Impact of aspirin on pancreatic cancer in the elderly: analysis of socioeconomic status and outcomes of national matched cohorts

Thanathip Suenghataiphorn^a, Tuntanut Lohawatcharagul^b, Narathorn Kulthamrongsri^c, Pojsakorn Danpanichkul^d, Kanokphong Suparan^e, Natchaya Polpichai^f, Jerapas Thongpiya^d, Sakditad Saowapa^d

Griffin Hospital, Derby, CT, USA; King Chulalongkorn Memorial Hospital, Bangkok, Thailand; Mayo Clinic, AZ, USA; Texas Tech University Health Science Center, Lubbock, TX; USA; Chiang Mai University; Weiss Memorial Hospital, Chicago, IL, USA

^aDepartment of Internal Medicine, Griffin Hospital, Derby, CT, USA (Thanathip Suenghataiphorn); ^bKing Chulalongkorn Memorial Hospital, Faculty of Medicine, Bangkok, Thailand (Tuntanut Lohawatcharagul); ^cMayo Clinic, AZ, USA (Narathorn Kulthamrongsri); ^dDepartment of Internal Medicine, Texas Tech University Health Science Center, Lubbock, TX, USA (Pojsakorn Danpanichkul, Jerapas Thongpiya, Sakditad Saowapa); ^eChiang Mai University Faculty of Medicine, Department of Microbiology, Thailand (Kanokphong Suparan); ^fDepartment of Internal Medicine, Weiss Memorial Hospital, Chicago, IL, USA (Natchaya Polpichai)

Correspondence to: Thanathip Suenghataiphorn, MD, Department of Internal Medicine, Griffin Hospital, 130 Division St, Derby, CT 06418, USA, e-mail: thanathip.sue@gmail.com

Received 15 March 2024; accepted 23 August 2024; published online 22 October 2024

DOI: https://doi.org/10.20524/aog.2024.09179

Abstract

Background Pancreatic cancer is a neoplastic condition with a high disease burden. It is projected to be the second most common cause of cancer-related deaths by 2030. However, evidence supporting the long-term use of aspirin in cancer prevention and treatment remains insufficient. We aimed to investigate the association between aspirin use and pancreatic cancer outcomes in the elderly population group.

Methods The 2020 National Inpatient Sample was used to investigate records of elderly patients admitted with pancreatic cancer, identified by ICD-10 CM codes. The data were categorized based on long-term aspirin use. We assessed inpatient mortality as the primary outcome, while secondary outcomes included costs and length of stay, as well as other inpatient complications.

Results We identified 19,249 hospitalizations of patients aged over 60 years. The mean age was 73.8 years, and 49.3% were male. In a survey multivariate logistic and linear regression model, adjusting for patient characteristics and hospital factors, long-term aspirin use was associated with lower inpatient mortality (adjusted odds ratio [aOR] 0.55, 95% confidence interval [CI] 0.33-0.92; P=0.023), a shorter hospital stay (beta coefficient -0.52, 95%CI -0.93 to -0.11; P=0.012), lower odds of acute kidney injury (aOR 0.76, 95%CI 0.59-0.98; P=0.039), and lower odds of shock (aOR 0.23, 95%CI 0.06-0.78; P=0.019]. Post-propensity matching revealed similar patterns.

Conclusions Long-term aspirin use is associated with a lower rate of inpatient mortality and other clinical outcomes in hospitalized elderly patients with pancreatic cancer. The etiologies behind this relationship should be explored with a view to better understanding.

Keywords Aspirin, pancreatic cancer, mortality

Ann Gastroenterol 2024; 37 (6): 750-757

Materials and methods

Data source

This study was based on data from the 2020 Health Care Utilization Project National Inpatient Sample (HCUP-NIS). The HCUP-NIS, sponsored by the Agency for Healthcare Research and Quality, is the largest publicly available all-payer inpatient database in the United States. It contains discharge data from non-federal, non-rehabilitation, acute-care and short-term hospitals. Cost-to-charge ratios, also available in the HCUP-NIS database, were used to capture the cost of care. Costs such as wages, supplies and utility, better reflect the actual resource consumption of healthcare [8]. The HCUP-NIS does not include other federal hospitals, psychiatric, substance abuse, and long-term care facility hospitalizations as they do not reflect each hospitalization episodes cost [9].

