Non-aspirin Non-aspirin Nonsteroidal Anti-inflammatory Drugs Use Research Articles

Abstract 5893: Analgesic use and renal cell carcinoma incidence and survival: Results from three prospective cohort studies

Abstract Background: Analgesics are the most commonly consumed over-the-counter drugs worldwide. Considerable evidence suggests a beneficial effect of analgesics, and especially aspirin, on cardiovascular disease and colorectal cancer risk. Studies examining whether widely used analgesics - aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen - play a role in renal cell carcinoma (RCC) have yielded mixed results. Methods: We examined associations between pre-diagnostic analgesic use and incidence of total and fatal RCC in the Health Professionals Follow-up Study (HPFS; 1986-2016), Nurses’ Health Study (NHS; 1980-2016 for aspirin; 1990-2016 for non-aspirin NSAIDs and acetaminophen), and Nurses’ Health Study 2 (NHS2; 1989-2015; total RCC only). Information on use of aspirin, non-aspirin NSAIDs, and acetaminophen was collected longitudinally on biennial questionnaires. We used Cox proportional hazards models to estimate cohort-specific, multivariable hazard ratios (HRs) and 95% confidence intervals (CIs) according to current use (updated in each questionnaire period) and, separately, duration of use (since study baseline) of each analgesic. Results across cohorts were combined using random-effects meta-analyses. We also used Cox regression to evaluate post-diagnostic analgesic use with respect to RCC-specific mortality among RCC cases in the pooled HPFS and NHS cohorts. Results: Among 259,545 participants, 796 incident RCC cases were diagnosed. Neither current nor duration of pre-diagnostic use of any of the analgesics was associated with the risk of total RCC in meta-analyses of the three study cohorts. For fatal RCC (n=175 cases), however, meta-analyses of the HPFS and NHS suggested covariate-adjusted positive associations with current (HR: 1.37, 95% CI: 0.96-1.96, p-heterogeneity: 0.80) and duration of (HR>10yrs vs. Never: 2.62, 95% CI: 1.23-5.58, p-trend: 0.006, p-heterogeneity: 0.30) pre-diagnostic non-aspirin NSAID use. In addition, in the HPFS only, current (HR: 2.35, 95% CI: 1.33-4.17) and duration of (HR>10yrs vs. Never: 1.83, 95% CI: 0.42-7.93, p-trend: 0.07) pre-diagnostic acetaminophen use indicated positive associations with fatal RCC. Analyses of RCC-specific mortality among participants diagnosed with RCC demonstrated an inverse association with current post-diagnostic aspirin use (HR: 0.68, 95% CI: 0.48-0.97), but not duration of post-diagnostic aspirin use (HR>10yrs vs. Never: 0.89, 95% CI: 0.53-1.51, p-trend: 0.98). Analgesics were not otherwise associated with RCC survival. Conclusions: Our findings support a potential positive association between non-aspirin NSAID use and incident fatal RCC. It remains possible that analgesics may operate differently in the setting of RCC from the context of other chronic diseases. Citation Format: Rebecca E. Graff, Alejandro Sanchez, Toni K. Choueiri, Meir J. Stampfer, Edward L. Giovannucci, Lorelei A. Mucci, Eunyoung Cho, Mark A. Preston. Analgesic use and renal cell carcinoma incidence and survival: Results from three prospective cohort studies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5893.

Prediction Factors of Early Postoperative Bleeding after Bariatric Surgery.

Identifying the possible predictors of postoperative bleeding is advantageous to reduce healthcare costs and promote patients' recovery. The aim of this study was to determine early postoperative bleeding predictors after bariatric surgery. This retrospective study was conducted using data from 2260 patients who underwent bariatric surgery. We diagnosed early postoperative bleeding by the following symptoms: abdominal pain, hypotension, tachycardia, hematemesis, melena, decreased hemoglobin level, the need for at least two units of packed red blood cells (PRBCs) transfusion, and reoperation within the first 48h after surgery. Our results showed the odds of early postoperative bleeding in laparoscopic Roux-en-Y gastric bypass (LRYGB) were higher than in laparoscopic sleeve gastrectomy (LSG) (OR 3.49, 95% CI 1.79 to 6.80). In addition, prior intragastric balloon (IGB) (OR 3.14, 95% CI 1.18 to 8.34) and oral non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) (OR 5.91, 95% CI 1.79 to 20.63) were positively associated with the occurrence of postoperative bleeding. In contrast, there was an inverse relationship between staple line oversewing and the odds of postoperative bleeding (OR 0.18, 95% CI 0.04 to 0.81). After stratification data based on the type of the surgery, the positive association between IGB and the odds of bleeding was constant in the LRYGB group. In the LSG group, use of non-aspirin NSAIDs was linked to a higher incidence of postoperative bleeding, while oversewing of the staple line lowered the incidence of this event. Our results demonstrated a positive association between type of procedure, history of IGB, and oral non-aspirin NSIADs use, as well as an inverse relationship between staple line oversewing and the odds of bleeding after bariatric surgery.

