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Dulaglutide 3.0 and 4.5 mg weekly doses were approved for additional glycemic control in adult patients with type 2 diabetes inadequately controlled with metformin and 0.75 or 1.5 mg weekly doses of dulaglutide. Effects such as nausea and vomiting are commonly reported with dulaglutide and other glucagon-like peptide-1 receptor agonist therapies. Based on a pharmacokinetic/pharmacodynamic model-informed approach, a stepwise dose-escalation scheme with 4-week intervals between dose increments was suggested to mitigate gastrointestinal events for dulaglutide. These gastrointestinal events are dose dependent and attenuate over time with repeated dosing. A Markov chain Monte Carlo pharmacokinetic/pharmacodynamic joint model was developed using AWARD-11 data (N = 1842) to optimize dulaglutide dose escalation to 3.0 and 4.5 mg to mitigate gastrointestinal events. Model simulations evaluated probabilities of nausea and vomiting events for various dosing scenarios in patients needing higher doses for additional glycemic control. The model indicated that patients may dose escalate from 1.5 to 3.0 mg, then 4.5 mg weekly after at least 4 weeks on each dose. No clinically meaningful differences in nausea or vomiting events were expected when patients escalated to 3.0 or 4.5 mg following initiation at 0.75 or 1.5 mg dulaglutide. Based on the findings of this model, a minimum 4-week duration at each dose before escalation was appropriate to reduce gastrointestinal events of dulaglutide, consistent with observed gastrointestinal events data from the AWARD-11 study and supporting the currently recommended dose-escalation regimen of dulaglutide doses of 3.0 and 4.5 mg for additional glycemic control.

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Background: There are concerns regarding the gastrointestinal (GI) safety of sodium polystyrene sulfonate (SPS), a medication commonly used in the management of hyperkalemia. Objective: To compare the risk of GI adverse events among users versus non-users of SPS in patients on maintenance hemodialysis. Design: International prospective cohort study. Setting: Seventeen countries (Dialysis Outcomes and Practice Patterns Study [DOPPS] phase 2-6 from 2002 to 2018). Patients: 50 147 adults on maintenance hemodialysis. Measurements: An adverse GI event defined by a GI hospitalization or GI fatality with SPS prescription compared with no SPS prescription. Methods: Overlap propensity score-weighted Cox models. Results: Sodium polystyrene sulfonate prescription was present in 13.4% of patients and ranged from 0.42% (Turkey) to 20.6% (Sweden) with 12.5% use in Canada. A total of 935 (1.9%) adverse GI events (140 [2.1%] with SPS, 795 [1.9%] with no SPS; absolute risk difference 0.2%) occurred. The weighted hazard ratio (HR) of a GI event was not elevated with SPS use compared with non-use (HR = 0.93, 95% confidence interval = 0.83-1.6). The results were consistent when examining fatal GI events and/or GI hospitalization separately. Limitations: Sodium polystyrene sulfonate dose and duration were unknown. Conclusions: Sodium polystyrene sulfonate use in patients on hemodialysis was not associated with a higher risk of an adverse GI event. Our findings suggest that SPS use is safe in an international cohort of maintenance hemodialysis patients.

