Aspirin Nonsteroidal Anti-inflammatory Drugs Research Articles

Chemoprevention of Colorectal Cancer

Although colorectal cancer (CRC) screening has reduced the incidence of and mortality from CRC, chemoprevention strategies have the potential to further reduce CRC incidence and mortality. Chemoprevention agents might be used for average-risk as well as high-risk groups, and to prevent CRC recurrence after therapy. CRC chemoprevention agents that have been studied include aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, statins, agents that target metabolic pathways, and vitamins and minerals. We review the prospect of chemoprevention of CRC, results from preclinical and human studies, challenges, and future directions.

Non-steroidal anti-inflammatory drugs use in older adults decreases risk of Alzheimer's disease mortality.

Alzheimer disease (AD) mortality risk in a large cohort of subjects treated or not with non-steroidal anti-inflammatory drugs (NSAIDs) is unknown. Our objective was to determine whether NSAIDs use is associated with decreased risk of AD mortality. In this prospective, population-based study (Neurological Disorders in Central Spain [NEDICES]) of 5,072 people without AD (aged 65 years and older), sociodemographic, comorbidity factors, and current medications were recorded at baseline. Community-dwelling older adults were followed for a median of 12.7 years, after which the death certificates of deceased participants were examined. 2,672 (52.7%) of 5,072 participants died, including 504 (18.9%) NSAIDs users and 2,168 (81.1%) non-users. Of the 2,672 deceased participants, 113 (4.2%) had AD as a cause of death (8 [1.6%] among NSAIDs users and 105 [4.8%] among non-users, chi-square = 10.70, p = 0.001). In an unadjusted Cox model, risk of AD mortality was decreased in NSAIDs users (hazard ratio [HR] for AD mortality = 0.35, 95% confidence interval [CI] 0.17–0.72, p = 0.004) when compared to non-users. After adjusting for numerous demographic factors and co-morbidities, the HR for AD mortality in NSAIDs users was 0.29, 95% CI 0.12–0.73, p = 0.009. Stratified analyses showed a significantly decreased risk of AD mortality with aspirin, whereas non-aspirin NSAIDs only showed a statistical trend toward significance in the adjusted Cox regression models. NSAIDs use was associated with 71% decreased risk of AD mortality in older adults. Our results support the hypothesis that NSAIDs use is a protective factor of developing AD.

Long-term assessment of aspirin desensitization shows successful bridging with non-aspirin nonsteroidal anti-inflammatory drugs for procedures.

Background: Aspirin (ASA) desensitization and continuous daily ASA therapy is the criterion standard treatment for ASA-exacerbated respiratory disease (AERD). However, the optimal maintenance dosage of ASA and safety of "bridging" patients with AERD and with alternative cyclooxygenase-1 inhibitors for surgery have not been determined and require further investigation. Objective: This study was designed to compare the long-term effects of different maintenance doses of ASA and to assess the success of bridging subjects with AERD for surgery without losing desensitization. Methods: We retrospectively assessed 36 subjects with AERD who successfully underwent ASA desensitization from 2011 to 2017. We performed comprehensive medical record reviews and subsequent telephone interviews with a questionnaire. Results: Of 36 subjects, the average age was 52.8 years, with an average of 3.2 years since desensitization, and 65% were women. The subjects reported a decrease in frequency of nasal symptoms (p < 0.001), asthma symptoms (p = 0.016), and sinus infections (p < 0.001) after desensitization. Improvements were reported in sense of smell, taste, quality of sleep, and quality of life (p < 0.001) in all dosage groups. Thirteen subjects required stopping of ASA for surgeries. Six subjects (46%) were bridged with ibuprofen on an average of 5.9 days before surgery and restarted ASA on an average of 1.3 days after surgery, with no incidence of major adverse events or loss of desensitization. Seven subjects (54%) were not bridged, with three subjects restarting ASA after surgery without symptoms and four subjects losing desensitization. Conclusion: There did not seem to be a difference of benefits between 325 mg once or twice a day compared with 650 mg once or twice a day, but our small subject numbers made this conclusion difficult to prove. Desensitization improved subjective reporting on sleep quality as well as quality of life. Bridging the subjects with AERD who required surgery by using ibuprofen seemed to be safe and effective in maintaining ASA desensitization.

Risks of Cardiovascular Disease and Beyond in Prescription of Nonsteroidal Anti-Inflammatory Drugs.