Non-aspirin NSAIDs and head and neck cancer mortality in a Danish nationwide cohort study

BackgroundEvidence suggests that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) have antineoplastic properties of potential importance for survival of head and neck cancer. MethodsWe conducted a nationwide cohort study including all individuals with primary head and neck squamous cell carcinoma in Denmark during 2000–2016 at age 30–84 years, with no history of cancer (except non-melanoma skin cancer), and alive at 1 year after diagnosis. Nationwide registries provided information on drug use, causes of death and potential confounders, and additional clinical information was obtained for a subpopulation. We conducted Cox proportional hazards regression to estimate multivariable-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for the association between post-diagnosis non-aspirin NSAID use (defined as ≥1 filled prescription within first year after diagnosis) and cancer-specific mortality. ResultsAmong 10,770 head and neck cancer 1-year survivors, the HR for cancer-specific mortality with non-aspirin NSAID use was 1.68 at 1 year after diagnosis, but declined and stabilized around 1.15 (95% CI 1.02–1.29) at 2 years after diagnosis. Among 2-year survivors, the HRs for cancer-specific mortality with non-aspirin NSAID use remained slightly increased in analyses stratified by age, sex, stage, and pre-diagnosis non-aspirin NSAID use. Similar results were seen in the subpopulation (n = 1029) with additional clinical information, and among 5-year survivors with additional non-aspirin NSAID exposure assessment. ConclusionIn this nationwide cohort of patients with head and neck cancer, use of non-aspirin NSAIDs was associated with a slightly increased mortality risk, warranting further evaluation.

Influence of Long-term Nonaspirin NSAID Use on Risk of Frailty in Men ≥60 Years: The Physicians' Health Study.

Inflammation is a central pathway leading to frailty but whether commonly used nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) can prevent frailty is unknown. Prospective cohort study of male physicians ≥60 who participated in the Physicians' Health Study. Annual questionnaires collected data on NSAID use, lifestyle, and morbidity. Average annual NSAID use was categorized as 0 days/year, 1-12 days/year, 13-60 days/year, and >60 days/year. Frailty was assessed using a validated 33-item frailty index. Propensity score inverse probability of treatment weighting was used to address confounding by indication and logistic regression models estimated odds ratios (ORs) of prevalent frailty according to nonaspirin NSAID use. A total of 12 101 male physicians were included (mean age 70 ± 7 years, mean follow-up 11 years). Reported NSAID use was 0 days/year for 2 234, 1-12 days/year for 5 812, 13-60 days/year for 2 833, and >60 days/year for 1 222 participants. A total of 2 413 participants (20%) were frail. Higher self-reported NSAID use was associated with greater alcohol use, smoking, arthritis, hypertension, and heart disease, while less NSAID use was associated with coumadin use and prior bleeding. After propensity score adjustment, all characteristics were balanced. ORs (95% confidence intervals) of prevalent frailty were 0.90 (0.80-1.02), 1.02 (0.89-1.17), and 1.26 (1.07-1.49) for average NSAID use of 1-12 days/year, 13-60 days/year, and >60 days/year, compared to 0 days/year (p-trend < .001). Long-term use of NSAIDs at high frequency is associated with increased risk of frailty among older men. Additional study is needed to understand the role of anti-inflammatory medication in older adults and its implication for overall health.

Associations of Aspirin and Non-Aspirin Non-Steroidal Anti-Inflammatory Drugs With Colorectal Cancer Mortality After Diagnosis.

Aspirin use reduces colorectal cancer (CRC) incidence, but there is limited evidence regarding associations of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) with CRC-specific survival. This prospective analysis includes women and men from the Cancer Prevention Study-II Nutrition Cohort who were cancer free at baseline (1992 or 1993) and diagnosed with CRC during incidence follow-up through 2015. Detailed information on aspirin and non-aspirin NSAID use was self-reported on questionnaires at baseline, in 1997, and every 2 years thereafter. Pre- and postdiagnosis data were available for 2686 and 1931 participants without distant metastases, respectively, among whom 512 and 251 died from CRC during mortality follow-up through 2016. Secondary analyses examined associations between prediagnosis aspirin use and stage at diagnosis (distant metastatic vs localized or regional). All statistical tests were 2-sided. Long-term regular use of aspirin (>15 times per month) before diagnosis was associated with lower CRC-specific mortality (multivariable-adjusted hazard ratio [HR] = 0.69, 95% confidence interval [CI] = 0.52 to 0.92). Postdiagnosis regular aspirin use was not statistically significantly associated with risk of CRC-specific mortality overall (HR = 0.82, 95% CI = 0.62 to 1.09), although participants who began regular aspirin use only after their diagnosis were at lower risk than participants who did not use aspirin at both the pre- and postdiagnosis periods (HR = 0.60, 95% CI = 0.36 to 0.98). Long-term aspirin use before diagnosis was also associated with lower odds of diagnosis with distant metastases (multivariable-adjusted odds ratio = 0.73, 95% CI = 0.53 to 0.99). Our results suggest that long-term aspirin use before a diagnosis of nonmetastatic colorectal cancer may be associated with lower CRC-specific mortality after diagnosis, consistent with possible inhibition of micrometastases before diagnosis.

