[Skip to Content]
[Skip to Content Landing]
Figure 1.  Flowchart of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Cohort Used in the Study Analysis
Flowchart of the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial Cohort Used in the Study Analysis

The current study cohort included participants who provided the baseline questionnaire with completed aspirin frequency and survived until age 65 years.

Figure 2.  Adjusted Hazard Ratios (HRs) and 95% CIs for Mortality by Aspirin Use Stratified by Body Mass Index (BMI)
Adjusted Hazard Ratios (HRs) and 95% CIs for Mortality by Aspirin Use Stratified by Body Mass Index (BMI)

No aspirin use was used as the reference for all comparisons. The model was adjusted for sex, race/ethnicity, randomization group, smoking status, ibuprofen use 3 times or more per week, and history of myocardial infarction, stroke, hypertension, and diabetes. Body mass index was calculated as weight in kilograms divided by height in meters squared.

Table 1.  Characteristics of 146 152 Participants at Baseline
Characteristics of 146 152 Participants at Baseline
Table 2.  Updated Aspirin Use and All-Cause, Cancer, GI Cancer, and CRC Mortality Among Individuals Aged 65 Years and Older
Updated Aspirin Use and All-Cause, Cancer, GI Cancer, and CRC Mortality Among Individuals Aged 65 Years and Older
Table 3.  Baseline and Follow-up Aspirin Use and Risk of All-Cause, Any Cancer, GI Cancer, and CRC Mortality Among Individuals Aged 65 Years and Older
Baseline and Follow-up Aspirin Use and Risk of All-Cause, Any Cancer, GI Cancer, and CRC Mortality Among Individuals Aged 65 Years and Older
1.
Cuzick  J, Thorat  MA, Bosetti  C,  et al.  Estimates of benefits and harms of prophylactic use of aspirin in the general population.  Ann Oncol. 2015;26(1):47-57. doi:10.1093/annonc/mdu225PubMedGoogle ScholarCrossref
2.
Cuzick  J.  Preventive therapy for cancer.  Lancet Oncol. 2017;18(8):e472-e482. doi:10.1016/S1470-2045(17)30536-3PubMedGoogle ScholarCrossref
3.
Algra  AM, Rothwell  PM.  Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials.  Lancet Oncol. 2012;13(5):518-527. doi:10.1016/S1470-2045(12)70112-2PubMedGoogle ScholarCrossref
4.
Rothwell  PM, Wilson  M, Elwin  C-E,  et al.  Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials.  Lancet. 2010;376(9754):1741-1750. doi:10.1016/S0140-6736(10)61543-7PubMedGoogle ScholarCrossref
5.
Shebl  FM, Hsing  AW, Park  Y,  et al.  Non-steroidal anti-inflammatory drugs use is associated with reduced risk of inflammation-associated cancers: NIH-AARP study.  PLoS One. 2014;9(12):e114633. doi:10.1371/journal.pone.0114633PubMedGoogle Scholar
6.
Chan  AT, Giovannucci  EL, Meyerhardt  JA, Schernhammer  ES, Curhan  GC, Fuchs  CS.  Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer.  JAMA. 2005;294(8):914-923. doi:10.1001/jama.294.8.914PubMedGoogle ScholarCrossref
7.
Khalaf  N, Yuan  C, Hamada  T,  et al.  Regular use of aspirin or non-aspirin nonsteroidal anti-inflammatory drugs is not associated with risk of incident pancreatic cancer in two large cohort studies.  Gastroenterology. 2018;154(5):1380-1390.e5. doi:10.1053/j.gastro.2017.12.001PubMedGoogle ScholarCrossref
8.
Cao  Y, Nishihara  R, Wu  K,  et al.  Population-wide impact of long-term use of aspirin and the risk for cancer.  JAMA Oncol. 2016;2(6):762-769. doi:10.1001/jamaoncol.2015.6396PubMedGoogle ScholarCrossref
9.
Verdoodt  F, Friis  S, Dehlendorff  C, Albieri  V, Kjaer  SK.  Non-steroidal anti-inflammatory drug use and risk of endometrial cancer: a systematic review and meta-analysis of observational studies.  Gynecol Oncol. 2016;140(2):352-358. doi:10.1016/j.ygyno.2015.12.009PubMedGoogle ScholarCrossref
10.
Cook  NR, Lee  I-M, Gaziano  JM,  et al.  Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial.  JAMA. 2005;294(1):47-55. doi:10.1001/jama.294.1.47PubMedGoogle ScholarCrossref
11.
Whitlock  EP, Williams  SB, Burda  BU, Feightner  A, Beil  T.  Aspirin Use in Adults: Cancer, All-Cause Mortality, and Harms: A Systematic Review of the Evidence for the Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
12.
Bibbins-Domingo  K; US Preventive Services Task Force.  Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force Recommendation Statement.  Ann Intern Med. 2016;164(12):836-845. doi:10.7326/M16-0577PubMedGoogle ScholarCrossref
13.
McNeil  JJ, Woods  RL, Nelson  MR,  et al; ASPREE Investigator Group.  Effect of aspirin on disability-free survival in the healthy elderly.  N Engl J Med. 2018;379(16):1499-1508. doi:10.1056/NEJMoa1800722PubMedGoogle ScholarCrossref
14.
McNeil  JJ, Nelson  MR, Woods  RL,  et al; ASPREE Investigator Group.  Effect of aspirin on all-cause mortality in the healthy elderly.  N Engl J Med. 2018;379(16):1519-1528. doi:10.1056/NEJMoa1803955PubMedGoogle ScholarCrossref
15.
Andriole  GL, Crawford  ED, Grubb  RL  III,  et al; PLCO Project Team.  Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up.  J Natl Cancer Inst. 2012;104(2):125-132. doi:10.1093/jnci/djr500PubMedGoogle ScholarCrossref
