Regular Use Of Nonsteroidal Anti-inflammatory Drugs Research Articles

The role of aspirin in the prevention of pancreatic cancer: A nested case-control study in the UK Biobank

BackgroundAspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) usage has been associated with pancreatic ductal adenocarcinoma (PDAC) prevention, though epidemiological data have not reliably demonstrated this. The aim of this study is to identify if aspirin and other NSAIDs are effective in the primary prevention of PDAC in a large UK prospective cohort. MethodsA nested case-control study was conducted using the UK Biobank cohort. Incident PDAC cases (n = 1129 of whom 239 (21.2 %) were using aspirin) were age and sex-matched with cancer-free controls (n = 8822 of whom 1752 (19.9 %) were using aspirin). Conditional logistic regression models were used to generate odds ratios (ORs) and 95 % confidence intervals (CI) for risk of PDAC with and without regular use of aspirin, non-aspirin NSAIDs and all NSAIDs respectively. Exploratory analyses were carried out assessing interactions with diabetes mellitus (DM) as a condition with increased pancreatic cancer risk. ResultsRegular aspirin use at initial recruitment was independently associated with a decreased risk of PDAC (OR [95 % CI] = 0.80 [0.68–0.95] P = 0.01). Regular non-aspirin NSAID use was not associated with a risk reduction of PDAC (OR [95 % CI] = 1.01 [0.84–1.23] P = 0.88). Exploratory analyses showed that in those with DM; regular aspirin use reduced risk of PDAC (OR [95 % CI] = 0.60 [0.42–0.85] P = 0.004) compared to non-use. DiscussionRegular aspirin use is associated with a reduction in risk of PDAC. The reduced risk is more apparent in participants with DM.

Frequent use of prescription NSAIDs among people with knee or hip osteoarthritis despite contraindications to or precautions with NSAIDs

ObjectiveTo describe use of Non-steroidal Anti-inflammatory Drugs (NSAID), opioid, and physiotherapy (PT) among persons with newly diagnosed knee or hip osteoarthritis (OA) with and without NSAID contraindications or precautions. DesignWe used population-based register data to identify adults aged ≥35 as of January 1, 2014 residing in Skåne region (Sweden) between 2004-2013, without a previous knee or hip OA diagnosis. Among this cohort, we identified people with incident knee or hip OA diagnosis between 2014-2018, and presence of contraindications to or precautions for oral NSAIDs at the time of OA diagnosis. We estimated the risk of: 1) regular oral NSAID use; 2) regular opioid use; 3) PT during the first year after diagnosis among those with vs. without contraindications or precautions using confounder-adjusted logistic regression with standardization. ResultsWe identified 35,173 persons with newly diagnosed OA, of whom 3,257 and 8,351 had ≥1 contraindication to oral NSAIDs and ≥1 precaution, respectively. Overall, 27% of individuals used oral NSAIDs (with or without opioids or PT), 10% used opioids, and 57% attended PT. Among patients with contraindications, 21% used oral NSAIDs compared to 31% without (absolute adjusted difference -0.06 (95% CIs: -0.08, -0.05)), 53% vs 59% used PT (adjusted difference -0.03 (-0.05, -0.01)), while 14% vs 8% had prescribed dispensed opioids (adjusted difference 0.02 (0.01, 0.03)). Similar results were observed for those with precautions. ConclusionsWe highlight the need for safer treatment options. People with OA and contraindications/precautions to NSAIDs have higher risk of opioid use, slightly lower risk of PT use, and continue to be prescribed NSAIDs. Availability of data and materialsAll the data used in the study are available upon request to the appropriate Swedish National authorities.

Regular Nonsteroidal Anti-Inflammatory Drug Use Increases Stress Fracture Risk in the General Population: A Retrospective Case-Control Study.

