established that regular aspirin use significantly reduces the risk CRC (2, 3, 26). Aspirin is currently the most promising agent for primary CRC prevention (4, 27); it has the potential to prevent an estimated 29,800 CRC cases per year (28).
In 2016, the U.S. Preventive Services Task Force (USPSTF) was the first organization to recommend aspirin use for the primary prevention of both CVD and CRC (9). In their comprehensive analysis, the combined benefit of CVD and CRC prevention outweighed the risks of aspirin use only in individuals with high CVD-risk. The American Heart Association (AHA) / American Stroke Association (29) and the American Diabetes Association (30) do not recommend aspirin use for any individuals without high CVD-risk, however these recommendations do not take into account any concomitant effect on CRC risk. Currently, no organization recommends aspirin use solely for CRC prevention among the general population. For patients with Lynch syndrome who have a 52–82% lifetime risk of CRC, the National Comprehensive Cancer Network (NCCN) suggests aspirin use for chemoprevention (31).
In this study, we found that high CVD-risk was associated with a higher risk of CRC. We also showed that women with both low/normal and high CVD-risk who used aspirin had a lower risk of CRC compared to those who did not. This is consistent with prior reports. An analysis of the Nurses’ Health Study and the Health Professionals Follow-up Study found that having ≥2 cardiac risk factors did not modify the association between aspirin use and CRC risk (28). In addition, a microsimulation model performed by the USPSTF suggested that aspirin use reduces the risk of CRC at all CVD risk levels (32).
On the other hand, the recently published Aspirin in Reducing Events in the Elderly (ASPREE) trial (7, 8, 33) suggests that aspirin use is harmful in healthy older adults. This trial randomized adults aged 70 years or older (or ≥65 years among blacks and Hispanics) without a history of CVD, dementia, or disability, to receive 100 mg of aspirin daily or placebo. The aspirin cohort had higher incidence of death from any cause (HR=1.14, 95%CI=1.01–1.29), primarily due to higher cancer mortality (HR=1.31, 95%CI=1.10–1.56), including CRC (HR=1.77, 95%CI=1.02–3.06) (33). Aspirin use was also associated with a higher risk of major hemorrhage (HR=1.38; 95%CI=1.18–1.62; p<0.001) (7). Aspirin use for CRC prevention must therefore be weighed against the likelihood of these potential complications and the appropriate risk stratification employed to identify individuals who will have the greatest overall benefit.
In this study, a family history of CRC was associated with a higher risk of CRC, but aspirin use among women in this subgroup was not associated with lower CRC risk (HRadj=0.97; 95%CI=0.70–1.36; p=0.882). This is consistent with an analysis of the National Institutes of Health-AARP Diet and Health Study that found that aspirin use was not associated with a lower risk of CRC among patients with a first-degree relative with a history of colon cancer (34). In another study, NSAID use was associated with a lower risk of CRC among individuals with a family history of CRC (OR=0.4, 95%CI=0.2–0.9) (35). Clinical trials by the Colorectal Adenoma/Carcinoma Prevention Program found that aspirin use had no effect on adenoma burden in patients with familial adenomatosis polyposis (FAP) (36), however it was associated with lower long-term risk of CRC in patients with Lynch syndrome (37). Whether aspirin use decreases CRC risk among all patients with a family history of CRC remains unclear, and we did not find evidence to support its use in this patient population.
In women with a history of colonoscopic polypectomy, aspirin use was associated with a lower risk of CRC. This is consistent with results of prior investigations of aspirin for the secondary prevention of colorectal neoplasms. In three clinical trials involving patients with a history of colorectal adenomas, aspirin use lowered the risk of recurrent adenomas (38–40). In another trial that included patients with a prior CRC that had been curatively resected, aspirin use lowered the risk of developing a new polyp (HRadj=0.64, 95%CI=0.43–0.94; p= 0.022) (20).
