Association Of Nonsteroidal Anti-inflammatory Drugs Research Articles

Abstract 3446: Associations of non-steroidal anti-inflammatory drug use and circulating inflammatory proteins with gallbladder dysplasia

Abstract Background: Most gallbladder cancer (GBC) cases arise from the metaplasia-dysplasia-GBC sequence, and chronic inflammation has been associated with its development. The use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced risk of GBC; however, little is known about these associations with preneoplastic lesions. We thus aimed to study the associations of the use of NSAIDs and inflammatory proteins with gallbladder dysplasia, a precursor to GBC. Methods: Associations of NSAIDs and gallbladder dysplasia were evaluated in 1,925 Chilean cholecystectomy patients, 82 with dysplasia and 1,843 with gallstones but not dysplasia. In addition, we measured 33 circulating inflammatory proteins in a subsample of 68 dysplasia cases diagnosed at the time of sample selection and 136 gallstone controls. Age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated, and associations of inflammatory proteins and gallbladder dysplasia were analyzed. Results: NSAID use was inversely associated with gallbladder dysplasia (OR: 0.48, 95% CI: 0.26-0.83). Comparing the highest versus lowest category of each immune-related protein, eight proteins were inversely associated with dysplasia with ORs ranging from 0.30 (95%CI: 0.12-0.77) for IL-33 to 0.76 (95%CI: 0.59-0.99) for MIP-1B. Of those, GRO remained associated with dysplasia (OR: 0.64, 95%CI: 0.45-0.91) and BCA-1 was borderline-associated (OR: 0.74, 95%CI: 0.54-1.01) in the multivariable logistic regression model additionally adjusted for sex, age and NSAID use. Conclusion: NSAID users were less likely to have gallbladder dysplasia, suggesting that NSAIDs might be beneficial for gallstones patients. Prospective studies are needed to understand the inverse association of immune-related markers and dysplasia, and to evaluate the biological effect of NSAIDs in GBC. Research supported by general funds from the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, and the Office of Research on Women’s Health, National Institutes of Health. Citation Format: Lorena Rosa, Paz Cook, Ruth M. Pfeiffer, Troy J. Kemp, Allan Hildesheim, Burcin Pehlivanoglu, Volkan Adsay, Enrique Bellolio, Juan Carlos Araya, Ligia Pinto, Catterina Ferreccio, Gloria Aguayo, Eduardo Viñuela, Jill Koshiol. Associations of non-steroidal anti-inflammatory drug use and circulating inflammatory proteins with gallbladder dysplasia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3446.

Association of Non-Steroidal Anti-Inflammatory Drugs, Genetic Risk, and Environmental Risk Factors with Incidence of Colorectal Cancer.

Simple SummaryIt remains unknown whether regular use of non-steroidal anti-inflammatory drugs (NSAIDs) could attenuate the impact of genetic risk and environmental risk factors on colorectal cancer (CRC). In the current study, we evaluated the association of NSAID use, genetic risk, and environmental risk factors with CRC incidence using data from a UK Biobank cohort. We found that regular use of NSAIDs was associated with a lower risk of CRC. Although there were no statistical interactions observed between NSAID use, environmental risk and genetic risk, regular NSAID use was still associated with lower CRC incidence among subjects with either high environmental risk or high genetic risk. Furthermore, low environmental risk was associated with lower CRC incidence among subjects with high genetic risk. These findings emphasized the importance of the chemopreventive effect of regular use of NSAIDs and controlling modifiable environmental risk factors to reduce CRC incidence, even among individuals with a moderate or high genetic risk of CRC.Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) was associated with the lower risk of colorectal cancer (CRC). However, whether regular use of NSAIDs could attenuate the effect of genetic risk and environmental risk factors on CRC is unknown. We aimed to evaluate the association of NSAID use, genetic risk, and environmental risk factors with CRC. Using data from a UK Biobank, a Cox proportional hazards model was performed to estimate the risk of CRC according to NSAID use, polygenic risk score, and environmental risk factors. Regular use of NSAIDs was associated with a 36.0% lower risk of CRC. No statistically significant interaction was observed between NSAID use and the genetic risk score (p = 0.190), and between NSAID use and the environmental risk score (p = 0.740). However, regular NSAID use was still associated with lower CRC incidence among subjects with either high environmental risk or high genetic risk. Furthermore, the genetic and environmental risk of CRC were additives. These findings appear to support the chemopreventive effect of regular NSAID use. Furthermore, controlling of modifiable environmental risk factors can reduce the CRC risk, especially among individuals with a moderate or high genetic risk of CRC.