Nonsteroidal anti-inflammatory drugs (NSAIDs) include aspirin, naproxen, diclofenac, and ibuprofen, as well as selective cyclooxygenase 2 inhibitors such as celecoxib. Their use is common, as well as their side effects which cause 100 000 hospitalizations and 17 000 deaths annually. Recently, the US Food and Drug Administration strengthened its warning about the risks of cardiovascular disease (CVD) attributed to nonaspirin NSAIDs. When the sample size is large, randomization provides control of confounding not possible to achieve with any observational study. Further, observational studies and, especially, claims data have inherent confounding by indication larger than the small to moderate effects being sought. While trials are necessary, they must be of sufficient size and duration and achieve high compliance and follow-up. Until then, clinicians should remain uncertain about benefits and risks of these drugs. Conclusions: Since the totality of evidence remains incomplete, health-care providers should consider all these aforementioned benefits and risks, both CVD and beyond, in deciding whether and, if so, which, NSAID to prescribe. The factors in the decision of whether and, if so, which NSAID to prescribe for relief of pain from inflammatory arthritis should not be limited to risks of CVD or gastrointestinal side effects but should also include potential benefits including improvements in overall quality of life resulting from decreases in pain or impairment from musculoskeletal pain syndromes. The judicious individual clinical decision-making about the prescription of NSAIDs to relieve pain based on all these considerations has the potential to do much more good than harm.

Population-based case-control study: chemoprotection of colorectal cancer with non-aspirin nonsteroidal anti-inflammatory drugs and other drugs for pain control.

Inflammation and overexpression of cyclooxygenase-2 (COX-2) have been described to play a key role in the progression from nonpathologic intestinal mucosa to colorectal cancer (CRC). To assess the chemoprotective effect of non-aspirin nonsteroidal anti-inflammatory drugs (NA-NSAIDs) under different patterns of use in a Mediterranean population and to explore the potential effect of symptomatic slow-acting drugs for osteoarthritis (SYSADOAs; chondroitin sulfate and glucosamine) and metamizole (or dipyrone), also reported to influence COX-2 activity. We performed a case-control study nested in a cohort extracted from the primary care database, BIFAP. From 2001 to 2014, we included 15491 incident cases and 60000 random controls. To estimate the association between the drugs of interest and CRC, we built logistic regression models to compute the adjusted-odds ratios (AOR) and 95% confidence intervals (CI). NA-NSAIDs use was associated with a reduced risk of CRC (AOR=0.67; 95% CI: 0.63-0.71) and increased linearly with duration of treatment (p for trend <0.001). The effect diminished upon discontinuation but persisted statistically significant up to 1year. All individual NA-NSAIDs examined showed a decreased risk. The concomitant use of proton-pump inhibitors (PPI) had no impact on the protective effect of NA-NSAIDs; AORPPI+NSAID =0.64; 0.58-0.71. SYSADOA use was associated with a reduced risk (0.79; 0.69-0.90) but disappeared after the exclusion of NSAID users during the previous 1 or 3years (0.85; 0.70-1.04 and 1.00; 0.76-1.31 respectively). Metamizole did not show a chemoprotective effect. NA-NSAID use is associated with a duration-dependent risk reduction of CRC not shared by SYSADOAs or metamizole.

Use of nonaspirin nonsteroidal anti-inflammatory drugs and risk of head and neck cancer: A nationwide case-control study.

Head and neck cancer (HNC) is the sixth most frequent malignancy with high mortality and substantial morbidity and hence there is a need for identification of preventive factors. Preclinical and observational studies have reported antineoplastic effects of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs), but studies of nonaspirin NSAID use and risk of HNC are sparse and with inconsistent results. We therefore conducted a register-based case-control study nested in the entire Danish population. Cases (n = 12,389) comprised all Danish residents aged 30-84 years with a histologically verified primary HNC diagnosis during 2000-2015. Based on the literature, cases were categorized into four groups of anticipated association with human papillomavirus (HPV): strong, potential, no/weak and uncertain. Age- and sex-matched population controls (n = 185,835) were selected by risk-set-sampling. We obtained information on filled prescriptions of nonaspirin NSAIDs, other drug use, comorbid conditions and socioeconomic parameters from nationwide Danish registries. Ever-use (≥2 prescriptions) of nonaspirin NSAIDs was not associated with the overall risk of HNC after adjustment for potential confounders (odds ratio [OR]: 0.99, 95% confidence interval [CI]: 0.95-1.03). However, long-term consistent use (≥5 years) was associated with a 25% reduction in HNC risk (OR: 0.75, 95% CI: 0.62-0.90). Stratified analyses by anticipated HPV-association showed no material differences in estimates. In conclusion, ever-use of nonaspirin NSAIDs was not associated with the risk of HNC with no apparent influence on the estimates by the anticipated HPV-association. However, long-term consistent use may be associated with a reduced risk of HNC and merits further investigation.