Risk of Multiple System Atrophy and the Use of Anti-Inflammatory Drugs: A Danish Register-Based Case-Control Study

Introduction: Multiple system atrophy (MSA) is a rare rapidly progressive atypical Parkinson disorder presenting clinically with parkinsonism and/or a cerebellar syndrome in combination with dysautonomia. Severe neuroinflammation develops along with hallmark neuropathological changes, and as in Parkinson’s disease, intake of anti-inflammatory medication has been hypothesized to be protective for development of disease. We aimed to investigate if use of non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin, or statins were associated with a reduced risk of MSA. Methods: We performed a register-based case-control study in MSA (n = 155) cases and population controls (n= 7,750) matched on age, gender, and place of residency by risk-set sampling. Pharmacological exposure prior to diagnosis was assessed in 2 categories (user vs. nonuser, cumulated dose in tertiles [T1-T3]). In an unconditional logistic regression model, adjusted for age, gender, residency, and chronic obstructive pulmonary disease (COPD), we estimated ORs and 95% CIs. Results: Data suggested a trend towards non-aspirin NSAID use to be associated with a decreased risk of MSA (OR 0.72 [95% CI 0.49–1.06]) compared to nonusers, decreasing dose-dependently (T2 OR 0.77 [95% CI 0.43–1.38]; T3 OR 0.55 [95% CI 0.29–1.06]). However, data were based on small numbers. Use of statins and low-dose aspirin was not associated with a decreased risk of MSA. Results were lagged 5 years from index date to address reverse causation. Conclusion: A trend toward use of non-aspirin NSAID and an associated reduced risk of MSA was observed in this study. However, our analyses had limited statistical precision, and further studies including larger sample sizes and longer exposure periods are needed.

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

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

Nonaspirin NSAIDs and contralateral breast cancer risk.

Laboratory studies suggest that inhibition of the cyclooxygenase (COX)-2 enzymes inhibits breast cancer development. We aimed to evaluate whether postdiagnosis use of COX-2 selective or other nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of contralateral breast cancer (CBC) among Danish breast cancer patients. From the clinical database of the Danish Breast Cancer Group, we identified 52,723 women diagnosed with breast cancer between 1996 and 2012. Data on nonaspirin NSAID use, CBC and potential confounding variables were obtained from nationwide registries. We defined postdiagnosis use (two or more prescriptions) as a time-varying covariate with a one-year lag. Cox proportional hazard regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for CBC associated with nonaspirin NSAID use. During a median follow-up of 4.8 years (interquartile range: 2.3-9 years), 1,444 patients were diagnosed with CBC. Overall, postdiagnosis use of nonaspirin NSAID was associated with an adjusted HR for CBC of 0.98 (95% CI: 0.87-1.11). The HRs did not vary substantially with duration or intensity of nonaspirin NSAID use. Moreover, similar associations were found for COX-2 selective (HR: 1.02; 95% CI: 0.85-1.23) and nonselective (HR: 0.96; 95% CI: 0.82-1.13) nonaspirin NSAIDs. In conclusion, our nationwide cohort study of breast cancer patients does not suggest a reduced risk of CBC with nonaspirin NSAID use regardless of the COX-2 selectivity.

Pre-diagnosis and post-diagnosis use of common analgesics and ovarian cancer prognosis (NHS/NHSII): a cohort study.