The HCUP-NIS employs a multilevel survey design database that captures approximately 20% of hospital admissions and discharges across the country. By doing so, it provides national estimates regarding patient characteristics, diagnoses and hospital-based procedures performed in acute-care hospitals across the United States. All hospital discharges within the sample are recorded and weighted to ensure accurate representation of the national landscape of inpatient care.

Study cohort

In our study, we focused on individuals aged 60 years and older who were hospitalized with pancreatic cancer during the period spanning January to December 2020. Although general guidelines have defined a threshold of over 65 years as elderly, we believe that the age of 60, as used by the World Health Organization, will provide a more comparable subpopulation group for future research [10]. We excluded records designated as elective hospitalizations and records with primary cancer other than pancreatic cancer. The International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) coding system was used to identify eligible discharge records for inclusion in our analysis. We then stratified eligible hospitalizations into 2 groups: those with long-term aspirin use and those without. We used the ICD-10 code Z79.82 to identify patients with long-term aspirin use, as in various prior publications that used this code to define aspirin use in various diseases [11-13]. The ICD-10-CM code for identification of pancreatic cancer was C25. We used C00-D49 as the ICD-10-CM code for non-pancreatic cancer. Fig. 1 demonstrates the inclusion and exclusion flow of records that were analyzed in this study.

Figure 1 Inclusion flow diagram for elderly patients admitted with pancreatic cancer

We used the Charlson Comorbidity Index (CCI), the most widely used comorbidity index, to categorize patient severity [14]. The CCI was developed to predict 1-year mortality among 604 patients based on comorbidity data obtained from a hospital chart review [15]. It contains 19 factors, including diabetes with diabetic complications, congestive heart failure, peripheral vascular disease, chronic pulmonary disease, mild and severe liver disease, hemiplegia, renal disease, leukemia, lymphoma, metastatic tumor, and acquired immunodeficiency syndrome (AIDS). Each of these comorbidities was weighted according to their potential influence on mortality.

Additionally, we used propensity score matching to balance between the 2 cohorts. Each of the variables is matched to generate a propensity-matched cohort [16], in order to ensure that there are minimal differences in baseline characteristics. A combination of various balancing, matching, weight readjustment, and interpretation strategies is used to ensure a balance between both cohorts. The process of using propensity score analysis has been well-described and was appropriate for use in our study [17]. In this paper, we used nearest-neighbor 1-to-5 matching to minimize confounding, and we achieved 1-to-3 matching cohorts. A standardized difference of <10% suggested adequacy of the match between 2 groups among the measured covariates, with less potential for bias [18]. Fig. 2 demonstrates the standardized difference before and after matching.

Figure 2 Comparison of cohorts before and after propensity matching

Outcome measures

In our study, the primary outcome was inpatient mortality, compared between the groups with and without long-term aspirin use, among patients hospitalized with pancreatic cancer. Additionally, we evaluated the presence of other clinical outcomes and operative complications, hospitalizations, and related costs. Other variables included demographics and socioeconomic information, such as comorbidities, race, hospital types and regions, and patient’s insurance status.

Statistical analysis

Data analyses were performed using StataBE 17.0 software (StataCorp, College Station, TX). To generate nationally representative estimates, we employed weighted sampling techniques in accordance with the HCUP-NIS guidelines. Descriptive statistics were computed for continuous variables, yielding mean and standard deviation (SD), and for categorical variables, expressed as percentages. To compare proportions, Fisher’s exact test was used for categorical variables, while the Student’s t-test was employed for continuous variables. Covariates included in our analyses were selected based on a comprehensive literature review, prior research findings, and well-established confounding factors. Multivariate survey logistic regression models were constructed to calculate adjusted odds ratios (aORs) for primary and secondary outcomes. For continuous outcomes, multivariable linear regression analyses were conducted. Outcomes were adjusted for potential patient and hospital-level confounders, including age, sex, race, CCI, median income, hospital size (no. of beds), hospital location, teaching status, insurance type, diagnoses for which aspirin is a major treatment option (such as stroke and coronary artery disease), presence of metastasis, history of chemotherapy, history of radiotherapy and other comorbidities. A P-value of <0.05 was considered statistically significant.

