Shielding Effects of Aspirin Use from Adverse in Hospital Outcomes in Non-Metastatic Pancreatic Cancer: An Evaluation of the National Inpatient Sample

1. Introduction

Aspirin, acetylsalicylic acid, initially recognized for its anti-inflammatory antipyretic and analgesic properties using willow bark extract in the late 1600s now holds a prominent role in the treatment of acute coronary syndrome and chronic cardiovascular disease [1]. Cardiovascular disease remains the leading cause of death worldwide, followed closely by malignancy. According to the American Cancer Society, an estimated 20 million new cancer cases were diagnosed worldwide in 2022, with approximately 9.7 million cancer-related deaths; these figures include both sexes combined [2,3]. This approximates that one in five men and one in nine women will develop cancer, and of these one in nine men and one in twelve women will subsequently die from it [2,3]. The leading causes of cancer related mortality in the United States are lung, colorectal and pancreatic cancer. Despite recent advancements in the treatment of pancreatic cancer it remains a deadly disease with grim 5-year survival rates of 11.2%; many patients present with advanced disease with local and diffuse metastasis that are not amenable to surgical intervention [2,3]. Current epidemiologic studies project that pancreatic cancer will be second, behind lung cancer, in leading causes of cancer related mortality within the next decade [2,3]. This uncontrolled increase in pancreatic cancer mortality, albeit alarming, serves as a driving force for innovation and development of novel therapeutic treatments. It also stimulates continual examination of current treatment modalities and our repertoire of medications for possible repurposed applications.

The utility of aspirin in cancer therapeutics has been studied by several groups and stratified into COX dependent and independent mechanisms. The cellular expression profiles that COX2 gene expression was significantly increased in pancreatic cancer and various other gastrointestinal malignancies; inclusive of colorectal, esophageal and gastric cancer. Further studies revealed that COX2 over expression is also associated with accelerated tumor growth, and the induction of molecular processes known to accelerate cancer progression. Aspirin demonstrates several COX independent molecular interactions with key mitotic regulators of the cell cycle, p53 and various cyclins, and other pathways implicated in tumor carcinogenesis. These interactions interfere with cancer genomics and biochemistry including cancer cell DNA replication, proliferation, protein expression and mechanisms of metastasis and angiogenesis [4,5,6]. These studies have garnered significant scientific attention with special interest into gaining a mechanistic understanding of how aspirin functions in the treatment of and prevention of malignancies including pancreatic cancer. A number of groups have identified aspirin’s association with decreased incidence of and mortality from pancreatic cancer [7,8,9,10,11,12]. However, these studies are limited by sample size and confounders including comorbidities, patient demographics and age. We conducted this analysis to measure the effects of long-term aspirin use on the incidence of in-hospital mortality, inpatient outcomes and decompensations in patients with non-metastatic pancreatic cancer on a national scale.

2. Materials and Methods

The National Inpatient Sample, NIS, represents the largest deidentified database containing information on various in hospital outcomes and is maintained by the healthcare cost and utilization project, HCUP; all information contained within NIS database files are uniquely represented and validated by HCUP to ensure accuracy of the information’s content and its origin.

2.1. Inclusion Criteria, Population of Study and Examined Variables

The primary outcome was comparing in-patient mortality between aspirin and non-aspirin-using non-metastatic pancreatic cancer patients. Secondary outcomes measures encompassed the odds of developing septic shock, portal vein thrombosis, upper gastrointestinal bleeding, pulmonary embolism, acute kidney injury, need for renal replacement therapy, and intensive care unit (ICU) admission.

In this study the primary exposure variable was the use of aspirin in patients with non-metastatic pancreatic cancer. Information on variables such as race, gender, age, median income and hospital characteristics including urban versus rural location, bed size and hospital region were also analyzed. The analysis of the comorbidity burden was investigated using the Charleson Comorbidity Index, CCI. The CCI is a well validated clinical index including 19 classes of comorbidities that serves as a clinical prediction tool of a patient’s risk of mortality.