Ovarian cancer is the fifth most common cause of cancer death among women in the USA. In this study, our objective was to determine whether modifiable exposures to common analgesics outside of standard treatment influence prognosis in patients with ovarian cancer. The Nurses' Health Study (NHS) and Nurses' Health Study II (NHSII) are ongoing prospective studies of 121 700 and 116 429 US nurses who have completed biennial questionnaires since 1976 and 1989, respectively. We retrieved information from medical records, death certificates, or linkage to a state or Surveillance, Epidemiology, and End Results (SEER) cancer registry on ovarian cancer cases. Eligible participants had confirmed invasive, stage I-III epithelial ovarian cancer, and had data available on analgesic use. The primary objective was to determine whether self-reported regular use (≥2 days per week) of aspirin, non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs), or paracetamol before and after ovarian cancer diagnosis, was associated with ovarian cancer-specific survival. We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% CIs for these associations, adjusting for age and year of diagnosis, disease stage, and histology. Between June 1, 1976, and May 31, 2012, for the NHS and between June 1, 1989, and May 31, 2013, for NHSII, 1789 participants of the NHS and NHSII studies were diagnosed with epithelial ovarian cancer and 1143 (64%) were eligible to be included in this study; 1031 (90%) of 1143 cases were included in the pre-diagnosis exposure analysis and 964 cases (84%) in the post-diagnosis exposure analysis. Compared with never-users, participants who reported recent (current use in the past 2 years) post-diagnosis use of aspirin (HR 0·68 [95% CI 0·52-0·89]) and non-aspirin NSAIDs (HR 0·67 [95% CI 0·51-0·87]) had an improved ovarian cancer-specific survival. Any type of analgesic use pre-diagnosis, and post-diagnosis use of paracetamol, were not positively associated with ovarian cancer-specific survival. In analyses of change in analgesic use from pre-diagnosis to post-diagnosis, those participants who became recent users of aspirin (HR 0·44 [95% CI 0·26-0·74]) or became recent users of non-aspirin NSAIDs (HR 0·46 [95% CI 0·29-0·73]) post-diagnosis had a lower risk of ovarian cancer-specific death than never-users. Recent use of aspirin or non-aspirin NSAIDs, defined as current use in the past 2 years, after diagnosis appears to improve ovarian cancer-specific survival. If these results are confirmed in further studies, further research should explore potential synergistic effects of anti-inflammatory medications used in combination with standard ovarian cancer therapies to improve the prognosis for patients diagnosed with ovarian cancer. National Institutes of Health, National Cancer Institute, The Marsha Rivkin Center for Ovarian Cancer Research.

Non-aspirin NSAID use and ovarian cancer mortality

ObjectivePreclinical studies suggest that non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) may improve survival of ovarian cancer. We examined the association between non-aspirin NSAID use and ovarian cancer mortality. MethodsAll women in Denmark with a first diagnosis of epithelial ovarian cancer between 2000 and 2012 were identified. We obtained information on drug use, mortality outcomes, and potential confounding factors from nationwide registries. Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between postdiagnosis non-aspirin NSAID use (≥1 prescription) and ovarian cancer-specific or other-cause mortality compared with non-use (no prescriptions). The influence of competing risks was evaluated using the sub-distribution hazards model proposed by Fine and Gray. ResultsAmong 4117 patients, any postdiagnosis use of non-aspirin NSAIDs was not associated with either ovarian cancer (HR = 0.97, 95% CI = 0.87–1.08) or other-cause (HR = 0.99, 95% CI = 0.77–1.27) mortality, however, inverse associations for ovarian cancer mortality were observed with high cumulative (HR = 0.75, 95% CI = 0.60–0.94) or high-intensity (HR = 0.86, 95% CI = 0.72–1.03) postdiagnosis use of non-aspirin NSAIDs. The associations differed substantially with histological subtype of ovarian cancer, with only inverse associations observed for serous ovarian cancer (HR = 0.87, 95% CI = 0.77–0.99). Among a smaller number of patients with a non-serous tumor, postdiagnosis non-aspirin NSAID use was associated with increased ovarian cancer mortality. ConclusionsAny postdiagnosis use of non-aspirin NSAIDs did not influence ovarian cancer mortality overall, however, more intensive use was associated with improved survival of serous ovarian cancer.

Regular Use of Aspirin or Non-Aspirin Nonsteroidal Anti-Inflammatory Drugs Is Not Associated With Risk of Incident Pancreatic Cancer in Two Large Cohort Studies