Abstract 5049: Associations of aspirin, non-aspirin NSAIDs, statins, and metformin with risk of biliary tract cancer: A Swedish population-based cohort study

Abstract Objectives: Biliary tract cancers (BTCs) comprise the second most common type of hepatobiliary cancer. Given the increase in global BTC incidence, with associated morbidity and mortality, together with the limited therapeutic options, there is increasing interest in strategies for disease prevention. We performed a population-based cohort study to determine the association between low dose aspirin, non-aspirin NSAIDs, statins, metformin, other risk factors and the risk of biliary tract cancer (BTC), while assessing confounding by sex. Methods: We conducted a nationwide Swedish population-based cohort study using the Swedish Prescribed Drug Registry, which virtually completely enumerates use of prescribed medications nationwide since 2005. BTC diagnosis (intrahepatic cholangiocarcinoma [iCCA], extrahepatic cholangiocarcinoma [eCCA] or gallbladder cancer [GBC]) was ascertained from the Swedish Cancer Registry. Age-scaled Cox models, with exposure as time-varying covariates, were used to calculate hazard ratios (HRs), separately for men and women. Results: In the 5.7 million person cohort, the risk of iCCA was significantly lower in men using statins (HR 0.62,95%CI 0.39-1.00,p=0.05), with a non-significant reduction in women. Statin use was associated with a significantly decreased risk of eCCA in both women (HR 0.60,0.38-0.94,p=0.03) and men (HR 0.47,0.28-0.80,p=0.01). Low dose aspirin (HR 0.76,0.60-0.97,p=0.03) was associated with a lower risk of GBC only in women, while statins (HR 0.72,0.55-0.93,p=0.01) showed a significantly decreased risk of GBC in women and a non-significant reduction in men. For all BTC subtypes, combined use of low dose aspirin and statins did not confer additional risk reductions beyond those achieved by statins alone. Male and female users of non-aspirin NSAIDs appeared to be at increased risk of BTC and its subtypes. Metformin did not significantly affect risk of BTC. Conclusion: We performed the largest population-based cohort study evaluating risk and protective factors for BTC. Our results provide strong evidence in favor of the chemopreventive roles of low dose aspirin and statins in a subtype-and sex-specific manner. Individual risk factors contribute to development of BTC subtypes in different magnitudes. If randomized controlled clinical trials validate our findings and provide favorable evidence of the efficacy and safety of these drugs in the prevention of BTCs, our results could potentially be practice-changing, leading to improvements in the outcomes in this population. Citation Format: Lorena Marcano-Bonilla, Cathy D. Schleck, W. Scott Harmsen, Omid Sadr-Azodi, Mitesh J. Borad, Tushar Patel, Gloria M. Petersen, Terry M. Therneau, Lewis R. Roberts, Nele Brusselaers. Associations of aspirin, non-aspirin NSAIDs, statins, and metformin with risk of biliary tract cancer: A Swedish population-based cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 5049.

Abstract 503: Prostaglandin E2 produced by tumor cells or by the host tumor microenvironment is not completely abolished by aspirin or celecoxib and limits the ability of the host immune system to control tumor growth

