Individual Non-steroidal Anti-inflammatory Drugs Research Articles

Use of Nonsteroidal Anti-Inflammatory Drugs and Pancreatic Cancer Risk in the Women's Health Initiative.

Pancreatic cancer is among the most fatal human cancers and the fourth leading cause of cancer death in the United States. Evidence suggests that chronic inflammation may play a role in pancreatic carcinogenesis and its inhibition through nonsteroidal anti-inflammatory drugs (NSAID) may reduce pancreatic cancer incidence. We examined associations of total and individual NSAIDs with pancreatic cancer risk among postmenopausal women participating in the Women's Health Initiative observational study and clinical trial cohorts. Among 117,452 women, aged 55 to 79 years, 727 incident pancreatic cancer cases were reported over 18 years of follow-up. Cox regression was used to estimate hazard ratio (HR) and 95% confidence interval (CI) for associations between NSAIDs and pancreatic cancer risk. Relative to non-use, consistent use of any NSAID was inversely associated with pancreatic cancer risk (HR 0.71, 95% CI, 0.59-0.87), primarily driven by strong associations for aspirin use (HR 0.67, 95% CI, 0.52-0.86). Use of total or individual non-aspirin NSAIDs was not associated with pancreatic cancer. Upon stratified analysis, we observed stronger associations for NSAIDs among participants with prevalent diabetes (HR 0.28, 95% CI, 0.10-0.75) relative to those without (HR 0.75, 95% CI, 0.61-0.92; P-interaction = 0.03). Additional large prospective studies with careful measurement of NSAID type, dose, and frequency are needed to further investigate the possibility of added benefit among individuals diagnosed with diabetes. This study adds to existing evidence from prospective studies and clinical trials suggesting that use of aspirin may provide moderate benefit for pancreatic cancer prevention.

Comparison of different nonsteroidal anti-inflammatory drugs for cesarean section: a systematic review and network meta-analysis.

Cesarean section is associated with moderate to severe pain and nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly employed. The optimal NSAID, however, has not been elucidated. In this network meta-analysis and systematic review, we compared the influence of control and individual NSAIDs on the indices of analgesia, side effects, and quality of recovery. CDSR, CINAHL, CRCT, Embase, LILACS, PubMed, and Web of Science were searched for randomized controlled trials comparing a specific NSAID to either control or another NSAID in elective or emergency cesarean section under general or neuraxial anesthesia. Network plots and league tables were constructed, and the quality of evidence was evaluated with Grading of Recommendations Assessment, Development and Evaluation (GRADE) analysis. We included 47 trials. Cumulative intravenous morphine equivalent consumption at 24 h, the primary outcome, was examined in 1,228 patients and 18 trials, and control was found to be inferior to diclofenac, indomethacin, ketorolac, and tenoxicam (very low quality evidence owing to serious limitations, imprecision, and publication bias). Indomethacin was superior to celecoxib for pain score at rest at 8-12 h and celecoxib + parecoxib, diclofenac, and ketorolac for pain score on movement at 48 h. In regard to the need for and time to rescue analgesia COX-2 inhibitors such as celecoxib were inferior to other NSAIDs. Our review suggests the presence of minimal differences among the NSAIDs studied. Nonselective NSAIDs may be more effective than selective NSAIDs, and some NSAIDs such as indomethacin might be preferable to other NSAIDs.

Cardiovascular risks of continuing vs. initiating NSAIDs after first-time myocardial infarction or heart failure: a nationwide cohort study.

It is unknown whether the cardiovascular risks associated with the use of non-steroidal anti-inflammatory drugs (NSAIDs) shortly after first-time myocardial infarction (MI) or heart failure (HF) differ between patients continuing and initiating use. Using nationwide health registries, we conducted a cohort study of all patients with first-time MI or HF during 1996-2018 (n=273 682). NSAID users (n=97 966) were categorized as continuing (17%) and initiating (83%) users according to prescription fillings<60 days before index diagnosis. The primary outcome was a composite of new MI, HF admission, and all-cause death. Follow-up started 30 days after the index discharge date. We used Cox regression to compute hazard ratios (HRs) with 95% confidence intervals (CIs) comparing NSAID users vs. non-users. The most commonly filled NSAIDs were ibuprofen (50%), diclofenac (20%), etodolac (8.5%), and naproxen (4.3%). The composite outcome HR of 1.25 (CI: 1.23-1.27) was driven by initiators (HR=1.39, 1.36-1.41) and not continuing users (HR=1.03, 1.00-1.07). The lack of association among continuing users was also observed for individual NSAIDs (ibuprofen and naproxen), except diclofenac (HR=1.11, 95% CI: 1.05-1.18). Among initiators, the HR was 1.63 (CI: 1.57-1.69) for diclofenac, 1.31 (CI: 1.27-1.35) for ibuprofen, and 1.19 (CI: 1.08-1.31) for naproxen. The results were consistent for both MI and HF patients, the individual components of the composite outcome, and various sensitivity analyses. NSAID initiators were more susceptible to adverse cardiovascular outcomes after first-time MI or HF than continuing users.