Use of aspirin and/or non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) reduces the risk of several cancers, but it is not clear if use of these drugs is associated with risk of pancreatic cancer. We evaluated aspirin and non-aspirin NSAID use and risk of pancreatic adenocarcinoma in 141,940 participants from theHealth Professionals Follow-up Study and Nurses' HealthStudy using multivariable-adjusted Cox proportional hazards regression. We considered several exposure classifications to model differing lag times between NSAID exposure and cancer development. We also conducted a nested case-control study of participants from 3 prospective cohorts using conditional logistic regression to evaluate pre-diagnosis levels of plasma salicylurate, a major metabolite of aspirin,in396 pancreatic cancer cases and 784 matched individuals without pancreatic cancer (controls). In the prospective cohort study, 1122 participants developed pancreatic adenocarcinoma over 4.2 million person-years. Use of aspirin or non-aspirin NSAIDs was not associated with pancreatic cancer risk, even after considering several latency exposure classifications. In a pre-planned subgroup analysis, regular aspirin use was associated with reduced pancreatic cancer risk among participants with diabetes (relative risk, 0.71; 95% CI, 0.54-0.94). In the nested case-control study, pre-diagnosis levels of salicylurate were notassociated with pancreatic cancer risk (odds ratio, 1.08; 95% CI, 0.72-1.61; Ptrend 0.81; comparing participants in thehighest quintile with those in the lowest quintile of plasma salicylurate). Regular aspirin or non-aspirin NSAID use was not associated with future risk of pancreatic cancer in participants from several large prospective cohort studies. A possible reduction in risk for pancreatic cancer among people with diabetes who regularly use aspirin should be further examined in preclinical and human studies.

Aspirin and NSAID use in association with molecular subtypes of prostate cancer defined by TMPRSS2:ERG fusion status.

The TMPRSS2:ERG (T2E) gene fusion is the most common rearrangement in prostate cancer (PCa). It is unknown if these molecular subtypes have a different etiology. We evaluated aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) in association with T2E fusion status. Subjects were from a population-based case-control study of PCa. T2E fusion status for prostatectomy cases (n=346) was determined by fluorescence in situ hybridization. Medication use was determined from questionnaires. Logistic regression, controlling for age, race, PCa family history and PSA screening, was used to evaluate the association of T2E fusion status according to medication use. T2E fusion was present in 171 (49%) cases, with younger cases more likely to be fusion positive (P<0.01). Current aspirin use was associated with a 37% risk reduction of T2E-positive tumors (adjusted odds ratio (OR) 0.63, 95% confidence interval 0.43-0.93). Aspirin use was not associated with T2E negative PCa (adjusted OR 0.99, 0.69-1.42). There were no associations between PCa fusion status and use of nonaspirin NSAIDs or acetaminophen. Aspirin was associated with a significant reduction in the relative risk of T2E fusion positive, but not T2E negative, PCa. As inflammation and androgen pathways are implicated in prostate carcinogenesis, additional studies of anti-inflammatory medications in relation to these PCa subtypes are warranted.

Use of nonsteroidal anti-inflammatory drugs and risk of endometrial cancer: a nationwide case-control study.

We examined the association between use of low-dose aspirin and non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) and endometrial cancer risk in a nationwide case-control study. Cases were all women in Denmark diagnosed with endometrial cancer during 2000-2009. Age-matched female controls were randomly selected by risk-set sampling. Information on NSAID use was collected from the Prescription Registry and classified according to duration and intensity. Conditional logistic regression was used to calculate odds ratios (ORs) and 95 % confidence intervals (CIs), adjusting for potential confounders. Analyses were stratified by endometrial cancer type, and potential effect modification by parity, obesity, and hormone replacement therapy (HRT) use was investigated. We identified 5,382 endometrial cancer cases and 72,127 controls. Endometrial cancer was not associated with use of low-dose aspirin (OR 0.97, 95 % CI 0.89-1.05) or non-aspirin NSAIDs (OR 0.96, 95 % CI 0.91-1.02) compared with nonuse. The ORs did not vary with increasing duration or intensity of NSAID use or with type of endometrial cancer. Interaction analyses showed reduced endometrial cancer risk associated with low-dose aspirin use among nulliparous women (OR 0.82, 95 % CI 0.70-0.95) and with non-aspirin NSAID use among women having used HRT (OR 0.90, 95 % CI 0.82-0.99). We found no association between use of NSAIDs and endometrial cancer risk overall, although there were some indications of risk reductions associated with low-dose aspirin use among nulliparous women and with non-aspirin NSAID use among women having used HRT.

Aspirin, nonaspirin nonsteroidal anti-inflammatory drugs, acetaminophen and ovarian cancer survival