Abstract Prostaglandins are lipid autacoids derived from arachidonic acid (AA). AA released from the cell membrane is metabolized by the sequential actions of prostaglandin G/H synthase or cyclooxygenase (COX) and respective synthases, such as mPGES-1, which forms the most abundant prostaglandin, PGE2. Prostaglandin biosynthesis is blocked by nonsteroidal anti-inflammatory drugs (NSAIDs), which inhibit the activity of either one or both cyclooxygenases. Besides their role in homeostasis, prostanoids can modulate immune responses and contribute to chronic inflammation associated with tumor initiation, vascularization, and growth. The prostanoid pathway is activated in many solid tumors, including breast cancer, and high levels of PGE2 have been associated with aggressive tumors and metastatic spread. The objective of this work was to define the pathways and cellular compartments that contribute to tumor PGE2 levels and their role in tumor growth and immune evasion. The anti-tumor impact of classical NSAIDs combined with immune checkpoint antibodies PD1 or CTLA4 (ICPAb) was also evaluated. 4T1 or CT26 murine tumors were grown in immune competent mice to confirm the presence of PGE2 in tumors. Mice were dosed with NSAIDs Aspirin or Celecoxib monotherapy, given at maximal tolerated dose, or combined with ICPAb. While ICPAb reduced tumor growth, nor Aspirin neither celecoxib was effective in monotherapy or combination with ICPAb. Interestingly, PGE2 concentration in tumors was reduced by NSAIDs but not abolished. To examine the production of PGE2 by tumors or host, we have used CRISPR/cas9 mutagenesis to generate tumor lines lacking various enzymes required for PGE2 production. Those lines were combined with mice carrying null mPGES1 alleles. We show that, while the host tumor microenvironment contributes to overall PGE2 levels in the tumor, large amounts of PGE2 are produced by the tumor epithelial cells. Despite high expression of Ptgs1 in these tumor lines, PGE2 production was dependent on COX-2 expression. Similarly, while 4T1 tumors express all three PGE2 synthases at relatively high levels, we found that mPGES1 was solely responsible for all PGE2 released from epithelial cells. Examining several independent Ptgs1/2 null 4T1 tumor lines, we show that loss of Ptgs1/2 results in decreased tumor growth in immune competent mice but not in an allogenic Rag1/2-/- line. Knowledge of tumor PGE2 metabolic and functional pathways is a critical first step in designing the most appropriate therapeutic interventions. Classical NSAIDs given as monotherapy or combined in mice with ICPAb are ineffective against tumors, possibly because they do not abolish PGE2 production, suggesting that better drugs against PGE2 pathway would be required to counter the immune suppression induced by PGE2. Citation Format: John N. Snouwaert, Leigh Jania, MyTrang Nguyen, Pragnya Dontu, Jérôme Besse, Barbara Akla, Pierre J. Ferré, Beverly H. Koller. Prostaglandin E2 produced by tumor cells or by the host tumor microenvironment is not completely abolished by aspirin or celecoxib and limits the ability of the host immune system to control tumor growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 503.

Benefits and Risks of Nonsteroidal Anti-inflammatory Drugs: Methodologic Limitations Lead to Clinical Uncertainties.

Nonsteroidal anti-inflammatory drugs (NSAIDs) include traditional (tNSAIDs), such as ibuprofen, naproxen, and diclofenac, as well as selective cyclooxygenase-2 inhibitors (COXIBs), principally celecoxib. COXIBs were developed to decrease gastrointestinal side effects. Recently, the US Food and Drug Administration strengthened its warning about the risks of non-aspirin NSAIDs on myocardial infarction and stroke. The Cyclooxygenase 2 and Non-Steroidal Anti-Inflammatory Drug Trialist collaboration conducted a comprehensive worldwide meta-analysis using individual patient data exploring the risks of various COXIBs and NSAIDs on cardiovascular disease (CVD). Recently, the results of the Prospective Randomized Evaluation of Celecoxib Integrated Safety versus Ibuprofen or Naproxen (PRECISION) trial were published that tested risks of COXIBs and NSAIDs on CVD. Generally, data from meta-analyses of trials not designed a priori to test hypotheses are less reliable than large-scale randomized trials to test small to moderate benefits or harm. When the sample size is large, randomization provides control of confounding not possible to achieve in any observational study. Further, observational studies, and especially claims data, have inherent confounding by indication larger than the effects being sought. Nonetheless, trials must be of sufficient size and duration and achieve high compliance and follow-up to avoid bias and confounding. In this regard, PRECISION has high rates of nonadherence and losses to follow-up that may have introduced bias and confounding. At present, therefore, it may be most prudent for clinicians to remain uncertain about benefits and risks of these drugs and make individual clinical judgments for each of their patients.