Impact of Lifestyle and Socioeconomic Position on the Association Between Non-steroidal Anti-inflammatory Drug Use and Major Adverse Cardiovascular Events: A Case-Crossover Study.

It is unknown whether the cardiovascular risks associated with non-steroidal anti-inflammatory drug (NSAID) use differ according to lifestyle and socioeconomic position. We examined the association between NSAID use and major adverse cardiovascular events (MACE) within subgroups defined by lifestyle and socioeconomic position. We conducted a case-crossover study of all adult first-time respondents to the Danish National Health Surveys of 2010, 2013, or 2017, without previous cardiovascular disease, who experienced a MACE from survey completion through 2020. We used a Mantel-Haenszel method to obtain odds ratios (ORs) of the association between NSAID use (ibuprofen, naproxen, or diclofenac) and MACE (myocardial infarction, ischemic stroke, heart failure, or all-cause death). We identified NSAID use and MACE via nationwide Danish health registries. We stratified the analyses by body mass index, smoking status, alcohol consumption, physical activity level, marital status, education, income, and employment. Compared with non-use, the OR of MACE was 1.34 (95% confidence interval: 1.23-1.46) for ibuprofen, 1.48 (1.04-2.43) for naproxen, and 2.18 (1.72-2.78) for diclofenac. When comparing NSAID use with non-use or the individual NSAIDs with each other, we observed no notable heterogeneity in the ORs within subgroups of lifestyle and socioeconomic position for any NSAID. Compared with ibuprofen, diclofenac was associated with increased risk of MACE in several subgroups with high cardiovascular risk, e.g., individuals with overweight (OR 1.52, 1.01-2.39) and smokers (OR 1.54, 0.96-2.46). The relative increase in cardiovascular risk associated with NSAID use was not modified by lifestyle or socioeconomic position.

Neonatal and maternal adverse outcomes and exposure to nonsteroidal anti-inflammatory drugs during early pregnancy in South Korea: A nationwide cohort study.

Existing data on the use of nonsteroidal anti-inflammatory drugs (NSAIDs) during late pregnancy is well established, providing assurance. However, the use of NSAIDs during early pregnancy remains inconclusive owing to conflicting findings on adverse neonatal outcomes as well as the limited data on adverse maternal outcomes. Therefore, we sought to investigate whether early prenatal exposure to NSAIDs was associated with neonatal and maternal adverse outcomes. We conducted a nationwide, population-based cohort study using Korea's National Health Insurance Service (NHIS) database with a mother-offspring cohort constructed and validated by the NHIS to include all live births in women aged 18 to 44 years between 2010 and 2018. We defined exposure to NSAIDs as at least two records of NSAID prescriptions during early pregnancy (first 90 days of pregnancy for congenital malformations and first 19 weeks for nonmalformation outcomes) and compared against three distinct referent groups of (1) unexposed, no NSAID prescription during the 3 months before pregnancy start to end of early pregnancy; (2) acetaminophen-exposed, at least two acetaminophen prescriptions during early pregnancy (i.e., active comparator); and (3) past users, at least two NSAID prescriptions before the start of pregnancy but no relevant prescriptions during pregnancy. Outcomes of interest were adverse birth outcomes of major congenital malformations and low birth weight and adverse maternal outcomes of antepartum hemorrhage and oligohydramnios. We estimated relative risks (RRs) with 95% CIs using generalized linear models within a propensity score (PS) fine stratification weighted cohort that accounted for various potential confounders of maternal sociodemographic characteristics, comorbidities, co-medication use, and general markers of burden of illness. Of 1.8 million pregnancies in the PS weighted analyses, exposure to NSAIDs during early pregnancy was associated with slightly increased risks for neonatal outcomes of major congenital malformations (PS-adjusted RR, 1.14 [CI, 1.10 to 1.18]) and low birth weight (1.29 [1.25 to 1.33]), and for maternal outcome of oligohydramnios (1.09 [1.01 to 1.19]) but not antepartum hemorrhage (1.05 [0.99 to 1.12]). The risks of overall congenital malformations, low birth weight, and oligohydramnios remained significantly elevated despite comparing NSAIDs against acetaminophen or past users. Risks of adverse neonatal and maternal outcomes were higher with cyclooxygenase-2 selective inhibitors or use of NSAIDs for more than 10 days, whereas generally similar effects were observed across the three most frequently used individual NSAIDs. Point estimates were largely consistent across all sensitivity analyses, including the sibling-matched analysis. Main limitations of this study are residual confounding by indication and from unmeasured factors. This large-scale, nationwide cohort study found that exposure to NSAIDs during early pregnancy was associated with slightly higher risks of neonatal and maternal adverse outcomes. Clinicians should therefore carefully weigh the benefits of prescribing NSAIDs in early pregnancy against its modest, but possible, risk of neonatal and maternal outcomes, where if possible, consider prescribing nonselective NSAIDs for <10 days, along with continued careful monitoring for any safety signals.