Ethical considerations

Since the NIS database lacks patient and hospital-specific identifiers, our study did not require Institutional Review Board approval. However, we ensured that our study adhered to the ethical standards for studies of human subjects.

Data availability

The NIS is a publicly available all-payer inpatient database, encompassing hospitalization data from over 7 million hospital stays. This extensive dataset allows for the assessment of national and regional estimates across a wide range of healthcare topics. The NIS database is available at: https://www.hcup-us.ahrq.gov.

Results

Baseline characteristic of the study cohorts

A total of 19,248 elderly hospitalizations of patients with pancreatic cancer were identified. Among these patients, 2914 (15.14%) were identified as long-term users of aspirin. Table 1 shows the baseline characteristics of the study population. Before propensity score matching, we found statistically significant differences between the aspirin-using and non-aspirin groups, in terms of race, hospital region, insurance status, and some comorbidities. After matching the cohorts, the total hospitalizations in the non-aspirin group came to 7294, whereas the aspirin cohort totaled 2724 cases. After post-propensity analysis, only hyperlipidemia and coronary artery disease proportion in each analysis group differ significantly in the post-propensity group.

Table 1 Baseline characteristics for elderly patients with pancreatic cancer, stratified by the long-term use of aspirin

Inpatient mortality

Crude mortality rates in both groups were reported. Supplementary Table 1 shows the outcomes for records hospitalized with pancreatic cancer, stratified by the use of aspirin, under multivariate analysis. After adjusting for socioeconomic status and potential cofounders, we found that patients with long-term aspirin use had statistically lower odds of inpatient mortality compared to the non-aspirin cohort (3.26% vs. 6.34%, aOR 0.55, 95% confidence interval [CI] 0.33-0.92; P=0.023). Fig. 3 illustrates the ORs for mortality across multiple patient variables. Table 2 shows the outcomes using the propensity-matched cohorts. Under propensity score matching, with matched socioeconomic status and other comorbidities (Table 2), patients taking aspirin still had statistically lower odds of inpatient mortality (3.12% vs. 6.03%, aOR 0.49, 95%CI 0.28-0.85; P=0.011). Supplementary Table 2 shows the inpatient mortality odds for socioeconomic data and comorbidities used in this study, for non-stratified records with pancreatic cancer, when compared to baseline for each factor. An analysis of other socioeconomic data and comorbidities without stratifying by the presence of aspirin (Supplementary Table 2) revealed that only stroke had statistically significant odds of altering inpatient mortality outcomes (0.81%, aOR 3.36, 95%CI 1.27-8.89; P=0.014). Supplementary Table 3 shows the inpatient mortality odds for socioeconomic and comorbidity data used in this study, in patients taking long-term aspirin, when compared to baseline in each factor. An analysis of factors predicting inpatient mortality rates (Supplementary Table 3) showed that only stroke increased the odds of inpatient mortality (0.86%, aOR 3.31, 95%CI 1.22-8.99; P=0.019). Using the adjusted cohorts, stroke still had a statistically significant impact on inpatient mortality. Supplementary Table 4 shows the factors predicting inpatient mortality, adjusted for socioeconomic status and comorbidities, after propensity score matching.

Figure 3 Odd ratios for effect of various demographic and socioeconomic data on inpatient mortality

Table 2 Outcomes for elderly patients with pancreatic cancer, stratified by the use of aspirin, with propensity score matching

Resource utilization and other clinical outcomes

In the aspirin cohort, our findings indicated a significantly shorter mean length of stay (beta coefficient -0.52, 95%CI -0.93 to -0.11; P=0.012), as well as lower odds of shock (aOR 0.23, 95%CI 0.06-0.78; P=0.019), and lower odds of acute kidney injury (aOR 0.76, 95% CI 0.59-0.98; P=0.039). After cohorts were matched using the propensity score method, the previous statistically significant outcomes remained mostly significant. It should be noted that no diagnosis of gastrointestinal bleeding was found in any of our elderly subpopulation.