Contexte: Des préoccupations sont soulevées quant à l'innocuité gastro-intestinale (GI) du sulfonate de polystyrène sodique (SPS), un médicament couramment utilisé dans la gestion de l'hyperkaliémie. Objectif: Comparer dans une population de patients sous hémodialyse d'entretien le risque d'effets indésirables gastro-intestinaux chez les utilisateurs du SPS par rapport aux patients non-utilisateurs. Conception: Étude de cohorte prospective internationale. Cadre: 17 pays (phases 2 à 6 de l'essai DOPPS [de 2002 à 2018]). Sujets: 50 147 adultes sous hémodialyse d'entretien. Mesures: La comparaison entre les événements gastro-intestinaux indésirables, définis par une hospitalisation ou un décès en lien avec un problème gastro-intestinal, selon que les patients avaient ou non une prescription de SPS. Méthodologie: Modèles de Cox pondérés par le score de propension au chevauchement. Résultats: Dans l'ensemble de la cohorte, 13,4 % des patients avaient une prescription de SPS; l'usage de SPS variait selon les pays entre 0,42 % (Turquie) et 20,6 % (Suède) avec 12,5 % au Canada. En tout, 935 (1,9 %) événements GI indésirables sont survenus dans l'ensemble de la cohorte, soit 140 (2,1 %) chez les patients avec prescription de SPS et 795 (1,9 %) chez les patients sans prescription de SPS (différence de risque absolue: 0,2 %). Le rapport de risque (RR) pondéré d'un événement GI n'était pas plus élevé avec l'utilisation de SPS (RR = 0,93; IC 95 %: 0,83-1,6). Les résultats étaient cohérents lorsque l'on a examiné séparément les événements gastro-intestinaux (hospitalisation et/ou décès). Limites: La dose et la durée du traitement par SPS étaient inconnues. Conclusion: L'utilisation de SPS chez les patients sous hémodialyse n'a pas été associée à un risque plus élevé d'événements indésirables d'origine gastro-intestinale. Nos résultats suggèrent que l'utilisation du SPS est sans danger dans la cohorte internationale de patients sous hémodialyse d'entretien étudiée.

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BACKGROUND/AIM: To identify predictors of adverse gastrointestinal (GI) events related to stereotactic body radiation therapy (SBRT) for liver tumors. PATIENTS AND METHODS: We retrospectively analyzed 56 patients who underwent SBRT for liver tumors at our institution between 2016 and 2021. The α/ß ratio of the GI tract (stomach, duodenum, and large intestine) was assumed to be 3 Gy in the Linear-Quadratic model (LQ model). The dose to the GI tract, that is, the biologically effective dose 3 (BED3) was converted to a 2 Gy equivalent dose (Gy2/3=2 Gy equivalent dose, α/ß=3). Using this 2 Gy equivalent dose, predictors of adverse GI events of Grade 2 or higher were investigated. RESULTS: The median observation period was 10 months (0-40 months) and median age was 77 years (range=29-93 years). Forty-three of the 56 patients had hepatocellular carcinoma and the other 13 had metastatic liver tumors. Tumors were irradiated with 30-54 Gy/5-18 fractions of planning target volume D95% prescription (80% isodose). Eight of the 56 patients had Grade 2 or higher adverse GI events. By univariate analysis, GI D1cc, Dmax, V20, V25, V30, and V35 were all significant predictors of Grade 2 or higher adverse GI events. Among these, gastrointestinal V35 was the most significant predictor of Grade 2 or higher adverse GI events. CONCLUSION: For SBRT of liver tumors, GI V35 was the best predictor of Grade 2 or higher adverse GI events.

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Objetivos: revisar la evidencia publicada sobre el uso de AINE (coxibs y clásicos) y evaluar el riesgo cardiovascular (RCV) y gastrointestinal (RGI) asociado. Material y métodos: fueron seleccionados los estudios de cohorte y caso-control que mostraban el RCV o RGI de los AINE versus no expuestos. Se calculó el RR ponderado y el intervalo de confianza 95% para todos los AINE conjuntamente y de forma individual. Resultados: se observó un RCV significativo tanto con coxibs [RR= 1.24 (1.19-1.31)] como con AINE clásicos [RR= 1.18 (1.13-1.24)]. Para los coxibs sería elevado incluso a dosis bajas y en sujetos con RCV basal bajo. Por fármaco individual, rofecoxib [RR= 1.41 (1.33-1.50)] junto con diclofenaco [RR= 1.36 (1.27-1.47)] y etoricoxib [RR= 1.26 (1.08-1.48)] son los AINE con mayor RCV. El metaanálisis sobre el RGI mostró riesgo con los coxibs [RR 1.64 (95% CI 1.44-1.86)]. Por fármaco individual, etoricoxib [RR 4.48 (95% CI 2.98-6.75)] presentó mayor riesgo seguido de rofecoxib [RR 2.02 (95% CI 1.56-2.61)] y celecoxib [RR 1.62 (95% CI 1.46-1.78)]. El riesgo también fue elevado para dosis bajas y edad <65 años. Conclusión: según nuestro estudio, el uso de AINE (coxibs y clásicos) está relacionado con un incremento similar del RCV, incluso a dosis bajas y en pacientes con un RCV bajo-medio. Por otro lado, el uso de coxibs se relacionaría con un incremento del RGI, siendo elevado incluso para dosis bajas y edad <65 años. El riesgo para etoricoxib podría ser superior que para celecoxib y rofecoxib.(AU)

