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Background and Aims: The bleeding risk of using non-steroidal anti-inflammatory drugs (NSAIDs) in patients treated with oral anticoagulants for venous thromboembolism (VTE) remains unclear., Methods: A nationwide cohort study of 51 794 VTE patients initiating oral anticoagulants between 1 January 2012 and 31 December 2022 was conducted. Time-dependent multivariate cause-specific Cox regression was used to compute adjusted hazard ratios between NSAID use and hospital-diagnosed bleeding episodes., Results: Event rates for any bleeding per 100 person-years were 3.5 [95% confidence interval (CI), 3.4-3.7] during periods without NSAID use and 6.3 (95% CI, 5.1-7.9) during periods with NSAID use (number needed to harm = 36 patients treated for 1 year). Compared with non-use, the adjusted hazard ratios for any bleeding associated with NSAID use were 2.09 (95% CI, 1.67-2.62) overall, 1.79 (95% CI, 1.36-2.36) for ibuprofen, 3.30 (95% CI, 1.82-5.97) for diclofenac, and 4.10 (95% CI, 2.13-7.91) for naproxen. Compared with non-use, the adjusted hazard ratios associated with NSAID use were 2.24 (95% CI, 1.61-3.11) for gastrointestinal bleeding, 3.22 (95% CI, 1.69-6.14) for intracranial bleeding, 1.36 (95% CI, .67-2.77) for thoracic and respiratory tract bleeding, 1.57 (95% CI, .98-2.51) for urinary tract bleeding, and 2.99 (95% CI, 1.45-6.18) for anaemia caused by bleeding. Results were consistent for anticoagulant and VTE subtypes., Conclusions: Patients treated with oral anticoagulants for VTE had a more than two-fold increased bleeding rate when using NSAIDs. This increased bleeding rate was not restricted to the gastrointestinal tract., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background/aims: The incidence of acute gastrointestinal bleeding (GIB) increases with the utilization of anticoagulant and nonsteroidal anti-inflammatory drugs (NSAIDs). This study aimed to compare the risk of GIB between anticoagulant and NSAIDs combotherapy and anticoagulant monotherapy in real-world practice., Methods: We investigated the relative risk of GIB in individuals newly prescribed anticoagulant and NSAIDs combination therapy and that in individuals newly prescribed anticoagulant monotherapy at three hospitals using "common data model." Cox proportional hazard models and Kaplan-Meier estimation were employed for risk comparison after propensity score matching., Results: A comprehensive analysis of 2,951 matched pairs showed that patients who received anticoagulant and NSAIDs combousers exhibited a significantly higher risk of GIB than those who received anticoagulant monousers (hazard ratio [HR], 1.66; 95% confidence interval [CI], 1.30 to 2.12; p<0.001). The risk of GIB associated with anticoagulant and NSAIDs combination therapy was also significantly higher than that associated with anticoagulant monotherapy in patients aged >65 years (HR, 1.53; 95% CI, 1.15 to 2.03; p=0.003) and >75 years (HR, 1.89; 95% CI, 1.23 to 2.90; p=0.003). We also found that the risk of GIB was significantly higher in the patients who received anticoagulant and NSAIDs combousers than that in patients who received anticoagulant monousers in both male (p=0.016) and female cohorts (p=0.010)., Conclusions: The risk of GIB is significantly higher in patients who receive anticoagulant and NSAIDs combotherapy than that in patients who receive anticoagulant monotherapy. In addition, the risk of GIB associated with anticoagulant and NSAIDs combotherapy was much higher in individuals aged >75 years. Therefore, physicians should be more aware of pay more attention to the risk of GIB when they prescribe anticoagulant and NSAIDs.

DA-9601 extracted from Artemisia asiatica contains a bioactive compound - eupatilin - that can protect against gastric mucosal damage through anti-inflammatory and anti-oxidative properties and is approved for treating acute and chronic gastritis in Korea, but their ability to protect gastrointestinal (GI) bleeding caused by nonsteroidal anti-inflammatory drugs (NSAIDs) is unclear. We aimed to compare the protective effects of DA-9601 to those of proton pump inhibitors (PPI) and rebamipide against upper and lower GI bleeding in patients with rheumatoid arthritis (RA) undergoing long-term NSAIDs therapy using the Korean Health Insurance Review and Assessment database. In this nationwide retrospective cohort study, we evaluated patients with RA who concurrently received NSAIDs for >3 months with DA-9601, PPI, or rebamipide between January 2015 and December 2017. The index date was the date of NSAIDs initiation, and all patients were followed up until December 2020 to detect upper and lower GI bleeding. In total, 24,258 patients with RA were eligible, and 5468 (22.5%), 4417 (18.2%), and 14,373 (59.3%) received DA-9601, PPI, or rebamipide, respectively, on the index date. During follow-up, upper and lower GI bleeding occurred in 508 (2.1%) and 402 (1.6%) patients with RA, respectively. The incidence rate of upper and lower GI bleeding was 615/100,000 and 485/100,000 person-years, respectively. Among patients with RA receiving DA-9601, PPI, or rebamipide, the frequencies of NSAIDs-induced upper GI bleeding were 0.5%, 0.4%, and 1.2%, respectively. The frequencies of NSAIDs-induced lower GI bleeding were 0.4%, 0.4%, and 0.9%, respectively. The incidence of NSAIDs-induced upper GI bleeding in patients with RA receiving DA-9601, PPI, and rebamipide was 601/100,000, 705/100,000, and 596/100,000 person-years, respectively, while the incidence of NSAIDs-induced lower GI bleeding in the same groups was 449/100,000, 608/100,000, and 465/100,000 person-years, respectively. In the multivariate Cox regression analysis, no significant difference was observed in lower and upper GI bleeding hazards between patients with RA using DA-9601, PPI, and rebamipide. Our results suggest that DA-9601 may exhibit protection against NSAIDs-induced GI bleeding that is comparable to those of PPI and rebamipide in patients with RA., Competing Interests: All authors declare no conflicts of interest., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Rheumatoid arthritis (RA) is a chronic inflammatory disease. It has been identified that non-steroidal anti-inflammatory drugs (NSAIDs) and corticosteroids can be essential risk factors for developing complications such as upper gastrointestinal bleeding (UGIB)., Objective: This study aimed to describe the safety profile of drugs used to treat RA focused in UGIB., Methods: A cross-sectional study of patients with RA between 2015 and 2021, a description of the population, and an evaluation of the relationship with UGIB through bivariate analysis and logistic regression., Results: Of 405 individuals, 16 presented UGIB (93.8% women, mean age was 65±13.6 years). No statistically significant differences were found regarding UGIB and medication use, except for the mean dose of corticosteroids. In the multivariate analysis, it was found that the presence of anemia in the last three months had an adjusted OR (AOR) of 16.1 (95% CI 2.74- 24.23) and higher HAQ values during the previous three months had an AOR of 6.17 (95% CI 1.79- 21.24)., Conclusion: This study found a low frequency of UGIB in patients with RA. More significant disability and anemia in the previous months were independently associated with UGIB. The low frequency of NSAID use in this population is noteworthy. In general, reasonable medication use related to this complication is recommended., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Introduction: Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used over-the-counter medications that can increase the risk of gastrointestinal (GI) bleeding through antiplatelet effects and loss of GI protection. Selective serotonin reuptake inhibitors (SSRIs), commonly used for mental and behavioral health, are another group of medications that can cause platelet dysfunction. Previous literature has shown a possible increased risk of GI bleeding with concurrent use of SSRIs and NSAIDs. We performed a network meta-analysis comparing NSAIDs, SSRIs, and combined SSRI/NSAIDs to assess the risk of GI bleeding., Methods: The following databases were searched: MEDLINE, Embase, Web of Science Core Collection, SciELO, KCI, and Cochrane database. All comparative studies, i.e., case-control, cohort, and randomized controlled trials were included. Direct and network meta-analysis was conducted using DerSimonian-Laird approach and random effect. For binary outcomes, odds ratio (OR) with 95% confidence interval (CI) and p value were calculated., Results: After a comprehensive search through November 10th, 2021, 15 studies with 82,605 patients were identified. 11 studies reported higher rates of GI bleeds in SSRI/NSAID than SSRI users (36.9% vs 22.8%, OR 2.14, 95% CI 1.52-3.02, p < 0.001, I 2  = 86.1%). 10 studies compared SSRI/NSAID to NSAID users with higher rates of bleeds in SSRI/NSAID group (40.9% vs 34.2%, OR 1.49, 95% CI 1.20-1.84, p < 0.001, I 2  = 68.8%). The results were consistent using network meta-analysis as well., Conclusion: Given higher risk of bleeding with concurrent NSAIDs and SSRIs, prescribers should exercise caution when administering NSAIDs and SSRIs concurrently especially in patients with higher risks of GI bleeding., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: Interindividual genetic variations contribute to differences in patients' response to drugs as well as to the development of certain disorders. Patients who use non-steroidal anti-inflammatory drugs (NSAIDs) may develop serious gastrointestinal disorders, mainly upper gastrointestinal haemorrhage (UGIH). Studies about the interaction between NSAIDs and genetic variations on the risk of UGIH are scarce. Therefore, we investigated the effect of 16 single nucleotide polymorphisms (SNPs) involved in drug metabolism on the risk of NSAIDs-induced UGIH., Materials and Methods: We conducted a multicenter case-control study of 326 cases and 748 controls. Participants were sub-grouped into four categories according to NSAID exposure and genetic profile. We estimated odds ratios (ORs) and their 95% confidence intervals (CI) using generalized linear mixed models for dependent binomial variables and then calculated the measures of interaction, synergism index (S), and relative excess risk due to interaction (RERI). We undertook stratified analyses by the type of NSAID (aspirin, non-aspirin)., Results: We observed an excess risk of UGIH due to an interaction between any NSAID, non-aspirin NSAIDs or aspirin and carrying certain SNPs. The greatest excess risk was observed for carriers of: rs2180314:C>G [any NSAID: S  = 3.30 (95%CI: 1.24-8.80), RERI = 4.39 (95%CI: 0.70-8.07); non-aspirin NSAIDs: S  = 3.42 (95%CI: 1.12-10.47), RERI = 3.97 (95%CI: 0.44-7.50)], and rs4809957:A>G [any NSAID: S  = 2.11 (95%CI: 0.90-4.97), RERI = 3.46 (95%CI: -0.40-7.31)]. Aspirin use by carriers of rs6664:C>T is also associated with increased risk of UGIH [OR aspirin(+),wild-type : 2.22 (95%CI: 0.69-7.17) vs. OR aspirin(+),genetic-variation : 7.72 (95%CI: 2.75-21.68)], yet larger sample size is needed to confirm this observation., Conclusions: The joint effect of the SNPs s2180314:C>G and rs4809957:A>G and NSAIDs are more than three times higher than the sum of their individual effects. Personalized prescriptions based on genotyping would permit a better weighing of risks and benefits from NSAID consumption.KEY MESSAGESMulticenter case-control study of the effect of genetic variations involved in drug metabolism on upper gastrointestinal haemorrhage (UGIH) induced by NSAIDs (aspirin and non-aspirin).There is a statistically significant additive synergism interaction between certain genetic polymorphisms and NSAIDs on UGIH: rs2180314:C>G and rs4809957:A>G. The joint effect of each of these single nucleotide polymorphisms and NSAIDs on UGIH is more than three times higher than the sum of their individual effects.Genetic profiling and personalized prescriptions would be useful in managing the risks and benefits associated with NSAIDs.