Chronic use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen and relationship with mortality among United States Veterans after testing positive for COVID-19.

Non-steroidal anti-inflammatory drugs (NSAIDs) and acetaminophen are among the most-frequently used medications. Although these medications have different mechanisms of action, they have similar indications and treatment duration has been positively correlated with cardiovascular risk although the degree of risk varies by medication. Our objective was to study treatment effects of chronic use of individual NSAID medications and acetaminophen on all-cause mortality among patients who tested positive for COVID-19 while accounting for adherence. We used the VA national datasets in this retrospective cohort study to differentiate between sporadic and chronic medication use: sporadic users filled an NSAID within the last year, but not recently or regularly. Using established and possible risk factors for severe COVID-19, we used propensity scores analysis to adjust for differences in baseline characteristics between treatment groups. Then, we used multivariate logistic regression incorporating inverse propensity score weighting to assess mortality. The cohort consisted of 28,856 patients. Chronic use of aspirin, ibuprofen, naproxen, meloxicam, celecoxib, diclofenac or acetaminophen was not associated with significant differences in mortality at 30 days (OR = 0.98, 95% CI: 0.95–1.00; OR = 0.99, 95% CI: 0.98–1.00; OR = 1.00, 95% CI: 0.98–1.01; OR = 0.99, 95% CI: 0.98–1.00; OR = 1.00, 95% CI: 0.98–1.01; OR = 0.99, 95% CI: 0.97–1.01; and OR = 1.00, 95% CI: 0.99–1.02, respectively) nor at 60 days (OR = 0.97, 95% CI: 0.95–1.00; OR = 1.00, 95% CI: 0.99–1.01; OR = 0.99, 95% CI: 0.98–1.01; OR = 0.99, 95% CI: 0.97–1.00; OR = 0.99, 95% CI: 0.97–1.01; OR = 0.99, 95% CI: 0.97–1.01; and OR = 1.01, 95% CI: 0.99–1.02, respectively). Although the study design cannot determine causality, the study should assure patients as it finds no association between mortality and chronic use of these medications compared with sporadic NSAID use among those infected with COVID-19.

NSAIDs and PPIs - review of new reports

The aim of this study is to systematise knowledge on non-steroidal anti-inflammatory drugs (NSAIDs) - cyclooxygenase (COX) enzyme inhibitors and proton pump inhibitors (PPIs) inhibiting potassium hydrogen ATPase. A review of recent reports on possible side effects and new therapeutic options will be presented.&#x0D; Results: Over the last few years, reports of PPI side effects have been published: drug-induced thrombocytopenia, severe hypomagnesemia, hyponatremia or rhabdomyolysis. In the case of NSAIDs, ancillary therapeutic effects in the supportive therapy of multiple myeloma or in the reduction of adenoma formation in the colon stand out, but also cases of acute kidney injury in children. On the basis of meta-analyses, attempts were made to demonstrate the effect of individual NSAIDs on the occurrence of cardiovascular complications, stroke or myocardial infarction&#x0D; Conclusions: Despite the fact that the indicated preparations were admitted to the list of drugs several decades ago, still their pharmacological potential (on the example of NSAIDs, which can be successfully used even in complementary therapy) has not been fully exploited. The aforementioned reports on side effects must not be forgotten. It is possible that the examples presented in the review will raise awareness in order to use these drugs with greater respect, in accordance with the recommendations in the leaflet.

NSAID use is not associated with Parkinson's disease incidence: A Norwegian Prescription Database study.