P1‐376: LONG‐TERM NSAID THERAPY IN OLDER ADULTS: EFFECTS ON AT(N)V IMAGING BIOMARKERS

Observational studies and animal model experiments have suggested that the regular use of nonsteroidal anti-inflammatory drugs (NSAIDs) may be protective against Alzheimer's disease (AD). However, randomized controlled trials have not supported this hypothesis. We sought to assess whether long-term use of NSAIDs would be associated with differences in neuroimaging biomarkers of aging and dementia. We analyzed data for adults over 65 years old from the population-based Mayo Clinic Study of Aging. Individuals were classified as NSAID-untreated (n=439) if they reported no regular use of NSAIDs (defined as fewer than 3 days per week) prior to neuroimaging. Individuals who reported taking NSAIDs for 3+ days per week or 5+ years were defined as long-term NSAID-treated (n=519). For these groups, we analyzed the following neuroimaging outcomes based on the A (amyloid)/T (tau)/N (neurodegeneration)/V (cerebrovascular) framework: global amyloid (11C-PiB-PET), global and entorhinal cortex tau (18F-AV-1451-PET), AD-pattern hypometabolism (18F-FDG-PET) and cortical thickness (MRI), and white matter hyperintensities (FLAIR MRI) and fractional anisotropy of the corpus callosum (diffusion tensor imaging MRI). Age and sex were included as covariates in all analyses. Statistical significance was defined as p<0.05. The NSAID-treated group was older (mean age 78.5 vs. 76.1, p<0.001) and more frequently male (61% vs. 46%, p<0.001) than the untreated group. NSAID-treated individuals had a higher burden of late-life cardiovascular and metabolic conditions (p<0.001) but did not differ in APOE ɛ4 allele status, education, or clinical diagnosis (cognitively unimpaired, mild cognitive impairment, dementia) compared to the NSAID-untreated group. Long-term NSAID therapy was not significantly associated with any neuroimaging biomarker analyzed. In this study, we identified no association between long-term NSAID therapy and alterations in AT(N)V neuroimaging biomarkers. Additional work is needed to determine whether aspirin may be associated with differential effects compared to non-aspirin NSAIDs and to assess whether NSAID therapy alters longitudinal biomarker trajectories, particularly in individuals with high burden of cerebrovascular risk factors. As candidates for multi-domain treatment regimens for causes of dementia become available, evaluation of these approaches using AT(N)V biomarkers in the population will allow for rapid and dynamic assessment of potential efficacy and putative mechanism of action.

The Cost to Society of Pharmaceutical Mass Tort Litigation

This lecture for the Foundation for Law, Justice and Society, at Wolfson College, University of Oxford, addresses the cost to society of pharmaceutical mass tort litigation, nearly 15 years after the withdrawal by Merck & Co., Inc. of Vioxx® (rofecoxib) from markets worldwide. When Merck withdrew Vioxx based on an increased relative risk of thrombotic cardiovascular events seen in the APPROVe study in “the interests of patients” and “as the responsible course to take,” the company’s stock dropped nearly 27%; it took a charge of more than USD 726 million to effect the withdrawal; physicians prescribed alternative pain relievers in the non-steroidal anti-inflammatory drug (NSAID) class such as celecoxib, diclofenac, ibuprofen, and naproxen that did not have rofecoxib’s gastrointestinal safety data; governments investigated the company; and lawyers launched more than 50,000 claims and class actions in the US and many jurisdictions across six continents. Although Merck won most of the cases heard in the United States and prevailed in jurisdictions around the world, the company spent more than USD 2 billion on its own legal defense and nearly USD 7 billion more for the resolution of Vioxx litigation and investigations through the end of 2016. When the interim results of APPROVe were received, “no other non-aspirin NSAIDs or selective COX-2 inhibitors had been studied in this large a patient group for this duration,” and no one knew whether a similar increased relative risk would be seen with other NSAIDs, such as diclofenac and ibuprofen. It now appears that all of the non-aspirin NSAIDs, with the possible exception of naproxen, have a similar cardiovascular safety profile to Vioxx. Merck spent approximately USD 10 billion in connection with withdrawing Vioxx and defending and resolving litigation and investigations. Those funds were not available to fund the discovery and development of up to four or more new breakthrough medications.

Development of transferrin-bearing vesicles encapsulating aspirin for cancer therapy

Originally developed for the treatment of inflammatory disorders, the non-steroidal anti-inflammatory drug aspirin was shown to have a preventive effect against cancer in the past decades. Most importantly, recent studies suggested that it might also provide a therapeutic benefit in the treatment of cancer in vitro. However, this drug failed to specifically reach tumors at a therapeutic concentration following intravenous administration, thus resulting in lack of efficacy on tumors. In this work, we demonstrated that aspirin could be formulated in transferrin-bearing vesicles and that this tumor-targeted formulation could lead to an increase in the anti-proliferative efficacy of the drug in three cancer cell lines in vitro. The in vitro therapeutic efficacy of aspirin was significantly improved when formulated in transferrin-bearing vesicles, by about 2-fold compared to that of drug solution. These results are promising and support the optimization of this delivery system to further improve its potential as a therapeutic tool in combination with other anti-cancer therapies.