16.
Prorok  PC, Andriole  GL, Bresalier  RS,  et al; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Project Team.  Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.  Control Clin Trials. 2000;21(6)(suppl):273S-309S. doi:10.1016/S0197-2456(00)00098-2PubMedGoogle ScholarCrossref
17.
National Cancer Institute.  Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial supplemental questionnaire. https://cdas.cancer.gov/datasets/plco/91/. Accessed March 8, 2019.
18.
National Cancer Institute.  Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial baseline questionnaire. https://cdas.cancer.gov/datasets/plco/90/. Accessed March 8, 2019.
19.
Pinsky  PF, Prorok  PC, Yu  K,  et al.  Extended mortality results for prostate cancer screening in the PLCO trial with median follow-up of 15 years.  Cancer. 2017;123(4):592-599. doi:10.1002/cncr.30474PubMedGoogle ScholarCrossref
20.
World Health Organization.  International Classification of Diseases, Ninth Revision (ICD-9). Geneva, Switzerland: World Health Organization; 1977.
21.
Chubak  J, Whitlock  EP, Williams  SB,  et al.  Aspirin for the prevention of cancer incidence and mortality: systematic evidence reviews for the US Preventive Services Task Force.  Ann Intern Med. 2016;164(12):814-825. doi:10.7326/M15-2117PubMedGoogle ScholarCrossref
22.
Rothwell  PM, Fowkes  FGR, Belch  JFF, Ogawa  H, Warlow  CP, Meade  TW.  Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.  Lancet. 2011;377(9759):31-41. doi:10.1016/S0140-6736(10)62110-1PubMedGoogle ScholarCrossref
23.
Albandar  HJ, Markert  R, Agrawal  S.  The relationship between aspirin use and mortality in colorectal cancer.  J Gastrointest Oncol. 2018;9(6):1133-1137. doi:10.21037/jgo.2018.08.13PubMedGoogle ScholarCrossref
24.
Jacobs  EJ, Newton  CC, Gapstur  SM, Thun  MJ.  Daily aspirin use and cancer mortality in a large US cohort.  J Natl Cancer Inst. 2012;104(16):1208-1217. doi:10.1093/jnci/djs318PubMedGoogle ScholarCrossref
25.
Chan  AT, Gibbs  P, Orchard  S,  et al.  Effect of initiating aspirin on cancer events in the healthy elderly: primary results from the ASPREE randomized controlled trial [AGA abstract 400a].  Gastroenterology. 2019;156(6):S78-S79. doi:10.1016/S0016-5085(19)36983-5Google ScholarCrossref
26.
Chan  AT, McNeil  J.  Aspirin and cancer prevention in the elderly: where do we go from here?  Gastroenterology. 2019;156(3):534-538. doi:10.1053/j.gastro.2018.11.063PubMedGoogle ScholarCrossref
27.
Huang  WY, Daugherty  SE, Shiels  MS,  et al.  Aspirin use and mortality in two contemporary US cohorts.  Epidemiology. 2018;29(1):126-133. doi:10.1097/EDE.0000000000000746PubMedGoogle ScholarCrossref
28.
Campbell  PT, Newton  CC, Dehal  AN, Jacobs  EJ, Patel  AV, Gapstur  SM.  Impact of body mass index on survival after colorectal cancer diagnosis: the Cancer Prevention Study-II Nutrition Cohort.  J Clin Oncol. 2012;30(1):42-52. doi:10.1200/JCO.2011.38.0287PubMedGoogle ScholarCrossref
29.
Wang  X, Chan  AT, Slattery  ML,  et al.  Influence of smoking, body mass index, and other factors on the preventive effect of nonsteroidal anti-inflammatory drugs on colorectal cancer risk.  Cancer Res. 2018;78(16):4790-4799. doi:10.1158/0008-5472.CAN-18-0326PubMedGoogle ScholarCrossref
30.
Ratnasinghe  LD, Graubard  BI, Kahle  L, Tangrea  JA, Taylor  PR, Hawk  E.  Aspirin use and mortality from cancer in a prospective cohort study.  Anticancer Res. 2004;24(5B):3177-3184.PubMedGoogle Scholar
31.
Movahedi  M, Bishop  DT, Macrae  F,  et al.  Obesity, aspirin, and risk of colorectal cancer in carriers of hereditary colorectal cancer: a prospective investigation in the CAPP2 study.  J Clin Oncol. 2015;33(31):3591-3597. doi:10.1200/JCO.2014.58.9952PubMedGoogle ScholarCrossref
32.
Afshin  A, Forouzanfar  MH, Reitsma  MB,  et al; GBD 2015 Obesity Collaborators.  Health effects of overweight and obesity in 195 countries over 25 years.  N Engl J Med. 2017;377(1):13-27. doi:10.1056/NEJMoa1614362PubMedGoogle ScholarCrossref
33.
Bhatt  DL, Grosser  T, Dong  JF,  et al.  Enteric coating and aspirin nonresponsiveness in patients with type 2 diabetes mellitus.  J Am Coll Cardiol. 2017;69(6):603-612. doi:10.1016/j.jacc.2016.11.050PubMedGoogle ScholarCrossref
34.
Patrono  C, Rocca  B.  Type 2 diabetes, obesity, and aspirin responsiveness.  J Am Coll Cardiol. 2017;69(6):613-615. doi:10.1016/j.jacc.2016.11.049PubMedGoogle ScholarCrossref
35.
Basili  S, Pacini  G, Guagnano  MT,  et al.  Insulin resistance as a determinant of platelet activation in obese women.  J Am Coll Cardiol. 2006;48(12):2531-2538. doi:10.1016/j.jacc.2006.08.040PubMedGoogle ScholarCrossref
36.
Cryer  B.  Reducing the gastrointestinal risks of low-dose aspirin.  Gastroenterology. 2010;138(1):30-33. doi:10.1053/j.gastro.2009.11.032PubMedGoogle ScholarCrossref
Limit 200 characters
Limit 25 characters
Conflicts of Interest Disclosure