2.2. Statement of Ethics

All data used in this study was captured from the NIS database which represents completely de-identified information. An IRB approval was not required for this study as all patient information is deidentified.

2.3. Statistical Analysis

Hospital-level discharge weights provided by NIS were used to generate national estimates. Categorical variables were compared using the chi-square test, whereas an independent sample t-test was used for continuous variables. To investigate the effect of defined variables on in-hospital outcomes, univariate logistic regression was performed using a p-value threshold of 0.2 for variable selection. Variables meeting this inclusion criterion were subsequently entered into a multivariable logistic regression model for further analysis. Adjusted odds ratios (aORs) were calculated with corresponding 95% confidence intervals (CIs), and statistical significance was defined as a two-tailed p-value < 0.05. All analyses were conducted using Stata/MP version 19.5.

3. Results

3.1. Patient Characteristics

During the 2017–2022 study period, the NIS captured 205,215,316 hospitalizations. Of these, 139,579 adult patients were identified with non-metastatic pancreatic cancer and comprised the analytic subpopulation. Within this cohort, 19,475 patients (13.9%) were identified as long-term aspirin users, while 120,177 patients (86.1%) had no documented aspirin use. Patients with long-term aspirin use were, on average, older than those without aspirin use (mean age 72 vs 68 years, respectively). Further characterization of baseline patient characteristics categorized by the use of aspirin are presented in Table 1.

3.2. Comorbidities

A greater incidence of chronic obstructive pulmonary disease, metabolic disorders including obesity, type 2 diabetes mellitus, dyslipidemia and cardiac arrythmias were observed amongst individuals with aspirin use. Interestingly, individuals with no aspirin use were observed to have greater incidences of ascitic liver disease, cirrhosis and polysubstance use disorder including cannabis use and alcohol use disorder; see further characterization below in Table 2.

For mortality and all other in-hospital outcomes examined in this study, statistical significance was assessed using multivariable regression analyses with adjustment for demographic factors and comorbidities. These characteristics are detailed in Table 3 and are graphically depicted by aspirin versus no aspirin use in Figure 1.

3.3. In-Hospital Mortality

Patients with non-metastatic pancreatic cancer and aspirin use demonstrated decreased odds of in-hospital mortality, adjusted odds ratio, (aOR) 0.531; p value <0.021 95% CI (confidence interval): 0.419 – 0.673. Those with non-metastatic pancreatic cancer and no aspirin use demonstrated increased rates of in-hospital mortality (aOR) 2.36; p value <0.001 95% CI: 1.87 – 2.987. The total proportion of mortality amongst patients with non-metastatic pancreatic cancer with aspirin use is 2.26% (112) versus 4.28% (239) in non-aspirin users; p:<0.0003

3.4. Upper Gastrointestinal Bleeding

Patients with non-metastatic pancreatic cancer and aspirin use demonstrated a decreased odds of developing an upper gastrointestinal bleeding event, (aOR) 0.641; p value <0.031 95% CI: 0.425 – 0.967. Those with non-metastatic pancreatic cancer and no aspirin use demonstrated increased rates of developing upper gastrointestinal bleeding (aOR) 1.648; p value <0.018 95% CI: 1.095 – 2.481. The total incidence of upper gastrointestinal bleeding in aspirin users was identified to be 0.69% versus 1.05% in non-aspirin users with non-metastatic pancreatic cancer; p:<0.0003

3.5. Pulmonary Embolism

Patients with non-metastatic pancreatic cancer and aspirin use demonstrated a decreased odds of developing pulmonary embolism, (aOR) 0.545; p value <0.004 95% CI: 0.312 – 0.713. Those with non-metastatic pancreatic cancer and no aspirin use demonstrated increased rates of developing pulmonary embolism (aOR) 1.83; p value <0.005 95% CI: 1.223 – 2.737. The total proportion of pulmonary emboli in aspirin users was identified to be 1.47% versus 1.9% in patients with non-metastatic pancreatic cancer; p: <0.0005.