Previous studies have shown that the use of nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with increased stress fracture risk. This phenomenon has been studied predominantly in high-activity individuals, so data regarding the general population are limited despite the substantial economic and resource burden of stress fracture injuries within the general US population. Furthermore, our preclinical studies demonstrate that regular use of NSAIDs also diminishes the intrinsic ability of bone to resist fracture. To determine the association of regular NSAID use with stress fractures in the general population, we surveyed subjects presenting with either stress fracture or uncomplicated ankle sprain to assess their use of NSAIDs over the three months before their injury. We hypothesized that subjects with stress fractures would have increased regular NSAID usage as compared to controls. Subjects diagnosed with a stress fracture (n = 56) and subjects with uncomplicated ankle sprains (n = 51; control) were surveyed about their NSAID use at the time of their diagnosis and in the previous three months using a questionnaire based on the National Health and Nutrition Examination Survey (NHANES). Subjects were surveyed in person on the day of their injury diagnosis or by phone within 30 days of their diagnosis. Fisher's exact test was used to determine significant differences in NSAID usage between stress fracture and control subjects. Subjects diagnosed with stress fractures had a statistically significant increase in both current use (p=0.03) and regular use (p=0.04) of ibuprofen/naproxen/celecoxib as compared to control subjects. There were no significant differences in the use of aspirin, acetaminophen, or prescription medications containing acetaminophen between groups. Consistent with previous clinical reports, we observed a strong correlation between regular ibuprofen/naproxen/celecoxib use and stress fracture incidence in the general population. These results indicate that patients at high risk of stress fracture should avoid regular use of ibuprofen, naproxen, or celecoxib.

Venous thromboembolism in users of hormonal contraception and non-steroidal anti-inflammatory drugs: a nationwide cohort study

Abstract Objective To study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism. Design: Nationwide cohort study. Setting: Denmark through national registries. Participants: All 15-49-year-old women living in Denmark between the years 1996-2017 with no medical history of any venous or arterial thrombotic event, cancer, thrombophilia, hysterectomy, bilateral oophorectomy, sterilisation, or infertility treatment. Main outcome measure: A first-time discharge diagnosis of lower-limb deep venous thrombosis or pulmonary embolism. Results Among 2.0 million women followed for 21.0 million person-years, 8710 venous thromboembolic events occurred. Compared to non-use of NSAIDs, use of NSAIDs was associated with an adjusted incidence rate ratio of venous thromboembolism of 8.1 (95% confidence interval (CI) 6.9 to 9.6) in women not using hormonal contraception, 12.1 (10.6 to 13.9) in women using high-risk hormonal contraception, 8.7 (6.5 to 11.6) in users of medium-risk hormonal contraception, and 5.1 (2.9 to 9.1) with low/no-risk hormonal contraception. Compared to non-use of NSAIDs, the number of extra venous thromboembolic events per 100,000 one-week NSAID treatments was 4 in women not using hormonal contraception, 18 in women using high-risk hormonal contraception, 9 in users of medium-risk hormonal contraception, and 2 in women using low/no-risk hormonal contraception. Conclusions NSAID use was positively associated with the development of venous thromboembolism. The association was stronger in women concomitantly using high-risk hormonal contraceptives and weaker in women using low/no-risk hormonal contraception. Women requiring both hormonal contraception and regular use of NSAIDs should be advised accordingly.

Venous thromboembolism with use of hormonal contraception and non-steroidal anti-inflammatory drugs: nationwide cohort study

ObjectiveTo study the influence of concomitant use of hormonal contraception and non-steroidal anti-inflammatory drugs (NSAIDs) on the risk of venous thromboembolism.DesignNationwide cohort study.SettingDenmark through national registries.ParticipantsAll 15-49 year old women...

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.

Abstract EP66: Racial Differences In The Use Of Over-the-counter Non-steroidal Anti-inflammatory Drugs Among Individuals At Risk Of Adverse Cardiovascular Events

