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Background & Aims: Early identification and accurate characterization of overt gastrointestinal bleeding (GIB) enables opportunities to optimize patient management and ensures appropriately risk-adjusted coding for claims-based quality measures and reimbursement. Recent advancements in generative artificial intelligence, particularly large language models (LLMs), create opportunities to support accurate identification of clinical conditions. In this study, we present the first LLM-based pipeline for identification of overt GIB in the electronic health record (EHR). We demonstrate 2 clinically relevant applications: the automated detection of recurrent bleeding and appropriate reimbursement coding for patients with GIB., Methods: Development of the LLM-based pipeline was performed on 17,712 nursing notes from 1108 patients who were hospitalized with acute GIB and underwent endoscopy in the hospital from 2014 to 2023. The pipeline was used to train an EHR-based machine learning model for detection of recurrent bleeding on 546 patients presenting to 2 hospitals and externally validated on 562 patients presenting to 4 different hospitals. The pipeline was used to develop an algorithm for appropriate reimbursement coding on 7956 patients who underwent endoscopy in the hospital from 2019 to 2023., Results: The LLM-based pipeline accurately detected melena (positive predictive value, 0.972; sensitivity, 0.900), hematochezia (positive predictive value, 0.900; sensitivity, 0.908), and hematemesis (positive predictive value, 0.859; sensitivity, 0.932). The EHR-based machine learning model identified recurrent bleeding with area under the curve of 0.986, sensitivity of 98.4%, and specificity of 97.5%. The reimbursement coding algorithm resulted in an average per-patient reimbursement increase of $1299 to $3247 with a total difference of $697,460 to $1,743,649., Conclusions: An LLM-based pipeline can robustly detect overt GIB in the EHR with clinically relevant applications in detection of recurrent bleeding and appropriate reimbursement coding., (Copyright © 2025 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Description: The purpose of this American Gastroenterological Association (AGA) Institute Clinical Practice Update (CPU) is to summarize the available evidence and offer expert Best Practice Advice on the integration of potassium-competitive acid blockers (P-CABs) in the clinical management of foregut disorders, specifically including gastroesophageal reflux disease, Helicobacter pylori infection, and peptic ulcer disease., Methods: This expert review was commissioned and approved by the AGA Institute Governing Board and CPU Committee to provide timely guidance on a topic of high clinical importance to the AGA membership. This CPU expert review underwent internal peer review by the CPU Committee and external peer review through the standard procedures of Gastroenterology. These Best Practice Advice statements were developed based on review of the published literature and expert consensus opinion. Because formal systematic reviews were not performed, these Best Practice Advice statements do not carry formal ratings of the quality of evidence or strength of the presented considerations. Best Practice Advice Statements BEST PRACTICE ADVICE 1: Based on nonclinical factors (including cost, greater obstacles to obtaining medication, and fewer long-term safety data), clinicians should generally not use P-CABs as initial therapy for acid-related conditions in which clinical superiority has not been shown. BEST PRACTICE ADVICE 2: Based on current costs in the United States, even modest clinical superiority of P-CABs over double-dose proton pump inhibitors (PPIs) may not make P-CABs cost-effective as first-line therapy. BEST PRACTICE ADVICE 3: Clinicians should generally not use P-CABs as first-line therapy for patients with uninvestigated heartburn symptoms or nonerosive reflux disease. Clinicians may use P-CABs in selected patients with documented acid-related reflux who fail therapy with twice-daily PPIs. BEST PRACTICE ADVICE 4: Although there is currently insufficient evidence for clinicians to use P-CABs as first-line on-demand therapy for patients with heartburn symptoms who have previously responded to antisecretory therapy, their rapid onset of acid inhibition raises the possibility of their utility in this population. BEST PRACTICE ADVICE 5: Clinicians should generally not use P-CABs as first-line therapy in patients with milder erosive esophagitis (EE) (Los Angeles classification of erosive esophagitis grade A/B EE). Clinicians may use P-CABs in selected patients with documented acid-related reflux who fail therapy with twice-daily PPIs. BEST PRACTICE ADVICE 6: Clinicians may use P-CABs as a therapeutic option for the healing and maintenance of healing in patients with more severe EE (Los Angeles classification of erosive esophagitis grade C/D EE). However, given the markedly higher costs of the P-CAB presently available in the United States and the lack of randomized comparisons with double-dose PPIs, it is not clear that the benefits in endoscopic outcomes over standard-dose PPIs justify the routine use of P-CABs as first-line therapy. BEST PRACTICE ADVICE 7: Clinicians should use P-CABs in place of PPIs in eradication regimens for most patients with H pylori infection. BEST PRACTICE ADVICE 8: Clinicians should generally not use P-CABs as first-line therapy in the treatment or prophylaxis of peptic ulcer disease. BEST PRACTICE ADVICE 9: Although there is currently insufficient evidence for clinicians to use P-CABs as first-line therapy in patients with bleeding gastroduodenal ulcers and high-risk stigmata, their rapid and potent acid inhibition raises the possibility of their utility in this population., (Published by Elsevier Inc.)