Introduction: the aim of this study is to review the current evidence on the clinical use of NSAIDs, coxibs and nonselective, and to evaluate its cardiovascular (CVR) and gastrointestinal risk (GIR) by means of a meta-analytic procedure. Materials and methods: cohort and case-control studies showing CVR and GIR associated with NSAIDs versus no treatment were selected. We estimated the pooled RR and the 95% confidence interval (CI) for all NSAIDs as a whole and individually. Results: both coxibs (RR, 1.22 [95%CI, 1.17-1.28]) and nonselective NSAIDs (RR 1.18 [95%CI, 1.12-1.24]) were associated with an increased CVR. The coxibs CVR remained even for low-dose and low-baseline CVR subgroups. Analysis by drug disclosed that rofecoxib (RR 1.39 [95%CI, 1.31- 1.47]), along with diclofenac (RR, 1.34 [95%CI, 1.26-1.42]) and etoricoxib (RR 1.27 [95%CI, 1.12-1.43]) were the NSAIDs associated with the highest CVR. Gastrointestinal risk meta-analysis showed that coxibs were associated with a GIR increment [RR1.64 (95% CI 1.44-1.86)]. Analysis by drug disclosed that etoricoxib [RR 4.48 (95% CI 2.98-6.75)]presented the highest GIR followed by rofecoxib [RR 2.02 (95% CI 1.56-2.61)] and celecoxib [RR1.62 (95% CI 1.46-1.78)]. GIR was also high for <65 year-old and low-dose coxibs subgroups. Conclusion: according to our study the use of NSAIDs (coxibs and nonselective) are associated with a similar CVR increment, even for low-dose and low-baseline CVR subgroups. On the other hand, the use of coxibs is associated with a GIR increased, which would be high even for low-dose coxibs and <65-year-old subgroups. The risk would be higher for etoricoxib than for celecoxib and rofecoxib.

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PURPOSE: This study aimed to assess the safety risks associated with using nonsteroidal anti-inflammatory drugs (NSAIDs) in elderly patients (≥65 years) compared with younger patients (<65 years) with osteoarthritis (OA) and/or chronic low back pain (CLBP). METHODS: A retrospective analysis was conducted on anonymized claims data of patients prescribed NSAIDs for OA and/or CLBP from 2009 to 2018 using hospital-based administrative database-Medical Data Vision (MDV). The key outcome was the incidence of developing gastrointestinal (GI), renal, and acute myocardial infarction (AMI) that are well-known events associated with NSAID use. RESULTS: Of 288,715 patients included, 23.7%, 60.5%, and 15.8% had OA, CLBP, or both, respectively. Elderly patients used non-oral NSAIDs more frequently than oral NSAIDs (57.8% and 38.7%, respectively), whereas younger patients showed comparable use (50.7% and 52.8%, respectively). The incidence of events per 10,000 person-years (95% CI) was higher in the elderly than in younger patients: GI, 29.68(27.67-31.68) vs. 16.61(14.60-18.63); renal, 124.77(120.56-128.99) vs. 39.88(36.72-43.03); and AMI, 27.41(25.48-29.35) vs. 10.90(9.27-12.53), respectively. After adjusting for covariates, the increase in risk for these events was seen in patients >70 years compared with younger patients (18-30 years) and was remarkable in patients >80 years with 2-fold, 10-fold, and 7-fold higher risk for developing GI, renal, and AMI events, respectively. CONCLUSION: Risk for developing NSAID-associated events was higher in the elderly; particularly, renal and AMI events that remarkably increased in patients >80 years. To reduce them, NSAIDs should be prescribed at the lowest effective dose for the shortest duration possible.