Introduction: Over-the-counter (OTC) non-steroidal anti-inflammatory drugs (NSAIDs) are commonly used despite conferring risk for adverse cardiovascular events (ACEs). ACEs disproportionately affect Black individuals, yet patterns of OTC NSAID and high-potency powder NSAID (HPP-NSAID) use among different racial groups remains understudied. Hypothesis: We hypothesized that use of OTC NSAIDs and HPP-NSAIDs is higher among Black individuals. Methods: We analyzed data from the North Carolina Colon Cancer study, a population-based case-control study in 1996-2000. Participants at risk of ACEs, defined as self-reported hypertension, diabetes, heart disease, or smoking history ≥ 20 years, were included in our analysis. Primary outcomes were any OTC NSAID use and HPP-NSAID use. Secondary outcomes included regular use of the primary outcome variables. Using multivariable logistic regression, we quantified the independent association of the outcomes with race after adjusting for age, sex, education, poverty, and pain interfering with daily activities. We investigated the effect modifications of poverty status and educational attainment separately on the noted associations. Results: Of the 1286 participants at risk for ACEs, 583 (45%) reported Black, 695 (54%) White, and 8 (<1%) Other race. Overall, 665 (52%) reported any NSAID use and 204 (16%) reported HPP-NSAID use. Any NSAID use was reported by 329 (57%) Black participants compared to 332 (48%) White participants. HPP-NSAID use was reported by 126 (22%) Black participants compared to 76 (11%) White participants. Of users, 174 (26%) reported regular NSAID use and 37 (18%) reported regular HPP-NSAID use; this pattern was similar across race. In multivariable analysis, Black (versus White) race was independently associated with higher odds of NSAID use (odds ratio [OR] 1.4 95% confidence interval [1.1, 1.8]). Pain interfering with daily activities (OR 1.4 [1.1, 1.8]) was also associated with NSAID use and older age was negatively associated with NSAID use (OR 0.96 [0.95, 0.97]). After adjustment, Black race was associated with HPP-NSAID use (OR 1.8 [1.3, 2.6]). Male sex (OR 1.6 [1.2, 2.3]) and being in or near poverty (OR 1.6 [1.0, 2.3]) were also independently associated with HPP-NSAID use and older age (OR 0.96 [0.94, 0.97]) and educational attainment of some college or greater (OR 0.5 [0.3, 0.7]) were negatively associated with HPP-NSAID use. The associations between race and either outcome were not significantly moderated by educational attainment nor poverty status. Conclusions: In this population-based study, Black individuals at risk of ACEs had higher odds of any NSAID and HPP-NSAID use than White participants, even after controlling for pain and socio-economic status. Further research is necessary to determine the impact of this differential use on established inequities in cardiovascular outcomes.

Analgesic use and the risk of renal cell carcinoma – Findings from the Consortium for the Investigation of Renal Malignancies (CONFIRM) study

PurposeThe incidence of renal cell carcinoma (RCC) is rising. Use of analgesics such as non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol may affect renal function. The aim of this study was to assess associations between analgesic use and risk of RCC. MethodsA population-based case-control family design was used. Cases were recruited via two Australian state cancer registries. Controls were siblings or partners of cases. Analgesic use was captured by self-completed questionnaire. Logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for RCC risk associated with regular analgesic use (at least 5 times per month for 6 months or more) and duration and frequency of use. ResultsThe analysis included 1064 cases and 724 controls. Regular use of paracetamol was associated with an increased risk of RCC (OR 1.41, 95%CI 1.13–1.77). Regular use of NSAIDs was associated with increased risk of RCC for women (OR 1.71, 95% CI 1.23–2.39) but not men (OR 0.83, 95% CI 0.58–1.18; p-interaction=0.003). There was no evidence of a dose-response for duration of use of paracetamol (linear trend p = 0.77) and weak evidence for non- aspirin NSAID use by women (linear trend p = 0.054). ConclusionThis study found that regular use of paracetamol was associated with increased risk of RCC. NSAID use was associated with increased risk only for women.

Non-steroidal anti-inflammatory drugs, polygenic risk score and colorectal cancer risk.

The regular use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced colorectal cancer (CRC) risk. To explore whether this association varies according to background polygenic risk for CRC. Data were collected from a large population-based case-control study on CRC in Germany. A polygenic risk score (PRS) based on 140 CRC-related risk loci was used to quantify the genetic risk. The associations of regular use of NSAIDs (≥2times per week for at least 1year) with CRC risk were estimated in the whole population and in subgroups according to PRS levels using multivariable logistic regression. The impact of NSAIDs on CRC risk was compared to PRS using the 'genetic risk equivalent' (GRE), a recently developed metric for effective risk communication. In total 5129 CRC cases and 4093 controls were included in this analysis. The regular use of NSAIDs (including aspirin) was associated with reduced CRC risk [odds ratio (OR) 0.66, 95% confidence interval (CI) 0.59, 0.74], as was regular use of aspirin only (OR 0.73, 95% CI 0.65, 0.83), without indication of interaction with the PRS (P=0.10 and 0.22 respectively). The effect of NSAID use was equivalent to the effect of having a 32 percentiles lower PRS (GRE -32, 95% CI -41, -22). The regular use of NSAIDs is associated with greatly reduced CRC risk regardless of individual genetic profile. With an equivalent reduction of relative risk across all polygenic risk groups, absolute risk reduction would be expected to be strongest among those with the highest polygenic risk score.

Nonsteroidal Anti-inflammatory Use and LRRK2 Parkinson's Disease Penetrance.