Concomitant nonsteroidal anti-inflammatory drug (NSAIDs) and antithrombotic drug use is associated with an increased risk of bleeding, mainly gastrointestinal. The goal of this study was to quantify the transient increase in the risk of hospitalization for bleeding associated with NSAID use in patients treated with antiplatelet agents or anticoagulants. We performed a unidirectional case-crossover study using the EGB (Échantillon généraliste de bénéficiaires), a permanent random sample of the French nationwide health database. Patients receiving antithrombotic therapy and hospitalized for bleeding between 2009 and 2017 were included. We compared their NSAID exposure during a 15-day hazard window immediately before hospital admission to 3 earlier 15-day control windows. The risk of hospitalization for bleeding associated with the recent use of NSAIDs was estimated using conditional logistic regression to estimate odds ratios (ORs). During the study period, 33 patients treated with anticoagulants and 253 treated with antiplatelet agents received NSAIDs and were included in the case-crossover analysis. We found an increased risk of hospitalization for gastrointestinal bleeding after exposure to NSAIDs, with an adjusted OR of 3.59 (95%CI, 1.58-8.17) in patients receiving anticoagulant therapy and 1.44 (95%CI, 1.07-1.94) in patients receiving antiplatelet therapy. The risk of nongastrointestinal bleeding was also increased after exposure to NSAIDs with an adjusted OR of 2.72 (95%CI, 1.23-6.04) in patients exposed to anticoagulant therapy. The risk of gastrointestinal and nongastrointestinal bleeding increases after NSAID use in patients treated with anticoagulants, while the risk of gastrointestinal bleeding increases, but to a lesser extent in those treated with antiplatelets., (© 2021, The American College of Clinical Pharmacology.)

Objective: Many prescribed and over-the-counter medications, for example, non-steroidal anti-inflammatory drugs (NSAIDs) are associated with upper gastrointestinal bleeding (UGIB). Recently, a decrease in prescribing of NSAIDs was observed in the Netherlands, but whether a similar decreasing trend could be observed in the incidence of severe UGIB (either fatal or requiring hospitalisation), contingent on medication prescription, is unknown., Design: We conducted a cohort study using Dutch national statistics on pharmacy claims, hospitalisation and mortality between 2013 and 2018. We explored the incidence of sex-specific and age-specific severe UGIB in four (sub)populations: (A) total population, (B) without a filled prescrption for NSAIDs, (C) without filled prescriptions for NSAIDs and antithrombotic agents, (D) without any risk factors for UGIB., Results: The cumulative incidence of severe UGIB did not decrease throughout the study period, regardless of the subgroup analysis. In the total population, it was 199 per 100 000 inhabitants (95% CI 197 to 201) in 2013-2014 and 260 (95% CI 258 to 263) in 2017-2018. The absolute risk of severe UGIB was 50% lower in the subgroup B than in the full cohort. It decreased further by 50% in the subgroup D when compared with subgroup B. The risk of severe UGIB was 1.5-1.9 fold higher in young women than in young men; an indication of over-the-counter NSAIDs use being more prevalent in women than men in this age group., Conclusion: We found no evidence to support a relationship between reduced prescribing of NSAIDs and the incidence of severe UGIB in the Netherlands since 2013. The relationship was also not observed when we removed the effect of risk factors., Competing Interests: Competing interests: All authors have completed the Conflict of Interest Statement form and declare: no support from any private organisation for the submitted work; AD has received research grants and personal fees from MSD, grants from Medasense, grants from Grunenthal, personal fees from Trevena, grants from AMO Pharma, grants from Center for Human Drug Research, outside the submitted work; no other relationships or activities that could appear to have influenced the submitted work., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Bleeding in non-steroidal anti-inflammatory drug (NSAID) users limited their prescription. This first multicenter full case-control study (325 cases and 744 controls), explored the association of e-NOS intron 4 variable number tandem repeat (VNTR) polymorphism with upper gastrointestinal hemorrhage (UGIH) in NSAID exposed and unexposed populations and assessed any interaction between this polymorphism and NSAIDs. NSAID users carrying e-NOS intron 4 wild type genotype or VNTR polymorphism have higher odds of UGIH than those unexposed to NSAIDs [Odds Ratio (OR): 6.62 (95% Confidence Interval (CI): 4.24, 10.36) and OR: 5.41 (95% CI 2.62, 11.51), respectively], with no effect modification from VNTR polymorphism-NSAIDs interaction [Relative Excess Risk due to Interaction (RERI): -1.35 (95% CI -5.73, 3.03); Synergism Index (S): 0.77 (95% CI 0.31, 1.94)]. Similar findings were obtained for aspirin exposure. Non-aspirin NSAID users who carry e-NOS intron 4 VNTR polymorphism have lower odds of UGIH [OR: 4.02 (95% CI 1.85, 8.75) than those users with wild type genotype [OR: 6.52 (95% CI 4.09, 10.38)]; though the interaction estimates are not statistically significant [RERI: -2.68 (95% CI -6.67, 1.31); S: 0.53 (95% CI 0.18, 1.55)]. This exploratory study suggests that the odds of UGIH in NSAID or aspirin users does not modify according to patient´s e-NOS intron 4 genotype., (© 2021. The Author(s).)

Overview of: Mahady SE, Margolis KL, Chan A, et al Major GI bleeding in older persons using aspirin: incidence and risk factors in the ASPREE randomised controlled trial. Gut. 2021. 717-24., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: There is a lack of robust data on significant gastrointestinal bleeding in older people using aspirin. We calculated the incidence, risk factors and absolute risk using data from a large randomised, controlled trial., Design: Data were extracted from an aspirin versus placebo primary prevention trial conducted throughout 2010-2017 ('ASPirin in Reducing Events in the Elderly (ASPREE)', n=19 114) in community-dwelling persons aged ≥70 years. Clinical characteristics were collected at baseline and annually. The endpoint was major GI bleeding that resulted in transfusion, hospitalisation, surgery or death, adjudicated independently by two physicians blinded to trial arm., Results: Over a median follow-up of 4.7 years (88 389 person years), there were 137 upper GI bleeds (89 in aspirin arm and 48 in placebo arm, HR 1.87, 95% CI 1.32 to 2.66, p<0.01) and 127 lower GI bleeds (73 in aspirin and 54 in placebo arm, HR 1.36, 95% CI 0.96 to 1.94, p=0.08) reflecting a 60% increase in bleeding overall. There were two fatal bleeds in the placebo arm. Multivariable analyses indicated age, smoking, hypertension, chronic kidney disease and obesity increased bleeding risk. The absolute 5-year risk of bleeding was 0.25% (95% CI 0.16% to 0.37%) for a 70 year old not on aspirin and up to 5.03% (2.56% to 8.73%) for an 80 year old taking aspirin with additional risk factors., Conclusion: Aspirin increases overall GI bleeding risk by 60%; however, the 5-year absolute risk of serious bleeding is modest in younger, well individuals. These data may assist patients and their clinicians to make informed decisions about prophylactic use of aspirin., Trial Registration Number: ASPREE. NCT01038583., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Observational studies estimating severe outcomes for paracetamol versus ibuprofen use have acknowledged the specific challenge of channeling bias. A previous study relying on negative controls suggested that using large-scale propensity score (LSPS) matching may mitigate bias better than models using limited lists of covariates., Objective: The aim was to assess whether using LSPS matching would enable the evaluation of paracetamol, compared to ibuprofen, and increased risk of myocardial infarction, stroke, gastrointestinal (GI) bleeding, or acute renal failure., Study Design and Setting: In a new-user cohort study, we used two propensity score model strategies for confounder controls. One replicated the approach of controlling for a hand-picked list. The second used LSPSs based on all available covariates for matching. Positive and negative controls assessed residual confounding and calibrated confidence intervals. The data source was the Clinical Practices Research Datalink (CPRD)., Results: A substantial proportion of negative controls were statistically significant after propensity score matching on the publication covariates, indicating considerable systematic error. LSPS adjustment was less biased, but residual error remained. The calibrated estimates resulted in very wide confidence intervals, indicating large uncertainty in effect estimates once residual error was incorporated., Conclusions: For paracetamol versus ibuprofen, when using LSPS methods in the CPRD, it is only possible to distinguish true effects if those effects are large (hazard ratio > 2). Due to their smaller hazard ratios, the outcomes under study cannot be differentiated from null effects (represented by negative controls) even if there were a true effect. Based on these data, we conclude that we are unable to determine whether paracetamol is associated with an increased risk of myocardial infarction, stroke, GI bleeding, and acute renal failure compared to ibuprofen, due to residual confounding.