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WHAT IS KNOWN AND OBJECTIVE: PARP inhibitors are currently one of the most promising PARP targeted drugs for patients with certain types of cancer. Gastrointestinal (GI) events are common adverse events for all PARP inhibitors. We conducted this meta-analysis of randomized controlled trials (RCTs) to fully investigate the incidence and the relative risk of GI events in cancer patients receiving PARP inhibitors. STUDY DESIGN: Randomized controlled trials in cancer patients treated with PARP inhibitors were retrieved, and the systematic evaluation was conducted. Embase and PubMed/Medline were searched for articles published till July 2020. RESULTS: Twenty-nine RCTs and 9529 patients were included. The present meta-analysis suggests that the use of PARP inhibitors significantly increases the risk of developing all-grade nausea (RR, 1.46; 95% CI, 1.29-1.66; p < .00001), vomiting (RR, 1.39; 95% CI, 1.17-1.64; p = .0001), diarrhoea (RR, 1.14; 95% CI, 1.06-1.23; p = .0003) and decreased appetite (RR, 1.24; 95% CI, 1.14-1.36; p < .00001), but not for constipation. And the use of these agents significantly increased the risk of high-grade nausea (RR, 1.99; 95% CI, 1.44-2.74; p < .0001), vomiting (RR, 1.54; 95% CI, 1.11-2.14; p = .01) and decreased appetite (RR, 2.03; 95% CI, 1.22-3.40; p = .007), except for diarrhoea and constipation. Nausea was the most common GI event for these agents. Patients receiving veliparib were associated with a relatively lower risk of all-grade nausea and vomiting. Patients with ovarian cancer tend to have a higher risk of all-grade nausea and vomiting than those with non-ovarian cancer. The risk of all-grade nausea and vomiting tended to be higher when PARP inhibitors treatment was longer. WHAT IS NEW AND CONCLUSION: PARP inhibitors were associated with a significant increased risk of GI events. Clinicians should be aware of these risks and perform regular monitoring.

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Oral bisphosphonates are effective medications for the prevention of fractures in people suffering from osteoporosis. They are associated with gastrointestinal adverse reactions the most severe being an esophageal ulcer. It is unclear if oral bisphosphonates have a similar gastrointestinal safety profile in the hospital setting as in the community setting because hospitalized patients are often bedridden which may hinder proper drug administration. INTRODUCTION: To evaluate the incidence of upper gastrointestinal symptoms in hospitalized patients taking oral bisphosphonate. METHODS: This single-center prospective cohort study included hospitalized adult patients actively taking risedronate or alendronate. Upper gastrointestinal symptoms were actively assessed at the baseline and 1 to 5 h following the administration of the oral bisphosphonate. RESULTS: A total of 298 patients were included in the study. The mean age was 64 ± 15 years. During the follow-up period, gastric and esophageal symptoms affected 32 patients (10.7%). Epigastric burning, dysphagia, and regurgitation were reported in 4.4% (n = 13), 3% (n = 9), 2.7 (n = 8), and 2.3% (n = 7) patients, respectively. Heartburn, retro-sternal pain, and odynophagia were observed in 1.7% (n = 5), 1.7% (n = 5), and 0.3% (n = 1) patients. CONCLUSION: The incidence of adverse reaction was similar to that reported in community trials. The administration of oral bisphosphonate in hospitalized patients does not represent an additional risk for upper gastrointestinal adverse events. Treatment should be optimized during the hospital stay to improve the pharmacological management of osteoporosis.

