AB0292 EFFECTS OF ACETAMINOPHEN ON THE KIDNEY FUNCTIONS OF PAITIENTS WITH MUSCULOSKERLTAL DISEASE TREATED WITH LONG-TERM NONSTEROIDAL ANTI-INFRAMMATORY DRUG THERAPY

This Month in Gastroenterology

Nonsteroidal anti-inflammatory drug (NSAID) use has been associated with a decreased colorectal cancer (CRC) risk. However, to the best of the authors' knowledge, the effects of NSAID on clinical outcomes after CRC diagnosis are not well defined. The authors investigated the association between prediagnosis NSAID use and mortality after CRC diagnosis among women in the California Teachers Study cohort. Women aged <85 years participating in the California Teachers Study, without a prior CRC diagnosis at baseline (1995-1996), and who were diagnosed with CRC during follow-up through December 2005, were eligible for analysis of the association between prediagnosis NSAID use and mortality. NSAID use (including aspirin and ibuprofen) was collected through a self-administered questionnaire. Cancer occurrence was identified through California Cancer Registry linkage. Multivariate Cox proportional hazards regression models were used to estimate hazards ratios (HR) for death and 95% confidence intervals (95% CIs). Among 621 CRC patients who were identified, 64% reported no prediagnosis regular NSAID use, 17% reported use of 1 to 6 days/week, and 20% reported daily use. A duration of NSAID use <5 years was reported by 17% of patients and a use of >or=5 years was reported by 18%. Regular prediagnosis NSAID use (1-3 days/week, 4-6 days/week, and daily) versus none was associated with improved overall survival (OS) (HR, 0.71; 95% CI, 0.53-0.95) and CRC-specific survival (HR, 0.58; 95% CI 0.40-0.84) after adjustment for clinically relevant factors. Prediagnosis NSAID use >or=5 years (vs none) was found to be associated with improved OS (HR, 0.55; 95% CI, 0.37-0.84) and CRC-specific survival (HR, 0.40; 95% CI, 0.23-0.71) in adjusted analyses. When used regularly or over a prolonged duration before CRC diagnosis, NSAIDs are associated with decreased mortality among female CRC patients.

Purpose: Regular NSAID (Non-Steroidal Anti-Inflammatory Drug) use results in an overall reduction in colorectal cancer (CRC) risk; however, this reduction may vary among molecularly defined subsets of CRC. Characterization of patients by regular NSAID use and molecular subtype will provide unique insight into the biology of NSAID-based CRC prevention. Methods: A sample of patients was selected from the Assessment of Targeted Therapies Against Colorectal Cancer (ATTACC) protocol, which is designed to molecularly profile tumors of patients with refractory metastatic CRC. Demographic data and NSAID use were collected from a risk-factor survey. Demographic characteristics were compared between 106 non-NSAID users, 75 regular aspirin users and 78 regular non-aspirin NSAID users. Chi-square analysis was used to compare categorical variables and ANOVA was used for continuous variables. Logistic regression was used to assess predictors of aspirin or non-aspirin NSAID use compared to non-use. Results: Preliminary results indicate that aspirin users tend to be older, male and more frequently engage in vigorous physical activity compared to non-users and users of non-aspirin NSAIDs (Table I). In univariate analyses, patients who are older or engage in more frequent vigorous physical activity are at increased odds of using aspirin. When controlling for other variables, only age at diagnosis predicts aspirin use. Table 1.Description and AssociationsNo NSAID useAspirin useNon-Aspirin usep valueN1067578Age at Stage IV Diagnosis, Mean (SE)55.2 (1.0)59.5 (1.1)53.1 (1.3)0.0006Gender, N (%)11884810.0251Male72 (61.0)59 (72.8)44 (52.4)Female46 (39.0)22 (27.2)40 (47.6)Vigorous Physical Activity, N (%)11780840.0214Little or none50 (42.7)18 (22.5)34 (40.5)Once/week10 (8.6)14 (17.5)13 (15.5)Twice/week or more57 (48.7)48 (60.0)37 (44.1)Logistic RegressionUnadjusted Odds of Aspirin UseAdjusted Odds of Aspirin Use*OR (95% CI)p valueOR (95% CI)p valueAge at Stage IV Diagnosis1.047 (1.013, 1.081)0.00571.049 (1.014, 1.085)0.0055Gender (Female)0.584 (0.316, 1.078)0.08550.701 (0.356, 1.379)0.3032Vigorous Physical Activity (overall effect)0.00850.0486Little or none (Ref)1.001.00Once/week3.889 (1.468, 10.300)0.03692.481 (0.892, 6.906)0.2997Twice/week or more2.339 (1.207, 4.533)0.58952.305 (1.137, 4.673)0.2662*Each variable is adjusted for the other variables in the table Conclusions: These preliminary data indicate that we will be able to distinguish aspirin users from non-NSAID users in a sample of late-stage CRC patients. Going forward, we will combine these demographic data with tumor molecular classification to determine the subtypes of CRC that are more or less prevalent in aspirin/NSAID users. Use of NSAIDs and overall survival will also be evaluated among different molecular subtypes of CRC. This data, combined with analysis of risk factors for each molecular subtype will provide unique insight into the biology of NSAID-based CRC prevention. Citation Format: Jennifer S. Davis, Shailesh Advani, Emilyn Banfield, Michael Overman, Zhi-Qin Jiang, Shanequa Manuel, Carrie Daniel, Shine Chang, Scott Kopetz. Demographics of colorectal cancer patients vary by aspirin use. [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 3704. doi:10.1158/1538-7445.AM2015-3704