The penetrance of leucine rich repeat kinase 2 (LRRK2) mutations is incomplete and may be influenced by environmental and/or other genetic factors. Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to reduce inflammation and may lower Parkinson's disease (PD) risk, but their role in LRRK2-associated PD is unknown. The objective of this study is to evaluate the association of regular NSAID use and LRRK2-associated PD. Symptomatic ("LRRK2-PD") and asymptomatic ("LRRK2-non-PD") participants with LRRK2 G2019S, R1441X, or I2020T variants (definitely pathogenic variant carriers) or G2385R or R1628P variants (risk variant carriers) from 2 international cohorts provided information on regular ibuprofen and/or aspirin use (≥2 pills/week for ≥6 months) prior to the index date (diagnosis date for PD, interview date for non-PD). Multivariate logistic regression was used to evaluate the relationship between regular NSAID use and PD for any NSAID, separately for ibuprofen and aspirin in all carriers and separately in pathogenic and risk variant groups. A total of 259 LRRK2-PD and 318 LRRK2-non-PD participants were enrolled. Regular NSAID use was associated with reduced odds of PD in the overall cohort (odds ratio [OR], 0.34; 95% confidence interval [CI], 0.21-0.57) and in both pathogenic and risk variant carriers (ORPathogenic , 0.38; 95% CI, 0.21-0.67 and ORRiskVariant , 0.19; 95% CI, 0.04-0.99). Similar associations were observed for ibuprofen and aspirin separately (ORIbuprofen , 0.19; 95% CI, 0.07-0.50 and ORAspirin , 0.51; 95% CI, 0.28-0.91). Regular NSAID use may be associated with reduced penetrance in LRRK2-associated PD. The LRRK2 protein is involved in inflammatory pathways and appears to be modulated by regular anti-inflammatory use. Longitudinal observational and interventional studies of NSAID exposure and LRRK2-PD are needed to confirm this association. © 2020 International Parkinson and Movement Disorder Society.

Pain severity and analgesics use in the community-dwelling older population: a drug utilization study from Germany

PurposeChronic pain is common in the older population and a significant public health concern. However, comprehensive studies on analgesics use in this age group from Germany are scarce. This study aims to give a comprehensive overview on the use of the most common therapeutic groups of analgesics in community-dwelling older adults from Germany.MethodsA cross-sectional study was carried out using data from a German cohort of 2038 community-dwelling adults aged 63–89 years. Descriptive statistics and logistic regression models were applied to assess the utilization of analgesics by age, sex, pain severity, pain duration, and locations.ResultsOne out of four study participants was suffering from high-intensity or disabling pain. Approximately half of those taking analgesics still reported to suffer from high-intensity or disabling pain. Among analgesics users, occasional non-steroidal anti-inflammatory drugs (NSAIDs) use was the most frequent pain therapy (in 43.6% of users), followed by metamizole (dipyrone) use (16.1%), regular NSAIDs use (12.9%), strong opioids use (12.7%), and weak opioids use (12.0%). In multivariate logistic regression models, higher age, higher pain severity, longer pain duration, abdominal pain, and back pain were statistically significantly associated with opioids use. Metamizole use was also statistically significantly associated with higher pain severity but inversely associated with pain duration.ConclusionsA significant number of older German adults are affected by high-intensity and disabling chronic pain despite receiving analgesics. Long-term studies are needed to compare the effectiveness and safety of different treatments for chronic pain in older adults.

Effects of nonsteroidal anti-inflammatory drug (NSAID) use upon male gonadal function: A national, population-based study.

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.

Aspirin and NSAID use and keratinocyte cancers

It is thought that aspirin and other nonsteroidal anti‐inflammatory drugs (NSAIDS) may protect against keratinocyte skin cancers, i.e. squamous cell carcinoma (SCC) and basal cell carcinoma (BCC). However, the evidence for this is scant. The authors, based in Queensland, Australia, studied a group of middle‐aged or elderly Queensland residents obtained from the register of voters (the QSkin study). They compared the incidence of keratinocyte cancers in a three‐year period in individuals who self‐reported taking aspirin or another NSAID regularly, with those who did not. In patients at high risk (such as having a history of previous skin cancer or multiple patches on the skin called actinic lesions) they found that taking aspirin infrequently (less than once a week) was associated with a slightly reduced risk of SCC. Regular use of other NSAIDS (at least once a week) led to a slightly reduced risk of BCCs. In low‐risk patients (no history of skin cancer and fewer than 5 actinic lesions) the authors found no reduced risk from taking aspirin or other NSAIDs. The authors comment that many patients are on low dose aspirin to reduce the risk of heart attacks or strokes, but this may be inadequate to prevent skin cancer. As most patients purchase non‐steroidal drugs over the counter, it was not possible to determine dosage and duration of treatment. They conclude that the protective effect of NSAIDS is slight and only of value in patients at high risk.