Whether use of nonsteroidal anti-inflammatory drugs (NSAIDs) reduce the risk of incident Parkinson's disease (PD) remains unresolved. Here, we employed the Norwegian Prescription Database to examine whether NSAID use is associated with a lower incidence of PD. We compared the incidence of PD among users of NSAIDs in a population-based retrospective study using the Norwegian Prescription Database from 2004 to 2017. In total 7580 PD patients were identified using dopaminergic therapy over time as proxy for PD diagnosis. Analyses were performed with minimum 90 and 365 defined daily dose (DDD) NSAID exposure, respectively. Time-dependent Cox regression model and a binary logistic regression analysis with a 5-year lag until PD diagnosis were performed for all NSAIDs. There was overall no decrease in incidence of PD among NSAID users compared to controls. Using a minimum of 90 or 365 DDD threshold of exposure produced similar results. Analysis of individual NSAIDs did not show difference in PD incidence compared to controls Age-specific incidence rates of PD were comparable to reported age-specific incidence rates in previous studies. Our findings provide no evidence that cumulative high exposure to NSAIDs affects the risk of developing PD.

Topical NSAIDs for acute local pain relief: in vitro characterization of drug delivery profiles into and through human skin

Objective The efficacy of topical nonsteroidal anti-inflammatory drugs (NSAIDs) relates not only to the individual NSAID used but also to differences in formulation design. The aim of this study was to investigate the fundamental differences in ibuprofen and diclofenac drug delivery vehicles, specifically gels and plasters, compared to a recently launched 200 mg ibuprofen medicated plaster and characterize the resulting dermatologic–pharmacokinetic profiles into and through ex vivo human skin layers. Methods In vitro skin permeation testing over 24 h and sacrificial timepoint penetration experiments (at 1, 4, 8, 12, and 24 h) were conducted using an automated flow-through diffusion cell system. The amount of drug delivered to the epidermis, dermis, and receptor solution (representing deeper tissue) was determined by liquid chromatography-tandem mass spectrometry. Skin protein binding of ibuprofen and diclofenac was investigated by spiking skin homogenate with increasing concentrations of each drug and determining the fraction unbound. Results Differences were observed in the amount of drug recovered at sacrificial timepoints and rate at which drug was delivered to the target site between plaster and gel formulations of ibuprofen and diclofenac and between plaster formulations of the same drug (ibuprofen). While the amount of drug quantified at sacrificial timepoints did not necessarily determine in vivo flux rates, differences in drug distribution within the skin layers indicated where drug reservoirs were formed. Conclusions These findings highlight the importance of intelligent formulation design in determining NSAID delivery through skin layers. Further work is required to quantify drug delivery into deeper tissues and the resultant local anti-inflammatory effects.

NSAIDs and self-medication: A serious concern.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used by the patients frequently for pain which may be acute, acute-on-chronic, and chronic. For the relief of pain and inflammation, some patients may take the analgesics without consulting the family physician as they can procure the same easily, not realizing that there may be adverse effects associated with regular self-medication of NSAIDs. The NSAIDs have a risk of upper gastrointestinal bleeding or perforation, which may vary between individual NSAIDs at the doses commonly used by the patients. Thus, there is a need to create awareness in the society regarding the same to prevent self-medication associated complications.

Non-steroidal anti-inflammatory drugs for heavy menstrual bleeding.

Heavy menstrual bleeding (HMB) is an important cause of ill health in premenopausal women. Although surgery is often used as a treatment, a range of medical therapies are also available. Non-steroidal anti-inflammatory drugs (NSAIDs) reduce prostaglandin levels, which are elevated in women with excessive menstrual bleeding and also may have a beneficial effect on dysmenorrhoea. To determine the effectiveness, safety and tolerability of NSAIDs in achieving a reduction in menstrual blood loss (MBL) in women of reproductive years with HMB. We searched, in April 2019, the Cochrane Gynaecology and Fertility specialised register, Cochrane Central Register of Studies Online (CENTRAL CRSO), MEDLINE, Embase, PsycINFO, the clinical trial registries and reference lists of articles. The inclusion criteria were randomised comparisons of individual NSAIDs or combined with other medical therapy with each other, placebo or other medical treatments in women with regular heavy periods measured either objectively or subjectively and with no pathological or iatrogenic (treatment-induced) causes for their HMB. We identified 19 randomised controlled trials (RCTs) (759 women) that fulfilled the inclusion criteria for this review and two review authors independently extracted data. We estimated odds ratios (ORs) for dichotomous outcomes and mean differences (MDs) for continuous outcomes from the data of nine trials. We described in data tables the results of the remaining seven cross-over trials with data unsuitable for pooling, one trial with skewed data, and one trial with missing variances. One trial had no data available for analysis. As a group, NSAIDs were more effective than placebo at reducing HMB but less effective than tranexamic acid, danazol or the levonorgestrel-releasing intrauterine system (LNG IUS). Treatment with danazol caused a shorter duration of menstruation and more adverse events than NSAIDs, but this did not appear to affect the acceptability of treatment, based on trials from 1980 to 1990. However, currently danazol is not a usual or recommended treatment for HMB. There was no clear evidence of difference between NSAIDs and the other treatments (oral luteal progestogen, ethamsylate, an older progesterone-releasing intrauterine system and the oral contraceptive pill (OCP), but most studies were underpowered. There was no evidence of a difference between the individual NSAIDs (naproxen and mefenamic acid) in reducing HMB. The evidence quality ranged from low to moderate, the main limitations being risk of bias and imprecision. NSAIDs reduce HMB when compared with placebo, but are less effective than tranexamic acid, danazol or LNG IUS. However, adverse events are more severe with danazol therapy. In the limited number of small studies suitable for evaluation, there was no clear evidence of a difference in efficacy between NSAIDs and other medical treatments such as oral luteal progestogen, ethamsylate, OCP or the older progesterone-releasing intrauterine system.