Purpose: Upper gastrointestinal bleeding (UGIB) is a severe and frequent drug-related event. In order to enable efficient drug safety alert generation in the French National Healthcare System database (SNDS), we assessed and calibrated empirically case-based designs to identify drug associated with UGIB risk., Methods: All cases of UGIB were extracted from SNDS (2009-2014) using two definitions. Positive and negative drug controls were used to compare 196 self-controlled case series (SCCS), case-control (CC) and case-population (CP) design variants. Each variant was evaluated in a 1/10 th population sample using area under the receiver operating curve (AUC) and mean square error (MSE). Parameters that had major impacts on results were identified through logistic regression. Optimal designs were replicated in the unsampled population., Results: Using a specific UGIB definition, AUCs ranged from 0.64 to 0.80, 0.44 to 0.61 and 0.50 to 0.67, for SCCS, CC and CP, respectively. MSE ranged from 0.07 to 0.39, 0.83 to 1.33 and 1.96 to 4.6, respectively. Univariate regressions showed that high AUCs were achieved with SCCS with multiple drug adjustment and a 30-day risk window starting at exposure. The top-performing SCCS variant in the unsampled population yielded an AUC = 0.84 and MSE = 0.14, with 10/36 negative controls presenting significant estimates., Conclusions: SCCS adjusting for multiple drugs and using a 30-day risk window has the potential to generate UGIB-related alerts in the SNDS and hypotheses on its potential population impact. Negative control implementation highlighted that low systematic error was generated but that protopathic bias and confounding by indication remained unaddressed issues., (© 2020 John Wiley & Sons Ltd.)

Purpose: Non-steroidal anti-inflammatory drugs (NSAIDs) are associated with many serious complications and they are widely used in New Zealand (NZ). However, differences in NSAID-associated risk for these complications between ethnic groups are largely unknown. We assessed ethnic disparities in risk of hospital admission for upper gastrointestinal bleeding (UGIB), heart failure, and acute kidney failure (AKF) in NZ's primary care population prescribed and dispensed NSAIDs., Methods: Retrospective cohort study utilising national pharmaceutical dispensing and hospital admissions data 2007 to 2015. Patient follow-up included 90-day periods following the dispensing of NSAIDs. Risk for each adverse outcome in Maori, Pacific, European, and Asian patients was estimated using multivariable Poisson regression adjusting for age, sex, deprivation, comorbidity and concurrent drug use., Results: 3 023 067 patients were dispensed NSAIDs between 2008 and 2015. Their total intended duration of NSAID treatment encompassed 2 353 140 patient-years. Maori, Pacific and Asian patients were younger than European patients (all P < .001). After adjusting for other risk factors, Maori (rate ratio: 2.54, 95% confidence interval: 2.23-2.90) and Pacific patients (3.17, 2.69-3.74) were more likely to be hospitalised for UGIB than Europeans (reference), and heart failure (Maori: 2.48, 2.24-2.74; Pacific: 1.97, 1.69-2.30). Risk of AKF was higher in Maori (1.46, 1.23-1.74). Higher risk for UGIB and HF in Maori and Pacific patients was most pronounced in males and patients aged <60 years., Conclusions: Inequalities exist in the incidence of serious adverse outcomes experienced by different ethnic groups in NZ while using NSAIDs. Interventions to promote safer use of these medicines are required to reduce this inequity., (© 2020 John Wiley & Sons Ltd.)

Objective: Flavocoxid is a prescription medical food used to manage osteoarthritis (OA) symptoms. Safety concerns based on case reports raised an association with acute liver injury and hypersensitivity pneumonitis. We determined incidence rates (IR) of these safety events in a cohort of new users of flavocoxid and prescription non-steroidal anti-inflammatory drugs (NSAIDs)., Method: MarketScan® claims data (2006-2017) was used to identify patients initiating flavocoxid or NSAIDs. Propensity score matching (1:2 ratio) was used to balance patient characteristics. Outcomes included hospitalization for hypersensitivity pneumonitis, liver injury, gastrointestinal bleeding, myocardial infarction, and acute kidney injury. Poisson regression was used to calculate IRs and Cox regression for calculating adjusted hazard ratios (aHR)., Results: 3,337 flavocoxid and 6,674 NSAID users met eligibility criteria. Before matching, flavocoxid users were older (mean 57 vs 51 years), had more polypharmacy (68% vs 29% taking ≥11 medications). After matching, characteristics were well balanced. The rate of hypersensitivity pneumonitis was 1.1 (95% CI 0.0-5.9) per 1,000 PY for flavocoxid and 0.0 (95% CI 0.0-2.2) for NSAIDs. For hospitalized liver injury, it was 3.2 (95% CI 0.7-9.3) for flavocoxid and 2.4 (95% CI 0.7-6.1) for NSAIDs, aHR = 1.16, 95% CI 0.23-6.01. A lower rate of GI bleed was observed, IR: 5.3 (1.7-12.3) for flavocoxid and 10.2 (5.9-16.3) for NSAIDs, aHR 0.49 (0.18-1.68). There were no significant differences for MI or AKI., Conclusion: The rate of hypersensitivity pneumonitis and liver injury associated with flavocoxid was low and minimally elevated compared to NSAIDs. Flavocoxid users had a significantly lower risk for hospitalized GI bleeding. The risk-benefit profile of flavocoxid may warrant reevaluation in light of these findings., (Copyright © 2020 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.)

Background: Small bowel (SB) bleeding accounts for 5% of all gastrointestinal (GI) bleeding cases and 80% of obscure GI bleeding cases. Although angioectasia is the common etiology of SB bleeding, nonsteroidal anti-inflammatory drug (NSAID)-induced SB lesions are also reported as a major cause in studies from Eastern countries. Herein, we assessed the frequency of occurrence of NSAID-induced SB lesions in Korean patients with obscure GI bleeding., Methods: We retrospectively analyzed medical records of all consecutive patients aged ≥18 years who underwent capsule endoscopy from March 2018 to February 2019 at Ulsan University Hospital and Kosin University Gospel Hospital., Results: Of the 83 subjects (all Korean; mean age ± standard deviation: 59 ± 18 years; age range: 18-84 years; men: n = 52; women: n = 31), 55 (66.2%) had stool with clear blood and 28 (33.8%) had normal stool with iron deficiency anemia. The detection rate of SB bleeding and lesions using capsule endoscopy was 72.3% (60 of 83 patients). A significantly higher frequency (40 of 51) of ulcerative/erosive lesions than other causes was observed in patients with inactive bleeding but visible SB lesions. As a result, NSAID-induced enteropathy accounted for 30.1% of 83 patients with obscure GI bleeding (25 of the all 60 SB bleeding cases)., Conclusions: Contrary to what is reported for patients in Western countries, this study in Korean patients showed an improved diagnostic yield of capsule endoscopy for obscure GI bleeding and that NSAID-induced enteropathy was the most common etiology of SB bleeding. Aggressive small intestine examination is required for patients with unexplained GI bleeding.

Upper gastrointestinal bleeding is a feared complication of using non-steroidal anti-inflammatory drugs (NSAIDs) or aspirin. Studies predicting the incidence rate for individuals with a given set of characteristics are lacking. The aim of this study was to develop a risk model to predict the incidence rate of upper gastrointestinal bleeding (UGIB) in users of aspirin/NSAID based on presence of well-defined risk factors for the individual patient., Methods: The model was developed from data from a case-control study, sampled from a well-defined source population, residents of the Funen County 1995-2006. All cases and controls were characterized in terms of factors known to affect the risk of UGIB. By using census data, we rescaled the control group, so their composition accurately reflected age and sex distribution of the source population. Only persons using NSAIDs or/and aspirin and no PPI were included in the analysis. As reference group, we chose 80- to 89-year-old women with no ulcer history, using NSAID, but neither aspirin, other platelet inhibitors, vitamin K antagonists, selective serotonin reuptake inhibitors nor corticosteroids., Results: We identified 1388 cases among non-users of PPIs. We found a modelled baseline incidence rate of 10.7 per 1000 person-years for the reference group. The strongest associations were found for ADP inhibitors (OR 5.80), followed by anticoagulants treatment (OR 2.62) and prior ulcer (OR 2.68). The model performed well in terms of calibration and discriminatory power., Conclusion: This study is the first to describe a model, which estimates the incidence rate of UGIB for patients using aspirin/NSAID, based on the specific combination of risk factors. Risk of upper gastrointestinal bleeding for a given patient can be accurately estimated using this model., (© 2019 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).)