Risk of serious adverse events associated with non-steroidal anti-inflammatory drugs in orthopaedic surgery. A protocol for a systematic review.

Postoperative pain is a common condition following orthopaedic surgeries and causes prolonged hospitalisation, delayed rehabilitation and hamper the quality of life. Non-steroidal anti-inflammatory drugs (NSAIDs) are effective analgesics and anti-inflammatory mediators in the treatment of postoperative pain. The association of NSAIDs with serious adverse events may however keep some clinicians and clinical decision makers from using NSAIDs perioperatively. The evidence regarding the risks of serious adverse events following perioperative use of NSAIDs in orthopaedic surgery is sparse and needs to be assessed in a systematic review. This is a protocol for a systematic review that aims to identify the risks of serious adverse events from perioperative use of NSAIDs in orthopaedic patients. Our methodology is based on the Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols and the eight-step assessment procedure suggested by Jakobsen and colleagues. We wish to assess if NSAIDs versus placebo, usual care or no intervention, will influence the risks of serious adverse events in patients undergoing orthopaedic surgery. We will include all randomised trials assessing the use of NSAIDs perioperatively. To identify trials we will search the Medical Literature Analysis and Retrieval System Online, Excerpta Medica database, Cochrane Central Register, Science Citation Index Expanded on Web of Science and BIOSIS. Two authors will screen the literature and extract data. We will use the 'Risk of Bias 2 tool' to assess trials. Extracted data will be analysed using RStudio and Trial Sequential Analysis. We will create a 'Summary of Findings' table in which we will present our primary and secondary outcomes. We will assess the quality of evidence using Grading of Recommendations Assessment, Development and Evaluation (GRADE). This systematic review can potentially aid clinicians and clinical decision makers in the use of NSAIDs for treatment of postoperative pain following orthopaedic surgeries.

Treatment with Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Does Not Affect Outcome in Patients with Acute Myocarditis or Myopericarditis.

Background: Previous animal studies reported an association of non-steroidal anti-inflammatory drugs (NSAIDs) with adverse outcomes in acute myocarditis, which is why these drugs are currently not recommended in affected patients. In this retrospective case-control study, we sought to investigate the effects of NSAID treatment in patients with acute myocarditis and myopericarditis to complement the available evidence. Method: A total of 114 patients with acute myocarditis were retrospectively enrolled. Demographical, clinical and laboratory data were extracted from hospital records. Patients who received NSAIDs (n = 39, 34.2%) were compared to controls. Follow-up on all-cause mortality was acquired for two years. Propensity score matching was additionally conducted to account for covariate imbalances between groups. Results: Treatment with NSAIDs was neither associated with a worse outcome (p = 0.115) nor with significant differences in left ventricular systolic function (p = 0.228) or in-hospital complications (p = 0.507). Conclusion: Treatment with NSAIDs was not associated with adverse outcomes in our study cohort. Together with the findings of previous studies, our results indicate that these drugs could be safely administered in patients with myocarditis and myopericarditis.

Correlation between perioperative parecoxib use and postoperative acute kidney injury in patients undergoing non-cardiac surgery: a retrospective cohort analysis

ObjectiveThe association of non-steroidal anti-inflammatory drugs with postoperative acute kidney injury (AKI) is controversial. However, there are few studies focusing on the association between parecoxib and postoperative AKI. Our study...

The Association of Non-Steroidal Anti-Inflammatory Drugs with COVID-19 Severity and Mortality

Background: No specific study has investigated the effect of non-steroidal anti inflammatory drugs (NSAIDs) and especially the effects of Ibuprofen on COVID-19, so far. Objectives: The purpose of this study was to investigate the effect of Ibuprofen on the severity of COVID-19 and mortality caused by the disease. Methods: This study was conducted on 158 patients with COVID-19 who had consumed Ibuprofen, Gelofen, and Novafen for at least one week in the last three months. Patients were divided into three groups (mild, moderate and sever). The relationship among the severity of the disease and the history of ibuprofen consumption, diabetes, history of cardiovascular problems, hypertension, and GFR was investigated. Also, the association between the history of ibuprofen consumption, GFR ≤ 60 mL/min, hypertension, LDH ≥ 500 U/L, lymphocyte count ≤ 1500, and mortality was examined. Results: Our findings showed a significant relationship between the history of Ibuprofen before COVID-19 and the severity of COVID-19, as well as the mortality rate (P value < 0.001, adjusted odd ratio: 2, respectively). This study also showed a significant relationship among the severity of the disease and the history of smoking, diabetes, hypertension, history of cardiovascular diseases, and GFR. In addition, a significant relationship was found among GFR ≤ 60 mL/min mortality, diabetes, LDH ≥ 500 U/L, and lymphocyte count ≤ 1500. Conclusions: Our study showed a significant relationship between the history of the consumption of ibuprofen and its compounds before COVID-19 and the severity of COVID-19, as well as the mortality rate of the patients with this disease, and accordingly, this result can suggest health policies during the epidemic of COVID-19.