Risk of acute myocardial infarction during use of individual NSAIDs: A nested case-control study from the SOS project.

BackgroundUse of selective COX-2 non-steroidal anti-inflammatory drugs (NSAIDs) (coxibs) has been associated with an increased risk of acute myocardial infarction (AMI). However, the risk of AMI has only been studied for very few NSAIDs that are frequently used.ObjectivesTo estimate the risk of AMI for individual NSAIDs.MethodsA nested case-control study was performed from a cohort of new NSAID users ≥18 years (1999–2011) matching cases to a maximum of 100 controls on database, sex, age, and calendar time. Data were retrieved from six healthcare databases. Adjusted odds ratios (ORs) of current use of individual NSAIDs compared to past use were estimated per database. Pooling was done by two-stage pooling using a random effects model (ORmeta) and by one-stage pooling (ORpool).ResultsAmong 8.5 million new NSAID users, 79,553 AMI cases were identified. The risk was elevated for current use of ketorolac (ORmeta 2.06;95%CI 1.83–2.32, ORpool 1.80; 1.49–2.18) followed, in descending order of point estimate, by indometacin, etoricoxib, rofecoxib, diclofenac, fixed combination of diclofenac with misoprostol, piroxicam, ibuprofen, naproxen, celecoxib, meloxicam, nimesulide and ketoprofen (ORmeta 1.12; 1.03–1.22, ORpool 1.00;0.86–1.16). Higher doses showed higher risk estimates than lower doses.ConclusionsThe relative risk estimates of AMI differed slightly between 28 individual NSAIDs. The relative risk was highest for ketorolac and was correlated with COX-2 potency, but not restricted to coxibs.

Non-steroidal anti-inflammatory drugs and risk of Parkinson's disease in the elderly population: a meta-analysis.

Several studies have explored the impact of non-steroidal anti-inflammatory drugs (NSAIDs) and the risk of Parkinson disease (PD). However, the extent to which NSAIDs may increase or decrease the risk of PD remains unresolved. We, therefore, performed a meta-analysis of relevant studies to quantify the magnitude of the association between NSAID use and PD risk in the elderly population. The electronic databases such as PubMed, EMBASE, Scopus, Google Scholar, and Web of Science were used to search the relevant articles published between January 1990 and December 2017. Large (n ≥ 1000) observational design studies with a follow-up at least 1year were considered. Two authors independently extracted information from the included studies. Random effect model was used to calculate risk ratios (RRs) with 95% confidence interval (Cl). A total of 17 studies with 2,498,258 participants and nearly 14,713 PD patients were included in the final analysis. The overall pooled RR of PD was 0.95 (95%CI 0.860-1.048) with significant heterogeneity (I2= 63.093, Q = 43.352, p < 0.0001). In the subgroup analysis, the overall pooled RR of PD was 0.90 (95%CI 0.738-1.109), 0.96 (95%CI 0.882-1.055), and 0.99 (95%CI 0.841-0.982) from the studies of North America, Europe, and Asia. Additionally, long-term use, study design, individual NSAID use, and risk of PD were also evaluated. Despite the neuroprotective potential of NSAIDs demonstrated in some experimental studies, our findings suggest that there is no association between NSAIDs and the risk of Parkinson disease at the population level. Until further evidence is established, clinicians need to be vigilant ensuring that the use of NSAIDs remains restricted to their approved anti-inflammatory and analgesic effect.

Nonsteroidal Anti-Inflammatory Drugs and Risk of First Hospitalization for Heart Failure in Patients with No History of Heart Failure: A Population-Based Case-Crossover Study.