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.

Regular use of aspirin and other non-steroidal anti-inflammatory drugs and breast cancer risk for women at familial or genetic risk: a cohort study

BackgroundThe use of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with reduced breast cancer risk, but it is not known if this association extends to women at familial or genetic risk. We examined the association between regular NSAID use and breast cancer risk using a large cohort of women selected for breast cancer family history, including 1054 BRCA1 or BRCA2 mutation carriers.MethodsWe analyzed a prospective cohort (N = 5606) and a larger combined, retrospective and prospective, cohort (N = 8233) of women who were aged 18 to 79 years, enrolled before June 30, 2011, with follow-up questionnaire data on medication history. The prospective cohort was further restricted to women without breast cancer when medication history was asked by questionnaire. Women were recruited from seven study centers in the United States, Canada, and Australia. Associations were estimated using multivariable Cox proportional hazards regression models adjusted for demographics, lifestyle factors, family history, and other medication use. Women were classified as regular or non-regular users of aspirin, COX-2 inhibitors, ibuprofen and other NSAIDs, and acetaminophen (control) based on self-report at follow-up of ever using the medication for at least twice a week for ≥1 month prior to breast cancer diagnosis. The main outcome was incident invasive breast cancer, based on self- or relative-report (81% confirmed pathologically).ResultsFrom fully adjusted analyses, regular aspirin use was associated with a 39% and 37% reduced risk of breast cancer in the prospective (HR = 0.61; 95% CI = 0.33–1.14) and combined cohorts (HR = 0.63; 95% CI = 0.57–0.71), respectively. Regular use of COX-2 inhibitors was associated with a 61% and 71% reduced risk of breast cancer (prospective HR = 0.39; 95% CI = 0.15–0.97; combined HR = 0.29; 95% CI = 0.23–0.38). Other NSAIDs and acetaminophen were not associated with breast cancer risk in either cohort. Associations were not modified by familial risk, and consistent patterns were found by BRCA1 and BRCA2 carrier status, estrogen receptor status, and attained age.ConclusionRegular use of aspirin and COX-2 inhibitors might reduce breast cancer risk for women at familial or genetic risk.

Naproxen impairs load-induced bone formation, reduces bone toughness, and diminishes woven bone formation following stress fracture in mice.

Debilitating stress fractures are surprisingly common in physically active individuals, including athletes, military recruits, and dancers. These individuals are overrepresented in the 30 million daily users of non-steroidal anti-inflammatory drugs (NSAIDs). We hypothesized that regular use of NSAIDs would predispose habitually loaded bones to stress fracture and delay the repair of these injuries. In this project, we used repetitive axial forelimb compression in mice as a model to test these hypotheses. First, adult mice were subjected to six bouts of forelimb compression over a period of two weeks, with aspirin, naproxen, or vehicle continuously administered through drinking water. Naproxen-treated mice had diminished load-induced bone formation as well as a significant loss in toughness in non-loaded bone, which were not observed in aspirin-treated mice. Furthermore, there were no differences in RANKL/OPG ratio or cortical bone parameters. Picrosirius red staining and second harmonic generation imaging revealed that alterations in bone collagen fibril size and organization were driving the loss of toughness in naproxen-treated mice. Separately, adult mice were subjected to an ulnar stress fracture generated by a single bout of fatigue loading, with NSAIDs provided 24 h before injury. Both aspirin-treated and naproxen-treated mice had normal forelimb use in the week after injury, whereas control mice favored the injured forelimb until day 7. However, woven bone volume was only significantly impaired by naproxen. Both NSAIDs were found to significantly inhibit Ptgs2 and Ngf expression following stress fracture, but only naproxen significantly affected serum PGE2 concentration. Overall, our results suggest that naproxen, but not aspirin, may increase the risk of stress fracture and extend the healing time of these injuries, warranting further clinical evaluation for patients at risk for fatigue injuries.

Association of Aspirin and Nonsteroidal Anti-Inflammatory Drugs With Colorectal Cancer Risk by Molecular Subtypes.