Utilização da escala composta Glasgow short form para avaliação de dois diferentes protocolos de analgesia pós-cirúrgica em cadelas submetidas à mastectomia

The concern with the treatment of postoperative pain is based on the prevention of unnecessary suffering of the patient, in addition to providing many physiological benefits. Post-surgical pain can be minimized more easily when preemptive analgesia is applied, that is, the administration of analgesics before tissue damage occurs. However, the association of non-steroidal anti-inflammatory drugs with opioids in anti-pain protocols is seen as a way to reduce the doses of each medication and ensure a greater coverage of inflammatory mediators. The modified Glasgow Scale (Short Form of the Glasgow Composite Pain Scale -CMPS-SF), allows the assessment of six behavioral categories. In view of this, the present study aims to evaluate and compare, by applying the modified Glasgow Scale, the effectiveness of two different preemptive analgesia protocols using transdermal fentanyl patch associated with two non-steroidal anti-inflammatory drugs (firocoxib and carprofen) for the control of postoperative pain in dogs undergoing mastectomy surgery. Thus, 16 bitches participated in the research and were randomly divided into two groups with 8 females constituting the 1 group and receiving preemptive analgesia with firocoxib associated with transdermal fentanyl patch and another 8 females constituting the 2 group receiving analgesia preemptive with carprofen associated with transdermal fentanyl. Postoperatively, patients were evaluated using the Glasgow Modified Scale in 5 steps (T1, T2, T3, T15 and T24). The analgesic rescue was only performed when the assessment exceeded 6 points on the scale. Among the 16 patients who participated in the research, 11 of them (68.75%) demonstrated adequate pain control, therefore, there was no need for rescue, 4 patients (25%) needed analgesic rescue and 1 patient (6.25%) was disqualified from the search. It was concluded that there was no difference in analgesic control with both protocols. The Glasgow Modified Scale is a useful method for assessing the degree of pain in bitches undergoing mastectomy. Transdermal fentanyl has demonstrated good performance in pain control simultaneously associated with both anti-inflammatory drugs, however it is of utmost importance that the patch is correctly attached to the skin for proper release of the active ingredient.

Editors' note: INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease

In the article, “INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease”, Meyer et al. reported that low-dose naproxen did not significantly reduce the progression of a composite indicator of presymptomatic Alzheimer Disease (AD)—the Alzheimer Progression Score (APS)—in a 2-year double-blind randomized placebo-controlled trial that enrolled 195 cognitively intact elderly participants with a family history of AD. In response, Dr. Ashford posits that the observed epidemiologic association of nonsteroidal anti-inflammatory drugs (NSAIDs) with decreased risk of AD may be related to the effect of these drugs on gamma-secretase rather than on inflammation, citing previous work showing that flurbiprofen and ibuprofen lower amyloidogenic Abeta42 independently of cyclooxygenase activity. He postulates that several years of treatment may be required to observe a benefit and wonders whether ibuprofen may be a better drug to test than naproxen. He also highlights the need for better tools to more accurately assess treatment effects in early AD. Responding to these comments, Drs. Breitner et al. noted that a meta-analysis of 6 prospective studies showed no significant differences in apparent risk modification of AD between gamma secretase-modifying and non-gamma secretase-modifying NSAIDS and suggested no difference between exposure to naproxen vs ibuprofen. Although they acknowledge that INTREPAD lacked an initially estimated degree of power, they note that the APS captured significant progression of apparent AD signs over the course of the trial and allowed a reasonably precise estimate of a lack of treatment effect, with naproxen also having no benefit on any of the APS components. With the largely unimpressive results of antiamyloid treatment strategies to date in AD, interest in alternative therapeutic targets, including anti-inflammatory strategies, is likely to continue growing in the coming years. In the article, “INTREPAD: A randomized trial of naproxen to slow progress of presymptomatic Alzheimer disease”, Meyer et al. reported that low-dose naproxen did not significantly reduce the progression of a composite indicator of presymptomatic Alzheimer Disease (AD)—the Alzheimer Progression Score (APS)—in a 2-year double-blind randomized placebo-controlled trial that enrolled 195 cognitively intact elderly participants with a family history of AD. In response, Dr. Ashford posits that the observed epidemiologic association of nonsteroidal anti-inflammatory drugs (NSAIDs) with decreased risk of AD may be related to the effect of these drugs on gamma-secretase rather than on inflammation, citing previous work showing that flurbiprofen and ibuprofen lower amyloidogenic Abeta42 independently of cyclooxygenase activity. He postulates that several years of treatment may be required to observe a benefit and wonders whether ibuprofen may be a better drug to test than naproxen. He also highlights the need for better tools to more accurately assess treatment effects in early AD. Responding to these comments, Drs. Breitner et al. noted that a meta-analysis of 6 prospective studies showed no significant differences in apparent risk modification of AD between gamma secretase-modifying and non-gamma secretase-modifying NSAIDS and suggested no difference between exposure to naproxen vs ibuprofen. Although they acknowledge that INTREPAD lacked an initially estimated degree of power, they note that the APS captured significant progression of apparent AD signs over the course of the trial and allowed a reasonably precise estimate of a lack of treatment effect, with naproxen also having no benefit on any of the APS components. With the largely unimpressive results of antiamyloid treatment strategies to date in AD, interest in alternative therapeutic targets, including anti-inflammatory strategies, is likely to continue growing in the coming years.

