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© The Author 2007. Published by Oxford University Press.
ARTICLES |
Association of Aspirin and Nonaspirin Nonsteroidal Anti-inflammatory Drugs With Cancer Incidence and Mortality
Affiliations of authors: Departments of Internal Medicine (AB, JOE, PJL) and Health Sciences Research (RAV, AHW, JEO, CMV, JRC), Mayo Clinic College of Medicine, Rochester, MN; Department of Epidemiology, University of Minnesota, Minneapolis, MN (KA, CMV)
Correspondence to: Jon O. Ebbert, MD, Department of Internal Medicine, Mayo Clinic College of Medicine, 200 First St SW, Rochester, MN 55905 (e-mail: ebbert.jon{at}mayo.edu).
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ABSTRACT |
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 Top Abstract Context and CaveatsSubjects and MethodsResultsDiscussionReferencesNotes |
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Background: The cancer chemopreventive benefits of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) are incompletely defined and may vary by smoking history. We evaluated associations between aspirin and nonaspirin NSAID use with cancer incidence and mortality stratified by smoking history in the Iowa Women's Health Study, a prospective cohort of postmenopausal women.
Methods: Aspirin and nonaspirin NSAID use was self-reported by questionnaire in 1992. Cancer incidence and mortality were ascertained by annual linkage to the Iowa Surveillance, Epidemiology, and End Results Cancer Registry and death certificates. Cox proportional hazards models were used to estimate multivariable relative risks (RRs) and 95% confidence intervals (CIs). All statistical tests were two-sided.
Results: During an average of 10 years of follow-up, 3487 incident cancer cases and 3581 deaths were observed in the cohort of 22507 women. Compared with nonuse, aspirin use was inversely associated with total cancer incidence (multivariable-adjusted RR = 0.84, 95% CI = 0.77 to 0.90), with age-adjusted incidence rates of 147 and 170 per 10000 person-years for ever and never users, respectively, and was inversely associated with cancer mortality (multivariable-adjusted RR = 0.87, 95% CI = 0.76 to 0.99), with age-adjusted rates of 47 and 52 per 10000 person-years. The inverse relationship was stronger among former and never smokers than current smokers, although not statistically significantly (P = .28). Aspirin use was also inversely associated with coronary heart disease mortality (multivariable-adjusted RR = 0.75, 95% CI = 0.64 to 0.89), with age-adjusted rates of 23 and 30 per 10000 person-years for ever and never users, respectively, and with all-cause mortality (multivariable-adjusted RR = 0.82, 95% CI = 0.76 to 0.89), with age-adjusted rates of 126 and 155 per 10000 person-years. Nonaspirin NSAID use was not associated with cancer incidence or mortality, coronary heart disease mortality, or all-cause mortality.
Conclusions: Aspirin use, but not nonaspirin NSAID use, was associated with lower risks of cancer incidence and mortality, which was more pronounced among former and never smokers than current smokers.
Prior knowledge The effectiveness of aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) in cancer prevention is unclear. Study design Cohort study of aspirin and NSAID use, cancer incidence, and overall and coronary heart disease mortality among female residents of Iowa who participated in the Iowa Women's Health Study. Smoking history was also incorporated into the analyses. Contribution Nonaspirin NSAID use was not associated with any of the outcomes in the study. However, aspirin use was inversely associated with cancer incidence and cancer-related, coronary heart disease–related, and overall mortality. The associations were slightly but not statistically significantly stronger among former and never smokers than among current smokers. Implications Compared with no use, use of aspirin was associated with reduced cancer incidence and mortality in this population; no associations were observed with the use of nonaspirin NSAIDs. Limitations The survey-based design may be subject to usage reporting error, and specific information such as the dose and type of agent used was not reported. Because the study was restricted to postmenopausal mainly white women, it is unknown whether these results also apply to other populations.
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Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) have received considerable interest as potential cancer chemopreventive agents due to their anti-inflammatory properties (1–3). Animal studies suggest that these agents may inhibit tumor growth by modulating cellular proliferation via suppression of endogenous prostaglandin synthesis through inhibition of cyclooxygenase (COX) enzymes (4,5). Aspirin is also considered to be a chemopreventive agent because of its antioxidant properties (6,7).