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INTRODUCTION: Sodium polystyrene sulphonate (SPS) and calcium polystyrene sulphonate (CPS) are commonly used cation-exchange resins for the treatment and control of hyperkalaemia. However, their use (particularly SPS) has been limited by reports of adverse gastrointestinal (GI) events. The safety of these compounds in patients undergoing dialysis requires larger investigation. AIMS: To study the occurrence of adverse GI events (occlusion, perforation, thrombosis/ischaemia) in the periods of SPS or CPS exposition versus the periods without exposition in dialysis patients. METHODS: Dialysis patients were extracted from the French National Registry and merged with the French hospital discharge database (between 2006 and 2017). For our primary analysis, we used patients who had any claim of SPS use (n = 43 771). Time-varying Cox models, negative binomial regression and pre- versus post-treatment average treatment effects. RESULTS: The mean age was 66 ± 15 years, 37% were female and 92% were undergoing haemodialysis. Over a 1-year follow-up, patients on periods with SPS (on-SPS) did not present an increased risk of adverse GI events versus the periods without SPS (off-SPS):  incidence rate (IR) (per 1000 person years) = 7.4 (6.4-8.7) versus 9.5 (8.1-11.0); adjusted hazard ratio (HR) (95% CI) = 0.81 (0.60-1.09), P = 0.17. Patients exposed to SPS did not experience a higher rate of adverse GI events in the year after SPS initiation versus the year before SPS initiation; P-value for parallel trend = 0.87. Patients on-CPS also did not show an increased risk of adverse GI events versus off-CPS: IR (per 1000 py) = 8.6 (5.1-11.9) versus 7.8 (5.1-11.9); adjusted HR (95% CI) = 0.76 (0.31-1.80), P = 0.52. The rates of adverse GI events in the periods on and off exposure were also similar over a follow-up of 5 years. CONCLUSION: Our large, nationwide study shows that the incidence of adverse GI events in patients undergoing dialysis was low and that neither the use of SPS nor CPS was associated with increased GI events risk.

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Recurrent upper gastrointestinal (UGI) and cardiovascular (CV) events of the three antiplatelet therapies in patients with cardiovascular diseases (CVD) were compared. Studies published in the PubMed, Embase, and Cochrane Central Register of Controlled Trials electronic databases that compared differences in adverse outcomes associated with the three antiplatelet therapies were reviewed. Five studies with a total number of 7,399 patients were included. No significant differences were found in the incidence of recurrent UGI events among the three antiplatelet therapies. However, in the aspirin-induced ulcer bleeding subgroups, aspirin plus proton pump inhibitors (PPIs) was associated with a significantly lower risk of recurrent UGI events (OR: 0.06, 95% CI: 0.01-0.32; z=3.30 and P=0.001) and UGI bleeding (OR: 0.06, 95% CI: 0.01-0.34; z=3.24 and P=0.001) compared to clopidogrel alone. Both aspirin plus PPIs (OR: 2.12, 95% CI: 1.58-2.84; z=5.00 and P<0.01) and clopidogrel plus PPIs (OR: 2.57, 95% CI: 1.89-3.51; z=5.97 and P<0.01) were related to a comparatively higher risk of recurrent CV events when compared to clopidogrel alone. In patients at high UGI bleeding risk (regardless of whether it was aspirin-induced) and under treatment of single antiplatelet therapy, aspirin plus PPIs should be considered as the first choice for UGI protection rather than clopidogrel alone and clopidogrel plus PPIs. However, in terms of CV protection, clopidogrel alone appears to be superior in reducing CV risk, while clopidogrel plus PPIs may relate to an increased CV risk due to the potential drug-drug interaction.

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INTRODUCTION: Delayed-release dimethyl fumarate (DMF) is an effective treatment for multiple sclerosis (MS). Some patients experience gastrointestinal (GI) adverse events (AEs) that may lead to premature DMF discontinuation. This study characterized the impact of site-specific GI management strategies on the occurrence of GI events and discontinuation patterns. METHODS: Data on GI events and DMF persistence were retrospectively abstracted from medical records of patients treated with DMF in routine medical practice in the EFFECT study (NCT02776072). GI management strategies were assessed via a study site questionnaire. Discontinuation rates were analyzed according to counseling patterns. RESULTS: Of 826 DMF-treated patients at 66 sites, 809 from 65 sites were eligible for the GI analysis; of these, 27% experienced GI AEs. Within 1 year of treatment, 14% (118/826) of patients discontinued DMF, 5% (44/809) due to GI events. Most sites (92%) reported that patients were very likely (> 75% of the time) to be counseled about GI events at/before DMF treatment initiation and/or to be recommended that DMF be taken with food (86%); 48% of sites reported to be very likely to recommend using symptomatic therapies for GI AEs. Lower discontinuation rates were reported at sites very likely versus not very likely (≤ 75% of the time) to (1) provide counseling; (2) provide specific details regarding GI events; or (3) recommend taking DMF with food, and/or using symptomatic GI therapies. CONCLUSION: Counseling and other GI management strategies at initiation of DMF treatment appear to reduce the burden of GI events, and a variety of GI management strategies may improve DMF persistence. TRIAL REGISTRATION: NCT02776072. FUNDING: Biogen (Cambridge, MA, USA).