Aspirin and nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to decrease tumor progression in pre-clinical models of ovarian cancer, however the influence of these drugs on survival in women following a diagnosis of ovarian cancer is unknown. We included 1305 Australian women diagnosed with incident invasive epithelial ovarian cancer, recruited into a population-based case–control study. Use of aspirin, nonaspirin NSAIDs and acetaminophen in the 5 years preceding ovarian cancer diagnosis was assessed from self-reports. Deaths were ascertained up to October 2011 via linkage with the Australian National Death Index. Cox proportional hazards regression models were used to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CI). During a mean follow-up time of 4.9 years (SD 2.8 years), there were 834 deaths, of which 779 (93% of deaths) were from ovarian cancer. We found uniformly inverse, but non-significant, HRs for ever use in the last five years of aspirin, nonaspirin NSAIDs and acetaminophen compared with no use (adjusted HRs 0.92 [95% CI 0.81–1.06], 0.91 [95% CI 0.80–1.05] and 0.91 [95% CI 0.69–1.20], respectively). There was no evidence of any dose response trends. The results remained unchanged when we limited the outcome to ovarian cancer mortality. Associations did not differ by histologic subtype, age at diagnosis or stage. Given current interest in the role of aspirin and nonaspirin NSAIDs in cancer survival these results are noteworthy given they are the first to investigate these associations in women with ovarian cancer. Our results provide no strong evidence that pre-diagnostic use of aspirin or nonaspirin NSAIDs are associated with improved survival in women with ovarian cancer.

Analgesic use and patterns of estrogen metabolism in premenopausal women.

Analgesic use has been hypothesized to reduce the risk of some cancers, with inverse associations between analgesics and colon cancer, and suggestive inverse associations for breast cancer. Estrogen metabolites (EM) have genotoxic and estrogenic potential; genotoxicity may differ by hydroxylation pathway. Analgesic use may impact patterns of estrogen metabolism; effects of analgesics on disease risk could be mediated through these patterns. We conducted a cross-sectional study among 603 premenopausal women in the Nurses' Health Study II. Frequency of aspirin, non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs), and acetaminophen use was reported via questionnaire; average frequency in 1997 and 1999 was calculated. Women provided urine samples between 1996 and 1999, collected during the mid-luteal phase of the menstrual cycle. Urinary EM were quantified using high-performance liquid chromatography-tandem mass spectrometry. We observed no association between analgesic use and estradiol, estrone, or specific pathways of estrogen metabolism. Women reporting more frequent aspirin use had lower methylated 2-catechols (e.g., 2-hydroxyestrone-3-methyl ether, 2+ days/week vs. non-use: 0.95 vs. 1.21pmol/mg creatinine; p difference = 0.01, p trend = 0.07). Non-aspirin NSAID use was positively associated with 17-epiestriol (4+ days/week vs. non-use: 2.48 vs. 1.52pmol/mg creatinine; p difference = 0.01, p trend = 0.11). Acetaminophen use was positively associated with total EM (2+ days/week vs. non-use: 236 vs. 198pmol/mg creatinine; p difference = 0.02, p trend = 0.11), 2-hydroxyestrone-3-methyl ether (1.6 vs. 1.1pmol/mg creatinine; p difference < 0.01, p trend = 0.02), and 16α-hydroxyestrone (17 vs. 12pmol/mg creatinine; p difference = 0.01, p trend = 0.05). This study provides the first assessment of analgesic use and patterns of estrogen metabolism in women. While we observed some associations between analgesics and individual EM, no clear patterns emerged.

Use of nonaspirin nonsteroidal anti-inflammatory drugs during pregnancy and the risk of spontaneous abortion

The association between the use of nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) during pregnancy and the risk of spontaneous abortion remains unclear because of inconsistent research results and the lack of evidence for an effect due to specific types or dosages of nonaspirin NSAIDs. We aimed to quantify the association between having a spontaneous abortion and types and dosages of nonaspirin NSAIDs in a cohort of pregnant women. Using a nested case-control design, we obtained data from the Quebec Pregnancy Registry for 4705 women who had a spontaneous abortion. For each instance, we randomly selected 10 controls from the remaining women in the registry who were matched by index date (date of the spontaneous abortion) and gestational age. Use of nonaspirin NSAIDs (identified by filled prescriptions) and nonuse were compared. We also looked for associations between different types and dosages of nonaspirin NSAIDs and having a spontaneous abortion. Analyses of associations and adjustment for confounding were done using conditional logistic regression. We identified 4705 cases of spontaneous abortion (352 exposed [7.5%]); 47 050 controls (1213 exposed [2.6%]). Adjusting for potential confounders, the use of nonaspirin NSAIDs during pregnancy was significantly associated with the risk of spontaneous abortion (odds ratio [OR] 2.43, 95% confidence interval [CI] 2.12-2.79). Specifically, use of diclofenac (OR 3.09, 95% CI 1.96-4.87), naproxen (OR 2.64, 95% CI 2.13-3.28), celecoxib (OR 2.21, 95% CI 1.42-3.45), ibuprofen (OR 2.19, 95% CI 1.61-2.96) and rofecoxib (OR 1.83, 95% CI 1.24-2.70) alone, and combinations thereof (OR 2.64, 95% CI 1.59-4.39), were all associated with increased risk of spontaneous abortion. No dose-response effect was seen. Gestational exposure to any type or dosage of nonaspirin NSAIDs may increase the risk of spontaneous abortion. These drugs should be used with caution during pregnancy.