Background/purpose: We aimed to identify the risk factors of first-time occurrence of non-variceal upper gastrointestinal bleeding (UGIB) among aspirin users after adjusting for confounding factors like age, gender, underlying co-morbidities, and medications., Methods: Using the National Health Insurance Research Database of Taiwan and matching age, gender, underlying co-morbidities and enrollment time by propensity score, 11105 aspirin users and 11105 controls were identified for comparison from a cohort dataset of 1,000,000 randomly sampled subjects. Cox proportional hazard regression models were used to identify independent risk factors for first-time occurrence of non-variceal UGIB in the study cohort and in the aspirin users after adjusting for age, gender, underlying co-morbidities, and medications (e.g., non-steroidal anti-inflammatory drugs [NSAIDs], cyclooxygenase-2 [COX-2] inhibitors, steroids, thienopyridines, selective serotonin reuptake inhibitors, warfarin, and dipyridamole)., Results: By Cox proportional hazard regression analysis, aspirin use increased the risk of first-time occurrence of UGIB (hazard ratio [HR]: 1.48; 95% confidence interval [CI]: 1.28-1.72). Age, male gender, Helicobacter pylori (H. pylori)infection, diabetes, chronic kidney disease (CKD), cirrhosis, history of uncomplicated peptic ulcer disease (PUD), and use of NSAIDs, COX-2 inhibitors, steroids, and thienopyridines were independent risk factors for UGIB among aspirin users., Conclusion: In addition to age, male gender, H. pylori infection, and concomitant use of NSAIDs, COX-2 inhibitors, steroids, and thienopyridines, underlying co-morbidities including diabetes, CKD, cirrhosis, history of PUD are also important risk factors for first-time occurrence of non-variceal UGIB in aspirin users., (Copyright © 2018 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background & Aims: There are few data on the incidence of upper and lower gastrointestinal bleeding (UGIB and LGIB) from observational studies of low-dose aspirin users. We aimed to estimate incidence rates of UGIB and LGIB in a large cohort of new users of low-dose aspirin in the United Kingdom, with subanalyses of hospitalization status and fatalities., Methods: We performed a population-based study of 199,079 new users of low-dose aspirin (median age, 64.0 years) identified from the Health Improvement Network primary care database (2000-2012). Individuals were followed for a median 5.4 years (maximum, 14 years) to identify new cases of UGIB and LGIB. Following multistep validation, we calculated overall and age- and sex-specific incidence rates; we performed subanalyses for health care use and death within 30 days of GIB. We also estimated rates within a matched (1:1) cohort of nonusers of low-dose aspirin at the start of the follow-up period., Results: The low-dose aspirin users had 1115 UGIB events and 1936 LGIB events; most subjects with UGIB events (58.9%) were hospitalized, whereas most subjects with LGIB events were referred to secondary care (72.8%). Crude incidence rates of GIB per 1000 person-years were 0.97 for subjects with UGIB (95% CI, 0.91-1.02) and 1.68 for subjects with LGIB (95% CI, 1.60-1.75). Incidence rates per 1000 person-years for patients hospitalized for GIB were 0.57 for UGIB (95% CI, 0.53-0.61) and 0.45 for LGIB (95% CI, 0.42-0.49); for referred (but not hospitalized) cases, these values were 0.39 for UGIB (95% CI, 0.36-0.43) and 1.22 for LGIB (1.16-1.29). Incidence rates per 1000 person-years were 0.06 for fatal UGIB (95% CI, 0.04-0.07), 0.01 for fatal LGIB (95% CI, 0.01-0.02), 0.91 for nonfatal UGIB (95% CI, 0.86-0.97), and 1.66 for nonfatal LGIB (95% CI, 1.59-1.74). Among nonusers of low-dose aspirin, incidence rates per 1000 person-years were 0.67 (95% CI, 0.63-0.75) for UGIB and 0.76 (95% CI, 0.72-0.82) for LGIB., Conclusion: In a population-based study of low-dose aspirin users, the incidence of LGIB was higher than the incidence of UGIB. However, incidence rates of hospitalized GI bleeds and 30-day mortality rates were lower for LGIB than for UGIB. These estimates are valuable for benefit-risk assessments of low-dose aspirin for cardiovascular and colorectal cancer prevention., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Older adults continue to take nonsteroidal anti-inflammatory drugs (NSAIDs) to manage chronic pain. The study's purpose was to identify predictors of gastrointestinal (GI) bleeding in older adults taking NSAIDs., Methods: A secondary analysis of the 2016 Food and Drug Administration's Adverse Events Reporting System data was conducted with 1,347 cases aged 65 years and older with an NSAID as the primary suspect for an adverse drug event (ADE). Data included age, sex, NSAID, multiple NSAID use, rivaroxaban, warfarin, clopidogrel, cardiovascular drug (proxy for cardiovascular disease), diabetes drug (proxy for diabetes mellitus), and primary adverse drug response., Conclusions: Aspirin was the primary suspect NSAID in 72.5% of cases. Rivaroxaban was taken in 67.9% of cases. Logistic regression was conducted to predict GI bleed versus other NSAID-related ADEs with age, sex, cardiovascular medication, diabetes medication, warfarin, clopidogrel, concurrent NSAID use, aspirin, and rivaroxaban as predictors. Aspirin, rivaroxaban, and concurrent NSAID were significant predictors of GI bleed. Gastrointestinal bleed risk versus other ADE risk increased by 39.77 times when taking aspirin, rivaroxaban, and another NSAIDs concurrently., Implications for Practice: Results support reduced NSAID use by older adults, especially aspirin, and avoidance of rivaroxaban in older persons taking NSAIDs.

Background: We aimed to identify the adverse effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and antithrombotics on the upper gastrointestinal (GI) mucosa in a clinical setting as a case-control study using a large-scale medical database in Japan., Methods: We evaluated the risk of upper GI mucosal injuries in patients receiving NSAIDs and antithrombotics using the Japan Medical Data Center claims database with data for 13 million accumulated patients, from January 2009 to December 2014. Endoscopically evaluated upper GI mucosal injuries were peptic ulcers (n = 143,271), upper GI bleeding (n = 10,545), and gastroesophageal reflux disease (n = 154,755). For each patient, ten controls were matched by age, sex, and diagnosis month., Results: The odds ratio (OR) for peptic ulcers was 1.45, 1.31, 1.50, 1.53, and 1.62; for upper GI bleeding: 1.76, 1.62, 1.96, 1.82, and 2.38; and for gastroesophageal reflux disease: 1.54, 1.41, 1.89, 1.67, and 1.91 for NSAIDs, COX-2 selective inhibitors, low-dose aspirin, antiplatelet drugs, and anticoagulants, respectively (all statistically significant: P < 0.001). Polypharmacy with NSAIDs and antithrombotic drugs increased the risk of upper GI injuries compared with single-drug therapy. The injury risk was also increased by lifestyle-related diseases, including diabetes mellitus and hyperlipidemia., Conclusions: This case-control study using the large organized Japanese claims database provided the risk of upper GI mucosal injuries in patients receiving NSAIDs and antithrombotic drugs.

Objective: To assess the non-inferiority of vonoprazan to lansoprazole for secondary prevention of non-steroidal anti-inflammatory drug (NSAID)-induced peptic ulcer (PU) and the safety of vonoprazan during extended use., Design: A phase 3, 24-week, multicenter, randomised, double-blind (DB), active-controlled study, followed by a phase 3, ≥28 week, multicenter, single-blind, parallel-group extension study (EXT) in outpatients (n=642) receiving long-term NSAID therapy who are at risk of PU recurrence. The patients received vonoprazan (10 mg or 20 mg) or lansoprazole 15 mg once daily. For DB, non-inferiority of the proportion of patients with recurrent PU within 24 weeks was analysed by Farrington and Manning test (significance level 2.5%, non-inferiority margin 8.3%; primary endpoint), recurrent PU within 12 weeks, bleeding and time-to-event of PU (secondary endpoint) and treatment-emergent adverse events (TEAEs). For EXT, TEAEs (primary endpoint), recurrent PU and safety (secondary) were assessed up to 104 weeks for patients in the extension study., Results: The non-inferiority of vonoprazan 10 mg and 20 mg to lansoprazole 15 mg was verified (percentage difference -2.2%,95% CI -6.2% to 1.8%, p<0.001; -2.1%,95% CI -6.1% to 2.0%, p<0.001, respectively). The proportion of patients with endoscopically confirmed recurrent PU within 24 weeks was 3.3%, 3.4% and 5.5%, for vonoprazan 10 mg, 20 mg and lansoprazole 15 mg, respectively. No significant safety concerns were identified., Conclusion: The non-inferiority of vonoprazan (10 and 20 mg) was verified in patients receiving long-term NSAIDs in DB; it was effective and well tolerated in EXT for longer than 1 year, with a safety profile similar to lansoprazole (15 mg)., Trial Registration Numbers: NCT01452750, NCT01456260; Results., Competing Interests: Competing interests: YM has served as a consultant for, received grant and honorarium from Takeda Pharmaceutical Company. KO, NF and AN are employees of Takeda Pharmaceutical Company. SS has served as a consultant for and received a grant, honorarium and travel fee from Takeda Pharmaceutical Company. TK, KA and KS have served as a consultant and received a grant and honorarium from Takeda Pharmaceutical Company., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objective: Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) are widely used but they increase the risk of gastrointestinal haemorrage among other adverse effects. The objective of this study was to compare potentially inappropriate medications (PIM) by NSAIDs using the original Beers Criteria, a global reference for evaluating elderly people's prescriptions, and the Spanish adaptation of the same; and the relation between PIM of NSAIDs and gastrointestinal bleeding., Methods: The study was a retrospective observational study carried out located in a primary care district in the province of de Murcia, south-eastern Spain. The study population (n=7.856) were citizens aged 65 and above, with at least one drug prescribed in a Spanish health district during the study period . We analized illnesses and treatments registered in the primary care's electronic medical history of patients and hospital admissions, during the 12 month study period (2012). The original Beers Criteria and their Spanish adaptation were used to evaluate PIM of NSAIDs in patients considering the medication globally and also each active substance. Gastrointestinal bleeding events recorded in the data bases studied were evaluated., Results: Detection of PIM of NSAIDs was 5,6% with the original version and 7,0% (Δ=25,5%; p less than 0,001) with the adapted one. PIM of NSAIDs was related with an increased incidence of gastrointestinal bleeding without significant differences between PIM exposed and NSAID exposed patients AINE (RR=1,6; IC:0,2-14,5)., Conclusions: The Spanish adaptation of the Beers criteria identified a greater degree of PIM of NSAIDs than the original version, and in both versions the detection of PIM was not related with a significant increase of gastrointestinal bleeding compared to patients exposed to NSAIDs., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Objective: Limited evidence is available on rebleeding due to nonsteroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy. Previous studies have primarily analyzed endoscopic findings. Therefore, there is a need to evaluate their clinical implications for patients. This study aimed to evaluate the rebleeding rate and its related risk factors in patients with NSAIDs-induced enteropathy., Methods: Of 402 patients with obscure gastrointestinal bleeding who were evaluated with capsule endoscopy, 49 were diagnosed with NSAIDs-induced enteropathy. The clinical characteristics of the patients were retrospectively analyzed. The Charlson comorbidity index was used to stratify the comorbidities. For patients who used additional drugs that influenced their tendency to bleeding, the odds ratio was calculated and used for a quantitative comparison., Results: The rebleeding rate in patients with NSAIDs-induced enteropathy was 20.4%, within a mean duration of 23.4 months. Age ≥65 years (hazard ratio [HR] 8.628, 95% confidence interval [CI] 1.152-64.625), no additional use of mucoprotective agents (HR 11.712, 95% CI 1.278-76.098) and the continuation of NSAIDs after the first bleeding episode (HR 9.861, 95% CI 1.395-98.344) were independently related to rebleeding due to NSAIDs-induced enteropathy. The underlying comorbidities, drug-related rebleeding risk scores and therapeutic use of proton pump inhibitors were not significantly different (P = 0.209, 0.212 and 0.720, respectively)., Conclusions: Approximately one-fifth of patients with NSAIDs-induced enteropathy showed rebleeding within 2 years. A careful long-term follow-up should be offered to elderly patients with NSAIDs-induced enteropathy who need continuous NSAID treatment without the additional use of mucoprotective medications., (© 2018 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