Recent data have suggested that short-term NSAID use induces a state of compensated hypogonadism. Our aim was to investigate the association between chronic, regular NSAID use and compensated hypogonadism in a large, nationally representative cohort, the US National Health and Nutrition Examination Survey (NHANES) database. Men 20-80years who answered the analgesic use questionnaire and underwent hormonal testing were included. Multivariable regression was utilised to determine the relationship between NSAID use and serum testosterone (T), anti-Mullerian hormone (AMH) and T:AMH ratio. Among 3,749 men, 505 (13.5%) reported regular NSAID use and 3,244 (86.5%) did not. Regular users had lower T (440.7±27.0 vs. 557.0±24.9ng/dl, p=.005) and albumin (43.8±0.2 vs. 45.1±0.1, p<.001) compared to nonregular users. On multivariable analysis, only active smoking was significantly associated with T, AMH and T:AMH ratio (p<.001, p=.036 and p=.005 respectively). Regular NSAID use was not associated with T, AMH or T:AMH ratio (p=.523, p=.974, and p=.872 respectively). In this nationally representative sample of US men, regular and chronic NSAID use was not associated with alterations in T or compensated hypogonadism. These data should reassure patients and clinicians regarding the safety of NSAID use with respect to the risk of alteration in the hypothalamic-pituitary-gonadal axis.