Traditional nonselective, nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause salt and fluid retention and should thus be used cautiously in patients with documented heart failure. Recent studies have found that some NSAIDs, including cyclooxygenase (COX)-2 inhibitors, are associated with an increased risk of incident heart failure regardless of the related medical history of the patient. This study aimed to investigate the potential link between NSAIDs (both COX-2 inhibitors and traditional nonselective NSAIDs) and heart failure in patients without a history of heart failure. We conducted a case-crossover study using the National Health Insurance Research Database (NHIRD) in Taiwan. A total of 5615 subjects with a first hospitalization for heart failure between 2005 and 2013 were identified from the NHIRD. Exposure to individual NSAIDs between the case period (1-30days before the index date) and control period (121-150days before the index date) were retrieved. Multivariable conditional logistic regression models were used to estimate the adjusted odds ratios (aORs) of the incident heart failure associated with NSAID use after adjustments for potential confounders. Multiple sensitivity analyses, including the case-time-control analysis, were performed to test the robustness of the study results. Overall, NSAID use was associated with a 1.58-fold risk [aOR 1.58; 95% confidence interval (CI) 1.40-1.79] of heart failure leading to hospitalization in the main analysis, and similar results were obtained in the case-time-control analysis [aOR 1.40 (95% CI 1.18-1.67)]. The increased risks of heart failure were comparable between traditional NSAIDs [aOR 1.53 (95% CI 1.35-1.74)] and COX-2 inhibitors [aOR 1.74 (95% CI 1.25-2.44)]. Among all NSAIDs, ketorolac was associated with the highest risk of heart failure [aOR 1.98 (95% CI 1.37-2.86)]. Both traditional NSAIDs and COX-2 inhibitors were associated with an increased risk of heart failure leading to hospitalization in patients without a related history of heart failure.

Risk of ischemic stroke and the use of individual non-steroidal anti-inflammatory drugs: A multi-country European database study within the SOS Project

Background and purposeA multi-country European study using data from six healthcare databases from four countries was performed to evaluate in a large study population (>32 million) the risk of ischemic stroke (IS) associated with individual NSAIDs and to assess the impact of risk factors of IS and co-medication.MethodsCase-control study nested in a cohort of new NSAID users. For each case, up to 100 sex- and age-matched controls were selected and confounder-adjusted odds ratios for current use of individual NSAIDs compared to past use calculated.Results49,170 cases of IS were observed among 4,593,778 new NSAID users. Use of coxibs (odds ratio 1.08, 95%-confidence interval 1.02–1.15) and use of traditional NSAIDs (1.16, 1.12–1.19) were associated with an increased risk of IS. Among 32 individual NSAIDs evaluated, the highest significant risk of IS was observed for ketorolac (1.46, 1.19–1.78), but significantly increased risks (in decreasing order) were also found for diclofenac, indomethacin, rofecoxib, ibuprofen, nimesulide, diclofenac with misoprostol, and piroxicam. IS risk associated with NSAID use was generally higher in persons of younger age, males, and those with a prior history of IS.ConclusionsRisk of IS differs between individual NSAIDs and appears to be higher in patients with a prior history of IS or transient ischemic attack (TIA), in younger or male patients. Co-medication with aspirin, other antiplatelets or anticoagulants might mitigate this risk. The small to moderate observed risk increase (by 13–46%) associated with NSAIDs use represents a public health concern due to widespread NSAID usage.

NSAID Exposure and Risk of Alzheimer's Disease: An Updated Meta-Analysis From Cohort Studies.

Background: Initial observational studies and a systematic review published recently have suggested that non-steroidal anti-inflammatory drug (NSAID) use has the trend to be associated with reduced risk of Alzheimer's disease (AD), while results remain conflicting. Thus, we performed an updated meta-analysis to reevaluate the evidence on this association.Methods: Data sources from PUBMED, Embase and Cochrane Library from inception through April 2017 were searched by two independent reviewers. Eligible cohort studies were selected according to predefined keywords. We did a meta-analysis of available study data using a random-effects model to calculate overall relative risks (RRs) for associations between NSAID exposure and AD risk.Results: From 121 potentially relevant studies, 16 cohort studies including 236,022 participants, published between 1995 and 2016, were included in this systematic review. Meta-analysis demonstrated that current or former NSAID use was significantly associated with reduced risk of AD (RR, 0.81, 95% CI0.70 to 0.94) compared with those who did not use NSAIDs. This association existed in studies including all NSAID types, but not in aspirin (RR, 0.89, 95% CI 0.70 to 1.13), acetaminophen (RR, 0.87, 95% CI 0.40 to 1.91) or non-aspirin NSAID (RR, 0.84, 95% CI 0.58 to 1.23).Conclusions: Current evidence suggests that NSAID exposure might be significantly associated with reduced risk of AD. However, further large-scale prospective studies are needed to reevaluate this association, especially the associations in individual NSAID type.