Identify all potential conflicts of interest that might be relevant to your comment.

Conflicts of interest comprise financial interests, activities, and relationships within the past 3 years including but not limited to employment, affiliation, grants or funding, consultancies, honoraria or payment, speaker's bureaus, stock ownership or options, expert testimony, royalties, donation of medical equipment, or patents planned, pending, or issued.

Err on the side of full disclosure.

If you have no conflicts of interest, check "No potential conflicts of interest" in the box below. The information will be posted with your response.

Not all submitted comments are published. Please see our commenting policy for details.

Limit 140 characters
Limit 3600 characters or approximately 600 words
    2 Comments for this article
    EXPAND ALL
    Aspirin should not substitute life style modification
    Kamran Lankarani, Professor of Medicine | Shiraz University of Medical Sciences, Iran
    Although the importance of use of ASA as a secondary preventive measure specially in cardiovascular disease has been well documented , there are controversial reports of its use as a primary preventive measure specially in elderly.(1) The possibility of death due to gastrointestinal or intracerebral hemorrhage is a real threat specially in this age group . While the reduced mortality from cancer specially colorectal cancer needs 5 to 8 years to be achieved, the risk of major bleeding is there from the beginning. (2)
    I read with interest the article by Loomans-Kropp and her colleagues to get an answer
    for this important question. (3) Unfortunately I found several obscured points which makes conclusion difficult. As this cohort were not randomized on receiving ASA, the direct effect of ASA could be due to confounders. For instance those who use ASA as a primary preventive measure may have more concerns about their health which may also lead to more healthier life style.This may confound the effect of ASA as a primary reason for reduced mortality .
    Some information on covariates are presented in supplement. All cause mortality, mortality from cancers and gastrointestinal cancers except for colorectal cancer were higher in those with body mass index of less than 20 even compared to overweight and obese persons. This is in contrast to the well established effect of obesity and overweight as a risk factor for all cause mortality and cancer mortality. The authors did not provide any explanation for this odd finding. Interestingly this group did not show any benefit with usage of ASA. Of interest there is no information on ethanol usage. There is possibility of contribution of effect of ethanol on this finding.
    In conclusion one important drawback of these type of studies is medicalization of public health and ignorance the importance of life style modification while exposing population to unwanted hazards of drugs even old drugs like ASA.



    1. McNeil JJ, Wolfe R, Woods RL, Tonkin AM, Donnan GA, Nelson MR, et al. Effect of Aspirin on Cardiovascular Events and Bleeding in the Healthy Elderly. New England Journal of Medicine. 2018;379(16):1509-18.
    2. B Lankarani K. Aspirin for the Primary Prophylaxis of Colorectal Cancer. Annals of Colorectal Research. 2013;1(3):7-8.
    3. Loomans-Kropp HA, Pinsky P, Cao Y, Chan AT, Umar A. Association of Aspirin Use With Mortality Risk Among Older Adult Participants in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. JAMA Network Open. 2019;2(12):e1916729-e.
    CONFLICT OF INTEREST: None Reported
    READ MORE
    BMI association not clear
    Jim Hendricks, Prof. (Kinesiology/Adptn) | Chicago State University
    I'm unclear of the correlation of ASA use in elderly persons with BMI > 20, especially the correlation of all cause mortality (in addition to the cancers outlined in the article). Is the issue of gastrointestinal and cerebral hemorrhage outweighed by ASA use in the elderly (3 times weekly or more)?
    CONFLICT OF INTEREST: None Reported
    Original Investigation
    Public Health
    December 4, 2019

    使用阿司匹林与前列腺癌、肺癌、结直肠癌及卵巢癌筛查试验中老年参与者的死亡风险之间的关联性

    Author Affiliations
    • 1Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland
    • 2Gastrointestinal and Other Cancers Branch, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland
    • 3Early Detection Research Branch, Division of Cancer Prevention, National Cancer Institute, Rockville, Maryland
    • 4Siteman Cancer Center, Division of Public Health Sciences, Department of Surgery, Washington University School of Medicine in St Louis, St Louis, Missouri
    • 5Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston
    • 6Division of Gastroenterology, Massachusetts General Hospital, Boston
    • 7Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts
    • 8Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
    JAMA Netw Open. 2019;2(12):e1916729. doi:10.1001/jamanetworkopen.2019.16729
    关键点 español English

    问题  使用阿司匹林是否与老年人死亡风险降低有关?

    结果  这项队列研究涉及 146,152 名参加前列腺癌、肺癌、结直肠癌以及卵巢癌筛查试验的参与者。研究发现,每周使用 3 次或 3 次以上阿司匹林与癌症、胃肠道癌和结直肠癌的全因死亡风险降低有关。

    意义  这些调查结果表明,预防性使用阿司匹林可以降低老年人的死亡风险。

    Abstract

    Importance  Aspirin use has been associated with reduced risk of cancer mortality, particularly of the colorectum. However, aspirin efficacy may be influenced by biological characteristics, such as obesity and age. With the increasing prevalence of obesity and conflicting data regarding the effect of aspirin in older adults, understanding the potential association of aspirin use with cancer mortality according to body mass index (BMI) and age is imperative.

    Objectives  To investigate the association of aspirin use with risk of all-cause, any cancer, gastrointestinal (GI) cancer, and colorectal cancer (CRC) mortality among older adults and to perform an exploratory analysis of the association of aspirin use with mortality stratified by BMI.

    Design, Setting, Participants  This cohort study evaluated aspirin use among participants aged 65 years and older in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial at baseline (November 8, 1993, to July 2, 2001) and follow-up (2006-2008). Analysis began in late 2018 and was completed in September 2019.

    Main Outcomes and Measures  All-cause, any cancer, GI cancer, or CRC mortality. Multivariable hazard ratios (HRs) and 95% CIs were calculated using time-varying Cox proportional hazards regression modeling, adjusting for additional factors.

    Results  A total of 146 152 individuals (mean [SD] age at baseline, 66.3 [2.4] years; 74 742 [51.1%] women; 129 446 [88.6%] non-Hispanic white) were included in analysis. The median (interquartile range) follow-up time was 12.5 (8.7-16.4) years, encompassing 1 822 164 person-years. Compared with no use, aspirin use 1 to 3 times per month was associated with reduced risk of all-cause mortality (HR, 0.84; 95% CI, 0.80-0.88; P < .001) and cancer mortality (HR, 0.87; 95% CI, 0.81-0.94; P < .001). Aspirin use 3 or more times per week was associated with decreased risk of mortality of all causes (HR, 0.81; 95% CI, 0.80-0.83; P < .001), any cancer (HR, 0.85; 95% CI, 0.81-0.88; P < .001), GI cancer (HR, 0.75; 95% CI, 0.66-0.84; P < .001), and CRC (HR, 0.71; 95% CI, 0.61-0.84; P < .001). When stratified by BMI (calculated as weight in kilograms divided by height in meters squared), aspirin use 3 or more times per week among individuals with BMI 20 to 24.9 was associated with reduced risk of all-cause mortality (HR, 0.82; 95% CI, 0.78-0.85; P < .001) and any cancer mortality (HR, 0.86; 95% CI, 0.79-0.92; P < .001). Among individuals with BMI 25 to 29.9, aspirin use 3 or more times per week was associated with reduced risk of all-cause mortality (HR, 0.82; 95% CI, 0.79-0.85; P < .001), any cancer mortality (HR, 0.86; 95% CI, 0.81-0.91; P < .001), GI cancer mortality (HR, 0.72; 95% CI, 0.60-0.86; P < .001), and CRC mortality (HR, 0.66; 95% CI, 0.51-0.85; P = .001).