Observational studies (8–27) and randomized trials (28–34) have evaluated the effect of aspirin and nonaspirin NSAIDs on site-specific cancer incidence, particularly in the colon and breast. Some, but not all, studies have demonstrated chemopreventive benefits from aspirin and/or nonaspirin NSAIDs. In the Iowa Women's Health Study (IWHS), aspirin use was inversely associated with the risks of leukemia (35) and colon (36), breast (37), and pancreatic (38) cancer, positively associated with non-Hodgkin lymphoma risk (39), and not associated with lung cancer risk (40). Because of their widespread use, the impact of aspirin and NSAIDs on total cancer incidence and all-cause mortality is of clinical and public health interest; however, only a few studies (32,41) have evaluated global endpoints.
Smoking may modify the effect of aspirin and nonaspirin NSAIDs on cardiovascular and cancer endpoints (42,43). In the Women's Health Study, the observed reduction in cardiovascular risk associated with aspirin use was greater among never and former smokers than current smokers (42). Investigators (44) have postulated that cigarette smoking acts as a proinflammatory stimulus and as an oxidant and can modify the association between aspirin and nonaspirin NSAIDs and cancer risk, although data are limited.
The objective of this study was to examine the association between the use of aspirin and nonaspirin NSAIDs and cancer incidence and mortality, overall and stratified by smoking status. We hypothesized that aspirin and nonaspirin NSAID use would be associated with lower rates of cancer incidence and mortality than nonuse and that these associations would be greater among current smokers than among former or never smokers. We also assessed associations between the use of aspirin and nonaspirin NSAIDs and coronary heart disease and all-cause mortality.
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Subjects and Methods |
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Study Population
The IWHS is a prospective cohort study of 41836 postmenopausal women aged 55–69 years at study entry; full details on study methods have been previously published (45,46). The IWHS was reviewed and approved by the institutional review boards of the University of Iowa and the University of Minnesota. A 16-page questionnaire was mailed in 1986 to 99826 randomly selected women and returned by 41836 women (42.7% response rate). Follow-up questionnaires were mailed in 1987, 1989, 1992, 1997, and 2002. Written informed consent of participation was assumed based on completion and return of the surveys.
Risk Factor Assessment
The use of aspirin and nonaspirin NSAIDs in the cohort was ascertained on the 1992 questionnaire. Aspirin use was ascertained by asking the respondents "How often do you take aspirin? Examples of aspirin include Bufferin, Anacin, enteric-coated aspirin, Ecotrin, and Excedrin (Do not include acetaminophen, Tylenol, Ibuprofen, Advil): never, less than one per week, one per week, 2–5 per week, and 6+ per week." Use of nonaspirin NSAIDs was ascertained by asking the respondents, "How often do you take other nonsteroidal antiinflammatory drugs or arthritis medicines? Examples include Ibuprofen, Advil, Nuprin, Motrin, Naprosyn, Feldene, and Clinoril (Do not include aspirin, acetaminophen, Tylenol, prednisone, corticosone, Deltasone): never, less than one per week, one per week, 2–5 per week, and 6+ per week."
Smoking information was ascertained on the baseline questionnaire by asking the respondents "Have you ever smoked cigarettes on a regular basis; that is, more than 100 cigarettes in your entire life?" In addition, the baseline and 1992 questionnaires asked respondents, "Do you smoke cigarettes now?" Women who responded that they had never smoked cigarettes at baseline and who were not currently smoking in 1992 were classified as never smokers. Women who reported that they had ever smoked cigarettes at baseline but who were not currently smoking in 1992 were classified as former smokers. Women who reported that they smoked cigarettes in 1992 were classified as current smokers.
Other data collected included age, marital status, level of education, waist and hip circumferences, height, weight, level of physical activity, alcohol use, and use of hormone replacement therapy, as well as information about prevalent chronic diseases (hypertension, diabetes, cardiovascular disease, rheumatoid arthritis, and osteoarthritis). Participants also completed a 126-item semiquantitative food-frequency questionnaire, which has been shown to be valid and reliable in this population (47). These data were ascertained on the 1992 questionnaire and were supplemented with data from the 1986 questionnaire.