Daily Aspirin Use Associated With Reduced Risk For Fibrosis Progression In Patients With Nonalcoholic Fatty Liver Disease

There are few data from prospective studies on the effects of aspirin on fibrosis in patients with nonalcoholic fatty liver disease (NAFLD). We performed a prospective cohort study of 361 adults with biopsy-confirmed NAFLD, from 2006 through 2015, examined every 3-12 months for incident advanced fibrosis defined using serial measurements of validated indices (the Fibrosis-4, NAFLD fibrosis score, and aspartate aminotransferase to platelet ratio indices). Histologic analyses of liver biopsies collected at baseline were performed by a blinded pathologist. Information collected at baseline and at each examination included frequency and duration of aspirin and nonsteroidal anti-inflammatory drug (NSAID) use. Using multivariable-adjusted logistic regression, we estimated the association of aspirin use with prevalent steatohepatitis (NASH) and fibrosis. Using multivariable-adjusted Cox proportional hazards modeling, we estimated the association between aspirin use and risk for fibrosis progression. At enrollment, 151 subjects used aspirin daily. Compared with non-regular use, daily aspirin use was associated with significantly lower odds of NASH (adjusted odds ratio, 0.68; 95% CI, 0.37-0.89) and fibrosis (adjusted odds ratio, 0.54; 95% CI, 0.31-0.82). Among individuals with baseline F0-F2 fibrosis (n = 317), 86 developed advanced fibrosis over 3692 person-years. Daily aspirin users had significantly lower risk for developing incident advanced fibrosis vs non-regular users (adjusted hazard ratio [aHR], 0.63; 95% CI, 0.43-0.85). This relationship appeared to be duration dependent (adjusted P trend=.026), with the greatest benefit found with at least 4 years or more of aspirin use (aHR, 0.50; 95% CI, 0.35-0.73). Conversely, use of nonaspirin NSAIDs was not associated with risk for advanced fibrosis (aHR, 0.93; 95% CI, 0.81-1.05). In a prospective study of patients with biopsy-proven NAFLD, daily aspirin use was associated with less severe histologic features of NAFLD and NASH, and lower risk for progression to advanced fibrosis with time.

779 – Use of Non-Aspirin Non-Steroidal Anti-Inflammatory Drugs and Risk of Post-Colonoscopy Colorectal Cancer: A Territory-Wide Study with Propensity Score Analysis

779 – Use of Non-Aspirin Non-Steroidal Anti-Inflammatory Drugs and Risk of Post-Colonoscopy Colorectal Cancer: A Territory-Wide Study with Propensity Score Analysis

SAT-LB005 Association of Serum Estrogens and Estrogen Metabolites with Use of Non-Steroidal Anti-Inflammatory Drugs in Postmenopausal Women

Background: In several recent studies of postmenopausal women, the use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with lower circulating estrogens. These analgesics have also been studied in association with breast cancer risks with inconsistent findings. Cross-talk between immune and endocrine factors may play important roles in the development of breast cancer. Methods: We conducted a study of postmenopausal women drawn from the Prostate, Lung, Colon and Ovarian Cancer Screening Trial cohort (PLCO). At study baseline, participants reported their frequency of use for aspirin, non-aspirin NSAIDs via questionnaire. High-performance liquid chromatography-tandem mass spectrometry was used to measure estrogens and estrogen metabolites (EM) in baseline serum samples from 354 women who went on to get breast cancer during study follow-up, and 423 women who remained healthy. All selected participants reported no use of menopausal hormones at study baseline. General linear models were used to estimate multivariable-adjusted mean EM by self-reported use of analgesics (daily, weekly, or less than weekly) in all participants, while adjusting for continuous age, baseline BMI and breast cancer outcome. Results: In comparison to women who reported that they did not use any NSAIDs on a daily basis, those reporting daily use of aspirin only, daily use of non-aspirin NSAIDs only and daily use of both aspirin and non-aspirin NSAIDs had lower multivariable adjusted serum concentrations of unconjugated estradiol (Pdiff<0.02). Greater frequency of non-aspirin NSAID use was associated with trends towards lower concentrations of total EM (Ptrend=.004), estrone (Ptrend=.004), and unconjugated estradiol (Ptrend=.04), and higher ratios of 2- and 4- hydroxylated EM to the parent estrogens (Ptrend=.02 and .04). Associations were similar in women who did and did not go on to have breast cancer. Discussion: In this sample of postmenopausal women, more frequent use of NSAIDs was associated with lower circulating estrogens and with patterns of estrogen metabolism that may be more favorable with respect to breast cancer risk. These results require independent confirmation in additional well-designed studies. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. s presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.