Gastrointestinal (GI) bleeding is an unwanted side effect common to all chemical types of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly in elderly people. However, the risk factors of GI bleeding associated with NSAIDs for elderly people remain unknown. This study aims to evaluate the risks of GI bleeding associated with NSAIDs in 4728 elderly people over 60 years old based on database from a hospital in Beijing.This retrospective hospital-based study included 4728 patients over 60 years old prescribed with NSAIDs, of which 928 patients had GI bleeding and 3800 did not have. Odds ratios (OR) for the risk of GI bleeding associated with NSAIDs were determined by logistic regression analysis. Mean Decrease Gini (MDG) involved in random forest algorithm was used to rank the associated factors with GI bleeding.In multivariate analysis, family history of GI bleeding (OR, 3.348; P = .000), history of peptic ulcers (OR, 4.068; P = .000), history of cardiovascular and cerebrovascular disease (OR, 1.476; P = .001), diabetes mellitus (OR, 1.408; P = .000), antiplatelet drugs (OR, 3.106; P = .000), Helicobacter pylori infection (OR, 1.312; P = .001), cholesterol level (OR, 0.516; P = .000), upper abdominal discomfort (OR, 3.467; P = .000), anorexia (OR, 2.038; P = .000), and NSAIDs used for 0.5 to 3 months (OR, 0.780; P = .000) were associated with GI bleeding. After ranked the MDG of each factor, the top 5 ranked factors associated with GI bleeding were melena, hematemesis, antiplatelet drugs, cholesterol level, and upper abdominal discomfort.We found that family history of GI bleeding, history of peptic ulcers, history of cardiovascular and cerebrovascular disease, diabetes mellitus, antiplatelet drugs, Helicobacter pylori infection, hypocholesterolemia, and NSAIDs used for 0.5 to 3 months were independent risk factors for GI bleeding on people over 60 years old. Meanwhile, upper abdominal discomfort might be the predictor of GI bleeding associated with NSAIDs elderly users.

Objective: To examine the comparative safety of individual NSAIDs when given concomitantly with clopidogrel., Methods: We conducted a retrospective cohort study using Medicaid claims from five US states during 1999-2010, supplemented with Medicare claims for dual-enrollees. The exposure of interest was the first concomitant use of clopidogrel and one of the 10 selected NSAIDs after a 1-year baseline period. The outcomes were: all-cause mortality; acute myocardial infarction (AMI)/ischemic stroke; and gastrointestinal bleeding (GIB)/intracranial hemorrhage (ICH). We calculated the hazard ratio of each NSAID for each outcome, with ibuprofen as the reference drug, using high-dimensional propensity score-adjusted proportional-hazards regression models., Results: Of 1,060,412 clopidogrel users, 268,114 concomitant NSAID users met inclusion/exclusion criteria, contributing 48,483 person-years. We observed 2,463 deaths, 2,822 AMI/ischemic stroke outcomes, and 2,620 GIB/ICH outcomes, for unadjusted incidence rates of 50.8, 58.6, and 54.3 per 1,000 person-years, respectively. Compared with ibuprofen and controlling for potential confounders, rofecoxib (hazard ratio [HR] = 1.22; 95% confidence interval [CI]: 1.04, 1.43) and valdecoxib (HR = 0.66; 95% CI: 0.48, 0.92) showed higher and lower hazards of mortality, respectively. Indomethacin showed an increased AMI/ischemic stroke hazard (HR = 1.38; 95% CI: 1.09, 1.74). For GIB/ICH, indomethacin (HR = 2.18; 95% CI: 1.74, 2.73), diclofenac (HR = 1.65; 95% CI: 1.39, 1.97), naproxen (HR = 1.47; 95% CI: 1.28, 1.70), and rofecoxib (HR = 1.26; 95% CI: 1.08, 1.48) showed higher hazards, and valdecoxib (HR = 0.73; 95% CI: 0.55, 0.98) showed a lower hazard., Conclusion: The bleeding risks of individual NSAIDs varied more markedly than thrombotic risks when used concomitantly with clopidogrel. Moreover, bleeding risk and thrombotic risk among individual NSAIDs did not appear to be inversely related to each other in the presence of clopidogrel. Further studies are needed to elucidate underlying biological mechanisms and help clinical decision-making for a better NSAID choice in clopidogrel users.

Background and Aim: The aim of this systematic review and meta-analysis was to assess the risk of post-polypectomy bleeding (PPB) in patients that underwent colorectal polypectomy and exposed to ASA/NSAIDs., Methods: Relevant publications were identified in MEDLINE/EMBASE for the period 1950-2016. Studies with specified ASA/NSAIDs exposure and bleeding rate were included. Study quality was ascertained according to Newcastle-Ottawa Scale. Forest plot was based on fixed or random effect models in relation to the heterogeneity., Results: 11 studies (4 prospective and 7 retrospective) including 9307 patients were included in the analyses. Overall, 344 patients (OR 1.8; 95% CI 1.2-2.7; p-value 0.001, I 2 52%) experienced rectal bleeding after procedure. While the rate of immediate PPB on aspirin and/or NSAIDs was not increased (OR 1.1; CI 95% 0.6-2.1; d.f.=1, p=0.64, I 2 0%), the risk of delayed PPB was augmented (OR 1.7; 95% CI 1.2-2.2; d.f.=8, p=0.127, I 2 36%)., Conclusions: ASA/NSAIDs are not a risk factor for immediate PPB but the chance of delayed is increased., (Copyright © 2017 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: The best available evidence regarding non-steroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) bleeding comes from randomized controlled trials including patients who use NSAIDs to manage chronic rheumatic diseases; however, patients with varying background profiles commonly take NSAIDs for many other reasons, often without prescription, and such usage has not been well studied., Objectives and Methods: To define the characteristics of patients hospitalized for upper GI bleeding in clinical practice, we conducted a case-control study among patients with endoscopy-proven major upper GI bleeding due to gastroduodenal peptic lesions and control subjects. We used adjusted logistic regression models to estimate bleeding risks. Data analysis was performed using SPSS 22.0., Results: Our analysis included 3785 cases and 6540 controls, including 1270 cases (33.55%) and 834 controls (12.75%) reporting recent use (<30 days) of NSAIDs including high-dose acetylsalicylic acid (ASA). NSAID use was associated with increased risk of upper GI bleeding, with an adjusted relative risk of 4.86 (95% CI, 4.32-5.46). Acute musculoskeletal pain (36.1%), chronic osteoarthritis (13.5%), and headache (13.6%) were the most common reasons for NSAID use. Among cases, only 17.31% took NSAIDs and 6.38% took high dose ASA due to chronic osteoarthritis. Demographic characteristics significantly differed between subjects with chronic vs. acute musculoskeletal pain. Proton pump inhibitor use was significantly higher in patients who used NSAIDs due to chronic osteoarthritis compared to patients with acute musculoskeletal pain. NSAID (65.15%) or high-dose ASA use (65.83%) preceding upper GI bleeding was most often short-term. In over half of cases (63.62%), the upper GI bleeding event was not preceded by dyspeptic warning symptoms., Conclusions: The majority of patients hospitalized due to NSAID-related upper GI bleeding reported short-term NSAID use for reasons other than chronic rheumatic disease. These findings suggest that current prevention strategies may not reach a wide population of short-term NSAID users.

Purpose: To assess the risk of gastrointestinal perforation, ulcers, or bleeding (PUB) associated with the use of conventional nonsteroidal anti-inflammatory drugs (NSAIDs) with proton pump inhibitors (PPIs) and selective COX-2 inhibitors, with or without PPIs compared with conventional NSAIDs., Methods: A case-control study was performed within conventional NSAIDs and/or selective COX-2 inhibitors users identified from the Dutch PHARMO Record Linkage System in the period 1998-2012. Cases were patients aged ≥18 years with a first hospital admission for PUB. For each case, up to four controls were matched for age and sex at the date a case was hospitalized (index date). Logistic regression analysis was used to calculate odds ratios (ORs)., Results: At the index date, 2634 cases and 5074 controls were current users of conventional NSAIDs or selective COX-2 inhibitors. Compared with conventional NSAIDs, selective COX-2 inhibitors with PPIs had the lowest risk of PUB (adjusted OR 0.51, 95% confidence interval [CI]: 0.35-0.73) followed by selective COX-2 inhibitors (adjusted OR 0.66, 95%CI: 0.48-0.89) and conventional NSAIDs with PPIs (adjusted OR 0.79, 95%CI: 0.68-0.92). Compared with conventional NSAIDs, the risk of PUB was lower for those aged ≥75 years taking conventional NSAIDs with PPIs compared with younger patients (adjusted interaction OR 0.79, 95%CI: 0.64-0.99). However, those aged ≥75 years taking selective COX-2 inhibitors, the risk was higher compared with younger patients (adjusted interaction OR 1.22, 95%CI: 1.01-1.47)., Conclusions: Selective COX-2 inhibitors with PPIs, selective COX-2 inhibitors, and conventional NSAIDs with PPIs were associated with lower risks of PUB compared with conventional NSAIDs. These effects were modified by age. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd., (© 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.)