The association between nonsteroidal anti-inflammatory drugs and skin cancer: Different responses in American and European populations

ObjectiveTo conduct a comprehensive systematic meta-analysis investigating the association of nonsteroidal anti-inflammatory drugs (NSAIDs) and their subtypes with skin cancer (SC) and its subclasses (basal cell carcinoma BCC; squamous cell carcinoma SCC; melanoma; nonmelanoma skin cancer NMSC) in general, American and European populations. MethodsPubMed, Embase, the Cochrane Library, the China National Knowledge Infrastructure and ClinicalTrials.gov were searched up to 24 February 2019. Pooled effect sizes and 95% confidence intervals were used to estimate associations. ResultsResults based on 26 original studies including 223,619 cases and 1,398,507 controls showed both NSAIDs and nonselective Cyclooxygenase (COX) inhibitors to be statistically significantly associated with a reduced risk of SC, BCC, SCC and NMSC but not with melanoma. Conversely, no association was observed between selective Cyclooxygenase 2 (COX-2) inhibitors and SC or its subclasses. Further subgroup analysis showed that the results analyzed for American populations were almost the same as those for the general population. For European populations, neither NSAIDs nor its subtypes correlated significantly with susceptibility to SC or its subclasses. ConclusionsThe use of NSAIDs might reduce the risk of SC, but many factors including study population, drug subtype, and disease subclass affect the significance of the association.

Nonsteroidal Anti-Inflammatory Therapy: A Journey Toward Safety.

The efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) against inflammation, pain, and fever has been supporting their worldwide use in the treatment of painful conditions and chronic inflammatory diseases until today. However, the long-term therapy with NSAIDs was soon associated with high incidences of adverse events in the gastrointestinal tract. Therefore, the search for novel drugs with improved safety has begun with COX-2 selective inhibitors (coxibs) being straightaway developed and commercialized. Nevertheless, the excitement has fast turned to disappointment when diverse coxibs were withdrawn from the market due to cardiovascular toxicity. Such events have once again triggered the emergence of different strategies to overcome NSAIDs toxicity. Here, an integrative review is provided to address the breakthroughs of two main approaches: (i) the association of NSAIDs with protective mediators and (ii) the design of novel compounds to target downstream and/or multiple enzymes of the arachidonic acid cascade. To date, just one phosphatidylcholine-associated NSAID has already been approved for commercialization. Nevertheless, the preclinical and clinical data obtained so far indicate that both strategies may improve the safety of nonsteroidal anti-inflammatory therapy.

Association of nonsteroidal anti-inflammatory drugs and aspirin use and the risk of head and neck cancers: a meta-analysis of observational studies.

PurposeNonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, have emerged as the potential chemopreventive agents for a number of cancer types, however, previous studies of head and neck cancers (HNC) have yielded inconclusive results. We performed a meta-analysis of observational studies to quantitatively assess the association between NSAIDs use and the risk for HNC.MethodsWe searched Pubmed, Embase, Google scholar, and Cochrane library for relevant studies that were published in any language, from January 1980 to April 2016. We pooled the odds ratio (OR) from individual studies and performed subgroup, heterogeneity, and publication bias analyses.ResultsA total of eleven studies (eight case-control studies and three cohort studies), involving 370,000 participants and 10,673 HNC cases contributed to this meta-analysis. The results of these studies suggested that neither use of overall NSAIDs (OR=0.95; 95% CI, 0.81-1.11), aspirin (OR=0.93; 95% CI, 0.79-1.10), nor nonsteroidal NSAIDs (OR=0.92; 95% CI, 0.76-1.10) were associated with HNC risk. Similar nonsteroidal results were observed when stratified by HNC sites, study design, sample size, and varied adjustment factors. However, we found significant protective effect of ibuprofen (OR=0.85; 95% CI, 0.72-0.99) and long-term aspirin use (≧5years) (OR=0.75; 95% CI, 0.65-0.85) on HNC risk, with low heterogeneity and publication bias.ConclusionsOur meta-analysis results do not support the hypothesis that overall use of NSAIDs significant reduces the risk of HNC. Whereas, we cannot rule out a modest reduction in HNC risk associated with ibuprofen and long-term aspirin use.

Associations of NSAID and paracetamol use with risk of primary liver cancer in the Clinical Practice Research Datalink

Liver cancer incidence has been rising rapidly in Western countries. Nonsteroidal anti-inflammatory drugs (NSAIDs) and paracetamol are widely-used analgesics that may modulate the risk of liver cancer, but population-based evidence is limited. We conducted a case-control study (1195 primary liver cancer cases and 4640 matched controls) within the United Kingdom’s Clinical Practice Research Datalink to examine the association between the use of prescription NSAIDs and paracetamol and development of liver cancer. Multivariable-adjusted odds ratios (aORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. Overall, ever-use of NSAIDs was not associated with risk of liver cancer (aOR=1.05, 95% CI=0.88–1.24), regardless of recency and intensity of use. Use of paracetamol was associated with a slightly increased risk of liver cancer (aOR=1.18, 95% CI=1.00–1.39), particularly among individuals with body mass index<25kg/m2 (aOR=1.56, 95% CI=1.17–2.09). Our results suggest that NSAID use was not associated with liver cancer risk in this population. Ever-use of paracetamol may be associated with slightly higher liver cancer risk, but results should be interpreted cautiously due to methodological limitations. Given that paracetamol is a widely-used analgesic, further examination of its relationship with liver cancer is warranted.

Isolation, identification and molecular docking as cyclooxygenase (COX) inhibitors of the main constituents of Matricaria chamomilla L. extract and its synergistic interaction with diclofenac on nociception and gastric damage in rats.

Chamomile (Matricaria chamomilla L., Asteraceae) is a medicinal plant widely used as remedy for pain and gastric disorders. The association of non-steroidal anti-inflammatory drugs (NSAIDs) with medicinal plant extracts may increase its antinociceptive activity, permit the use of lower doses and limit side effects. The aim was to isolate and identify the main chemical constituents of Matricaria chamomilla ethanolic extract (MCE) as well as to explore their activity as cyclooxygenase (COX) inhibitors in silico; besides, to examine the interaction between MCE and diclofenac on nociception in the formalin test by isobolographic analysis, and to determine the level of gastric injury in rats. Three terpenoids, α-bisabolol, bisabolol oxide A, and guaiazulene, were isolated and identified by (1)H NMR. Docking simulation predicted COX inhibitory activity for those terpenoids. Diclofenac, MCE, or their combinations produced an antinociceptive effect. The sole administration of diclofenac and the highest combined dose diclofenac-MCE produced significant a gastric damage, but that effect was not seen with MCE alone. An isobologram was constructed and the derived theoretical ED35 for the antinociceptive effect was significantly different from the experimental ED35; hence, the interaction between diclofenac and MCE that mediates the antinociceptive effect is synergist. The MCE contains three major terpenoids with plausible COX inhibitory activity in silico, but α-bisabolol showed the highest affinity. Data suggest that the diclofenac-MCE combination can interact at the systemic level in a synergic manner and may have therapeutic advantages for the clinical treatment of inflammatory pain.

Automated evaluation of protein binding affinity of anti-inflammatory choline based ionic liquids

In this work, an automated system for the study of the interaction of drugs with human serum albumin (HSA) was developed. The methodology was based on the quenching of the intrinsic fluorescence of HSA by binding of the drug to one of its binding sites. The fluorescence quenching assay was implemented in a sequential injection analysis (SIA) system and the optimized assay was applied to ionic liquids based on the association of non-steroidal anti-inflammatory drugs with choline (IL-API).In each cycle, 100µL of HSA and 100µL of IL-API (variable concentration) were aspirated at a flow rate of 1mLmin−1 and then sent through the reaction coil to the detector where the fluorescence intensity was measured.In the optimized conditions the effect of increasing concentrations of choline ketoprofenate and choline naproxenate (and respective starting materials: ketoprofen and naproxen) on the intrinsic fluorescence of HSA was studied and the dissociation constants (Kd) were calculated by means of models of drug–protein binding in the equilibrium. The calculated Kd showed that all the compounds bind strongly to HSA (Kd<100µmolL−1) and that the use of the drugs in the IL format does not affect or can even improve their HSA binding.The obtained results were compared with those provided by a conventional batch assay and the relative errors were lower than 4.5%. The developed SIA methodology showed to be robust and exhibited good repeatability in all the assay conditions (rsd<6.5%).