Cohort Follow-up
Cohort members who were diagnosed with cancer, except for nonmelanoma skin cancer, through 2003 were identified using the Iowa Cancer Registry, a member of the National Cancer Institute's Surveillance, Epidemiology, and End Results Program (48). Each year, registry patients and cohort members were matched to registry files by name, maiden name, zip code, birth date, and social security number. Deaths were identified through annual linkage to Iowa state death certificates supplemented by linkage to the National Death Index.
Exclusions
For this analysis, of the 41836 women who responded to the questionnaire in 1986, we excluded women who were premenopausal (n = 569), had cancer other than nonmelanoma cancer, or were receiving chemotherapy through 1992 (n = 3881), reported a history of heart disease through 1992 (n = 7294), died between 1986 and 1992 (n = 2177), or did not complete the 1992 questionnaire (n = 6642). A total of 22507 participants were included in the analytic cohort (exclusions were not mutually exclusive).
Statistical Analyses
Two outcomes were of primary interest: cancer incidence and cancer mortality [International Classification of Diseases, 9th Revision (ICD-9) (49) codes 140–239 and International Classification of Diseases, 10th Revision (ICD-10) (50) codes C, D]. Coronary heart disease mortality (ICD-9 codes 410–414, 429.2 and ICD-10 codes I20–I25, I51.6) and all-cause mortality were secondary outcomes. For cancer incidence, follow-up for incident events was calculated as the subject's age at completion of the 1992 questionnaire until her age at cancer diagnosis, at emigration from Iowa, or at death, whichever came first. If none of these events occurred, the subject was assumed to be alive, cancer free, and living in Iowa through December 31, 2003. For the mortality analyses, follow-up was calculated from the subject's age at completion of the 1992 questionnaire to her age at death or on December 31, 2003, whichever came first. We examined incidence and mortality rates by levels of aspirin and NSAID use and adjusted for age using Poisson regression analysis with a log-link function.
Cox proportional hazards regression analyses were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between aspirin or nonaspirin NSAID use and the outcomes of interest, with controlling for the following set of potential confounding factors: education status (no high school diploma, high school graduate, post–high school education), physical activity (low, moderate, high), use of hormone replacement (never, former, current), marital status (currently married, formerly married, never married), body mass index (included as a continuous covariate), diabetes status (no, yes), fruit and vegetable intake (<400, 400–800, >800 g/day), waist-to-hip ratio (included as a continuous covariate), history of hypertension (no, yes), alcohol use (never, former monthly, former weekly, former daily, current monthly, current weekly, current daily), vitamin supplement use (no, yes); total caloric intake (included as a continuous covariate), red meat consumption (included as a continuous covariate), whole wheat consumption (included as a continuous covariate), vitamin E intake (included as a continuous covariate), cholesterol intake (included as a continuous covariate), history of osteoarthritis (no, yes), history of rheumatoid arthritis (no, yes), and smoking status (never, former, current). Exposures to aspirin and nonaspirin NSAIDs were characterized by ever use as well as by frequency of use. For the latter analyses, subjects who reported using less than or equal to one time per week were combined into one group, resulting in categories of never, one or less times per week, two to five times per week, and six or more times per week. Tests for trend were carried out for each frequency of use variable by ordering the values from lowest to highest and including the resulting variable as a 1 df linear term in a Cox proportional hazards model. For all such analyses, never users were modeled as the referent group. We also examined combinations of the two agents, defined as follows: use of aspirin only, use of nonaspirin NSAIDs only, use of both, and use of neither. Incidence was modeled as a function of age (51).
Initial analyses examined the overall effect of aspirin and nonaspirin NSAID use; subsequent analyses were stratified by smoking status (never, former, or current). Analyses of former and current smokers included pack-years smoked as a covariate. We formally assessed the modifying effects of smoking status on the association between aspirin use and outcomes of interest using standard tests of interaction. For all such analyses, never users were modeled as the referent group.