    Conclusions and Relevance  In this cohort study, aspirin use 3 or more times per week was associated with a reduction in all-cause, cancer, GI cancer and CRC mortality in older adults.

    Introduction

    Aspirin use of 10 years or more is estimated to reduce cancer incidence and mortality.1-4 Across epidemiological studies, the most significant reductions in risk have been noted in gastrointestinal (GI) cancers.2,4 Notably, results from the NIH-AARP study,5 the Nurses’ Health Study,6 and Health Professionals Follow-up Study7,8 demonstrated that long-term regular aspirin use was associated with reduced risk of obesity- and inflammation-associated cancers, particularly colorectal cancer (CRC). This result has been additionally illustrated in a 2010 meta-analysis of randomized clinical trials.4 The association of aspirin with reduced cancer incidence and mortality has been consistently robust among GI cancers; however, there is limited evidence suggesting that aspirin use is associated with reduced mortality risk among other cancer types.3,9-11 The US Preventive Services Task Force (USPSTF) recommends low-dose aspirin use for the prevention of cardiovascular disease and CRC among average-risk individuals aged 50 to 59 years with a 10% or greater 10-year risk of cardiovascular disease; however, individuals aged 60 to 69 years should have an individualized approach, while evidence for use among individuals 70 years and older remains insufficient.12 It is important to note that a 2015 systematic review of the literature by the USPSTF11 found that individuals with daily aspirin dosing up to 1200 mg for a duration of 4 or more years exhibited a significant reduction in all-cause and cancer mortality, demonstrating a similar benefit of low-dose and standard aspirin.

    Recently, the results of the Aspirin in Reducing Events in the Elderly (ASPREE) study13 drew further attention of the potential cancer preventive effect of aspirin. The ASPREE study was a randomized clinical trial conducted in the United States and Australia investigating the efficacy of 100 mg of aspirin daily vs placebo in extending disability-free survival among elderly individuals (recruitment age 65 years or 70 years) during 4.7 years of follow-up.13 Unexpectedly, an increased risk of all-cause and cancer-related death was observed in the group randomized to aspirin.14

    Thus, based on the results of the ASPREE randomized clinical trial that conflict with the preponderance of data showing a benefit of aspirin use, we examined the association of aspirin use with mortality risk among older adults enrolled in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. In addition, given data suggesting that aspirin may be less effective among individuals who are overweight or obese, we conducted exploratory analyses stratified by body mass index (BMI), calculated as weight in kilograms divided by height in meters squared.1

    Methods

    This study is a post hoc analysis of PLCO study data. The original trial was approved by the institutional review boards at all study sites (University of Alabama at Birmingham, Georgetown University, University of Pittsburgh, Washington University in St. Louis, University of Utah, University of Colorado, University of Minnesota, Pacific Health Research and Education Institute, Henry Ford Health System, and Marshfield Clinic Research Foundation). All enrolled participants provided written informed consent. The use of their data for additional studies and analysis was included in the original informed consent. This study adhered to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

    Study Design

    The design and methods of the PLCO Cancer Screening Trial have been previously described.15,16 Briefly, participants aged 55 to 74 years were randomized to the intervention (screening) or control arm at 10 screening centers in the United States between November 8, 1993, and July 2, 2001. Pertinent exclusion criteria for this study were individuals with a history of CRC or lung, prostate, or ovarian cancer, previous surgical removal of the colon, lung, or prostate, or, starting in 1995, individuals who had a colonoscopy, sigmoidoscopy, or barium enema in the 3 years prior to study randomization. This cohort included participants who were 65 years or older or survived until age 65, had a valid baseline questionnaire (BQ) after study enrollment, and had reported information on aspirin use at baseline. Completion of a follow-up supplemental questionnaire (SQ) by participants between 2006 and 2008 was not required for inclusion into the study cohort. All responses to the BQ and SQ were ascertained by self-report. The full content of both questionnaires has been published previously.17,18 Briefly, the BQ asked, “During the last 12 months, have you regularly used aspirin or aspirin-containing products, such as Bayer, Bufferin, or Anacin (Please do not include aspirin-free products such as Tylenol and Panadol).” If the respondent answered yes, the frequency categories were given as less than 2 per month, 2 to 3 per month, 1 per week, 2 per week, 3 to 4 per week, 1 per day, or 2 or more per day. The SQ asked, “During the last 12 months, about how often did you usually take aspirin (examples of aspirin include Bayer, Bufferin, Anacin, and baby aspirin)?” The frequency categories were given as none or less than once per month, 1 to 3 times per month, 1 to 2 times per week, 3 to 6 times per week, and 7 or more times per week. To allow for consistent values between BQs and SQs, we collapsed the aspirin use frequency variables into no aspirin use or less than once per month, 1 to 3 times per month, 1 to 2 times per week, and 3 or more times per week. Usual dose information was not available on the BQ; therefore, this analysis does not consider dose. We categorized BMI as less than 20, 20 to 24.9, 25 to 29.9, and 30 or higher.

    Initial analysis of the PLCO Cancer Screening Trial was completed after 13 years of follow-up or on December 31, 2009, whichever came first.15 Deaths were ascertained via annual study update questionnaire, individual reports, or death certificates. Beginning in 2011, participants were reconsented for follow-up. This allowed for linkage to the National Death Index, which extended mortality follow-up for up to 20 years after randomization.19 For those reconsenting, the end of mortality follow-up was December 31, 2015 or their date of death, whichever came first. For the approximately 15% of individuals who were alive in 2011 but who declined extended follow-up, the end of mortality follow-up was their declining date, which was generally in 2011.