Abstract 862: Association of non-steroidal anti-inflammatory drugs with colorectal cancer by subgroups in the Vitamins and Lifestyle (VITAL) Study

Abstract Background: There is substantial evidence that use of non-steroidal anti-inflammatory drugs (NSAIDs) reduces the risk of colorectal cancer (CRC), but no subgroup has been identified for which the chemoprevention effect outweighs the risk of side effects. Methods: We tested the interaction between NSAID use and multiple risk factors on CRC risk in the VITAL cohort. A total of 73,458 individuals aged 50-76 completed a questionnaire between 2000 and 2002, and 674 incidental colorectal cancer cases were identified through 2010. Results: In stratified analysis, high use of any type of NSAIDs (4+days/week for 4+ years) was statistically significantly associated with a lower risk of CRC across all subgroups stratified by sex, BMI, physical activity, smoking, alcohol intake, screening and dietary factors, with a suggestion of stronger association among men, obese individuals, and heavier drinkers; however, none of these tests for interaction reached statistical significance. The associations were almost identical for subjects with higher overall CRC risk scores (HR: 0.62; 95% CI: 0.49-0.79) and those with lower risk scores (HR: 0.61; 95% CI: 0.42-0.88). Differential effects by cancer subsites and stages were tested. NSAID use was associated with a greater risk reduction of proximal colon cancer vs distal (p for difference = 0.06) and distant stage vs local (p for difference = 0.04). Conclusion: The association between high use of NSAIDs and CRC risk does not differ significantly among subgroups. Impact: Our results suggest that NSAIDs have a generally beneficial role in colorectal cancer prevention, largely unmodified by other exposures. Citation Format: Xiaoliang Wang, Ulrike Peters, John D. Potter, Emily White. Association of non-steroidal anti-inflammatory drugs with colorectal cancer by subgroups in the Vitamins and Lifestyle (VITAL) Study. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 862. doi:10.1158/1538-7445.AM2015-862

Association of Nonsteroidal Anti-Inflammatory Drugs with Colorectal Cancer by Subgroups in the VITamins and Lifestyle (VITAL) Study.

There is substantial evidence that use of NSAIDs reduces the risk of colorectal cancer, but no subgroup has been identified for which the chemoprevention effect outweighs the risk of side effects. We tested the interaction between NSAID use and multiple risk factors on colorectal cancer risk in the VITAL cohort. A total of 73,458 individuals ages 50 to 76 years completed a questionnaire between 2000 and 2002, and 674 incidental colorectal cancer cases were identified through 2010. In stratified analysis, high use of any type of NSAIDs (4+ days/week for 4+ years) was statistically significantly associated with a lower risk of colorectal cancer across all subgroups stratified by sex, body mass index, physical activity, smoking, alcohol intake, screening, and dietary factors. There was a suggestion of stronger associations among men, obese individuals, and heavier drinkers; however, none of these tests for interaction reached statistical significance. The associations were almost identical for subjects with higher overall colorectal cancer risk scores [HR, 0.62; 95% confidence interval (CI), 0.49-0.79] and those with lower risk scores (HR, 0.61; 95% CI, 0.42-0.88). Differential effects by cancer subsites and stages were tested. NSAID use was associated with a greater risk reduction of proximal colon cancer versus distal (P for difference = 0.06) and distant stage versus local (P for difference = 0.04). The association between high use of NSAIDs and colorectal cancer risk does not differ significantly among subgroups. Our results suggest that NSAIDs have a generally beneficial role in colorectal cancer prevention, largely unmodified by other exposures.

The Association between Cyclo-oxygenase Inhibitor Medications and Clinical Relapse in Inflammatory Bowel Disease: Review of Current Perspectives

Background: Patients with inflammatory bowel disease (IBD) often have associated conditions which may benefit from treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or selective cyclo-oxygenase-2 (COX-2) inhibitors. However, evidence has suggested there may be an association between COX- inhibition and relapse in IBD, which leads to clinicians being reluctant to prescribe these agents. Aims: The aim of this review is to review the possible biological mechanisms, linking NSAIDs and IBD-relapse and current knowledge on the possible association of NSAIDs and clinical relapse in IBD. Results: IBD relapse due to NSAID use is most likely due to prostaglandin inhibition via dual COX

Editorial comment.