Population-attributable risk estimates were calculated on the basis of coefficients generated by the Cox models for the cohort (52). Confidence intervals were generated using bootstrap resampling methodology (53). The assumption of proportional hazards for aspirin and nonaspirin NSAIDs was tested by examining interactions with the time variable and found not to be violated. All statistical tests were two-sided, and P values less than .05 were considered to be statistically significant. All analyses were carried out using the SAS (SAS Institute, Inc, Cary, NC) and Splus (Insightful, Inc, Seattle, WA) software systems.
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Results |
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A total of 22507 postmenopausal women aged 55–69 years at baseline were in the analytic dataset, 99% of whom were Caucasian. On the 1992 survey, 28% of the women reported never using aspirin, 36% used it once a week or less, 18% used it two to five times per week, and 18% used it six or more times per week. Sixty-one percent reported never using nonaspirin NSAIDs, 19% used them once a week or less, 8% used them two to five times per week, and 12% used them daily. Both aspirin and nonaspirin NSAIDs were used concomitantly by 28% of the cohort. In 1992, 72% of the cohort were never smokers, 18% were former smokers, and 9% were current smokers. Compared with nonusers of both aspirin and nonaspirin NSAIDs, women who used only nonaspirin NSAIDs (or those using both aspirin and nonaspirin NSAIDs) had slightly higher body mass indices, higher intake of vitamin E, and greater use of estrogen replacement therapy and were more likely to have a history of rheumatoid arthritis or osteoarthritis (Table 1). Little variation of other characteristics by use of aspirin or nonaspirin NSAIDs was observed.
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Cancer Incidence
During an average of approximately 10 years of follow-up (226798 person-years), 3487 incident cases of cancer were observed. Compared with never use of aspirin, ever use of aspirin was associated with a lower risk of cancer (multivariable RR = 0.84, 95% CI = 0.77 to 0.90; Table 2) with age-adjusted incidence rates of 147 and 170 per 10000 person-years for ever and never users, respectively. An inverse trend for cancer risk with frequency of aspirin use (Ptrend<.001) was observed. No association between use of nonaspirin NSAIDs and cancer incidence was observed (Table 2). Compared with never use of either agent, use of both agents was inversely associated with cancer incidence (multivariable RR = 0.81, 95% CI = 0.72 to 0.90), similar to that of aspirin use alone.
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Mortality
A total of 3581 deaths were recorded as of December 31, 2003, with 1193 deaths attributable to cancer and 734 deaths attributable to coronary heart disease in the analytic cohort. Compared with never use of aspirin, aspirin ever use was inversely associated with cancer mortality (multivariable RR = 0.87, 95% CI = 0.76 to 0.99), with age-adjusted rates of 47 and 52 per 10000 person-years for ever and never use, respectively, coronary heart disease mortality (multivariable RR = 0.75, 95% CI = 0.64 to 0.89), with age-adjusted rates of 23 and 30 per 10000 person-years, for ever and never use, respectively, and all-cause mortality multivariable RR = 0.82, 95% CI = 0.76 to 0.89), with age-adjusted rates of 126 and 155 per 10000 person-years for ever and never use, respectively. No association with nonaspirin NSAIDs was observed for these outcomes (Table 3).
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A weak inverse association between the frequency of aspirin use and cancer mortality was observed, whereas for coronary heart disease and all-cause mortality, there were U-shaped associations. By contrast, we observed no associations between the frequency of nonaspirin NSAID use and cancer mortality, coronary heart disease mortality, or all-cause mortality, although the most frequent users had a slightly higher risk of coronary heart disease mortality than never users (multivariable RR = 1.23, 95% CI = 0.96 to 1.57). Use of nonaspirin NSAIDs did not appear to modify the associations between aspirin use and mortality among women who reported use of both agents (Table 3).