3.6. Portal Vein Thrombosis

The aOR of developing portal vein thrombosis for patients with non-metastatic pancreatic cancer and aspirin use is 0.741; p value <0.022 95% CI: 0.574 – 0.955. Those with non-metastatic pancreatic cancer and no aspirin use demonstrated increased rates of developing portal vein thrombosis aOR 1.35; p value <0.020 95% CI: 1.049 – 1.743. The total proportion of portal vein thrombosis in aspirin users was identified to be 0.076% as compared to 0.15% in non-aspirin users: p: <0.0004.

3.7. Septic Shock

Patients with non-metastatic pancreatic cancer and aspirin use demonstrated decreased odds of developing septic shock, aOR 0.472; p value <0.001 95% CI: 0.364 – 0.814. Those with non-metastatic pancreatic cancer and no aspirin use demonstrated increased rates of septic shock (aOR) 2.09; p value <0.00021 95% CI: 1.389 – 3.162. The total proportion of septic shock in aspirin users was identified to be 0.6% versus 1.4% in patients with no aspirin use; p: <0.0002.

3.8. ICU Stay

Patients with non-metastatic pancreatic cancer and aspirin use demonstrated decreased odds of requiring an ICU admission, aOR 0.648; p value <0.001 95% CI: 0.521 – 0.805. Those with non-metastatic pancreatic cancer and no aspirin use demonstrated increased rates of requiring an ICU level of care (aOR) 1.52; p value <0.001 95% CI: 1.224 – 1.887. The total proportion of critical care escalation as determined by in hospital ICU admission was measured to be 4.65% in non-aspirin users vs 4.00% in patients with aspirin use; p: <0.0005.

3.9. Acute Kidney Injury, AKI

The aOR of developing AKI for patients with non-metastatic pancreatic cancer and aspirin use is 0.771; p value <0.001 95% CI: 0.696 – 0.855. Those with non-metastatic pancreatic cancer and no aspirin use demonstrated increased rates of developing an AKI (aOR) 1.284; p value <0.021 95% CI: 1.159 – 1.423. The total proportion of AKI in aspirin users was identified to be 14.8% versus 14.9% in patients with no aspirin use; p: 0.935.

3.10. Continuous Renal Replacement Therapy, CRRT

The aOR of requiring CRRT for patients with non-metastatic pancreatic cancer and aspirin use is 0.134; p value <0.044 95% CI: 0.018 – 0.972. Those with non-metastatic pancreatic cancer and no aspirin use demonstrated increased rates of in hospital mortality (aOR) 7.419; p value <0.048 95% CI: 1.028 – 53.498. The total proportion of requiring CRRT in aspirin users was identified to be 0.0002% versus 0.017% in patients with no aspirin use; p: <0.0002.

Aspirin use significantly reduces the incidence of in hospital mortality and the occurrence of pulmonary embolism, portal vein thrombosis, upper gastrointestinal bleeding, acute kidney injury, the onset of septic shock and from requiring an ICU level of care. Those with non metastatic pancreatic cancer and no aspirin use demonstrated significantly increased incidence of in hospital mortality and the occurrence of pulmonary embolism, portal vein thrombosis, upper gastrointestinal bleeding, acute kidney injury, the onset of septic shock and from requiring an ICU level of care as demonstrated in Table 3.

Aspirin use in those with non metastatic pancreatic cancer demonstrates protective effects from in hospital mortality and the development of major secondary complications including pulmonary embolism, portal vein thrombosis, acute kidney injury, the onset of septic shock and from requiring an ICU level of care. Those with non metastatic pancreatic cancer and no aspirin use demonstrate significantly increased odds of in hospital mortality and of developing major comorbid conditions associated with colorectal malignancies including pulmonary emboli, portal vein thrombosis and secondary complications including acute kidney injury, septic shock and of requiring an ICU level of care.