Discussion

To our knowledge, this is the first study to explore the effect of long-term use of aspirin on elderly patients admitted with pancreatic cancer. Furthermore, this is also the first study to investigate the factors that predict the odds of inpatient mortality, using comprehensive socioeconomic status factors in the analysis. We report that the long-term use of aspirin is associated with a lower risk of inpatient mortality and other clinical outcomes, even after compensating for socioeconomic status and comorbidities. In addition, some socioeconomic factors and comorbidities contribute to the risk of overall inpatient mortality. However, after propensity matching of both cohorts, those factors may not impact the odds of inpatient mortality.

We found higher proportions of Caucasians and African Americans associated with long-term aspirin use. This is similar to a study by Sanchez et al [19], who found a larger proportion of Caucasians who used aspirin, compared to other races. We also found statistically significant differences in the prevalence of aspirin use in relation to hospital region. Although some prior publications have reported this association [20], exploring it further may provide a better context for aspirin use in the future. As expected, the aspirin cohort had a lower prevalence of hypertension, hyperlipidemia, coronary artery disease, chronic kidney disease, chronic obstructive pulmonary disease and peripheral artery disease. This is due to the possible or prior use of aspirin in these patient groups, as similarly reported in the literature [21]. The role of aspirin in the prevention of atherosclerotic cardiovascular disease is well documented in the literature [22], and supports the results in our study. The capability of aspirin to reduce vascular complications is primarily attributed to its inhibition of cyclooxygenase, which leads to a decrease in thromboxane A2 levels, thereby preventing platelet activation and aggregation. Additionally, aspirin interferes with the release of inflammatory cytokines and growth factors, disrupting key processes that contribute to the development of cardiovascular-related complications [23,24]. Similarly, aspirin use was associated with a lower prevalence of metastases. This association is similar to that reported by Algra et al [25], who found that regular aspirin decreases metastasis for various cancers, and to the finding of Rothwell et al [26] that aspirin use reduced the risk of distant metastasis. These outcomes may be attributed to several proposed mechanisms, including reduction of growth factors that promote metastatic migration, inhibition of tumor suppressor genes, and reduction of pro-metastatic signals through disruption of the phospholipid metabolism [27].

We found a reduction in the odds of inpatient mortality, in pancreatic cancer hospitalizations with long-term aspirin usage, even after adjusting using propensity score matching. Although prior research found that aspirin use was linked to a lower incidence of pancreatic cancer [28-30], this is the first study to establish an association between inpatient mortality and long-term aspirin use. In a study of a population with hepatocellular carcinoma [31], a similar inverse association of long-term aspirin use and inpatient mortality was also observed. We postulate several reasons that may contribute to this result. First, aspirin is a cyclooxygenase inhibitor, and cyclooxygenase enzymes are directly involved in the proliferation of cancer cells [32,33]. Aspirin also contains other interference mechanisms, such as lowering chemoradiation resistance [34], cancer-associated inflammation [35] and platelet driven anticarcinogenic activities [36]. These may help counteract the high mortality rates pancreatic cancer patients usually encounter [37]. Second, the lower odds of shock in the aspirin cohort may indirectly reduce the inpatient mortality rates. In our study, aspirin cohorts had lower odds of shock, as reported in the studies of Iqbal et al study [38] and Ahsberg et al [39], in which aspirin use had a lower risk of a fatal outcome. We hypothesize that aspirin could reduce the activation of inflammation cascades and increase their resolution, as seen in a study by Otto et al [40], but additional investigation needs to be conducted regarding this relationship. Finally, the lower prevalence of metastasis in aspirin-taking cohorts compared to non-aspirin cohorts may indirectly affect the inpatient mortality rates. Metastasis is one of the major conditions that contribute to mortality in cancer patients [41], and the reduction of metastasis in the aspirin population group, may have contributed to the lower inpatient mortality.