Stratification by Smoking History
The inverse association between aspirin use and cancer incidence was stronger among former and never smokers than current smokers (Table 2, Fig. 1, A), although a formal test for interaction between frequency of aspirin use and smoking status was not statistically significant (P = .28). Similarly, the inverse association between aspirin use and cancer mortality (Fig. 1, B) was evident among never smokers (for aspirin use six or more times per week versus never use, multivariable RR = 0.78, 95% CI = 0.61 to 0.99) and suggestive among former smokers (for aspirin use six or more times per week versus never use, multivariable RR = 0.80, 95% CI = 0.51 to 1.24) but not among current smokers (for aspirin use six or more times per week versus never use, multivariable RR = 0.95, 95% CI = 0.63 to 1.46), although the interaction was not statistically significant (P = .50).
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1, 2–5, and 
6 times per week) and smoking status (never, former, current) with outcomes in the Iowa Women's Health Study. A) Cancer incidence. B) Cancer mortality. C) Coronary heart disease mortality. D) All-cause mortality. The relative risks (black squares) and corresponding 95% confidence intervals (error bars) were calculated using Cox proportional hazards regression analysis. All models account for the effects of age (modeled as the time variable), education status (no high school diploma, high school graduate, post–high school education), physical activity (low, moderate, high), use of hormone replacements (never, former, current), marital status (currently married, formerly married, never married), body mass index (included as a continuous covariate), diabetes status (no, yes), fruit and vegetable intake (<400, 400–800, >800 g/day), waist-to-hip ratio (included as a continuous covariate), history of hypertension (no, yes), alcohol use (never, former monthly, former weekly, former daily, current monthly, current weekly, current daily), vitamin supplement use (no, yes), total caloric intake (included as a continuous covariate), red meat consumption (included as a continuous covariate), whole wheat consumption (included as a continuous covariate), vitamin E intake (included as a continuous covariate), cholesterol intake (included as a continuous covariate), history of osteoarthritis (no, yes), and history of rheumatoid arthritis (no, yes). Models for former and current smokers also adjust for pack-years smoked.The inverse association of aspirin use two to five times per week with coronary heart disease mortality was apparent among never smokers (multivariable RR = 0.71, 95% CI = 0.52 to 0.96) and former smokers (multivariable RR = 0.46, 95% CI = 0.23 to 0.93) and suggestive, but not statistically significant, among current smokers (multivariable RR = 0.67, 95% CI = 0.36 to 1.24) (Fig. 1, C). Similarly, the inverse association of aspirin use two to five times per week with all-cause mortality was apparent among never smokers (multivariable RR = 0.79, 95% CI = 0.69 to 0.91) and former smokers (multivariable RR = 0.69, 95% CI = 0.53 to 0.89) and suggested (but not statistically significant) among current smokers (multivariable RR = 0.78, 95% CI = 0.60 to 1.03) (Fig. 1, D).
Nonaspirin NSAID use was not associated with cancer mortality, coronary heart disease mortality, or all-cause mortality irrespective of smoking status, and there was no interaction between nonaspirin NSAID use and smoking for any of the study outcomes (data not shown). The observed risk estimates also did not change after adjustment for smoking status by pack-years, including pack-years as a continuous (i.e., uncategorized) covariate, or excluding those subjects for whom less than 2 years of follow-up data were available (data not shown).
Population-Attributable Risk
Population-attributable risks (in percentage) were calculated to estimate the potential public health disease burden associated with lack of exposure to aspirin based on data from Tables 2 and 3. Multivariable-adjusted population-attributable risks were 4.7% (95% CI = 2.6 to 6.8) for cancer incidence, 3.5% (95% CI = 0.0 to 7.5) for cancer mortality, 7.6% (95% CI = 1.4 to 11.9) for coronary heart disease mortality, and 5.9% (95% CI = 3.5 to 8.4) for all-cause mortality.
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Discussion |
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TopAbstractContext and CaveatsSubjects and MethodsResultsDiscussionReferencesNotes |
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In this prospective, population-based study of postmenopausal women, we found that aspirin use was inversely associated with cancer incidence, cancer mortality, coronary heart disease mortality, and all-cause mortality. Contrary to our hypothesis, the inverse association for cancer-related outcomes was weakest among current smokers, although formal tests of interaction were not statistically significant. Nonaspirin NSAID use was not associated with any of these outcomes, either overall or in analyses stratified by smoking status. Nonaspirin NSAID use also did not appear to modify the associations between these outcomes and aspirin use. To our knowledge, this is the first comprehensive, prospective assessment of aspirin and nonaspirin NSAID use on cancer incidence and mortality, overall and stratified by smoking status.