4. Discussion

In our evaluation of the effects of aspirin in 139,580 cases of non-metastatic pancreatic cancer we identified a statistically significant reduction of in hospital mortality amongst patients with long term aspirin use as compared to non-aspirin users. These findings are supported by those in several other groups such as a population-based study analyzed a Connecticut state-maintained registry of patients with pancreatic cancer, n=362, compared to 690 randomly sampled controls for the effects of aspirin use on rates of mortality. This group identified that aspirin use was associated with a reduction in mortality amongst patients with pancreatic cancer [7]. Another study reported a significant reduction in the rate of pancreatic cancer related mortality amongst patients with concurrent aspirin use [8]. Researchers have also examined the rates of incidence of pancreatic cancer in patients with aspirin use. A meta-analysis involving 7252 cases of pancreatic cancer demonstrated a decreased odds of developing pancreatic cancer in patients with aspirin use [9]; furthermore, their study identified a possible dose dependent relationship of aspirin use and the incidence of pancreatic cancer. Another meta-analysis of observational studies, cohort based and case control studies, revealed a reduction in the incidence of pancreatic cancer with the use of aspirin [10].

While these findings suggest a survival benefit of aspirin use in pancreatic cancer the precise biological mechanisms by which aspirin may exert these protective effects in those with pancreatic malignancies and against the molecular events that drive its progression remain largely unknown. The targets of aspirin, cyclooxygenase one and two, COX1 and COX2, and their expression profiles in pancreatic malignancies have been evaluated by several groups [13,14]. Cancer cells derived from these tissues have demonstrated differential protein expression of both COX1 and COX2 with significant elevations of COX2 enzyme levels [13,14]. Increased COX2 expression has been identified to promote tumor cell growth and to affect the structural integrity of mucosal and vascular tissue through molecular changes that drive and promote chronic tissue inflammation. COX2 has been identified as an integral promoter of the pathophysiology in pancreatic malignancies [13,14]. It is well documented in scientific and clinical literature that states of chronic inflammation are known drivers of malignancy through increased production of inflammation induced reactive oxygen species, ROS. Healthy pancreatic tissue in vivo is known to have significantly decreased expression of superoxide dismutase, glutathione peroxidase and catalase as compared to other healthy tissues [14]. Significantly decreased innate levels of protective antioxidant enzymes support the notion of marked susceptibility of pancreatic tissue for DNA damage, cytotoxicity and increased accumulation of pro-oncogenic mutations. Persistent proinflammatory signaling therefore induces prolonged states of oxidative stress and DNA mutations both of which contribute to tissue carcinogenesis; particularly in pancreatic tissue [14]. The anti-inflammatory properties of aspirin, through decreased generation of COX1 and COX2 enzyme products, may be a key contributor to the observed decrease of inhospital mortality identified in our study.

Despite the well known anti inflammatory effects driven by cyclooxygenase inhibition, aspirin has been demonstrated to exert protective antineoplastic properties. Several studies of aspirins potential role in the treatment of pancreatic cancer has been stratified into COX dependent and independent mechanisms. Loss of function, LOF, mutations of the tumor suppressor TP53 gene, encoding the p53 protein, are a known inciting molecular event leading to several malignancies. LOF of TP53 has been characterized in approximately 50 -75% of patients with pancreatic malignancies [15]. p53 primarily serves as a cell cycle checkpoint inhibitor, G1-S phase and G2-M phase [15]. When activated p53 mediates apoptosis in atypical cells ultimately protecting the organism from proliferation of cells with damaged DNA and dysregulated cellular growth signaling [15]. Aspirin has been shown to directly acetylate and activate p53 proteins in vivo and vitro in several gastrointestinal malignancies [16]. These molecular and genetic derangements therefore remain molecular targets of interest in the augmentation of pancreatic cancer therapeutics. Recent studies reveal a growing number of patients with pancreatic cancer phenotypes with greater amounts of resistance to current chemotherapy treatment [17,18,19]. This highlights the need for innovation and reevaluation of current medications regimens in managing this disease. This COX independent mechanism may explain the observed decreased incidence of pancreatic cancer and mortality in patients with aspirin use identified by other groups [9,10]. Alongside the antimalignancy properties of aspirin are the clinically significant benefits of aspirin use in mitigating the development of clinical complications noted to significantly enhance morbidity and mortality.