Aim: To assess the prevalence of possible risk factors of upper gastrointestinal bleeding (UGIB) and their age-group specific trend among the general population and osteoarthritis patients., Methods: We utilized data from the National Health Insurance Service that included claims data and results of the national health check-up program. Comorbid conditions (peptic ulcer, diabetes, liver disease, chronic renal failure, and gastroesophageal reflux disease), concomitant drugs (aspirin, clopidogrel, cilostazol, non-steroidal anti-inflammatory drugs, steroid, anticoagulants, and SSRI), personal habits (smoking, and alcohol consumption) were considered as possible UGIB risk factors. We randomly imputed the prevalence of infection in the data considering the age-specific prevalence of Helicobacter pylori ( H. pylori ) infection in Korea. The prevalence of various UGIB risk factors and the age-group specific trend of the prevalence were identified. Prevalence was compared between osteoarthritis patients and others., Results: A total of 801926 subjects (93855 osteoarthritis patients) aged 20 and above were included. The prevalence of individual and concurrent multiple risk factors became higher as the age increased. The prevalence of each comorbid condition and concomitant drug were higher in osteoarthritis patients. Thirty-five point zero two percent of the overall population and 68.50% of osteoarthritis patients had at least one or more risk factors of UGIB. The prevalence of individual and concurrent multiple risk factors in younger age groups were also substantial. Furthermore, when personal habits (smoking, and alcohol consumption) and H. pylori infection were included, the prevalence of concurrent multiple risk factors increased greatly even in younger age groups., Conclusion: Prevalence of UGIB risk factors was high in elderly population, but was also considerable in younger population. Patient with osteoarthritis was at higher UGIB risk than those without osteoarthritis. Physicians should consider individualized risk assessment regardless of age when prescribing drugs or performing procedures that may increase the risk of UGIB, and take necessary measures to reduce modifiable risk factors such as H. pylori eradication or lifestyle counseling., Competing Interests: Conflict-of-interest statement: The authors declare that they have no competing interests.

Background: Colorectal cancer (CRC) is one of the most common cancers in the developed world and is the second leading cause of cancer-related mortality in the UK and USA. Regular use of aspirin can reduce cancer incidence, recurrence, metastasis and cancer-related mortality., Sources of Data: Peer-reviewed journals, governmental and professional society publications., Areas of Agreement: There is a wide body of evidence from observational studies and randomized trials that aspirin reduces risk of CRC. There is a delay of several years between initiation and effect. There is interpersonal variation in aspirin metabolism but pharmacogenetic testing is not yet sufficiently sensitive or specific to justify routine use., Areas of Disagreement: There is uncertainty about the optimal dose and the duration of aspirin. There is debate around use for the general population but there is growing consensus on use in those at increased risk of developing cancer., Growing Points: Understanding is growing of the possible mechanisms by which aspirin exerts its anticancer effects. Large-scale meta-analyses are quantifying the cost-benefit ratio in the general population. International trials are underway to assess the optimal dose in high-risk individuals and the role of aspirin as an adjuvant in those who present with a malignancy., (© The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Low-dose aspirin has proven effectiveness in secondary and primary prevention of cardiovascular events, but is also associated with an increased risk of major bleeding events. For primary prevention, this absolute risk must be carefully weighed against the benefits of aspirin; such assessments are currently limited by a lack of data from general populations., Methods: Systematic searches of Medline and Embase were conducted to identify observational studies published between 1946 and 4 March 2015 that reported the risks of gastrointestinal (GI) bleeding or intracranial hemorrhage (ICH) with long-term, low-dose aspirin (75-325 mg/day). Pooled estimates of the relative risk (RR) for bleeding events with aspirin versus non-use were calculated using random-effects models, based on reported estimates of RR (including odds ratios, hazard ratios, incidence rate ratios and standardized incidence ratios) in 39 articles., Findings: The incidence of GI bleeding with low-dose aspirin was 0.48-3.64 cases per 1000 person-years, and the overall pooled estimate of the RR with low-dose aspirin was 1.4 (95% confidence interval [CI]: 1.2-1.7). For upper and lower GI bleeding, the RRs with low-dose aspirin were 2.3 (2.0-2.6) and 1.8 (1.1-3.0), respectively. Neither aspirin dose nor duration of use had consistent effects on RRs for upper GI bleeding. The estimated RR for ICH with low-dose aspirin was 1.4 (1.2-1.7) overall. Aspirin was associated with increased bleeding risks when combined with non-steroidal anti-inflammatory drugs, clopidogrel and selective serotonin reuptake inhibitors compared with monotherapy. By contrast, concomitant use of proton pump inhibitors decreased upper GI bleeding risks relative to aspirin monotherapy., Conclusions: The risks of major bleeding with low-dose aspirin in real-world settings are of a similar magnitude to those reported in randomized trials. These data will help inform clinical judgements regarding the use of low-dose aspirin in prevention of cardiovascular events.

Objective: To investigate the incidence, clinical characteristics and risk factors of upper gastrointestinal bleeding (UGIB) in patients with acute coronary syndrome (ACS) who were administrated with aspirin and clopidogrel dual antiplatelet therapy after percutaneous coronary intervention (PCI)., Methods: ACS patients who had undergone PCI in the cardiovascular institute of Guangdong General Hospital from September 2009 to August 2014 were retrospectively enrolled.The incidence of UGIB and clinical characteristics of ACS patients on dual antiplatelet therapy for 1 year after PCI were analyzed.Risk factors of UGIB were screened in the cohort of patients and sex and age matched controls with ratio 1∶3., Results: A total of 9 118 ACS patients had undergone PCI and UGIB occurred in 189 patients (2.07%, 189/9 118) from September 2009 to August 2014. UGIB patients with history over one year, gastrointestinal tumors or varices or negative endoscopy were excluded.Thus the revised incidence of UGIB occurred was 0.61% in 56 patients (0.61%, 56/9 118) and appeared to decline year by year.Most patients (91.07%, 51/56) had melena or stool occult blood positive (OB+ ), while others had bloody stool or haematemesis.Most UGIB were ulcer-related which was proved by endoscopy, accounting for 67.86% (38/56). There were 24 cases with duodenal ulcer, 13 with gastric ulcer and 1 with complex ulcer, while others were gastric erosion, gastritis and duodenitis.The risk factors of UGIB were previous history of peptic ulcer (P<0.01) and renal impairment (P<0.01). On the other side, PPI intake was a protective factor (P<0.05). The incidence of new-onset ACS was 1.44% (50/3 464) in PPI group, compared with 1.34% (76/5 654) in no PPI group (P>0.05). PPI use for the prevention of UGIB after PCI didn't increase the recurrence of ACS., Conclusions: The incidence of UGIB is 0.61% in ACS patients on dual antiplatelet therapy (aspirin and clopidogrel) for 1 year after PCI and falls year by year.Administration of PPI after PCI protects patients from UGIB, especially in those with precious history of peptic ulcer and renal impairment.

Objectives: Studies on the association of acute lower gastrointestinal bleeding (ALGIB) and drugs are scarce. We aimed to investigate the association of drugs and ALGIB, especially regarding specific causes of ALGIB, and their role in the severity of ALGIB., Materials and Methods: The study was prospective and included all patients undergoing colonoscopy in 2010 and 2013 at the National University Hospital of Iceland. Use of nonsteroidal anti-inflammatory drugs (NSAIDs), low-dose aspirin (LDA), and warfarin before ALGIB was registered. Clinically significant bleeding was defined as: hemoglobin <100 g/L, hemodynamic instability, blood transfusion, surgery, or death., Results: Overall, 2392 patients underwent 2751 colonoscopies, of those, 325 (14%) had ALGIB, mean age 64 years (±20). The commonest diagnoses were diverticulosis (22%) and ischemic colitis (14%). In multivariate analysis, NSAIDs, LDA, and warfarin use was associated with ALGIB, odds ratio (OR) 3.3 [95% confidence interval (95% CI), 1.99-5.82], OR 1.5 (95% CI, 1.01-2.13), and OR 2.7 (95% CI, 1.61-4.57), respectively. Clinically significant bleeders were more likely than nonclinically significant bleeders to use NSAIDs or LDA+warfarin, OR 2.3 (95% CI, 1.26-3.76) and OR 33.0 (95% CI, 6.74-595), respectively. Patients with diverticular bleeding had greater odds than controls of NSAID, LDA, and warfarin use, OR 8.3 (95% CI, 3.8-18.3), OR 2.1 (95% CI, 1.15-3.67), and OR 2.6 (95% CI, 1.24-5.56), respectively. Patients with ischemic colitis were more likely than controls to use LDA, OR 2.3 (95% CI, 1.14-4.45)., Conclusions: NSAIDs, LDA, and warfarin were associated with ALGIB and diverticular bleeding. These drugs may have a role in other etiologies of ALGIB and seem to increase the risk of clinically significant bleeding.