    Statistical Analysis

    The purpose of this analysis was to assess the associations among aspirin use, BMI, and mortality of all causes, any cancer, gastrointestinal (GI) cancer, and CRC among individuals in the PLCO Cancer Screening Trial who survived to age 65 years and older (Figure 1). Participant follow-up time was measured from the time of cohort entry, which was either the date of PLCO Cancer Screening Trial enrollment or age 65 years, whichever occurred last, until the date of death or December 31, 2015, whichever came first. Survival time was measured from the time of cohort entry, until time of death of any cause. Hazard ratios (HRs) were calculated using Cox proportional hazards regression models to analyze the associations among aspirin use (no use, 1-3 times per month, 1-2 times per week, and ≥3 times per week), BMI (<20, 20-24.9, 25-29.9, ≥30), and mortality, controlling for covariates. As aspirin use, BMI, and other covariates may have changed between completion of the BQ and SQ, time-varying proportional hazards models were used. Initial aspirin use and covariate values were taken from the BQ for participants 65 years or older at randomization and for participants younger than 65 years at randomization who either did not fill out the SQ or filled it out after reaching age 65 years; initial values were taken from the SQ for those younger than 65 years at randomization completing the SQ before age 65 years. Among those with initial aspirin use and covariate values taken from the BQ and who also completed the SQ, values were updated at that time to the corresponding SQ values. Time-varying variables included in the model were aspirin use, BMI, smoking status (ie, never, current, or former smoker), history of myocardial infarction, history of stroke, history of hypertension, history of diabetes, and ibuprofen use 3 or more times per week. Static variables included in the models were sex (male or female), race/ethnicity (white non-Hispanic, black non-Hispanic, or other), and randomization arm (intervention or control). We additionally stratified by BMI to evaluate the association of aspirin use and BMI with mortality.

    Finally, as an exploratory assessment of longitudinal patterns of aspirin use, we examined risk of mortality only among participants who had completed aspirin frequency questions on the BQ and SQ. Follow-up for this cohort subset began at age 65 years or completion of the SQ, whichever occurred last. Participants were categorized according to baseline and follow-up aspirin use as (1) consistent nonusers (use >1 time per week or no use at baseline and follow-up), (2) users at baseline only (use ≥1 time per week at baseline only), (3) users at follow-up only (use ≥1 time per week at follow-up only), or (4) consistent users (use ≥1 time per week at baseline and follow-up). We used weekly aspirin use as our metric in this analysis for consistency with previous analyses and to include the maximum number of participants with BQ and SQ data. Supplemental questionnaire variables included in the model were randomization arm, sex (male or female), race/ethnicity (white non-Hispanic, black non-Hispanic, or other), BMI, smoking status (never, current, or former smoker), history of myocardial infarction, history of stroke, history of hypertension, history of diabetes, and ibuprofen use 3 or more times per week.

    Causes of death were determined by International Classification of Diseases, Ninth Revision (ICD-9) codes.20 All-cause mortality was defined as a reported death of any cause. Any cancer mortality was defined as a reported cause of death by cancer based on the official PLCO Cancer Screening Trial definitions, derived from standard ICD-9 groupings. Cause of death by GI cancer was determined by ICD-9 codes for esophagus (150), gastric (151), and colorectal (153 and 154) cancer, whereas CRC was determined by ICD-9 codes for CRC only (153 and 154). All statistical analyses were performed in SAS statistical software version 9.4 (SAS Institute). P values were 2-tailed, and statistical significance was set at less than .05.

    Results

    The eligibility criteria for the study analysis are outlined in Figure 1. After excluding individuals who died before age 65 years, there were 146 152 participants (mean [SD] age at baseline, 66.3 [2.4] years; 74 742 [51.1%] women; 129 446 [88.6%] non-Hispanic white) included in our analysis. The mean (SD) duration from baseline to completing the SQ was 9.1 (1.9) years and the median (range) was 9.2 (4.6-14.2) years, with a median (interquartile range) follow-up time of 12.5 8.7-16.4) years. Among the total cohort included in our study, 40 419 individuals (27.7%) died during follow-up, including 12 421 individuals (30.7%) who died of any cancer, 1425 individuals (3.5%) who died of GI cancers (including 353 individuals with esophageal cancer [2.8%] and 258 individuals with gastric cancer [2.1%]), and 814 individuals (6.6%) who died of CRC. Demographic characteristics of the cohort are summarized in Table 1.

    The results of the Cox proportional hazards regression model are presented in Table 2. In our model, any aspirin use was associated with reduced all-cause and cancer-specific mortality. Reduced risk of all-cause mortality was associated with using aspirin 1 to 3 times per month (HR, 0.84; 95% CI, 0.80-0.88; P < .001), 1 to 2 times per week (HR, 0.86; 95% CI, 0.81-0.90; P < .001), or 3 or more times per week (HR, 0.81; 95% CI, 0.80-0.83; P < .001). A similar association was noted for risk of cancer mortality and aspirin use 1 to 3 times per month (HR, 0.87; 95% CI, 0.81-0.94; P < .001) or 3 or more times per week (HR, 0.85; 95% CI, 0.81-0.88; P < .001). Use of aspirin 3 or more times per week was also associated with significantly reduced risk of GI cancer mortality (HR, 0.75; 95% CI, 0.66-0.84; P < .001) and CRC mortality (HR, 0.71; 95% CI, 0.61-0.84; P < .001). Data for the additional covariates included in the model are provided in the eTable in the Supplement.

    To explore the potential association of aspirin use and BMI with mortality risk, we stratified the cohort according to BMI. The results are shown in Figure 2. Compared with no aspirin use and among individuals with a BMI of 20 or higher, aspirin use was associated with reduced risk of all-cause mortality when used 1 to 3 times per month (BMI 20-24.9: HR, 0.83; 95% CI, 0.76-0.89; P < .001; BMI 25-29.9: HR, 0.82; 95% CI, 0.78-0.93; P < .001; BMI ≥30: HR, 0.85; 95% CI, 0.78-0.93; P < .001), 1 to 2 times per week (BMI 20-24.9: HR, 0.85; 95% CI, 0.77-0.94; P = .002; BMI 25-29.9: HR, 0.85; 95% CI, 0.78-0.93; P = .001; BMI ≥30: HR, 0.86; 95% CI, 0.76-0.96; P = .01), or 3 or more times per week (BMI 20-24.9: HR, 0.82; 95% CI, 0.78-0.85; P < .001; BMI 25-29.9: HR, 0.82; 95% CI, 0.79-0.85; P < .001; BMI ≥30: HR, 0.78; 95% CI, 0.75-0.82; P < .001) (Figure 2A). Reduced risk of cancer-specific mortality was noted among individuals with reported aspirin use 3 or more times per month and BMI 20 to 24.9 (HR, 0.86; 95% CI, 0.79-0.92; P < .001), BMI 25-29.9 (HR, 0.86; 95% CI, 0.81-0.91; P < .001) or BMI 30 or higher (HR, 0.81; 95% CI, 0.75-0.88; P < .001) (Figure 2B). No statistically significant risk reduction was observed for cancer mortality among participants who used aspirin 1 to 2 times per week or 1 to 3 times per month, except for aspirin use 1 to 3 times per month among individuals with BMI 20 to 24.9 (HR, 0.83; 95% CI, 0.72-0.95; P = .007) (Figure 2B). Individuals with BMI 25 to 29.9 who used aspirin 3 or more times per week were associated with reduced risk of GI cancer mortality (HR, 0.72; 95% CI, 0.60-0.86; P < .001) and CRC mortality (HR, 0.66; 95% CI, 0.51-0.85; P < .001) (Figure 2C and D).