Evidence from both observational (case-control or prospective cohort) studies and randomized clinical trials (primarily focused on vascular events) suggests that regular use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of a number of epithelial cancers, including prostate cancer. The magnitude of the prostate cancer risk reduction associated with aspirin is modest, with pooled estimates from meta-analyses suggesting reductions on the order of 10%-20% compared to nonusers. 1 Algra A.M. Rothwell P.M. Effects of regular aspirin on long-term cancer incidence and metastasis: a systematic comparison of evidence from observational studies versus randomized trials. Lancet Oncol. 2012; 13: 518-527 Abstract Full Text Full Text PDF PubMed Scopus (605) Google Scholar , 2 Bosetti C. Rosato V. Gallus S. et al. Aspirin and prostate cancer prevention. Recent Results Cancer Res. 2014; 202: 93-100 Crossref PubMed Scopus (11) Google Scholar , 3 Huang T.B. Yan Y. Guo Z.F. et al. Aspirin use and the risk of prostate cancer: a meta-analysis of 24 epidemiologic studies. Int Urol Nephrol. 2014; 46: 1715-1728 Crossref PubMed Scopus (40) Google Scholar A number of recent studies also suggest that aspirin or other NSAIDs are associated with a decrease in serum prostate-specific antigen (PSA) of approximately 10%. 4 Chang S.L. Harshman L.C. Presti Jr., J.C. Impact of common medications on serum total prostate-specific antigen levels: analysis of the National Health and Nutrition Examination Survey. J Clin Oncol. 2010; 28: 3951-3957 Crossref PubMed Scopus (97) Google Scholar , 5 Nieder C. Norum J. Geinitz H. Impact of common medications on serum total prostate-specific antigen levels and risk group assignment in patients with prostate cancer. Anticancer Res. 2011; 31: 1735-1740 PubMed Google Scholar , 6 Fowke J.H. Motley S.S. Smith Jr., J.A. et al. Association of nonsteroidal anti-inflammatory drugs, prostate specific antigen and prostate volume. J Urol. 2009; 181: 2064-2070 Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar These results raise the question of whether aspirin OR NSAID use may lower PSA level to a degree that reduces the likelihood of being referred for biopsy. If true, this would be a significant clinical problem given that approximately 30% of men aged ≥50 years are reported to regularly use aspirin. 7 Brasky T.M. Velicer C.M. Kristal A.R. Nonsteroidal anti-inflammatory drugs and prostate cancer risk in the VITamins And Lifestyle (VITAL) Cohort. Cancer Epidemiol Biomarkers Prev. 2010; 19: 3185-3188 Crossref PubMed Scopus (29) Google Scholar The Impact of the Use of Aspirin and Other Nonsteroidal Anti-inflammatory Drugs on the Risk of Prostate Cancer Detection on BiopsyUrologyVol. 84Issue 5PreviewTo evaluate the association between nonsteroidal anti-inflammatory drug (NSAID) use and the risk of prostate cancer (PC) detection in men undergoing biopsy. Full-Text PDF ReplyUrologyVol. 84Issue 5PreviewWe would like to thank Dr. Bruce J. Trock for his insightful editorial and thoughtful commentary. Full-Text PDF

A Retrospective Analysis of the Epidemiology and Outcomes of Gastrointestinal Bleeding With Respect to the Use of Non-steroidal Anti-inflammatory Drugs