Our study has some limitations. The observational study design has less internal validity than an experimental (i.e., randomized controlled trial) design would have, particularly with respect to bias due to self-selection and confounding. Also, our questionnaire did not assess the type, dose, or duration of aspirin or nonaspirin NSAID use, although we were able to distinguish between use of these two classes of agents, and data on frequency of use was collected. In addition, the study was restricted to postmenopausal women, the majority of whom were white.
The strengths of this study include its prospective cohort design, ascertainment of cancer incidence (except nonmelanoma skin cancer) using high-quality Surveillance, Epidemiology, and End Results Cancer Registry data, virtually complete follow-up for mortality, and availability of information on multiple chronic disease risk and protective factors to evaluate potential confounding. The study was population based, which enhances its external validity.
The inverse association between use of aspirin and cancer incidence seen in this study is broadly consistent with results from observational studies reporting on specific cancer sites, particularly colon cancer (10,14,15,22,23,26,54). In a recent large prospective cohort study (the Nurses’ Health Study) (10) involving 82911 women with 20 years of follow-up, women who took standard-dose aspirin (325 mg) two or more times per week had a lower incidence of colorectal cancer (RR = 0.77, 95% CI = 0.67 to 0.88) than women who were not regular users. However, a statistically significant risk reduction was not observed until after 10 years of use, and use of lower doses of aspirin (0.5 to 1.5 standard aspirin tablets per week) had no apparent effect on colorectal cancer risk (RR = 1.10, 95% CI = 0.92 to 1.31). In addition, a recent meta-analysis of 13 cohort studies and 34 case–control studies (16) concluded that aspirin use was associated with a reduced risk for breast (RR = 0.77, 95% CI = 0.66 to 0.88), esophageal (RR = 0.51, 95% CI = 0.38 to 0.69), and gastric (RR = 0.73, 95% CI = 0.63 to 0.84) cancers.
Results from randomized trials evaluating associations between aspirin use and cancer incidence have been somewhat contradictory. Although some randomized trials (29,30,34) have shown that aspirin use reduces the risk of colorectal adenomas in patients with history of previous colorectal adenomas or colorectal cancer, results from others (32,33) were less impressive with respect to the effect of aspirin on primary incident colorectal cancer. The Women's Health Study (32) evaluated the effect of 100 mg aspirin taken on alternate days on cancer risk and observed that aspirin had no effect on total cancer incidence compared with placebo after about 10 years of follow-up. No association was observed with respect to breast cancer or colon cancer incidence, but a suggestive association with a risk reduction for lung cancer was observed (RR = 0.78, 95% CI = 0.59 to 1.03). The investigators suggested that the null results could be due to aspirin dose because low-dose aspirin does not inhibit the COX-2 isoenzyme, which is considered to have an important role in chemoprevention. In fact, two recent studies (28,31) showed that use of COX-2 inhibitors is associated with a reduced incidence of colon polyps. Another potential explanation could be related to the duration of follow-up, because it may require more than 10 years of use to observe a chemoprevention effect (10,12,14,19,25).
Our results suggest that aspirin use is associated with reduced cancer mortality, which is consistent with the results of the Cancer Prevention Study-II, a prospective study involving 635031 people (41). By contrast, however, the Women's Health Study observed that low-dose aspirin use did not reduce overall cancer mortality compared with placebo (32). The reasons for the discrepancy between the two studies could again relate to aspirin dosage, the duration of follow-up, or the different study designs.
Multiple studies (42,55,56,57), including a recent meta-analysis (58), have found that aspirin use is associated with a reduced incidence of cardiovascular events; however, the association with cardiovascular mortality is less clear. One randomized trial involving 4495 subjects (57) found that the use of low-dose aspirin was effective in reducing cardiovascular mortality (RR = 0·56, 95% CI = 0.31 to 0.99), but results from two other trials among women (42,56) did not find such an effect. The meta-analysis of these three trials found that use of low-dose aspirin (50–100 mg/day for 3.6–10 years) did not reduce cardiovascular mortality among women (RR = 0.90, 95% CI = 0.64 to 1.28) (58).