Multiple observational studies and large, randomized controlled trials indicate that non-steroidal anti-inflammatory drugs (NSAIDs) strongly reduce risk for colorectal neoplasms. The strengths of these findings suggest that NSAIDs may so mask various risk factor-colorectal neoplasm associations, that they may be undetectable among NSAID users. Temporal changes and between-population differences in regular NSAID use prevalence may account for some of the inconsistencies in reported findings for risk factor-colorectal neoplasm associations. We investigated whether associations of known colorectal cancer risk factors with colorectal adenoma differed by non-aspirin NSAID use using pooled data from 3 colonoscopy-based case-control studies of incident, sporadic colorectal adenoma conducted in Minnesota, North Carolina, and South Carolina between 1991 and 2002. Participants (n=789 cases, 2,035 polyp-free controls) provided risk factor data prior to colonoscopy. The multivariable-adjusted odds ratios (OR) (95% confidence intervals [CI]) for those in the highest relative to the lowest quartiles of exposure, by regular non-aspirin NSAID non-use/use, respectively, were 1.57 (CI 0.96, 2.55) vs. 1.22 (CI 0.40, 3.70) for total fat, 1.37 (CI 0.86, 2.18) vs. 0.78 (CI 0.26, 2.35) for saturated fat, 0.92 (CI 0.67, 1.26) vs. 1.31 (CI 0.62, 2.76) for total calcium, 0.88 (CI 0.64, 1.22) vs. 1.38 (CI 0.65, 2.93) for total fruits and vegetables, 1.05 (CI 0.73, 1.50) vs. 0.73 (CI 0.33, 1.62) for red and processed meats, and 0.84 (CI 0.65, 1.10) vs. 0.97 (CI 0.54,1.75) for physical activity. For current smokers relative to never smokers, the ORs (CIs) among regular non-NSAID users/non-users were 2.88 (CI 2.20, 3.77) vs. 1.64 (CI 0.85, 3.17), respectively, and for those who were obese relative to those who were normal weight, they were 1.65 (CI 1.27, 2.16) vs. 1.20 (CI 0.70, 2.04). The associations of age, height, and intakes of alcohol, dietary fiber, and total folate with adenoma did not substantially differ according to NSAID use. These findings suggest that regular non-aspirin NSAID use may mask, beyond simple confounding, associations of various risk factors with colorectal adenoma, suggesting that differential proportions of regular NSAID users between study populations may explain some inconsistencies in reported risk factor-colorectal neoplasm associations, and support routinely assessing such associations stratified by regular non-aspirin NSAID use. Citation Format: Sobia Mujtaba, Roberd M. Bostick. Differences in risk factor-colorectal adenoma associations according to non-steroidal anti-inflammatory drug use [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2302. doi:10.1158/1538-7445.AM2017-2302

To determine the role of nonsteroidal anti-inflammatory drugs (NSAIDs) in activation of inflammatory bowel disease (IBD). NSAIDs may activate inflammatory pathways in IBD. Crohn's and Colitis Foundation of American Partners is an ongoing cohort study of patients living with IBD. All data are self-reported using the internet. We identified a subcohort of participants whose disease activity, based on short Crohn's Disease Activity Index and simple clinical colitis activity index, indicated remission. Pattern of use of NSAIDs was measured at baseline, and disease activity assessment was performed 6 months later. We used multivariate binomial regression to determine effects of NSAIDs on disease activity. A total of 791 individuals in remission had baseline and follow-up data available for analysis. Of these, 247 Crohn's disease (CD) patients (43.2%) and 89 ulcerative colitis (UC) patients (40.6%) reported NSAID use. CD patients with NSAID use ≥5 times/month had greater risk of active disease at follow-up (23% vs. 15%, P=0.04); [adjusted risk ratio (RR), 1.65; 95% confidence interval (CI), 1.12-2.44). No effect was observed in patients with UC (22% vs. 21%, P=0.98; adjusted RR, 1.25; 95% CI, 0.81-1.92). Acetaminophen use was associated with active disease at follow-up in CD (adjusted RR, 1.72; 95% CI, 1.11-2.68). Regular (≥5 times/mo) NSAID and acetaminophen use were associated with active CD, but not UC. Less frequent NSAID use was not associated with active CD or UC. These findings indicate that regular NSAID use may increase CD activity, or that NSAID use may be a marker of a less robust remission; thus reflecting subclinical disease activity.

Regular continuous non-steroidal anti-inflammatory drug (NSAID) use has been associated with a reduction in risk of colorectal cancer. Our objective was to investigate whether or not a number of the polymorphic genes involved in the metabolism of NSAIDs, including cytochrome P450 s (CYPs), act as modifiers of this protective effect. As part of a multi-centre case-control study, 478 colorectal cancer patients and 733 controls (433 matched case-control pairs) answered questions on NSAID use. These individuals were then genotyped for common polymorphisms in P450 CYP2C8, P450 CYP2C9, UDP-glucuronosyl transferase (UGT)1A6 and peroxisome proliferator-activated receptor isoforms delta and gamma (PPARdelta and PPARgamma). Our study confirmed the reduction in risk of colorectal cancer with regular NSAID use (odds ratio (OR) = 0.73, 95% confidence interval (CI) (0.56, 0.95)) but showed that none of the polymorphic genes studied appeared to modify the protective effect of regular NSAID use.