New drug candidates for bipolar disorder-A nation-wide population-based study.

Drug repurposing is an increasingly promising idea in many fields of medicine. We systematically used Danish nation-wide population-based registers to investigate whether continued use of non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, high-dose aspirin, statins, allopurinol, and angiotensin agents decrease the rate of incident mania/bipolar disorder. A nation-wide population-based longitudinal study using Poisson regression analyses including all persons in Denmark who purchased the exposure medication of interest and a random sample of 30% of the Danish population. The follow-up period comprised a 10years period from 2005 to 2015. Two different outcome measures were included, (1) a diagnosis of mania/bipolar disorder at a psychiatric hospital contact as inpatient or outpatient and (2) a combined measure of a diagnosis of mania/bipolar disorder or initiation of lithium use. A total of 1,605,365 subjects were exposed to one of the six drugs of interest during the exposure period from 2005 to 2015, median age 57years [quartiles: 43;69], and female proportion of 53.1%. Continued use of low-dose aspirin, statins, and angiotensin agents were associated with decreased rates of incident mania/bipolar disorder on both outcome measures. Continued uses of non-aspirin NSAIDs as well as high-dose aspirin were associated with an increased rate of incident bipolar disorder. There were no statistically significant associations for allopurinol. The study supports the potential of agents acting on inflammation and the stress response system in bipolar disorder and illustrates that population-based registers can be used to systematically identify drugs with repurposing potentials.

Aspirin: Does it Have a Role for Chemoprevention of Hepatocellular Carcinoma?

Aspirin: Does it Have a Role for Chemoprevention of Hepatocellular Carcinoma?

Aspirin and Non-Aspirin NSAID Use and Prostate Cancer Incidence, Mortality, and Case Fatality in the Atherosclerosis Risk in Communities Study.

NSAIDs appear to moderately reduce prostate cancer risk. However, evidence is limited on whether NSAIDs protect against prostate cancer mortality (death from prostate cancer among men without a cancer history) and case fatality (death from prostate cancer among men with prostate cancer), and whether benefits are consistent in white and black men. This study investigated associations of aspirin and non-aspirin (NA) NSAID use with prostate cancer incidence, mortality, and case fatality in a population-based cohort of white and black men. We included 6,594 men (5,060 white and 1,534 black) from the Atherosclerosis Risk in Communities study without a cancer history at enrollment from 1987 to 1989. NSAID use was assessed at four study visits (1987-1998). Cancer outcomes were ascertained through 2012. Cox proportional hazards regression was used to estimate adjusted HRs, overall and by race. Aspirin use was not associated with prostate cancer incidence. However, aspirin use was inversely associated with prostate cancer mortality [HR, 0.59; 95% confidence interval (CI), 0.36-0.96]. This association was consistent among white and black men and appeared restricted to men using aspirin daily and/or for cardiovascular disease prevention. Aspirin use was inversely associated with case fatality (HR, 0.45; 95% CI, 0.22-0.94). NA-NSAID use was not associated with these endpoints. Aspirin use was inversely associated with prostate cancer mortality and case fatality among white and black men. If confirmed by additional studies, benefits of aspirin for preventing prostate cancer mortality may need to be factored into risk-benefit calculations of men considering an aspirin regimen.