Our study also demonstrates a decreased rate of developing thrombotic events such as pulmonary emboli and deep vein thromboses, DVTs. Malignancies are well known drivers of hypercoagulable states due to local and systemic deregulatory processes affecting vascular structural integrity and causing pathological derangements of the clotting cascade. Pancreatic malignancies have been identified to be associated with the highest rate of thrombotic event when compared to other malignancies [20]. Our data demonstrates statistically significant decreased odds of developing several thrombotic conditions all of which carry significantly increased risk of mortality and worsened outcomes. Although aspirin does not demonstrate great capacity to dissolve and treat an active thrombosis it is, however, significantly associated with the ability to decrease the incidence of these events. Suppression of COX1 activity decreases platelet production of thromboxane A2, TxA2, a key mediator of platelet activation and aggregation [21]. TxA2 is enzymatically synthesized from COX1 activity on arachidonic acid within platelets. Once synthesized and released by activated platelets, TxA2 acts as a potent secondary messenger augmenting further downstream platelet activation, aggregation and vasoconstriction. Aspirin inhibits COX1 activity and therefore TxA2 synthesis preventing activation of the TxA2 receptor on other platelets and dampening downstream procoagulant signaling cascade. Aspirin also mediates downregulation of tissue factors, the formation of thrombin and by extension thrombin coordinated downstream coagulation reactions; all important components of a mature and stable thrombus [22,23,24]. This suggests a protective or shielding effect of aspirin use against the development of thrombotic disorders in a particularly high-risk population of patients. This features an important consideration for a potential prophylactic application of aspirin against the development of such thromboses in patients with pancreatic malignancies. Pancreatic cancer remains the malignancy most highly associated with the development of thrombosis. Although venous thrombotic events of distal lower extremity vasculature and pulmonary emboli occur more commonly, less frequent events such as portal vein thrombosis are associated with disproportionately increased morbidity and mortality. This includes the development of venous thromboembolisms, VTEs, DVTs, pulmonary emboli, however this also extends to more rare sites of thrombosis such as the portal vein. In patients with pancreatic cancer the formation of portal vein thrombosis does represent a rare event; estimated incidence rate of less than 1% [25]. Although rare, portal vein thrombosis is associated with a statistically significant 60% increase in odds of mortality in patients with pancreatic cancer [25]. The occurrence of portal vein thrombosis in patients with pancreatic cancer was also associated with increased length of stay and total hospital charges [25]. Our findings of decreased odds of developing portal vein thrombosis, aOR 0.741; p value <0.022 95% CI: 0.574 – 0.955, with aspirin use highlights an application for this medication in the prevention of a rare but deadly and costly complication of pancreatic cancer.