Regular use of aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) for a longer period has been inversely associated with colorectal cancer (CRC) risk. However, CRC is a heterogenic disease, and little is known regarding the associations with molecular pathological subtypes. Analyses included 2444 cases with a first diagnosis of CRC and 3130 healthy controls from a German population-based case control study. Tumor tissue samples were analyzed for major molecular pathological features: microsatellite instability (MSI), CpG island methylator phenotype, B-Raf proto-oncogene serine/threonine kinase (BRAF) mutation, and Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation. Information on past and current use of NSAIDs, including aspirin, was obtained by standardized interviews. Multinomial logistic regression models were used to calculate adjusted odds ratios (ORs) and 95% confidence intervals (CIs). All statistical tests were two-sided. Regular use of NSAIDs was associated with a reduced CRC risk if tumors were MSS (OR = 0.66, 95% CI = 0.57 to 0.77), BRAF wildtype (OR = 0.67, 95% CI = 0.58 to 0.78), or KRAS wildtype (OR = 0.68, 95% CI = 0.58 to 0.80). Regular NSAID use was less clearly and mostly not statistically significantly associated with CRC risk reduction for MSI-high, BRAF-mutated, or KRAS-mutated CRC. In more specific analyses on MSI-high CRC, regular use of NSAIDs was associated with much stronger risk reduction in the absence of BRAF or KRAS mutations (OR = 0.34, 95% CI = 0.18 to 0.65) but not with KRAS- or BRAF-mutated MSI-high CRC (Pheterogeneity < .001). Results for just aspirin use were similar. Our study suggests variation in risk reduction of CRC subtypes following regular use of NSAIDs and aspirin. Regular use of NSAIDs and aspirin may be more strongly associated with risk reduction of MSI-high CRC without KRAS or BRAF mutation.

Non-steroidal anti-inflammatory drug use and breast cancer risk in a prospective cohort study

Introduction In past decades, evidence from both experimental and observational studies has accumulated suggesting that chronic inflammation could promote breast cancer development. Therefore, nonsteroidal anti-inflammatory drugs (NSAIDs), a class of drugs commonly used to treat pain, fever and inflammation, has been proposed as potential chemo-preventive agents for breast cancer. Although inverse associations between NSAIDs and breast cancer risk have been reported in most case-control studies, results from cohort studies are less consistent. Our objective was to assess the association between NSAID use and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Self-reported information on NSAID use at baseline has been collected in five EPIC countries (France, Denmark, United Kingdom, the Netherlands and Germany). Multivariable Cox regression models were used to estimate hazard ratios (HRs) for the association of NSAID use with breast cancer incidence with adjustment for potential confounders. We also assessed effect modification by breast cancer risk factors and examined the associations within specific breast cancer subtypes. Results Among the 140,981 women included in the analysis, 7% were regularly using NSAIDs at baseline. During a median follow-up time period of 13 years, 7379 incident breast cancer cases were diagnosed (816 in situ and 6563 invasive). In multivariable models, there was no statistically significant association between regular NSAID use and breast cancer risk overall. Compared with women who were not regular users at baseline, the HR for regular users of NSAIDs was 0.99 (95% CI = 0.90 to 1.08). Risk estimates did not vary significantly by histological subtypes, by hormone receptor status of the tumor, by breast cancer risk factors or by country (all Pinteraction/heterogeneity between 0.10 and 0.92). However, among postmenopausal women, a statistically significant interaction was observed between NSAID use and ever use of menopausal hormonal therapy (MHT) for invasive breast cancer cases [among MHT ever users: HRNSAID use = 0.84 (0.73–0.96); among MHT never users: HRNSAID use = 1.08 (0.93–1.25); Pinteraction = 0.05], but not for in situ cases [among MHT ever users: HR NSAID use = 1.25 (0.82–1.92); among MHT never users: HR NSAID use = 1.18 (0.81–1.73); Pinteraction = 0.99]. Conclusions and perspectives Our results indicate potential effect modification of MHT use on the association between use of NSAIDs and breast cancer risk which deserves in-depth investigation in studies with accurate data on both NSAID and MHT use, including type, dosage, frequency and duration of use. We are currently exploring this further in a study within the French-EPIC cohort (E3 N cohort) including 61,107 women with individual drug-reimbursement data available from years 2004 to 2011, including dose, duration and subtypes of NSAIDs. If the interaction between MHT use, NSAIDs and breast cancer risk is confirmed, this could have public health implications with respect to how MHT is administered.

Abstract 2302: Differences in risk factor-colorectal adenoma associations according to non-steroidal anti-inflammatory drug use

Abstract 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

Prevalence and Associated Factors of Regular Nonsteroidal Anti-inflammatory Drugs used in a Rural Community, Thailand

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.