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Prior meta-analyses have shown a higher gastrointestinal risk of nonselective NSAIDs versus placebo and a lower gastrointestinal risk of coxibs versus nonselective NSAIDs. However, the available data about gastrointestinal risk for coxibs versus placebo are scarce. The aim of this study was to review the current evidence on the use of coxibs and to evaluate the risk of gastrointestinal adverse outcomes (GAO) associated with coxibs versus nonexposed. Search was conducted on PubMed and Embase databases. We selected cohort observational, case-control, nested case-control and case-crossover studies that reported the risk of GAO associated with coxibs versus nonexposed as relative risk (RR), odds ratio (OR), hazard ratio (HR) or incidence rate ratio (IRR). It was estimated the pooled RR and the 95% confidence interval (CI) for coxibs both individually and as a whole by the DerSimonian and Laird method. Twenty-eight studies met inclusion criteria. Overall, coxibs were associated with a significant increment in the risk of GAO [RR 1.64 (95% CI 1.44-1.86)]. The analysis by individual drugs showed that etoricoxib [RR 4.85 (95% CI 2.64-8.93)] presented the highest gastrointestinal risk, followed by rofecoxib [RR 2.02 (95% CI 1.56-2.61)] and celecoxib [RR 1.53 (95% CI 1.19-1.97)]. Gastrointestinal risk was also high for the subgroups aged <65 years and low-dose coxibs. The use of coxibs is associated with a statistically significant increased risk of GAO, which would be high even for low-dose coxibs and <65-year-old subgroups. The risk would be higher for etoricoxib than for celecoxib and rofecoxib.

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BACKGROUND AND AIM: The predictors of severe gastrointestinal (GI) events in GI lymphoma patients are unclear. We aimed to develop a risk scoring system for GI events requiring surgery. METHODS: In this retrospective study of 192 patients with GI lymphoma, the state of lymphoma, macroscopic findings, examination results, and International Prognostic Index were assessed. We developed a risk score for GI events that required surgery and assessed its accuracy by calculating the area under the receiver operating characteristic curve (AUC). Internal validation was performed using bootstrap resampling. RESULTS: Severe GI events occurred in 21 (11%) patients. We developed a 4-point scoring system (the FLASH score) comprising the following three independent predictors (weighted by regression coefficients): (i) focal appearance and large size (≥ 40 mm), 1 point; (ii) aggressive lymphoma of the small bowel, 2 points; and (iii) high (18)F-fluorodeoxyglucose positron emission tomography uptake, 1 point. The score predicted severe GI events with an AUC value of 0.91 (internal validation; AUC, 0.86). Risk was classified into three categories: the GI event rate was 0% in the low-risk group (0 points), 9% in the intermediate-risk group (1-2 points), and 61% in the high-risk group (3-4 points) (AUC, 0.89). CONCLUSIONS: We developed and internally validated a risk scoring system (the FLASH score) that included macroscopic findings to predict severe GI events in GI lymphoma patients. Patients with high scores are candidates for elective surgery to prevent GI events.