These observations provide strong support for the antithrombotic and vascular benefit of aspirin use in pancreatic cancer however the clinical application of aspirin is often tempered due to concerns for risk of compromise of the gastrointestinal mucosa and bleeding events. The effects of antiplatelet agents, primarily aspirin, on gastrointestinal, GI, mucosa have been studied by several groups. Several meta-analyses have conveyed an increased risk for GI bleeding in various subsets of patients [26,27]. Aspirin mechanistically irreversibly acetylates both COX1 and COX2 at a critical serine residue necessary for its catalytic function. It is well established that COX1 activity leads to the production of gastroprotective agents such as prostaglandin I2, PGI2. However, there remains an important consideration, that aspirin non-selectively inhibits both COX1 and COX2. Several randomized controlled studies have studied the relationship of selective COX2 inhibitors and GI bleeding where they identified decreased incidence of GI bleeding and loss of GI mucosal integrity with COX2 inhibitor use as compared to other NSAIDs and PPI therapy and compared to placebo [28,29,30,31,32]. Another large scale randomized controlled study involving 4484 patients and a systematic review of 7616 patients conveyed a lower risk of GI bleeding events throughout the GI tract with the use of COX2 inhibitors as compared to other NSAIDs [28]. Interestingly, there are currently a small number of studies that have specifically studied the effects of aspirin use and the incidence of GI bleeding in patients with pancreatic cancer. Our findings demonstrate a decreased incidence of upper GI bleeding events in patients with pancreatic cancer and concurrent aspirin use; aOR 0.601; p value <0.004 95% CI: 0.399 – 0.905. COX1 activity is associated with the production of gastroprotective prostaglandins, and selective COX2 inhibition has demonstrated decreased incidence in the rates of GI bleeding and intestinal perforation or injury. Our findings support that aspirin use in patients with non-metastatic pancreatic cancer is associated with a significantly reduced risk of developing upper GI bleeding. It can therefore be deduced that non-selective irreversible inhibition of both COX1 and COX2, although it induces the loss of protective COX1 activity, produces a net protective effect as it relates to the development of upper GI bleeding. Specifically, the benefit of COX2 inhibition, as identified by previous studies, may outweigh the increase in susceptibility towards GI bleeding resulting from the absence of COX1 mediated prostacyclin production. This suggests that integration of COX1 and COX2 expression levels rather than a singular focus on individual levels may hold greater significance for the maintenance of a healthy gastrointestinal mucosal barrier, tissue integrity, and ultimately susceptibility to bleeding. Further longitudinal prospective studies are required to delineate the susceptibility of patients with pancreatic cancer in developing upper GI bleeding with and without aspirin use.

In addition to pancreatic cancer induced vascular and gastrointestinal pathology this malignancy is associated with derangements in immune cell function that precipitate infectious complications driving clinical decompensation. Pancreatic cancer, like other malignancies, lead to several immune dysregulations that both suppress and alter the immune system in ways that promote its growth. One such mechanism involves pancreatic cancer cells acquiring the ability to synthesize and secrete immunosuppressive molecules such as interleukin, IL,10, TGFB, MUC5A and MUC1 [33]. These signaling molecules normally play a key role in the regulation of immune cell responses in normal physiology, however, their secretion in a dysregulated, constitutive fashion, allows for dampening of the host immune response at both local and systemic scales and support rapid tumor growth [33]. Another major consequence of this immune dysregulation becomes the host’s inability to properly fight and clear infections. Infections impose a significant clinical burden on patients with malignancies and often precipitate major complications and a worse prognosis [34]. Several recent studies have identified that up to 60% of malignancy related mortality is derived both directly and indirectly from the incidence of infections [34,35]. The nature of cancer treatment, including chemo and radiation therapy in pancreatic cancer greatly predisposes to the development of infections. If infectious disease occurs their treatment necessitates complete cessation of cancer treatment which directly impinges on the treatment course of the illness.