    We additionally examined the association between reported aspirin use at baseline and at the time of the SQ with risk of mortality. Participants who had reported aspirin use at follow-up only or consistent users were associated with a reduced risk of mortality (Table 3). Individuals who reported aspirin use at follow-up only were associated with reduced risk of all-cause mortality (HR, 0.79; 95% CI, 0.76-0.82; P < .001), cancer mortality (HR, 0.82; 95% CI, 0.76-0.88; P < .001), and GI cancer mortality (HR, 0.74; 95% CI, 0.59-0.94; P = .01). Individuals who were consistent aspirin users were also associated with reduced risk of all-cause mortality (HR, 0.80; 95% CI, 0.76-0.83; P < .001), cancer mortality (HR, 0.77; 95% CI, 0.72-0.83; P < .001), and GI cancer mortality (HR, 0.75; 95% CI, 0.59-0.94; P = .01). Of particular interest, the HRs for CRC-associated mortality were 0.88 (95% CI, 0.58-1.33; P = .53) for users at baseline only, 0.62 (95% CI, 0.46-0.85; P = .003) for users at follow-up only, and 0.62 (95% CI, 0.46-0.85; P = .003) for consistent users, compared with nonusers of aspirin.

    Discussion

    This cohort study found that aspirin use among individuals 65 years and older was associated with a lower risk of mortality. This observation was consistent across all causes of mortality (ie, all-cause, cancer, GI cancer, and CRC); however, the greatest reduction in risk was noted for CRC mortality among individuals who used aspirin 3 or more times per week. Additionally, our exploratory analyses investigating the potential associations among aspirin use, BMI, and mortality risk suggest that the efficacy of aspirin as a cancer preventive agent may be associated with BMI. Participants in the PLCO Cancer Screening Trial who were underweight (ie, BMI <20) had no observable benefit associated with aspirin use, while those with BMI 20 or higher were associated with reduced mortality risk, particularly with aspirin use 3 or more times per week. reduced risk of CRC mortality was only associated with individuals with BMI 20 to 29.9 who reported aspirin use 3 or more times per week.

    The efficacy of prophylactic aspirin use for prevention of cancer incidence and mortality has been debated; however, the most evidence from prospective cohorts and secondary analyses from clinical trials indicates a protective association with aspirin use. A 2016 systematic analysis of primary and secondary cardiovascular prevention trials21 found reduced CRC incidence 10 to 19 years after aspirin use initiation. This association persists among investigations of aspirin use and cancer mortality. A 2011 systematic analysis of 8 clinical trials22 found that daily aspirin use was associated with reduced risk of death of several cancers, with increased benefit associated with long-term use. A similar association was observed in a 2018 cohort study23 of veterans in which aspirin users were associated with reduced risk of CRC mortality compared with nonusers. This association was additionally examined in the Cancer Prevention Study-II Nutrition Cohort,24 in which daily aspirin use was associated with reduced overall cancer mortality. These observations are in contrast with data from the ASPREE trial.13 However, the interpretation of the ASPREE results is limited owing a lack of an association of aspirin with cancer and CRC incidence and the short duration of follow-up.25 With additional follow-up, an association of aspirin with lower cancer incidence and death may have emerged.26 In addition, a 2018 combined analysis of the NIH-AARP Diet and Health Study and the PLCO Cancer Screening Trial27 reported decreased risk of all-cause, cancer, and cardiovascular mortality associated with daily aspirin use. However, a dosage that exceeded 1 per day was associated with an increased risk of mortality. These data also did not account for effect modifications by BMI on mortality risk. Previous studies have also found that variables, such as BMI, are associated with the efficacy of prophylactic aspirin. In a 2012 study of the Cancer Prevention Study-II Nutrition Cohort,28 individuals with prediagnostic BMI 30 or higher were associated with increased risk of all-cause and CRC death. A similar association was demonstrated across several other cohort and case-control studies, cancers, and causes of death.27,29-31

    The observation that BMI may be associated with efficacy of aspirin in individuals 65 years and older is notable; however, our findings require further confirmation. Increasing rates of overweight and obesity globally may substantially alter the population-based efficacy of cancer prevention prophylatics.32 Studies have suggested that aspirin has reduced effectiveness as a primary prevention modality among individuals who are obese owing to decreased bioavailability and antithrombotic efficacy; however, this study did not find an association of overweight or obesity with decreased efficacy.5,33-35 Therefore, although aspirin use is associated with benefit as a cancer preventive agent, the changing characteristics of the global population may alter its efficacy and must be considered along with age and risk of bleeding before recommending aspirin for cancer prevention.

    Limitations and Strengths

    Our study has several limitations. First, this is a secondary analysis of a randomized intervention (screening) trial with self-reported data on aspirin use. When collecting self-reported data, one must be aware of the limitations to these data, such as underreporting parameters of interest and the potential effect of this error in the analyses, such as biasing toward the null. For example, it is possible that aspirin use was underreported if the participant was unaware that a given agent, based upon its trade name, was classified as aspirin. Next, the information on aspirin use may be subject to participant interpretation and measurement error. Regular use of aspirin was not defined in the BQ, so participants could then have interpreted regular aspirin use differently, which may have affected their categorization (eg, none, monthly, weekly, daily). Furthermore, the information collected regarding aspirin dosage was limited. These issues may, in addition to confounding by unmeasured covariates, help explain the lack of a dose-response association for mortality risk in the observed data. Though there is substantial evidence documenting the association of frequent aspirin use with cancer prevention, the biological effect of low frequency use (eg, 1-3 times per month) is uncertain. Therefore, the noted risk reduction associated with this group may be due to unmeasured confounders. Along similar lines, it remains possible that individuals who reported low or no use of aspirin were unable to tolerate aspirin use for an extended length of time, perhaps owing to risk of bleeding or gastrointestinal injury, and may be inherently different than those who reported aspirin use.36 Additionally, our analysis was focused on individuals in the PLCO Cancer Screening Trial cohort who survived to and began follow-up at or after age 65 years. However, only a small percentage (5.5%) of the PLCO cohort was ineligible for our study.