Comparative cardiovascular safety of nonsteroidal anti‐inflammatory drugs in patients with hypertension: a population‐based cohort study

Previous studies have suggested that nonsteroidal anti-inflammatory drugs (NSAIDs) may be associated with higher cardiovascular risks. However, few have been active comparison studies that directly assessed the potential differential cardiovascular risk between NSAID classes or across individual NSAIDs. We compared the risk of major cardiovascular events between cyclooxygenase 2 (COX-2)-selective and nonselective NSAIDs in patients with hypertension. We conducted a cohort study of patients with hypertension who initiated COX-2-selective or nonselective NSAIDs in a population-based Taiwanese database. The outcomes included hospitalization for the following major cardiovascular events: ischaemic stroke, acute myocardial infarction, congestive heart failure, transient ischaemic attack, unstable angina or coronary revascularization. We followed patients for up to 4weeks, based on the as-treated principle. We used inverse probability weighting to control for baseline and time-varying covariates, and estimated the on-treatment hazard ratios (HRs) and 95% conservative confidence interval (CIs). We identified 2749 eligible COX-2-selective NSAID users and 52 880 eligible nonselective NSAID users. The HR of major cardiovascular events comparing COX-2-selective with nonselective NSAIDs after adjusting for baseline and time-varying covariates was 1.07 (95% CI 0.65, 1.74). We did not observe a differential risk when comparing celecoxib to diclofenac (HR 1.17; 95% CI 0.61, 2.25), ibuprofen (HR 1.36; 95% CI 0.58, 3.18) or naproxen (HR 0.75; 95% CI 0.23, 2.44). There was an increased risk with COX-2-selective NSAIDs, however, when comparing COX-2-selective NSAIDs with mefenamic acid (HR 2.11; 95% CI 1.09, 4.09). Our results provide important information about the comparative cardiovascular safety of NSAIDs in patients with hypertension.

Undigested Food Trapped in a Pre-Pyloric Ulcer

CASE REPORT An 85-year-old woman was sent to the emergency department for weakness of 1-week duration. She recently broke her left hip and was status-post surgical repair. She had been taking naproxen 500 mg by mouth twice a day since the surgery. In the emergency department, her hemoglobin was 6.4 mg/dL. She responded appropriately to blood transfusions. Esophagogastroduodenoscopy (EGD) revealed a 4-cm, deeply cratered, clean-based ulcer located above the pylorus. In the ulcer was an undigested mushroom (Figure 1). On further questioning, the patient revealed that she hated mushrooms and would never eat them. However, she was at a catered event one week earlier where mushrooms were the only available vegetable, so she had swallowed one whole. The mushroom remained undigested in the ulcer cavity until the time of EGD, when it was removed.Figure 1.: An undigested mushroom situated in a 4-cm, deeply cratered, clean-based ulcer located above the pylorus.This case raises the question of whether the ulcer was caused by the naproxen and ended up trapping the mushroom, or if the mushroom initially caused pressure necrosis, which was worsened by the naproxen use and ended up causing an ulcer. To this end, many studies and national guidelines have documented the risk of ulcer formation with nonsteroidal antiinflammatory drug (NSAID) consumption.1 There is wide variability in bleeding rates caused by individual NSAIDs. Naproxen is associated with an intermediate risk of bleeding that increases with age, a history of previous gastrointestinal event, concomitant use of anticoagulants, corticosteroids, other NSAIDs, and chronic debilitating disorders.2,3 However, the morphology of our patient's ulcer was less suspicious for naproxen-induced injury because these tend to be much smaller in diameter (<2 cm). Benign or malignant neoplasms can also lead to ulcer formation. Up to 6% of gastric ulcers have been associated with underlying malignancy. However, our patient did not have a history or symptoms of malignancy, and imaging and biopsy studies were negative for neoplastic etiologies. To our knowledge, no cases of food-related foreign bodies being trapped in an ulcer have been reported in the literature. After removing the mushroom, the patient was given a course of proton pump inhibitors, and on follow-up she reported no further bleeding complications. DISCLOSURES Author Contributions: All authors contributed to the writing and editing of this submission equally. V. Shahnazarian is the article guarantor.