3437 Associations of aspirin, non-aspirin NSAIDs, statins, and metformin with risk of biliary cancer: A Swedish population-based cohort study

OBJECTIVES/SPECIFIC AIMS: In an effort to elucidate the role of potentially cancer chemopreventive drugs, we leveraged the Mayo Clinic-Karolinska Institute collaboration to create a multidisciplinary team that included an epidemiologist, statisticians, and physicians. We performed a population-based cohort study to examine the association between low dose aspirin, non-aspirin NSAIDs, statins, metformin, other risk factors and the risk of biliary tract cancer (BTC), while assessing confounding by sex. METHODS/STUDY POPULATION: We conducted a nationwide Swedish population-based cohort study using the Swedish Prescribed Drug Registry, which virtually completely enumerates use of prescribed medications nationwide since 2005. BTC diagnosis (intrahepatic cholangiocarcinoma [iCCA], extrahepatic cholangiocarcinoma [eCCA] or gallbladder cancer [GBC]) was ascertained from the Swedish Cancer Registry. Age-scaled Cox models, with exposure as time-varying covariates, were used to calculate hazard ratios (HRs), separately for men and women. RESULTS/ANTICIPATED RESULTS: In the 5.7 million person cohort, the risk of iCCA was significantly lower in men using statins (HR 0.62,95%CI 0.39-1.00, p = 0.05), with a non-significant reduction in women. Statin use was associated with a significantly decreased risk of eCCA in both women (HR 0.60,0.38-0.94, p = 0.03) and men (HR 0.47,0.28-0.80, p = 0.01). Low dose aspirin (HR 0.76,0.60-0.97, p = 0.03) was associated with a lower risk of GBC only in women, while statins (HR 0.72,0.55-0.93, p = 0.01) showed a significantly decreased risk of GBC in women and a non-significant reduction in men. For all BTC subtypes, combined use of low dose aspirin and statins did not confer additional risk reductions beyond those achieved by statins alone. Male and female users of non-aspirin NSAIDs appeared to be at increased risk of BTC and its subtypes. Metformin did not significantly affect risk of BTC. DISCUSSION/SIGNIFICANCE OF IMPACT: Our collaborative efforts allowed us to develop the largest population-based cohort evaluating risk and protective factors for BTC. Our results provide strong evidence in favor of the chemopreventive roles of low dose aspirin and statins in a subtype- and sex-specific manner. Individual risk factors contribute to development of BTC subtypes in different magnitudes. The next steps to translate these findings into clinical practice require randomized clinical trials that validate our results and provide a more complete picture of the risk-benefit ratio.

Nonaspirin Nonsteroidal Antiinflammatory Drug Use in the Nordic Countries from a Cardiovascular Risk Perspective, 2000-2016: A Drug Utilization Study.

Evidence on the cardiotoxicity of nonaspirin nonsteroidal antiinflammatory drugs (NSAIDs), particularly diclofenac and the newer selective cyclooxygenase (COX)-2 inhibitors, has accumulated over the last decade. Our objective was to examine whether the use of NSAIDs in the Nordic countries changed with the emerging evidence, regulatory statements, and clinical guidelines advocating caution for the use of specific NSAIDs. Drug utilization study. Nationwide wholesale statistics and prescription registries in Denmark, Finland, Iceland, Norway, and Sweden (2000-2016). Our main outcome measures were yearly total sales, expressed as number of sold defined daily doses (DDDs)/1000 inhabitants/day, and yearly prevalence of prescription use, expressed as number of prescription users per 1000 inhabitants. The DDD is the assumed average maintenance dose per day for a drug used for its main indication in adults. Total sales of NSAIDs increased in all countries and were highest in Iceland, with 74.3 DDDs/1000 inhabitants/day sold in 2016, followed by Finland (73.9), Sweden (54.4), Norway (43.8), and Denmark (31.8). Diclofenac use declined after 2008 in all countries but remained the most widely prescribed NSAID in Norway, with 63 prescription users/1000 inhabitants in 2016. Diclofenac sales also remained high in Iceland (12.7 DDD/1000 inhabitants/day), Norway (8.1), and Sweden (7.8). Since its introduction in 2003, the use of etoricoxib, a newer selective COX-2 inhibitor, increased in all countries except Denmark, with highest sales in Finland (6.7 DDD/1000 inhabitants/day in 2016). Sales and prescription patterns of NSAIDs in the Nordic countries has changed along with the accumulating evidence for the cardiovascular risks of specific NSAIDs. However, given existing evidence on the cardiovascular risks associated with the use of diclofenac and etoricoxib, the persistent high use of diclofenac in Iceland, Norway, and Sweden, the persistent over-the-counter availability of diclofenac in Norway and Sweden, and the increasing use of etoricoxib in most of the Nordic countries pose a cardiovascular health concern.