    Although this study had several limitations, the research questions investigated examining the associations among aspirin use, BMI, and mortality adds to our knowledge of modifiable factors associated with cancer prevention efficacy. We were able to explore this question in a large, prospective study with an extended follow-up period.

    Conclusions

    In this cohort study, we found a significant association of aspirin use with reduced all-cause, any cancer, GI cancer, and CRC mortality among individuals 65 years and older in the PLCO Cancer Screening Trial. Aspirin use was associated with reduced risk of all-cause and any cancer mortality, and aspirin use 3 or more times per week was associated with reduced risk of GI cancer mortality and CRC mortality when stratified by BMI. Future studies should further examine the association of BMI with the efficacy of aspirin as a cancer preventive agent to adapt to the changing global obesity trends.

    Back to top
    Article Information

    Accepted for Publication: October 14, 2019.

    Published: December 4, 2019. doi:10.1001/jamanetworkopen.2019.16729

    Correction: This article was corrected on January 17, 2020, to fix a data error in the Results section of the Abstract.

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Loomans-Kropp HA et al. JAMA Network Open.

    Corresponding Author: Holli A. Loomans-Kropp, PhD, MPH, Division of Cancer Prevention, National Cancer Institute, 9609 Medical Center Dr, Room 5E232, Rockville, MD, 20850 (holli.loomans@nih.gov).

    Author Contributions: Drs Loomans-Kropp and Pinsky had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Loomans-Kropp, Umar.

    Acquisition, analysis, or interpretation of data: Loomans-Kropp, Pinsky, Cao, Chan.

    Drafting of the manuscript: Loomans-Kropp.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Loomans-Kropp, Pinsky, Chan.

    Administrative, technical, or material support: Umar.

    Supervision: Chan, Umar.

    Conflict of Interest Disclosures: Dr Chan reported receiving grants and personal fees from Bayer Pharma AG, personal fees from Pfizer Janssen Pharmaceuticals, and support from the Stuart and Suzanne Steele MGH Research Scholarship outside the submitted work. No other disclosures were reported.

    Funding/Support: This study was funded by grants from the National Cancer Institute (Dr Cao: K07CA218377; Dr Chan: R01-CA137178) and the Stuart and Suzanne Steele MGH Research Scholarship (Dr Chan).

    Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

    References
    1.
    Cuzick  J, Thorat  MA, Bosetti  C,  et al.  Estimates of benefits and harms of prophylactic use of aspirin in the general population.  Ann Oncol. 2015;26(1):47-57. doi:10.1093/annonc/mdu225PubMedGoogle ScholarCrossref
    2.
    Cuzick  J.  Preventive therapy for cancer.  Lancet Oncol. 2017;18(8):e472-e482. doi:10.1016/S1470-2045(17)30536-3PubMedGoogle ScholarCrossref
    3.
    Algra  AM, Rothwell  PM.  Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomised trials.  Lancet Oncol. 2012;13(5):518-527. doi:10.1016/S1470-2045(12)70112-2PubMedGoogle ScholarCrossref
    4.
    Rothwell  PM, Wilson  M, Elwin  C-E,  et al.  Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials.  Lancet. 2010;376(9754):1741-1750. doi:10.1016/S0140-6736(10)61543-7PubMedGoogle ScholarCrossref
    5.
    Shebl  FM, Hsing  AW, Park  Y,  et al.  Non-steroidal anti-inflammatory drugs use is associated with reduced risk of inflammation-associated cancers: NIH-AARP study.  PLoS One. 2014;9(12):e114633. doi:10.1371/journal.pone.0114633PubMedGoogle Scholar
    6.
    Chan  AT, Giovannucci  EL, Meyerhardt  JA, Schernhammer  ES, Curhan  GC, Fuchs  CS.  Long-term use of aspirin and nonsteroidal anti-inflammatory drugs and risk of colorectal cancer.  JAMA. 2005;294(8):914-923. doi:10.1001/jama.294.8.914PubMedGoogle ScholarCrossref
    7.
    Khalaf  N, Yuan  C, Hamada  T,  et al.  Regular use of aspirin or non-aspirin nonsteroidal anti-inflammatory drugs is not associated with risk of incident pancreatic cancer in two large cohort studies.  Gastroenterology. 2018;154(5):1380-1390.e5. doi:10.1053/j.gastro.2017.12.001PubMedGoogle ScholarCrossref
    8.
    Cao  Y, Nishihara  R, Wu  K,  et al.  Population-wide impact of long-term use of aspirin and the risk for cancer.  JAMA Oncol. 2016;2(6):762-769. doi:10.1001/jamaoncol.2015.6396PubMedGoogle ScholarCrossref
    9.
    Verdoodt  F, Friis  S, Dehlendorff  C, Albieri  V, Kjaer  SK.  Non-steroidal anti-inflammatory drug use and risk of endometrial cancer: a systematic review and meta-analysis of observational studies.  Gynecol Oncol. 2016;140(2):352-358. doi:10.1016/j.ygyno.2015.12.009PubMedGoogle ScholarCrossref
    10.
    Cook  NR, Lee  I-M, Gaziano  JM,  et al.  Low-dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial.  JAMA. 2005;294(1):47-55. doi:10.1001/jama.294.1.47PubMedGoogle ScholarCrossref
    11.
    Whitlock  EP, Williams  SB, Burda  BU, Feightner  A, Beil  T.  Aspirin Use in Adults: Cancer, All-Cause Mortality, and Harms: A Systematic Review of the Evidence for the Preventive Services Task Force. Rockville, MD: Agency for Healthcare Research and Quality; 2015.
    12.
    Bibbins-Domingo  K; US Preventive Services Task Force.  Aspirin use for the primary prevention of cardiovascular disease and colorectal cancer: US Preventive Services Task Force Recommendation Statement.  Ann Intern Med. 2016;164(12):836-845. doi:10.7326/M16-0577PubMedGoogle ScholarCrossref
    13.
    McNeil  JJ, Woods  RL, Nelson  MR,  et al; ASPREE Investigator Group.  Effect of aspirin on disability-free survival in the healthy elderly.  N Engl J Med. 2018;379(16):1499-1508. doi:10.1056/NEJMoa1800722PubMedGoogle ScholarCrossref
    14.
    McNeil  JJ, Nelson  MR, Woods  RL,  et al; ASPREE Investigator Group.  Effect of aspirin on all-cause mortality in the healthy elderly.  N Engl J Med. 2018;379(16):1519-1528. doi:10.1056/NEJMoa1803955PubMedGoogle ScholarCrossref
    15.
    Andriole  GL, Crawford  ED, Grubb  RL  III,  et al; PLCO Project Team.  Prostate cancer screening in the randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial: mortality results after 13 years of follow-up.  J Natl Cancer Inst. 2012;104(2):125-132. doi:10.1093/jnci/djr500PubMedGoogle ScholarCrossref
    16.
    Prorok  PC, Andriole  GL, Bresalier  RS,  et al; Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial Project Team.  Design of the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial.  Control Clin Trials. 2000;21(6)(suppl):273S-309S. doi:10.1016/S0197-2456(00)00098-2PubMedGoogle ScholarCrossref
    17.
    National Cancer Institute.  Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial supplemental questionnaire. https://cdas.cancer.gov/datasets/plco/91/. Accessed March 8, 2019.
    18.
    National Cancer Institute.  Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial baseline questionnaire. https://cdas.cancer.gov/datasets/plco/90/. Accessed March 8, 2019.
    19.
    Pinsky  PF, Prorok  PC, Yu  K,  et al.  Extended mortality results for prostate cancer screening in the PLCO trial with median follow-up of 15 years.  Cancer. 2017;123(4):592-599. doi:10.1002/cncr.30474PubMedGoogle ScholarCrossref
    20.
    World Health Organization.  International Classification of Diseases, Ninth Revision (ICD-9). Geneva, Switzerland: World Health Organization; 1977.
    21.
    Chubak  J, Whitlock  EP, Williams  SB,  et al.  Aspirin for the prevention of cancer incidence and mortality: systematic evidence reviews for the US Preventive Services Task Force.  Ann Intern Med. 2016;164(12):814-825. doi:10.7326/M15-2117PubMedGoogle ScholarCrossref
    22.
    Rothwell  PM, Fowkes  FGR, Belch  JFF, Ogawa  H, Warlow  CP, Meade  TW.  Effect of daily aspirin on long-term risk of death due to cancer: analysis of individual patient data from randomised trials.  Lancet. 2011;377(9759):31-41. doi:10.1016/S0140-6736(10)62110-1PubMedGoogle ScholarCrossref
    23.
    Albandar  HJ, Markert  R, Agrawal  S.  The relationship between aspirin use and mortality in colorectal cancer.  J Gastrointest Oncol. 2018;9(6):1133-1137. doi:10.21037/jgo.2018.08.13PubMedGoogle ScholarCrossref
    24.
    Jacobs  EJ, Newton  CC, Gapstur  SM, Thun  MJ.  Daily aspirin use and cancer mortality in a large US cohort.  J Natl Cancer Inst. 2012;104(16):1208-1217. doi:10.1093/jnci/djs318PubMedGoogle ScholarCrossref
    25.
    Chan  AT, Gibbs  P, Orchard  S,  et al.  Effect of initiating aspirin on cancer events in the healthy elderly: primary results from the ASPREE randomized controlled trial [AGA abstract 400a].  Gastroenterology. 2019;156(6):S78-S79. doi:10.1016/S0016-5085(19)36983-5Google ScholarCrossref
    26.
    Chan  AT, McNeil  J.  Aspirin and cancer prevention in the elderly: where do we go from here?  Gastroenterology. 2019;156(3):534-538. doi:10.1053/j.gastro.2018.11.063PubMedGoogle ScholarCrossref
    27.
    Huang  WY, Daugherty  SE, Shiels  MS,  et al.  Aspirin use and mortality in two contemporary US cohorts.  Epidemiology. 2018;29(1):126-133. doi:10.1097/EDE.0000000000000746PubMedGoogle ScholarCrossref
    28.
    Campbell  PT, Newton  CC, Dehal  AN, Jacobs  EJ, Patel  AV, Gapstur  SM.  Impact of body mass index on survival after colorectal cancer diagnosis: the Cancer Prevention Study-II Nutrition Cohort.  J Clin Oncol. 2012;30(1):42-52. doi:10.1200/JCO.2011.38.0287PubMedGoogle ScholarCrossref
    29.
    Wang  X, Chan  AT, Slattery  ML,  et al.  Influence of smoking, body mass index, and other factors on the preventive effect of nonsteroidal anti-inflammatory drugs on colorectal cancer risk.  Cancer Res. 2018;78(16):4790-4799. doi:10.1158/0008-5472.CAN-18-0326PubMedGoogle ScholarCrossref
    30.
    Ratnasinghe  LD, Graubard  BI, Kahle  L, Tangrea  JA, Taylor  PR, Hawk  E.  Aspirin use and mortality from cancer in a prospective cohort study.  Anticancer Res. 2004;24(5B):3177-3184.PubMedGoogle Scholar
    31.
    Movahedi  M, Bishop  DT, Macrae  F,  et al.  Obesity, aspirin, and risk of colorectal cancer in carriers of hereditary colorectal cancer: a prospective investigation in the CAPP2 study.  J Clin Oncol. 2015;33(31):3591-3597. doi:10.1200/JCO.2014.58.9952PubMedGoogle ScholarCrossref
    32.
    Afshin  A, Forouzanfar  MH, Reitsma  MB,  et al; GBD 2015 Obesity Collaborators.  Health effects of overweight and obesity in 195 countries over 25 years.  N Engl J Med. 2017;377(1):13-27. doi:10.1056/NEJMoa1614362PubMedGoogle ScholarCrossref
    33.
    Bhatt  DL, Grosser  T, Dong  JF,  et al.  Enteric coating and aspirin nonresponsiveness in patients with type 2 diabetes mellitus.  J Am Coll Cardiol. 2017;69(6):603-612. doi:10.1016/j.jacc.2016.11.050PubMedGoogle ScholarCrossref
    34.
    Patrono  C, Rocca  B.  Type 2 diabetes, obesity, and aspirin responsiveness.  J Am Coll Cardiol. 2017;69(6):613-615. doi:10.1016/j.jacc.2016.11.049PubMedGoogle ScholarCrossref
    35.
    Basili  S, Pacini  G, Guagnano  MT,  et al.  Insulin resistance as a determinant of platelet activation in obese women.  J Am Coll Cardiol. 2006;48(12):2531-2538. doi:10.1016/j.jacc.2006.08.040PubMedGoogle ScholarCrossref
    36.
    Cryer  B.  Reducing the gastrointestinal risks of low-dose aspirin.  Gastroenterology. 2010;138(1):30-33. doi:10.1053/j.gastro.2009.11.032PubMedGoogle ScholarCrossref
    ×