Undigested Food Trapped in a Pre-Pyloric Ulcer

CASE REPORT An 85-year-old woman was sent to the emergency department for weakness of 1-week duration. She recently broke her left hip and was status-post surgical repair. She had been taking naproxen 500 mg by mouth twice a day since the surgery. In the emergency department, her hemoglobin was 6.4 mg/dL. She responded appropriately to blood transfusions. Esophagogastroduodenoscopy (EGD) revealed a 4-cm, deeply cratered, clean-based ulcer located above the pylorus. In the ulcer was an undigested mushroom (Figure 1). On further questioning, the patient revealed that she hated mushrooms and would never eat them. However, she was at a catered event one week earlier where mushrooms were the only available vegetable, so she had swallowed one whole. The mushroom remained undigested in the ulcer cavity until the time of EGD, when it was removed.Figure 1.: An undigested mushroom situated in a 4-cm, deeply cratered, clean-based ulcer located above the pylorus.This case raises the question of whether the ulcer was caused by the naproxen and ended up trapping the mushroom, or if the mushroom initially caused pressure necrosis, which was worsened by the naproxen use and ended up causing an ulcer. To this end, many studies and national guidelines have documented the risk of ulcer formation with nonsteroidal antiinflammatory drug (NSAID) consumption.1 There is wide variability in bleeding rates caused by individual NSAIDs. Naproxen is associated with an intermediate risk of bleeding that increases with age, a history of previous gastrointestinal event, concomitant use of anticoagulants, corticosteroids, other NSAIDs, and chronic debilitating disorders.2,3 However, the morphology of our patient's ulcer was less suspicious for naproxen-induced injury because these tend to be much smaller in diameter (<2 cm). Benign or malignant neoplasms can also lead to ulcer formation. Up to 6% of gastric ulcers have been associated with underlying malignancy. However, our patient did not have a history or symptoms of malignancy, and imaging and biopsy studies were negative for neoplastic etiologies. To our knowledge, no cases of food-related foreign bodies being trapped in an ulcer have been reported in the literature. After removing the mushroom, the patient was given a course of proton pump inhibitors, and on follow-up she reported no further bleeding complications. DISCLOSURES Author Contributions: All authors contributed to the writing and editing of this submission equally. V. Shahnazarian is the article guarantor.

Non-Steroidal Anti-Inflammatory Drug Use and the Risk of Acute Myocardial Infarction in the General German Population: A Nested Case-Control Study.

IntroductionUse of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with an increased relative risk of acute myocardial infarction (AMI), but the label warnings refer particularly to patients with cardiovascular risk factors. The magnitude of relative AMI risk for patients with and without cardiovascular risk factors varies between studies depending on the drugs and doses studied.ObjectivesThe aim of our study was to estimate population-based relative AMI risks for individual and widely used NSAIDs, for a cumulative amount of NSAID use, and for patients with and without a prior history of cardiovascular risk factors.MethodsBased on data from the German Pharmacoepidemiological Research Database (GePaRD) of about 17 million insurance members from four statutory health insurance providers, for the years 2004–2009, a nested case–control study was conducted within a cohort of 3,476,931 new NSAID users classified into current, recent, or past users. Up to 100 controls were matched to each case by age, sex, and length of follow-up using risk set sampling. Multivariable conditional logistic regression was applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Duration of NSAID use was calculated by the cumulative amount of dispensed defined daily doses (DDDs), and stratified analyses were conducted for potential effect modifiers.ResultsOverall, 17,236 AMI cases were matched to 1,714,006 controls. Elevated relative AMI risks were seen for current users of fixed combinations of diclofenac with misoprostol (OR 1.76, 95% CI 1.26–2.45), indometacin (1.69, 1.22–2.35), ibuprofen (1.54, 1.43–1.65), etoricoxib (1.52, 1.24–1.87), and diclofenac (1.43, 1.34–1.52) compared with past use. A low cumulative NSAID amount was associated with a higher relative AMI risk for ibuprofen, diclofenac, and indometacin. The relative risk associated with current use of diclofenac, fixed combinations of diclofenac with misoprostol, etoricoxib, and ibuprofen was highest in the younger age group (<60 years) and similar for patients with or without major cardiovascular risk factors.ConclusionRelative AMI risk estimates differed among the 15 investigated individual NSAIDs. Diclofenac and ibuprofen, the most frequently used NSAIDs, were associated with a 40–50% increased relative risk of AMI, even for low cumulative NSAID amounts. The relative AMI risk in patients with and without cardiovascular risk factors was similarly elevated.Electronic supplementary materialThe online version of this article (doi:10.1007/s40801-017-0113-x) contains supplementary material, which is available to authorized users.