Long-Term Use of Acetaminophen, Aspirin, and Other Non-Steroidal Anti-Inflammatory Drugs and Risk of Hematologic Malignancies: Results From the Large, Prospective VITamins and Lifestyle (VITAL) Cohort Study

AbstractAbstract 2153 Background:Several epidemiological studies have examined the association of aspirin use and other over-the-counter analgesics or anti-inflammatory drugs and the incidence of hematologic malignancies. Although previous results have been inconsistent, some studies have suggested a reduced risk of leukemia or lymphoma with regular use of aspirin or non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs). On the other hand, some but not all studies have reported an increased risk of leukemia or lymphoma with regular use of acetaminophen. Methods:We evaluated the association of analgesic use to hematologic malignancies in a prospective cohort of 64,839 men and women aged 50 to 76 years from Washington State recruited in 2000 to 2002 to the VITamins And Lifestyle (VITAL) study. Eligible participants completed a 24-page baseline questionnaire, including detailed questions about medication use during the previous 10 years. Incident cases of hematologic malignancies (n=577, including MDS [n=54], AML [n=36], myeloproliferative disorders [n=46], CLL/SLL [n=88] and other non-Hodgkin lymphomas [n=235], Hodgkin lymphomas [n=22], plasma cell disorders [n=66], mature NK/T cell neoplasms [n=17], and other entities [n=13]) were identified through December 2008 by linkage to the Seattle-Puget Sound Surveillance, Epidemiology, and End Results (SEER) cancer registry. The censored date was the date of withdrawal from the study, death, move out of the SEER catchment area, or last date of linkage to SEER for diagnosis of hematologic malignancy. In addition, participants were excluded if they had any cancer prior to baseline other than non-melanoma skin cancer and were censored at the time of diagnosis of a non-hematologic malignancy during follow-up to remove treatment for a prior cancer as a cause of any subsequent hematologic cancer. Medication use was categorized as “no use”, “low use” (use for either less than 4 days/week or less than 4 years), and “high use” (use for at least 4 days/week and at least 4 years). Hazards ratios (HRs) and 95% confidence intervals (95% CI) associated with use of acetaminophen, aspirin, and non-aspirin NSAIDs for total incident hematologic malignancies and cancer subcategories were estimated by Cox proportional hazards models. Multivariable-adjusted models were fit by adjusting for age, sex, race/ethnicity, education, smoking, self-rated health, history of fatigue/lack of energy, and family history of leukemia or lymphoma. All models except low-dose aspirin were further adjusted for history of rheumatoid arthritis, history or non-rheumatoid arthritis or chronic neck/back/joint pain, and history of migraines or frequent headaches. The model for low-dose aspirin was further adjusted for history of coronary artery disease, stroke, diabetes, or use of antihypertensive or lipid-lowering medications. Results:After adjustment, there was an increased risk of incident hematologic malignancies associated with increasing use of acetaminophen (HR=1.81 [95% CI: 1.33–2.46] for high use; p=0.009 for trend). The association with high use of acetaminophen was seen for MDS/AML (HR=2.23 [1.09-4.56]), non-Hodgkin lymphomas (HR=1.82 [1.14-2.92]), and plasma cell disorders (HR=2.32 [0.98-5.50]) but not CLL/SLL (HR=0.83 [0.30-2.35]). By comparison, there was no association with risk of incident hematologic malignancies for increasing use of low-dose aspirin (HR=1.04 [0.81-1.33] for high use; p=0.856 for trend), regular-dose aspirin (HR=0.86 [0.67-1.11] for high use; p=0.329 for trend), non-aspirin NSAIDs (HR=1.04 [0.75-1.43] for high use; p=0.820 for trend), or ibuprofen (HR=0.98 [0.67-1.44] for high use; p=0.956 for trend). Conclusion:Use of acetaminophen increased the risk of incident hematologic malignancies other than CLL/SLL in a usage-dependent manner, with an almost 100% increased risk for use least 4 days/week for of at least 4 years. Neither aspirin nor non-aspirin NSAIDs decreased risk and are unlikely to be useful for chemoprevention. Disclosures:No relevant conflicts of interest to declare.