Introduction: Research has demonstrated that use of non-steroidal anti-inflammatory drugs (NSAIDs) decreases the risk of developing colorectal cancer as well as the recurrence of the disease among those with prior colorectal cancer. Limited prior studies investigating the association with colorectal cancer (CRC) survival have also observed a beneficial effect of NSAID use, specifically aspirin, against colorectal cancer mortality. We examined the role of pre-diagnostic aspirin and non-aspirin NSAID use on colorectal cancer-specific mortality in a population-based study. Methods: We investigated the effect of NSAID use on CRC mortality after diagnosis among 1,737 incident colorectal cancer cases identified from the Seattle Colon Cancer Family Registry. Type of medication, duration, and timing of use relative to diagnosis were collected for NSAIDs, including aspirin and ibuprofen. Cases were followed up for mortality through linkages to the National Death Index records to obtain date and cause of death. Cox proportional hazards regression models were used to assess the relationship between pre-diagnostic NSAID use and colorectal cancer-specific mortality and to estimate hazard ratios and 95% confidence intervals. Results: Regular, pre-diagnostic use of NSAID medications was associated with a 21% decrease in CRC mortality (HR: 0.79; 95% CI 0.65–0.97); current use was associated with a 25% decreased risk of CRC mortality (HR: 0.75; 95% CI 0.58–0.96); former use was not associated with a significant survival benefit. Among cases with advanced disease, regular use of NSAID medications was not observed to significantly alter CRC mortality. However, regular and current pre-diagnostic use of NSAID medications was associated with a 31% and 37% decrease, respectively, in CRC mortality (95% CI: 0.53– 0.90; 0.46–0.87) among cases with non-advanced disease. Although cases with distal and rectal tumors did not experience a survival benefit from NSAID use, regular pre-diagnostic NSAID use was associated with a 32% decreased risk of CRC mortality among cases with proximal tumors (HR: 0.68; 95% CI 0.51–0.92). Conclusion: Our results demonstrate that regular pre-diagnostic use of NSAIDs, including aspirin, is associated with improved colorectal cancer survival, particularly if the medications are taken recently prior to diagnosis. This improvement in survival may be mediated through alteration in disease progression, resulting in lower stage of disease at presentation, among those with regular NSAID use. The survival benefit was not explained by increased screening among NSAID users, and the improvement appears to be particularly strong among patients diagnosed with proximal tumors and with non-advanced disease. Citation Information: Cancer Prev Res 2010;3(1 Suppl):A134.

Colorectal Cancer After Start of Nonsteroidal Anti-Inflammatory Drug Use

Professional guidelines advise against regular or long-term NSAID use in most patients with chronic kidney disease (CKD), heart failure (HF), and hypertension (HTN) due to risk of adverse events. Nevertheless, over-the-counter (OTC) NSAIDs are broadly accessible and frequently used among this population. Efforts to decrease high-risk OTC NSAID use have the potential to improve safety and reduce chronic disease burden. This randomized controlled trial evaluated the effectiveness of a brief, electronically-administered educational video in reducing high-risk OTC NSAID use. Adult participants with CKD, HF, and/or HTN who self-identified as regular NSAID users (≥3 times/week for 3 months) were invited to participate. Participants (n = 425) were randomized to either view an electronically-administered educational video informed by the COM-B behavioral change model (VIDEO, n = 223) or the FDA Drug Facts label for NSAIDs (CONTROL, n = 202). Intent to decrease OTC NSAIDs was evaluated via 11-point contemplation ladder immediately and 4 weeks post-intervention, with self-reported NSAID Exposure assessed at 4 weeks. We also evaluated current and recent pain levels at baseline and 4 weeks. Intent to decrease OTC NSAID use (4.28 (SD: 3.45) ladder rungs) and NSAID exposure (20.14 (SD: 13.66) dose-days per month) did not differ between groups at baseline. Intent to decrease OTC NSAID use increased more from baseline to immediately post-intervention in VIDEO vs. CONTROL (1.32 (SD: 2.80) vs. 0.55 (SD: 1.99) rungs, p < 0.001), with greater improvements for those with lower baseline intent. VIDEO and CONTROL were associated with a similar rise in intent to decrease OTC NSAID use (1.92 (SD: 4.41) vs. 1.36 (SD: 3.46), p = 0.150) and a similar decrease in NSAIDs exposure (−32.8% in VIDEO and −36.5% in CONTROL, p = 0.520) 4 weeks post-intervention. Pain levels did not differ between groups. Results suggest that a low-burden, electronically-administered intervention reduce high-risk medication use among patients with CKD, HF, and/or HTN.