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Patient-reported outcomes (PROs) provide practical guides for treatment; however, studies that have evaluated PROs of women in Korea with postmenopausal osteoporosis (PMO) are lacking. This cross-sectional, multi-center (29 nationwide hospitals) study, performed from March 2013 to July 2014, aimed to assess PROs related to treatment satisfaction, medication adherence, and quality of life (QoL) in Korean PMO women using osteoporosis medication for prevention/treatment. Patient demographics, clinical characteristics, treatment patterns, PROs, and experience using medication were collected. The 14-item Treatment Satisfaction Questionnaire for Medication (TSQM) (score-range, 0-100; domains: effectiveness, side effects, convenience, global satisfaction), Osteoporosis-Specific Morisky Medication Adherence Scale (OS-MMAS) (score-range, 0-8), and EuroQol-5 dimensions questionnaire (index score range, - 0.22 to 1.0; EuroQol visual analog scale score range, 0-100) were used. To investigate factors associated with PROs, linear (treatment satisfaction/QoL) or logistic (medication adherence) regression analyses were conducted. A total of 1804 patients (age, 62 years) were investigated; 60.1% used bisphosphonate, with the majority (67.2%) using weekly medication, 27.8% used daily hormone replacement therapy, and 12.1% used daily selective estrogen receptor modulator. Several patients reported gastrointestinal (GI) events (31.6%) and dental visits due to problems (24.1%) while using medication. Factors associated with the highest OS-MMAS domain scores were convenience and global satisfaction. GI events were associated with non-adherence. TSQM scores for effectiveness, side effects, and GI risk factors were significantly associated with QoL. Our study elaborately assessed the factors associated with PROs of Korean PMO women. Based on our findings, appropriate treatment-related adjustments such as frequency/choice of medications and GI risk management may improve PROs.

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The risk of gastrointestinal (GI) events induced by nonoperative therapies in patients with neuroendocrine tumors (NETs) is unclear. Nonoperative therapies include somatostatin analogs, molecular targeted agents, cytotoxic chemotherapy, interferon-α, and peptide receptor radionuclide therapy. We undertook an up-to-date meta-analysis to determine the incidence and relative risks (RRs) of GI events in NET patients treated with these therapies. MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov were searched to identify relevant trials. Eligible trials were selected according to the PRISMA statement. Summary incidence, RR, and 95% CIs were calculated using random- and fixed-effects models. We included 2,890 patients from 17 randomized controlled trials in this meta-analysis. The experimental treatments led to increased incidence and risks of GI events compared to the control treatments (P<0.05). Diarrhea was the most common GI event. The experimental treatments were associated with increased risks of high-grade nausea (RR 2.36; 95% CI 1.05-5.25; P<0.01) and vomiting (RR 1.89; 95% CI 1.04-3.44; P<0.05). In regard to specific therapy regimens, everolimus led to increased risks of diarrhea (RR 2.97; 95% CI 1.83-4.83; P<0.05), vomiting (RR 2.19; 95% CI 1.38-3.48; P<0.05), and anorexia (RR 3.20; 95% CI 1.69-6.06; P<0.05), whereas VEGFR inhibitors led to increased risk of diarrhea (RR 2.12; 95% CI 1.39-3.25; P<0.05). Additionally, GI NETs led to higher risk of GI events than pancreatic NETs. Thus, nonoperative therapies are associated with increased risks of GI events in NET patients, and rigorous management is warranted to minimize the adverse impact on treatment outcomes and to improve quality of life.