Analgesic Use and Sex Steroid Hormone Concentrations in Postmenopausal Women

Prior epidemiologic studies suggest that regular use of analgesics may decrease risk of breast and ovarian cancer. We explored possible hormone-mediated mechanisms for these associations by examining the relationship between use of aspirin, nonaspirin nonsteroidal anti-inflammatory drugs (NSAID), and acetaminophen and sex steroid hormone concentrations among 740 postmenopausal women in the Nurses' Health Study. All women reported their analgesic use in 1988 or 1990 and provided a blood sample in 1989 to 1990. We calculated adjusted geometric mean estrogen and androgen levels for each category of analgesic use and calculated the P value for trend with increasing frequency of use. There was no association between days of use per month of aspirin, nonaspirin NSAIDs, or acetaminophen in 1990 and hormone levels (all P(trend) > or = 0.09). However, we observed significant inverse trends between the estimated number of aspirin tablets per month in 1988 and concentrations of estrone (P(trend) = 0.04) and estrone sulfate (P(trend) = 0.03). In analyses of total (aspirin and nonaspirin) NSAID use in 1990, women who used NSAIDs at least 15 days per month had significantly lower levels of estradiol compared with women with no NSAID use (P(trend) = 0.03). Frequency of use of all analgesics (aspirin, nonaspirin NSAIDs, and acetaminophen) in 1990 was inversely associated with concentrations of estradiol (P(trend) = 0.001), free estradiol (P(trend) = 0.01), estrone sulfate (P(trend) = 0.03), and the ratio of estradiol to testosterone (P(trend) = 0.04). Among postmenopausal women, regular users of aspirin and other analgesics may have lower estrogen levels than nonusers, which could contribute to a decreased risk of breast or ovarian cancer among analgesic users.

Aspirin and other non-steroidal anti-inflammatory drugs and risk of colorectal cancer: A Danish cohort study

The optimal duration and dose of aspirin and non-aspirin non-steroidal anti-inflammatory drugs (NSAIDs) in the potential prevention of colorectal cancer (CRC) have not been established. We examined this issue in the Danish Diet, Cancer, and Health Study. Self-reported NSAID use at entry (January 1995-May 1997) was updated through June 2006, using a nationwide prescription database. CRC incidence was ascertained from nationwide registers. Cox proportional hazards regression was used to compute confounder-adjusted incidence rate ratios (RRs) and 95% confidence intervals (CIs). From 51,053 cohort subjects, we identified 615 CRC cases during 1995-2006. Daily aspirin use at entry was associated with a decreased risk of CRC (RR, 0.73; 95% CI, 0.49-1.10). A similar risk reduction was seen among subjects with 10 or more prescriptions for aspirin or non-aspirin NSAIDs and five or more years of follow-up. Most aspirin prescriptions were for 75-150 mg aspirin tablets. Among non-aspirin NSAID users, only those with body mass index (BMI) above 25 showed risk reductions [RR, 0.69 (0.47-1.03) for 10 or more prescriptions]. Long-term consistent use of aspirin or non-aspirin NSAIDs appears necessary to achieve a protective effect against CRC. Further studies of the effective dose of aspirin and the potential interaction between NSAID use and BMI are warranted.

Abstract A116: Nonsteroidal anti-inflammatory drug use and risk of gastric and esophageal adenocarcinoma in a large cohort study

Abstract A116 Background Previous studies suggest that the use of aspirin or non-aspirin nonsteroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of gastric and esophageal adenocarcinomas, but few studies have been prospective, have used data collected directly from subjects, and have controlled for the many potential confounders. Methods: We examined the association between aspirin or non-aspirin NSAID use and incident gastric noncardia (N=182), gastric cardia (N=178), and esophageal adenocarcinomas (N=228) in the NIH-AARP Diet and Health prospective cohort study with subjects followed for up to 7 years. We estimated the hazard ratios (HR) and 95% confidence intervals (CI) in Cox models for any use of aspirin or non-aspirin NSAIDs in the previous twelve months or for the typical frequency of use (at least monthly, weekly, or daily) with adjustment for age, sex, smoking, alcohol, BMI, education, physical activity, and fruit and vegetable intake. Results For gastric noncardia cancer, we found that any aspirin use had an HR (95%CI) of 0.64 (0.47-0.86) and for daily use 0.57 (0.39-0.85). The age-standardized incidence rates (95% CI) per 100,000 person years dropped from 11.0 (8.4-13.6) in non-aspirin users to 7.0 (5.7-8.3) in users. For any non-aspirin NSAID use we found an HR (95%CI) of 0.68 (0.51-0.92) and for daily use 0.82 (0.50-1.34). We found no significant association between NSAID use and gastric cardia cancer or esophageal adenocarcinoma. For the latter, any or daily aspirin use had HR (95% CI) of 1.00 (0.73-1.37) and 1.11 (0.78-1.57), respectively. Conclusions We found a strong association between NSAID use, especially aspirin, and reduced risk of noncardia gastric adenocarcinoma, but not adenocarcinoma of the gastric cardia or esophagus. Citation Information: Cancer Prev Res 2008;1(7 Suppl):A116.