Professional guidelines advise against regular or long-term NSAID use in most patients with chronic kidney disease (CKD), heart failure (HF), and hypertension (HTN) due to risk of adverse events. Nevertheless, over-the-counter (OTC) NSAIDs are broadly accessible and frequently used among this population. Efforts to decrease high-risk OTC NSAID use have the potential to improve safety and reduce chronic disease burden. This randomized controlled trial evaluated the effectiveness of a brief, electronically-administered educational video in reducing high-risk OTC NSAID use. Adult participants with CKD, HF, and/or HTN who self-identified as regular NSAID users (≥3 times/week for 3 months) were invited to participate. Participants (n = 425) were randomized to either view an electronically-administered educational video informed by the COM-B behavioral change model (VIDEO, n = 223) or the FDA Drug Facts label for NSAIDs (CONTROL, n = 202). Intent to decrease OTC NSAIDs was evaluated via 11-point contemplation ladder immediately and 4 weeks post-intervention, with self-reported NSAID Exposure assessed at 4 weeks. We also evaluated current and recent pain levels at baseline and 4 weeks. Intent to decrease OTC NSAID use (4.28 (SD: 3.45) ladder rungs) and NSAID exposure (20.14 (SD: 13.66) dose-days per month) did not differ between groups at baseline. Intent to decrease OTC NSAID use increased more from baseline to immediately post-intervention in VIDEO vs. CONTROL (1.32 (SD: 2.80) vs. 0.55 (SD: 1.99) rungs, p < 0.001), with greater improvements for those with lower baseline intent. VIDEO and CONTROL were associated with a similar rise in intent to decrease OTC NSAID use (1.92 (SD: 4.41) vs. 1.36 (SD: 3.46), p = 0.150) and a similar decrease in NSAIDs exposure (-32.8% in VIDEO and -36.5% in CONTROL, p = 0.520) 4 weeks post-intervention. Pain levels did not differ between groups. Results suggest that a low-burden, electronically-administered intervention reduce high-risk medication use among patients with CKD, HF, and/or HTN.

BACKGROUND: In Thailand, 67.2% of the population widely uses analgesics including nonsteroidal anti-inflammatory drugs (NSAIDs), which may lead to serious side effects. However, the information of regular NSAIDs used in Thailand is still limited.METHODS: A mixed method cross-sectional study was conducted. Quantitative data were collected using questionnaires to determine the prevalence and factors associated with regular NSAID use. The qualitative study was conducted using group and in-depth interviews to determine the knowledge, attitudes and practices of NSAID users.RESULTS: Of 771 participants, the prevalence of NSAID use was 31.1 and regular NSAID use was 7.4. Age, pain at the hips or thighs and pain score were independent factors associated with regular NSAID use. The qualitative study indicated that the use of NSAIDs was influenced by drug effectiveness, sources of NSAIDs and consideration of benefits and risks of the drugs.CONCLUSION: This was the first report on the prevalence and associated factors of regular NSAID use in Thailand. In this community, nonprescribed NSAIDs might cause some serious side effects and undesirable drug interaction. Information on side effects of pain medications should be disseminated to the public including guidelines on how to use pain medications.

NSAIDs and a Lower Risk of Prostate Cancer: Causation or Confounding?

The effects of nonsteroidal anti-inflammatory medications after rotator cuff surgery: a randomized, double-blind, placebo-controlled trial.

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.