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BACKGROUND: Gastrointestinal (GI) events are common adverse events (AEs) associated with delayed-release dimethyl fumarate (DMF), an approved treatment for relapsing-remitting multiple sclerosis (RRMS). The objective of the TOLERATE study was to evaluate GI tolerability and GI mitigation via symptomatic therapies in patients initiating DMF in a real-world clinical setting in Germany. METHODS: TOLERATE was a multicentre, open-label, single-arm study performed at 25 German sites. Endpoints were frequency, severity, duration (all primary) and mitigation of GI-related events (secondary). Patients were instructed to take DMF according to the prescribing information for up to 12 weeks and to document GI events and intake of GI-symptomatic therapy on numerical rating scales, using eDiaries. RESULTS: A total of 211 patients were included in the safety population (71% female; mean age 40 ± 11 years). Of these, 185 patients (87.7%) reported GI-related events, out of which nearly half received GI-symptomatic therapy (84/185; 45.4%). The most frequently reported GI events were upper abdominal pain, flatulence and nausea. GI-related events peaked during the first 3 weeks of therapy and rapidly decreased thereafter. The severity of GI events over 12 weeks according to the Modified Overall Gastrointestinal Symptom Scale were mild to moderate in the majority of patients reporting GI-related events and taking symptomatic GI medication (53.6%). Only 10% of all patients discontinued study treatment due to AEs in general, while 6.6% discontinued due to GI-related events. The severity of GI-related events decreased over time in patients who received symptomatic treatment with one or more medications (e.g. acid secretion blockers, antidiarrhoeals or antiemetics). CONCLUSION: Gastrointestinal events associated with delayed-release DMF were mainly mild to moderate in severity. Prevalence of GI events peaked during the first 3 weeks of therapy and rapidly faded thereafter. Although 44.9% of patients experiencing GI events used common GI symptomatic therapies, only 6.6% of patients discontinued DMF because of GI events, suggesting that GI events could be managed well with common symptomatic therapy.

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The goal of this multinational, prospective, observational study was to examine the relationship between gastrointestinal (GI) events and self-reported levels of medication adherence and persistence in postmenopausal women. A total of 73.9% of patients remained on their osteoporosis (OP) therapy at month 12, although the presence of a GI event at baseline, month 3, and month 6 significantly reduced month 12 persistence among new users. The odds of a month-12 ADEOS score ≥ 20 were significantly lower among patients who experienced a GI event between baseline and month 6. The occurrence of GI events was observed to be associated with a lower likelihood of patient adherence and persistence to OP medication. INTRODUCTION: This study examines the relationship between gastrointestinal (GI) events and self-reported adherence and persistence with initial osteoporosis (OP) therapy over the course of the first 12 months of treatment. METHODS: The Medication Use Patterns, Treatment Satisfaction, and Inadequate Control of Osteoporosis Study was a multinational, prospective, observational study examining the impact of GI events on OP management in postmenopausal women. Information regarding GI events was collected at the time of enrollment and at months 3, 6, and 12 of follow-up. Patients reported GI events and medication persistence and completed the 12-item Adherence Evaluation of Osteoporosis treatment (ADEOS) questionnaire. Multivariate logistic and general linear models examined the association between GI events at various time points and persistence and adherence at month 12. RESULTS: The study enrolled 2943 women; 22.8% were classified as new users of OP therapy and the remainder were considered experienced users. Across all patients, 68.1% reported GI events at baseline; by month 12, over 80% of subjects who completed follow-up reported at least one GI problem. The majority of patients (86.7%) were treated only with bisphosphonates at baseline. At month 12, 73.9% of patients remained on therapy; logistic regression revealed that those with GI problems by month 6 were significantly less likely to persist with treatment, after adjusting for other factors. The odds of a month 12 ADEOS score ≥ 20 (considered predictive of adherence) were significantly lower among patients who experienced a GI event between baseline and month 6. CONCLUSIONS: The occurrence of GI events was associated with a lower likelihood of patient adherence to and persistence with OP medication.

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PURPOSE: We performed a meta-analysis to systematically review the gastrointestinal (GI) events (diarrhea, nausea, vomiting, anorexia) of five newly approved (after 2011) VEGFR-TKIs in cancer patients. METHODS: The relevant studies of the randomized controlled trials (RCTs) in cancer patients treated with cabozantinib, vandetanib, lenvatinib, regorafenib, and axitinib were retrieved and the systematic evaluation was conducted. RESULTS: Forty-one randomized controlled trials and 10,860 patients were included. Current analysis suggested that the use of these agents increased the risk of all-grade and high-grade GI events, and the diarrhea was the most common GI events. The risk of all-grade and high-grade GI events varies significantly within drug types, tumor types, and VEGFR-TKIs-based regimens. CONCLUSION: The available data suggested that the use of the five newly approved VEGFR-TKIs may increase risk of GI events in cancer patients. Physicians and patients should be aware of these risks and frequent monitoring and careful management should be emphasized when managing these VEGFR-TKIs.

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