Although gastrointestinal bleeding is one of the major concerns for the use of aspirin, our study find no records of co-diagnosis of this complication. The current literature reports a lower severity of these bleedings with the use of aspirin [42], and additional studies should be conducted to verify these safety concerns.

Regarding the factors predicting inpatient mortality for elderly hospitalizations with pancreatic cancer, we found that only stroke increased the risk of inpatient mortality in our nationally representative sample, in the absence of stratification by the presence of aspirin. The results build upon those of Chan et al [43], who found that pancreatic cancer is linked to higher odds of stroke. Our study is similar to that of Bonnerot et al [44], who suggested that inflammatory cytokines may play a role in developing stroke and worsening outcomes. Although a temporal relationship cannot be established, given the nature of the study database, stroke prevention care may provide more benefits for those who are admitted with pancreatic cancer.

The study’s substantial strength derives from its extensive, nationally representative sample, which effectively mitigates the referral bias commonly observed in single-center cohort studies. The diverse patient population accurately reflects the inpatient disease burden and clinical characteristics of pancreatic cancer patients across the United States. Furthermore, the sizable dataset enhances the study’s statistical power, enabling the detection of even subtle disparities between groups [45]. Through rigorous adjustments for patient demographics, hospital characteristics, and the CCI, coupled with propensity score matching, we sought to mitigate the potential confounding effects of these variables on our analysis.

However, this study was not without limitations. The administrative and cross-sectional nature of the NIS database restricted the acquisition of crucial patient-level data, such as clinical characteristics, radiographic, echocardiographic and laboratory results, which are essential for stratifying patient severity and accurately characterizing their health status. In addition, the lack of detail of aspirin use, such as dose, duration and rationale of use, may reduce the level of granularity in applying these findings in practice. Despite our best efforts to capture patient cancer status and staging by chemotherapy use, radiotherapy use and distant metastasis, additional staging data would assist the clinician in applying these data in a more practical approach. Moreover, the database’s exclusive emphasis on in-hospital occurrences may inadvertently overlook significant post-discharge sequelae, including out-of-hospital sudden cardiac death, long-term mortality and the emergence of complications. Additionally, the inherent constraints of observational research impede the definitive establishment of causal linkages between in-hospital complications and pancreatic cancer, as the temporal sequence between these events cannot be conclusively ascertained.

In the context of pancreatic cancer, there is very limited literature exploring the association between non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) and inpatient mortality. While a study by Lad et al found no association between non-aspirin NSAIDs and pancreatic cancer mortality, it also reported no significant association between aspirin use and pancreatic cancer mortality, which contrasts with our findings [46]. This also warrants further studies to explore the effect of other NSAIDs or antiplatelet agents on pancreatic cancer mortality. Our findings underscore the inverse relationship in pancreatic cancer patients, linking the use of aspirin with lower mortality rates and a lower incidence of adverse events. Future research can be expanded to investigate the association between different types of antiplatelet agents or other non-aspirin NSAIDs and inpatient mortality in patients with pancreatic cancer. Further epidemiological investigations are necessary to elucidate the causal mechanisms underlying the observed associations between aspirin and adverse outcomes in elderly patients with pancreatic cancer. Understanding the etiology and causality between aspirin and pancreatic cancer may lead to better outcomes in this subpopulation group. To enhance the care of elderly patients, it may be necessary to optimize care pathways, implement early interventions to mitigate adverse outcomes, and provide comprehensive multidisciplinary support to address their complex medical needs.

Summary Box

What is already known:

Pancreatic cancer is one of the leading causes of death in the United States
Aspirin has a promising role in cancer prevention and treatment
Racial status has an impact on clinical care in this subpopulation group

What the new findings are:

Aspirin use was associated with lower inpatient mortality in elderly patients with pancreatic cancer
Stroke was associated with higher inpatient mortality in this subpopulation
Propensity matching, after adjusting for possible bias, produced similar results

References

2. Thorat MA, Cuzick J. Role of aspirin in cancer prevention. Curr Oncol Rep 2013;15:533-540.

3. Dahiya DS, Inamdar S, Perisetti A, et al. Decreasing length of stay and inpatient mortality associated with pancreatic cancer hospitalizations:a United States national survey from 2008 to 2017. Pancreatology 2022;22:590-597.

4. Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030:the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res 2014;74:2913-2921.

5. Samaan JS, Abboud Y, Oh J, et al. Pancreatic cancer incidence trends by race, ethnicity, age and sex in the United States:a population-based study, 2000-2018. Cancers (Basel) 2023;15:870.

6. Petric J, Handshin S, Jonnada PK, Karunakaran M, Barreto SG. The influence of socioeconomic status on access to cancer care and survival in resectable pancreatic cancer:a systematic review and meta-analysis. ANZ J Surg 2022;92:2795-2807.

7. Zell JA, Rhee JM, Ziogas A, Lipkin SM, Anton-Culver H. Race, socioeconomic status, treatment, and survival time among pancreatic cancer cases in California. Cancer Epidemiol Biomarkers Prev 2007;16:546-552.

8. Finkler SA. The distinction between cost and charges. Ann Intern Med 1982;96:102-109.

9. Liang L, Moore B, Soni A. In:National Inpatient Hospital Costs:The Most Expensive Conditions by Payer, 2017. Agency for Healthcare Research and Quality (US), Rockville (MD), 2020.

10. Singh S, Bajorek B. Defining 'elderly'in clinical practice guidelines for pharmacotherapy. Pharm Pract (Granada) 2014;12:489.

11. Iqbal H, Arora GS, Singh I, et al. The impact of aspirin use on outcomes in patients with inflammatory bowel disease:Insights from a national database. Int J Colorectal Dis 2023;39:6.

12. Dasenbrock HH, Yan SC, Gross BA, et al. The impact of aspirin and anticoagulant usage on outcomes after aneurysmal subarachnoid hemorrhage:a Nationwide Inpatient Sample analysis. J Neurosurg 2017;126:537-547.

13. Chaudhry H, Sohal A, Dukovic D, et al. Does use of long-term aspirin impact outcomes in patients with acute pancreatitis?Eur J Gastroenterol Hepatol 2023;35:721-727.

14. de Groot V, Beckerman H, Lankhorst GJ, Bouter LM. How to measure comorbidity. a critical review of available methods. J Clin Epidemiol 2003;56:221-229.

15. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies:development and validation. J Chronic Dis 1987;40:373-383.

16. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res 2011;46:399-424.

17. Garrido MM, Kelley AS, Paris J, et al. Methods for constructing and assessing propensity scores. Health Serv Res 2014;49:1701-1720.

18. Mamdani M, Sykora K, Li P, et al. Reader's guide to critical appraisal of cohort studies:2. Assessing potential for confounding. BMJ 2005;330:960-962.

19. Sanchez DR, Diez Roux AV, Michos ED, et al. Comparison of the racial/ethnic prevalence of regular aspirin use for the primary prevention of coronary heart disease from the multi-ethnic study of atherosclerosis. Am J Cardiol 2011;107:41-46.

20. Opotowsky AR, McWilliams JM, Cannon CP. Gender differences in aspirin use among adults with coronary heart disease in the United States. J Gen Intern Med 2007;22:55-61.

21. Merzon E, Green I, Vinker S, et al. The use of aspirin for primary prevention of cardiovascular disease is associated with a lower likelihood of COVID-19 infection. FEBS J 2021;288:5179-5189.

22. Boakye E, Uddin SMI, Obisesan OH, et al. Aspirin for cardiovascular disease prevention among adults in the United States:Trends, prevalence, and participant characteristics associated with use. Am J Prev Cardiol 2021;8:100256.

23. Weisman SM, Angiolillo DJ. Aspirin for primary prevention of cardiovascular disease:what we now know. J Cardiol Cardiovasc Med 2024;9:006-013.

24. Capodanno D, Angiolillo DJ. Aspirin for primary cardiovascular risk prevention and beyond in diabetes mellitus. Circulation 2016;134:1579-1594.

25. 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;13:518-527.