Strengths of this study include the large cohort size, detailed data regarding CVD risk factors, long follow-up duration, and adjudicated cancer outcomes in the WHI. Our study had several limitations. First, we could not assess the risk of aspirin-related complications, including gastrointestinal (GI) and intracranial hemorrhage, because these data were not collected in the WHI. Previous studies have found that the risk of gastrointestinal complications is highest within the first weeks of starting aspirin and decreases with continued aspirin use (41). In this study, the duration of aspirin use was at least 3 years, so there was likely a relatively low incidence of GI complications as therapy likely would have been discontinued if significant adverse effects occurred. In addition, we used a generalized definition of regular aspirin use (any dose used ≥2 times per week at study enrollment and at the year 3 follow-up visit), so variations in dosage, frequency of use, and duration were not considered. A recent study found that current users of aspirin, regardless of dose, had a significantly reduced risk of CRC (42). Other studies have found that at least 10 years of use are required for a chemo-preventative benefit (43). Although aspirin use in our study included a range of dosages, frequencies, and durations, the 23% risk reduction in the non-stratified analysis was remarkably similar in magnitude to the 24% risk reduction found in a pooled analysis of four clinical trials (HR=0.76, 95%CI=0.60–0.96, p=0.02) (3). Another potential limitation of this study was the use of the non-laboratory based Framingham Risk Score rather than the commonly used American College of Cardiology (ACC)/AHA risk calculator (10). We used the non-laboratory-based Framingham Risk Score because only a fraction of the selected WHI participants had the serum lipid measurements required for the ACC/AHA risk calculator. Finally, polypectomy data were self-reported by the study participants and were not adjudicated, and the histopathology of the polyps was not known.
Conclusion
In our analysis of the WHI, high CVD-risk and a family history of CRC were both independently associated with higher risk of CRC. Among women who had a prior colonoscopy, a polypectomy was also associated with a higher risk of CRC. Aspirin use was associated with a lower risk of CRC among women with low/normal or high CVD-risk, no family history of CRC, or a history of colonoscopy with polypectomy. Aspirin use was not associated with CRC risk in women with a family history of CRC or a history of colonoscopy without polypectomy. Additional prospective trials that also evaluate complications of therapy are needed to confirm the effects of aspirin on CRC risk in these subgroups of women, as well as guide future treatment recommendations.
Acknowledgements
The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, U.S. Department of Health and Human Services through contracts HHSN268201100046C, HHSN268201100001C, HHSN268201100002C, HHSN268201100 003C, HHSN268201100004C, and HHSN271201100004C.
The Authors would like to thank the WHI participants who made this study possible. The Authors would also like to thank the WHI coordinators: Program Office: (National Heart, Lung, and Blood Institute, Bethesda, MD, USA) Jacques Rossouw, Shari Ludlam, Dale Burwen, Joan McGowan, Leslie Ford, and Nancy Geller; Clinical Coordinating Center: (Fred Hutchinson Cancer Research Center, Seattle, WA, USA) Garnet Anderson, Ross Prentice, Andrea LaCroix, and Charles Kooperberg Investigators and Academic Centers: (Brigham and Women’s Hospital, Harvard Medical School, Boston, MA, USA) JoAnn E. Manson; (MedStar Health Research Institute/Howard University, Washington, DC, USA) Barbara V. Howard; (Stanford Prevention Research Center, Stanford, CA, USA) Marcia L. Stefanick; (The Ohio State University, Columbus, OH, USA) Rebecca Jackson; (University of Arizona, Tucson/Phoenix, AZ, USA) Cynthia A. Thomson; (University at Buffalo, Buffalo, NY, USA) Jean Wactawski-Wende; (University of Florida, Gainesville/Jacksonville, FL, USA) Marian Limacher; (University of Iowa, Iowa City/Davenport, IA, USA) Robert Wallace; (University of Pittsburgh, Pittsburgh, PA, USA) Lewis Kuller; (Wake Forest University School of Medicine, Winston-Salem, NC, USA) Sally Shumaker; Women’s Health Initiative Memory Study: (Wake Forest University School of Medicine, Winston-Salem, NC, USA) Sally Shumaker.
Footnotes
Conflicts of Interest
The Authors have no conflicts of interest regarding this study.
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