We observed that aspirin use once or less and use two to five times per week (but not six or more times per week) was inversely associated with coronary heart disease mortality. These results could be due to a confounding effect of poor health among individuals who use aspirin most frequently. Women who were taking aspirin daily could have been doing so because of an underlying illness, such as myocardial infarction. Although we excluded those with self-reported heart disease at the start of the analysis, the possibility of misclassification remains. We did attempt to control for this possible bias by excluding women who had died within 2 years of follow-up, but the results were similar. It is interesting that we observed an association between aspirin use two to five times per week and lower coronary heart disease mortality but not with use for six or more times per week, which was previously observed in the Nurses’ Health Study (55).
Contrary to our study hypothesis, we found that the associations between aspirin use and the study outcomes, particularly cancer incidence and cancer mortality, were strongest among never and former smokers. Although these results could be due to the small number of active smokers in our study, similar results were seen in the Women's Health Study (32). For example, an inverse association between the use of 100 mg of aspirin and the risk of cardiovascular events was observed among never and former smokers (RR = 0.80, 95% CI = 0.69 to 0.93), whereas aspirin use was positively associated with cardiovascular event risk among current smokers (RR = 1.30; 95% CI = 1.03 to 1.64). This study (32) also reported that aspirin use was associated with a lower cancer incidence among former smokers (RR = 0.89, 95% CI = 0.79 to 1.00) but not among current smokers (RR = 0.98, 95 % CI = 0.82 to 1.17), which is similar to our findings. However, in a subgroup analysis of this study (32), aspirin use among never smokers was associated with an increase cancer incidence (RR = 1.12, 95% CI = 1.01 to 1.25), which is not consistent with our findings. The lack of an inverse association with aspirin among current smokers could be related to cigarette smoke negating the effects of antioxidants (59,60). This phenomenon has been suggested to account for the increase in lung cancer seen among people who consume antioxidants such as beta-carotene (61,62).
In contrast to aspirin use, nonaspirin NSAID use was not associated with either cancer incidence or mortality (both all-cause and cause specific). The lack of an association between NSAIDs use and coronary heart disease mortality (and possibly increased coronary heart disease mortality) has been reported in other studies, including a recent meta-analysis (63,64). Previous IWHS cohort studies (11,21,35,37,38) have noted an inconsistent relationship between aspirin and NSAIDs and the incidence of site-specific cancers. By contrast, other studies (10,12,20,22,23) have found both aspirin and nonaspirin NSAIDs use were similarly associated with reduced risk for cancer, particularly the risk of colorectal neoplasia. Although it is plausible that the use of nonaspirin NSAIDs is associated with a reduced risk for colorectal cancer but not for cancers at other organ sites, heterogeneity in the doses, types, and durations of nonaspirin NSAIDs used could also account for variations in observed results. The observed differences in associations could be also due to the additional biologic effects of aspirin, such as the permanent inhibition of COX enzymes (65).
If the association of aspirin use with these outcomes is causal, the population-attributable risk calculated from our data suggest that aspirin use could potentially prevent approximately 4.7% of the cancer incidence burden, 3.5% of the cancer mortality burden, and 7.6% of the coronary heart disease mortality burden in the population. Although these percentages may seem small, the impact on public health could be important. However, these potentially positive benefits must be weighed against the potential risks associated with aspirin use, such as gastrointestinal bleeding and hemorrhagic stroke (65).
Our data suggest that aspirin use but not nonaspirin NSAID use is associated with lower cancer incidence, cancer mortality, coronary heart disease mortality, and all-cause mortality, and the inverse association for cancer incidence and mortality may be stronger for never and former smokers. However, these observations require confirmation in other studies.
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NOTES |
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The IWHS was supported in part by National Cancer Institute R01 CA39742 (Aaron F. Folsom). The authors had full responsibility for study design; collection, analysis, and interpretation of the data; and the decision to submit the manuscript for publication.
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Manuscript received November 28, 2006; revised March 2, 2007; accepted April 20, 2007.
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