Background: High-risk prescribing and preventable drug-related complications are common in primary care. We evaluated whether the rates of high-risk prescribing by primary care clinicians and the related clinical outcomes would be reduced by a complex intervention., Methods: In this cluster-randomized, stepped-wedge trial conducted in Tayside, Scotland, we randomly assigned participating primary care practices to various start dates for a 48-week intervention comprising professional education, informatics to facilitate review, and financial incentives for practices to review patients' charts to assess appropriateness. The primary outcome was patient-level exposure to any of nine measures of high-risk prescribing of nonsteroidal antiinflammatory drugs (NSAIDs) or selected antiplatelet agents (e.g., NSAID prescription in a patient with chronic kidney disease or coprescription of an NSAID and an oral anticoagulant without gastroprotection). Prespecified secondary outcomes included the incidence of related hospital admissions. Analyses were performed according to the intention-to-treat principle, with the use of mixed-effect models to account for clustering in the data., Results: A total of 34 practices underwent randomization, 33 of which completed the study. Data were analyzed for 33,334 patients at risk at one or more points in the preintervention period and for 33,060 at risk at one or more points in the intervention period. Targeted high-risk prescribing was significantly reduced, from a rate of 3.7% (1102 of 29,537 patients at risk) immediately before the intervention to 2.2% (674 of 30,187) at the end of the intervention (adjusted odds ratio, 0.63; 95% confidence interval [CI], 0.57 to 0.68; P<0.001). The rate of hospital admissions for gastrointestinal ulcer or bleeding was significantly reduced from the preintervention period to the intervention period (from 55.7 to 37.0 admissions per 10,000 person-years; rate ratio, 0.66; 95% CI, 0.51 to 0.86; P=0.002), as was the rate of admissions for heart failure (from 707.7 to 513.5 admissions per 10,000 person-years; rate ratio, 0.73; 95% CI, 0.56 to 0.95; P=0.02), but admissions for acute kidney injury were not (101.9 and 86.0 admissions per 10,000 person-years, respectively; rate ratio, 0.84; 95% CI, 0.68 to 1.09; P=0.19)., Conclusions: A complex intervention combining professional education, informatics, and financial incentives reduced the rate of high-risk prescribing of antiplatelet medications and NSAIDs and may have improved clinical outcomes. (Funded by the Scottish Government Chief Scientist Office; ClinicalTrials.gov number, NCT01425502.).

Aim: To investigate gastrointestinal complications associated with non-steroidal anti-inflammatory drug (NSAIDs) use in children., Methods: A retrospective, multicenter study was conducted between January 2005 and January 2013, with the participation of 8 Italian pediatric gastroenterology centers. We collected all the cases of patients who refer to emergency room for suspected gastrointestinal bleeding following NSAIDs consumption, and underwent endoscopic evaluation. Previous medical history, associated risk factors, symptoms and signs at presentation, diagnostic procedures, severity of bleeding and management of gastrointestinal bleeding were collected. In addition, data regarding type of drug used, indication, dose, duration of treatment and prescriber (physician or self-medication) were examined., Results: Fifty-one patients, including 34 males, were enrolled (median age: 7.8 years). Ibuprofen was the most used NSAID [35/51 patients (68.6%)]. Pain was the most frequent indication for NSAIDs use [29/51 patients (56.9%)]. Seven patients had positive family history of Helicobacter pylori (H. pylori) infection or peptic ulcer, and 12 had associated comorbidities. Twenty-four (47%) out of 51 patients used medication inappropriately. Hematemesis was the most frequent symptom (33.3%). Upper gastrointestinal endoscopy revealed gastric lesions in 32/51 (62%) patients, duodenal lesions in 17 (33%) and esophageal lesions in 8 (15%). In 10/51 (19.6%) patients, a diagnosis of H. pylori gastritis was made. Forty-eight (94%) patients underwent medical therapy, with spontaneous bleeding resolution, while in 3/51 (6%) patients, an endoscopic hemostasis was needed., Conclusion: The data collected in this study confirms that adverse events with the involvement of the gastrointestinal tract secondary to NSAID use are also common in children.

Study Question: What is the effect of proton pump inhibitors (PPIs) on the risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with non-steroidal anti-inflammatory drugs (NSAIDs)?, Methods: This was a nationwide cohort study based on linked administrative registry data from all hospitals in Denmark between 1997 and 2011. The study included patients aged 30 years and over admitted with a first myocardial infarction who survived at least 30 days after discharge. The association between PPIs and risk of gastrointestinal bleeding according to NSAID plus antithrombotic therapy was estimated using adjusted time dependent Cox regression models., Study Answer and Limitations: The use of PPIs was independently associated with decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and treated with NSAIDs. Of 82,955 post-myocardial infarction patients (mean age 67.4 years, 64% (n=53,070) men), all of whom were taking single or dual antithrombotic therapy, 42.5% (n=35,233) filled at least one prescription for NSAIDs and 45.5% (n=37,771) received PPIs. Over a mean follow-up of 5.1 years, 3229 gastrointestinal bleeds occurred. The crude incidence rates of bleeding (events/100 person years) on NSAID plus antithrombotic therapy were 1.8 for patients taking PPIs and 2.1 for those not taking PPIs. The adjusted risk of bleeding was lower with PPI use (hazard ratio 0.72, 95% confidence interval 0.54 to 0.95) regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used. The main limitation of the study is its observational non-randomised design. The results suggest that PPI treatment probably has a beneficial effect regardless of underlying gastrointestinal risk and that when NSAIDs cannot be avoided in post-myocardial infarction patients, physicians might prescribe a PPI as well. The study does not clarify whether PPIs might be safely omitted in specific subgroups of patients with a low risk of gastrointestinal bleeding., What This Study Adds: In post-myocardial infarction patients, bleeding complications have been associated with both antithrombotic and NSAID treatment. Concurrent use of PPIs was independently associated with a decreased risk of gastrointestinal bleeding in post-myocardial infarction patients taking antithrombotics and NSAID, regardless of antithrombotic treatment regimen, type of NSAID, and type of PPI used., Funding, Competing Interests, Data Sharing: AMSO has received a grant from the Danish Council of Independent Research (grant 12-132760). GHG is supported by an unrestricted research scholarship from the Novo Nordisk Foundation., (© Schjerning Olsen et al 2015.)

Objective: The incidence of nonsteroidal anti-inflammatory drugs (NSAIDs)-induced enteropathy is currently increasing. However, the predictors of small bowel bleeding (SBB) associated with NSAIDs are unknown. This study aimed to assess the risk factors of SBB in chronic NSAIDs users., Methods: We retrospectively compared the medical records of 147 patients receiving NSAIDs in a tertiary-care setting (31 with SBB and 116 without previous bleeding events) and analyzed the predictors of SBB., Results: In total, 31 patients underwent video capsule endoscopy to detect SBB, 74.2% of whom showed the evidence of SBB. Non-invasive treatment was performed in 90.3% of the patients. Multivariate logistic regression analysis revealed that the presence of coronary artery disease [adjusted odds ratio (aOR) 12.43, 95% confidence interval (CI) 1.19-130.34, P = 0.04], use of thienopyridine (aOR 16.93, 95% CI 3.78-75.72, P < 0.001) and prior use of rebamipide (aOR 0.31, 95% CI 0.12-0.82, P = 0.02) were independently associated with SBB in NSAIDs users., Conclusions: Coronary artery disease and co-use of thienopyridine were associated with SBB in NSAIDs users. The patients with coronary artery disease co-using thienopyridine need to be monitored for the occurrence of SBB when they were prescribed with NSAIDs., (© 2015 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and Wiley Publishing Asia Pty Ltd.)

Although the incidence of nonvariceal upper gastrointestinal bleeding (UGIB) has been decreasing worldwide, nonvariceal UGIB continues to be a significant problem. Even with the advent of advanced endoscopic procedures and potent medications to suppress acid production, UGIB carries significant morbidity and mortality. Some of the most common risk factors for nonvariceal UGIB include Helicobacter pylori infection, nonsteroidal antiinflammatory drugs (NSAIDs), aspirin, selective serotonin reuptake inhibitors, and other antiplatelet and anticoagulant medications. In patients with cardiovascular disease and kidney disease, UGIB tends to be more severe and has greater morbidity. Many of the newer NSAIDs have been removed from the market., (Published by Elsevier Inc.)

Background & Aims: Treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) or low-dose aspirin is associated with increased risk of upper gastrointestinal bleeding. There is little evidence on the risk of lower gastrointestinal bleeding with NSAIDs, antiplatelet agents (APAs), or anticoagulants. We aimed to quantify the relative risk (RR) of upper and lower gastrointestinal bleeding associated with use of NSAIDs, APAs, or anticoagulants., Methods: We performed a case-control study that used data collected from consecutive patients hospitalized for gastrointestinal bleeding (563 upper, mean age, 63.6 ± 16.7 years and 415 lower, mean age, 70.8 ± 13.8 years), confirmed by endoscopy or other diagnostic procedures. Unhospitalized patients were used as controls (n = 1008) and matched for age, hospital, and month of admission. Drug use was considered current when taken within 7 days or less before hospitalization. RRs and 95% confidence intervals (CIs) were estimated by unconditional logistic regression analysis., Results: Use of anticoagulants, low-dose aspirin, and other drugs (non-aspirin-APA, 82.3% thienopiridines) was associated with upper and lower gastrointestinal bleeding; the risk was 2-fold higher for anticoagulants (RR, 4.2; 95% CI, 2.9-6.2) than for low-dose aspirin (RR, 2.1; 95% CI, 1.4-3.3) or other non-aspirin-APA drugs (RR, 2.0; 95% CI, 1.6-2.6). NSAID use was also associated with increased risk of gastrointestinal bleeding and greater for upper (RR, 2.6; 95% CI, 2.0-3.5) than lower gastrointestinal bleeding (RR, 1.4; 95% CI, 1.0-1.9). Use of proton pump inhibitors was associated with reduced risk of upper, but not lower, gastrointestinal bleeding., Conclusions: Anticoagulants, low-dose aspirin, NSAIDs, and other non-aspirin-APA drugs are associated with increased risk of upper and lower gastrointestinal bleeding. Use of anticoagulants appears to be the strongest risk factor for gastrointestinal bleeding., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