Introduction: The association of non-steroidal anti-inflammatory drugs (NSAIDs) with gastrointestinal bleeding (GIB) has been a well-studied correlation. The mechanism of toxicity has been clearly defined and is known to result from the inhibition cyclo-oxgenase and prostaglandin synthesis, as have the risk factors that predispose to GIB. We retrospectively studied 336 consecutive patients presenting to the emergency room with GIB and separated them based on NSAID use. The aim of the study was to improve our understanding as to how NSAID use may have a changing role in the epidemiology of GIB. Methods: Retrospective analysis of 336 consecutive patients admitted to the University of Massachusetts Medical Center Emergency Department between 2011 and 2012. Two cohorts were identified of patients who were taking NSAIDS at admission or not. Analysis of medical records was performed identically for both cohorts. Information obtained from analysis includes initial laboratory values, patient characteristics, and final diagnosis. Results: Of the 336 patients, a significantly greater percentage were not taking NSAIDs (61.9%) compared to those that were (38.1%; p<0.001). Patients who taking NSAIDs were significantly older (69.9 years old vs. 57.9 years old; p<0.0001), required significantly more units of red blood cell transfusion (2.4 units vs. 1.7 units; p=0.03), and had higher admission BUN levels (33.8 mg/dL vs. 24. 3 mg/dL; p=0.002). The most common diagnoses in the NSAID group were duodenal ulcer (14.06%), gastric ulcer (7.03%), and small bowel angioectasia (6.25%). In the non-NSAID group, the most common diagnoses were gastric ulcer (6.25%, esophageal varices 5.7%, and duodenal ulcer 5.3%). In patients on proton pump inhibitors PPI or H2 receptor antagonists, gastric ulcers were seen in 3.2% of the NSAID group and 4.8% of the non-NSAID (p=0.68), and duodenal ulcers were seen in 9.8% of the NSAID group and 2.4% of the non-NSAID group (p <0.05). In patients not on a PPI or H2 blocker, gastric ulcers were seen in 10.4% of the NSAID group and 7.1% of the non-NSAID group (p=0.22), and duodenal ulcers were seen in 17.9% of the NSAID group and 7.1% of the non-NSAID group (p<0.01). Conclusion: Analysis of a 12-month cohort of patients with GIB demonstrates that we have found that NSAIDs continue to play an important role in those with GIB. We also found that those taking NSAIDs still had bleeding from peptic ulcers even when taking a PPI or H2 receptor antagonists, suggesting that protection from peptic ulcer disease is incomplete and that the diagnosis of peptic ulcer should still be considered when evaluating patients taking NSAIDs.

Abstract 2159: A prospective study of non-steroidal anti-inflammatory drug use and colorectal adenoma and colorectal cancer

Abstract Background: Use of non-steroidal anti-inflammatory drugs (NSAIDs), such as aspirin and ibuprofen, has been shown to yield a chemopreventive effect against colorectal cancer. Whether NSAIDs protect against the initiation vs. the progression of colorectal cancer remains a debate. To explore its role in the course of colorectal carcinogenesis, we evaluated the associations of NSAIDs with incident adenoma, recurrent adenoma, and colorectal cancer in the context of a large population-based screening trial, where participants were randomized to undergo endoscopic examinations in a controlled setting. Methods: We prospectively evaluated the associations between self-reported baseline NSAIDs use and risk of incident distal adenoma (1,127 cases), recurrent adenoma (755 cases), and colorectal cancer (840 cases) among men and women, ages 55-74, enrolled between 1993-2001, and randomized to receive flexible sigmoidoscopy screening (n=77,445) as part of the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial. Incident adenoma cases were those with a negative sigmoidoscopy at baseline, but then were found to have adenoma on a follow-up sigmoidoscopy 3 or 5 years later. Recurrent adenoma cases were identified via an ancillary study nested within the PLCO among participants who had an adenoma at baseline and another adenoma on a surveillance colonoscopy 6 months to 10 years after their baseline screen. Participants were followed for cancer incidence for the median of 11.9 years following the baseline screen. All diagnoses of colorectal adenoma and cancer were pathologically confirmed through medical record review. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for adenoma incidence and recurrence and hazard ratios (HRs) and 95% CIs for colorectal cancer incidence using multivariable-adjusted models. Results: Compared to no or infrequent use (&amp;lt;4 times/month), we found aspirin use ≥2 times/day to be associated with a reduced risk of incident adenoma (OR=0.72, 95% CI:0.52-1.00). Although not significantly associated with recurrent adenoma (OR=1.00) or colorectal cancer (OR=0.80), a marginally significant dose trend was observed for colorectal cancer (P=0.05). Similarly, ibuprofen use ≥2 times/day was associated with a reduced risk for incident adenoma (OR=0.72, 95% CI:0.54-0.97), but not associated with adenoma recurrence or cancer. No systematic differences in risk patterns were found by anatomic site, i.e., proximal colon, distal colon or rectum. Conclusion: Our data suggest that use of aspirin and ibuprofen significantly reduces adenoma initiation, but benefit against progression to adenoma recurrence or cancer growth may be weaker. Given the recognized adverse effects of NSAIDs, such as gastric ulcer perforation and upper gastrointestinal bleeding, any chemopreventive recommendations associated with NSAID use need to be tailored by individual cost-benefit assessment. Citation Format: Wen-Yi Huang, L. Joseph Su, Christine C. Johnson, Mark P. Purdue, Sonja I. Berndt. A prospective study of non-steroidal anti-inflammatory drug use and colorectal adenoma and colorectal cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2159. doi:10.1158/1538-7445.AM2014-2159