This immune dysfunction frequently precipitates infections leading to systemic hemodynamic compromise, driving multiorgan involvement necessitating an ICU level of care. AKI represents a major complication in those with malignancies with recent evaluations indicating a frequency of up to 18% within the first year of diagnosis and up to 60% in those who become critically ill [36]. A significant proportion of these patients will progress to overt renal failure, requiring some form of renal replacement therapy and admission to the critical care setting [36,37]. Acute renal failure in malignancy patients often is attributed to rapid cellular turnover from aggressive cancer or the development of tumor lysis syndrome in the setting of tumor cell destruction from chemo or radiation therapy. Several studies have evaluated the healthcare resource utilization and average cost of CRRT and have identified that the incidence of AKI and CRRT dramatically increase healthcare costs [37,38]; some evaluations have identified an approximate average increase of $3,700 per day [37,38]. Our findings demonstrate that aspirin use was indeed associated with a significantly decreased odds of developing septic shock, hemodynamic decompensation in the setting of any infection, in patients with non-metastatic pancreatic cancer. We also demonstrate that aspirin use was associated with a concurrent significantly reduced incidence of requiring an ICU level of care, of developing an AKI and requiring renal replacement therapy in the form of CRRT. Other groups have identified a significant incidence of AKI in patients with pancreatic cancer who undergo varying treatment modalities [39,40,41]. This features another potential application of aspirin use in patients with pancreatic cancer. These complications are noted to significantly increase both the mortality and morbidity in patients with pancreatic cancer. Our data supports the notion that aspirin use may help prevent further decompensation in patients admitted for clinical manifestations related to pancreatic cancer or its progression. The impact of these in hospital complications influence short term mortality however extend well beyond this and have longer lasting implications for utilization of healthcare resources and the patients quality of life. Aspirin’s therapeutic potential not only resides in its clinical benefits however also in protecting from major ICU admissions. The ICU, although a lifesaving escalation of care, is also not without complications. Several single and multi-center analysis evaluated the factors that influence the development of post intensive care syndrome, PICS [42,43]. The incidence of septic shock, hypotension, use of vasoactive medications, age at time of admission and infections were identified to significantly increase the risk of PICS and subsequently decrease quality of life [42,43]. Our findings support that aspirin use in non-metastatic pancreatic cancer not only provides inhospital clinical benefit but is also shown to protect patients from severe clinical decompensations with significant likelihood of negatively impacting their quality of life. Aspirin use therefore also serves to minimize healthcare resource utilization, further decreasing total hospital length of stay and decreased overall total hospital charges with translation to decreased financial burden on the healthcare system.

Our observations provide compelling support for the multifaceted benefits of aspirin use in patients with pancreatic cancer however several limitations must also be considered when evaluating this data. We conducted a retrospective analysis of the NIS where the study population is selected for inclusion by the user and is therefore subject to selection bias. To mitigate this effect standardized selection protocols using the ICD 10 coding system was implemented to identify patients with long term aspirin use and non-metastatic pancreatic cancer. The accuracy of which is reliant on correct and consistent entry of appropriate ICD 10 codes during patient encounters. This is subject to varying degrees of fluctuation in different hospital systems with varying policies. Although vast in nature, the NIS database does not capture information on indications for medications, the total duration of therapy or dosage. Unique, ICD 10 codes were used to identify patients with non-metastatic pancreatic cancer, long-term use of aspirin and the inhospital outcomes in our study. This was performed to maximize the accuracy of data collection, to minimize user error when designing codes and to ensure reproducibility of our study. Our study has successfully investigated the effects of aspirin exposure in patients with non-metastatic pancreatic cancer while also integrating the impact of patient demographic factors and age into the analysis. The findings in our study are supported by high statistical power. Our study utilizes data obtained and maintained by the HCUP over an interval of six years therefore conferring a large enough sample size that counterbalances several of these limitations and supports larger power of our study findings in comparison to several current single center or smaller based multicenter studies.

5. Conclusions

Fundamentally our study demonstrates that patients with non metastatic pancreatic cancer and aspirin use demonstrate a significant reduction of in hospital mortality and known decompensations and comorbidities that drive increased mortality and healthcare resource utilization. Given the retrospective nature of NIS analysis, future prospective longitudinal studies must be performed to further investigate and corroborate the findings in our study. Considering the ubiquitous availability and relatively minimal cost of aspirin these findings both reveal and support the multifaceted benefits for its use in these patients and future research needs to be performed to analyze the role of aspirin in both primary prevention of malignancies and as an adjunctive treatment agent.