26. Rothwell PM, Wilson M, Price JF, Belch JF, Meade TW, Mehta Z. Effect of daily aspirin on risk of cancer metastasis:a study of incident cancers during randomised controlled trials. Lancet 2012;379:1591-1601.

27. Elwood P, Protty M, Morgan G, Pickering J, Delon C, Watkins J. Aspirin and cancer:biological mechanisms and clinical outcomes. Open Biol 2022;12:220124.

28. Streicher SA, Yu H, Lu L, Kidd MS, Risch HA. Case-control study of aspirin use and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2014;23:1254-1263.

29. Tan XL, Reid Lombardo KM, Bamlet WR, et al. Aspirin, nonsteroidal anti-inflammatory drugs, acetaminophen, and pancreatic cancer risk:a clinic-based case-control study. Cancer Prev Res (Phila) 2011;4:1835-1841.

30. Risch HA, Lu L, Streicher SA, et al. Aspirin use and reduced risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 2017;26:68-74.

31. Dhaliwal A, Sohal A, Bains K, et al. Impact of aspirin use on outcomes in patients with hepatocellular cancer:a nationwide analysis. World J Oncol 2023;14:195-204.

32. Henry WS, Laszewski T, Tsang T, et al. Aspirin suppresses growth in PI3K-mutant breast cancer by activating AMPK and inhibiting mTORC1 signaling. Cancer Res 2017;77:790-801.

33. Uddin S, Ahmed M, Hussain A, et al. Cyclooxygenase-2 inhibition inhibits PI3K/AKT kinase activity in epithelial ovarian cancer. Int J Cancer 2010;126:382-394.

34. Jiang MJ, Dai JJ, Gu DN, Huang Q, Tian L. Aspirin in pancreatic cancer:chemopreventive effects and therapeutic potentials. Biochim Biophys Acta 2016;1866:163-176.

35. Markowitz SD. Aspirin and colon cancer—targeting prevention?N Engl J Med 2007;356:2195-2198.

36. Lichtenberger LM, Vijayan KV. Are platelets the primary target of aspirin's remarkable anticancer activity?Cancer Res 2019;79:3820-3823.

37. Lippi G, Mattiuzzi C. The global burden of pancreatic cancer. Arch Med Sci 2020;16:820-824.

38. Iqbal H, Haddadin R, Zhang P, Haidary H, Prajapati D. Long-term aspirin use in patients hospitalized with ischemic colitis. Ann Gastroenterol 2024;37:31-36.

39. Åhsberg K, Höglund P, Staël von Holstein C. Mortality from peptic ulcer bleeding:the impact of comorbidity and the use of drugs that promote bleeding. Aliment Pharmacol Ther 2010;32:801-810.

40. Otto GP, Sossdorf M, Boettel J, et al. Effects of low-dose acetylsalicylic acid and atherosclerotic vascular diseases on the outcome in patients with severe sepsis or septic shock. Platelets 2013;24:480-485.

41. Dillekås H, Rogers MS, Straume O. Are 90% of deaths from cancer caused by metastases?Cancer Med 2019;8:5574-5576.

42. Elwood P, Morgan G, Watkins J, et al. Aspirin and cancer treatment:systematic reviews and meta-analyses of evidence:for and against. Br J Cancer 2024;130:3-8.

43. Chan PC, Chang WL, Hsu MH, et al. Higher stroke incidence in the patients with pancreatic cancer:A nation-based cohort study in Taiwan. Medicine (Baltimore) 2018;97:e0133.

44. Bonnerot M, Humbertjean L, Mione G, et al. Cerebral ischemic events in patients with pancreatic cancer:a retrospective cohort study of 17 patients and a literature review. Medicine (Baltimore) 2016;95:e4009.

45. Serdar CC, Cihan M, Yücel D, Serdar MA. Sample size, power and effect size revisited:simplified and practical approaches in pre-clinical, clinical and laboratory studies. Biochem Med (Zagreb) 2021;31:010502.

46. Lad AA, Ma Y, Lee JA, et al. No association between nonsteroidal anti-inflammatory drug use and pancreatic cancer incidence and survival. Pancreas 2017;46:e43-e45.

Notes

Conflict of Interest: None