A careful assessment of benefits and harms is required to assess suitability of aspirin as a prophylactic public health measure. However, comprehensive population-level data on harms are lacking. We collected and synthesized age and sex-specific data on harms relevant to aspirin use in average-risk individuals aged 50 years or older. We conducted systematic literature searches to identify baseline rates of gastrointestinal (GI) bleeding, peptic ulcer, major extra-cranial bleeding, and case-fatality rates due to GI bleeding or peptic ulcer in general population. The magnitude of aspirin-associated increase, the prevalence and attributable risk of Helicobacter pylori infection on these events in aspirin users was also assessed. Baseline rates of major extracranial bleeding events and GI complications increase with age; an almost threefold to fourfold increase is observed from age 50-54 to 70-74 years. Low or standard-dose aspirin use increases GI bleeding events by 60% leading to an annual excess of 0.45 and 0.79 GI bleeding events per 1,000 women and men aged 50-54 years respectively. 5-10% of major GI complications are fatal; a clear age dependence--higher fatality in older individuals, is seen. Eradication of H. pylori infection before aspirin use could reduce the incidence of upper GI complications by 25-30%. GI complications are increased by about 60% due to aspirin use but are fatal only in a very small proportion of individuals younger than 70 years of age. Major bleeding events that are comparable in severity to cancer or CVD, are infrequent. Screening and eradication of H. pylori infection could substantially lower aspirin-related GI harms.

Gastrointestinal (GI) damage by non-steroidal anti-inflammatory drugs (NSAIDs) is an important Public Health problem due to morbility and elevated mortality rate. The logic behind the development and sale of molecules which are selective cyclooxegnase-2 (COX-2) inhibitors called coxibs, is to limit the undesired effects of traditional NSAIDs, which should theoretically derive from the inhibition of COX-1. With respect to the emphasis of the initial trials, to now epidemiological studies, open-label studies, meta-analyses and reviews of the same data with longer follow-up, have produced opposite conclusions. Indeed, a recent series of meta-analyses has shown that the risks of GI events are similar for coxib and diclofenac, while they are significantly higher during the assumption of ibuprofen or naproxen. Moreover, the presumed lower gastrolesivity of coxibs is based on a highly simplified hypothesis, that the gastroprotective PGs derive from COX-1 and that the phlogistic processes are related to COX-2. Also in geriatric populations, though less tolerated than coxibs, diclofenac presents minor GI side effects when compared with naproxen and ibuprofen. In this context, in the case of moderate pain intensity, it is possible to use combinations with weak opioids, such as paracetamol-tramadol. Though intestinal damage by NSAIDs are a nosological entity of growing interest, to now no trial has been conducted with optimal criteria to demonstrate the superiority of coxibs over traditional NSAIDs. For this reason, chronic inflammation of the intestine still represents a contraindication to the administration of coxibs.

Aim: Complications of colonic diverticula, perforation and bleeding are a source of morbidity and mortality. A variety of drugs have been implicated in these complications. We present a systemic review and meta-analysis of the literature to assess the importance of this relationship., Method: A systematic review of articles in PubMed, Cochrane Reviews, Embase and Google Scholar was undertaken in February 2013. An initial literature search yielded 2916 results that were assessed for study design and topicality. Twenty-three articles were included in the review. A qualitative data synthesis was conducted using forest plots of studies comparing single medication with complications., Results: Individual studies demonstrated the odds of perforation and abscess formation with nonsteridal anti-inflammatory drugs (NSAIDs) (1.46-10.30), aspirin (0.66-2.40), steroids (2.17-31.90) and opioids (1.80-4.51) and the odds of bleeding with NSAIDs (2.01-12.60), paracetamol (0-3.75), aspirin (1.14-3.70) and steroids (0.57-5.40). Pooled data showed significantly increased odds of perforation and abscess formation with NSAIDs (OR = 2.49), steroids (OR = 9.08) and opioids (OR = 2.52). They also showed increased odds of diverticular bleeding from NSAIDs (OR = 2.69), aspirin (OR = 3.24) and calcium-channel blockers (OR = 2.50). Most studies did not describe the duration or dosage of medication used and did not systematically describe the severity of diverticular complications., Conclusion: Various common medications are implicated in complications of diverticular disease., (Colorectal Disease © 2013 The Association of Coloproctology of Great Britain and Ireland.)

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) and low-dose acetylsalicylic acid (ASA) have several adverse gastrointestinal (GI) effects, including upper GI bleeding. We aimed to develop a simple risk score to identify high risk NSAID and ASA users for primary upper GI bleeding., Methods: Using data from two large anonymized health insurance databases, we defined a development and validation cohort with NSAID and ASA users which were followed-up for the occurrence of a primary upper GI bleeding. Cox regression analyses identified risk factors which were combined into simple risk scores. C-statistics were used to evaluate the discriminative ability of these scores in a validation cohort., Results: In total, 421 cases of upper GI bleeding were identified in the initial cohort of 784,263 NSAID users (incidence rate 54.2 per 10,000 person-years), while 1,295 cases of upper GI bleeding were identified in 235,531 ASA users (incidence rate 37.9 per 10,000 person-years). The risk of upper GI bleeding increased with a higher risk score, which for NSAID users included age, male gender, anemia and concomitant use of ASA or anticoagulants. For ASA users, age, anemia, diabetes and concomitant use of other antiplatelet drugs or anticoagulants were included in the risk score. The C-statistics in the validation cohort were 0.68 and 0.63 or NSAID and ASA users, respectively., Conclusion: Risk factors for primary upper GI bleeding are to a large extent similar for NSAID and ASA users. Using a risk score based on these risk factors, patients at the highest risk can be identified with moderate accuracy.

It is thought that both selective serotonin reuptake inhibitors (SSRIs) and non-steroidal anti-inflammatory drugs (NSAIDs) can cause the adverse reaction of upper gastrointestinal hemorrhage (UGIH). To evaluate differences in the probability of UGIH occurring when SSRIs, NSAIDs, or both combined are administered, the authors performed a systematic review of related articles and a meta-analysis of data in those articles, which were identified by searching the literature published between 1999 and 2012 using PubMed, Scirus, and Google Scholar. The odds ratios were calculated using the Mantel-Haenszel method. The integrated odds ratios for SSRIs only, NSAIDs only, and the combination were 1.73 (0.65-2.82), 2.55 (1.51-3.59), and 4.02 (2.89-5.15), respectively. Use of the combination resulted in an odds ratio 2.32 times higher than use of either alone. Since the combination of SSRIs and NSAIDs resulted in a significantly higher risk of UGIH than either type of drug alone, clinicians should avoid use of the combination as much as possible. If it is necessary to administer both kinds of drugs, the minimum dosage should be prescribed for the shortest time period possible, and patients, particularly elderly patients, should be closely monitored for development of UGIH and other complications.

Background: Use of acetylsalicylic acid (ASA) or thienopyridines in monotherapy or combination of both drugs is associated with increased risk of gastrointestinal (GI) bleeding. The administration of drugs inhibiting gastric acid production represents an effective way to avoid GI disorders associated with antiplatelet therapy., Objectives: The aim of our study was to evaluate the use of gastroprotective medication in elderly antiplatelet users in relation to risk factors for GI bleeding., Methods: Patients (n = 428) aged ≥ 65 years who were prescribed low dose ASA or clopidogrel in monotherapy or combination at hospital discharge were enrolled in the study., Results: Only 39.7 % of patients with 2 or more risk factors for GI bleeding were prescribed gastroprotective medication at hospital discharge. The probability of elderly antiplatelet drug user for prescription of gastroprotective medication was improved with following risk factors: age ≥ 85 years (OR = 2.99); history of peptic ulcer disease/ GI bleeding (OR = 15.79); other GI disorders (OR = 15.48); concomitant therapy with drugs increasing the risk of GI bleeding - systemic corticosteroids (OR = 29.03) and NSAIDs (OR = 4.79)., Conclusion: Results of our study indicate the necessity to increase the awareness of GI bleeding risk in long-term antiplatelet users among prescribing physicians.

Purpose: To validate the International Classification of Diseases, 9th Revision, Clinical Modification discharge codes used to identify cases of upper gastrointestinal complications (UGICs) in hospitals of Friuli Venezia Giulia, Italy., Methods: Cohort study on the risk of UGIC in users of nonsteroidal anti-inflammatory drugs conducted in Friuli Venezia Giulia between 2001 and 2008. Cases were identified through primary and secondary International Classification of Diseases, 9th Revision Clinical specific codes 531 (gastric ulcer), 532 (duodenal ulcer), 533 (peptic ulcer), 534 (gastrojejunal ulcer), and nonspecific code 578 (gastrointestinal hemorrhage). Potential cases were confirmed through hospital chart review., Results: The chart retrieval percentage was 98.4%.The positive predictive value (PPV) was 94.3% for primary codes 531 and 532, 79.5% for code 533, 83.1% for code 534, 40.2% for code 578. The PPV for secondary codes was 34.7% but increased to 88.9% and 79.2% when the primary code was for peritonitis or acute post-hemorrhagic anemia, respectively. Validation of secondary codes increased case ascertainment by 4.9%. Endoscopy confirmed 79.4% of cases but only 67.2% of those above age 84 years., Conclusions: The PPV was high for specific primary codes and moderate to low for nonspecific primary and secondary codes. The inclusion of confirmed cases identified by nonspecific and secondary codes can be of value in studies that need a complete ascertainment of cases occurring in the study population. In this cohort, not including these cases would underestimate the incidence of UGICs. A potential for case misclassification exists in particular in eldest ages., (Copyright © 2013 John Wiley & Sons, Ltd.)