Background & Aims: Guidelines recommend use of risk stratification scores for patients presenting with gastrointestinal bleeding (GIB) to identify very-low-risk patients eligible for discharge from emergency departments. Machine learning models may outperform existing scores and can be integrated within the electronic health record (EHR) to provide real-time risk assessment without manual data entry. We present the first EHR-based machine learning model for GIB., Methods: The training cohort comprised 2546 patients and internal validation of 850 patients presenting with overt GIB (ie, hematemesis, melena, and hematochezia) to emergency departments of 2 hospitals from 2014 to 2019. External validation was performed on 926 patients presenting to a different hospital with the same EHR from 2014 to 2019. The primary outcome was a composite of red blood cell transfusion, hemostatic intervention (ie, endoscopic, interventional radiologic, or surgical), and 30-day all-cause mortality. We used structured data fields in the EHR, available within 4 hours of presentation, and compared the performance of machine learning models with current guideline-recommended risk scores, Glasgow-Blatchford Score, and Oakland Score. Primary analysis was area under the receiver operating characteristic curve. Secondary analysis was specificity at 99% sensitivity to assess the proportion of patients correctly identified as very low risk., Results: The machine learning model outperformed the Glasgow-Blatchford Score (area under the receiver operating characteristic curve, 0.92 vs 0.89; P < .001) and Oakland Score (area under the receiver operating characteristic curve, 0.92 vs 0.89; P < .001). At the very-low-risk threshold of 99% sensitivity, the machine learning model identified more very-low-risk patients: 37.9% vs 18.5% for Glasgow-Blatchford Score and 11.7% for Oakland Score (P < .001 for both comparisons)., Conclusions: An EHR-based machine learning model performs better than currently recommended clinical risk scores and identifies more very-low-risk patients eligible for discharge from the emergency department., (Copyright © 2024 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: For decades, proton pump inhibitors (PPIs) have been the mainstay of treatment for erosive esophagitis. The potassium-competitive acid blocker vonoprazan provides more potent acid inhibition than PPIs, but data on its efficacy for erosive esophagitis are limited., Methods: Adults with erosive esophagitis were randomized to once-daily vonoprazan, 20 mg, or lansoprazole, 30 mg, for up to 8 weeks. Patients with healing were rerandomized to once-daily vonoprazan, 10 mg, vonoprazan, 20 mg, or lansoprazole, 15 mg, for 24 weeks. Primary end points, percentage with healing by week 8 endoscopy, and maintenance of healing at week 24 endoscopy, were assessed in noninferiority comparisons (noninferiority margins, 10%), with superiority analyses prespecified if noninferiority was demonstrated. Analyses of primary and secondary end points were performed using fixed-sequence testing procedures., Results: Among 1024 patients in the healing phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the exploratory analysis of healing (92.9 vs 84.6%; difference, 8.3%; 95% confidence interval [CI], 4.5%-12.2%). Secondary analyses showed vonoprazan was noninferior in heartburn-free days (difference, 2.7%; 95% CI, -1.6% to 7.0%), and superior in healing Los Angeles Classification Grade C/D esophagitis at week 2 (difference, 17.6%; 95% CI, 7.4%-27.4%). Among 878 patients in the maintenance phase, vonoprazan was noninferior to lansoprazole in the primary analysis and superior on the secondary analysis of maintenance of healing (20 mg vs lansoprazole: difference, 8.7%; 95% CI, 1.8%-15.5%; 10 mg vs lansoprazole: difference, 7.2%; 95% CI, 0.2%-14.1%) and secondary analysis of maintenance of healing Grade C/D esophagitis (20 mg vs lansoprazole: difference, 15.7%; 95% CI, 2.5%-28.4%; 10 mg vs lansoprazole: difference, 13.3%; 95% CI, 0.02%-26.1%)., Conclusions: Vonoprazan was noninferior and superior to the PPI lansoprazole in healing and maintenance of healing of erosive esophagitis. This benefit was seen predominantly in more severe erosive esophagitis. (ClinicalTrials.gov: NCT04124926)., (Published by Elsevier Inc.)

Background & Aims: Novel, effective treatments for Helicobacter pylori infection are needed. This study evaluated the efficacy of vonoprazan, a potassium-competitive acid blocker, vs standard treatment on H pylori eradication in the United States and Europe., Methods: In a randomized, controlled, phase 3 trial, treatment-naïve adults with H pylori infection were randomized 1:1:1 to open-label vonoprazan dual therapy (20 mg vonoprazan twice daily; 1 g amoxicillin 3 times daily), or double-blind triple therapy twice a day (vonoprazan 20 mg or lansoprazole 30 mg; amoxicillin 1 g; clarithromycin 500 mg) for 14 days. The primary outcome was noninferiority in eradication rates in patients without clarithromycin- and amoxicillin-resistant strains (noninferiority margin = 10%). Secondary outcomes assessed superiority in eradication rates in clarithromycin-resistant infections, and in all patients., Results: A total of 1046 patients were randomized. Primary outcome eradication rates (nonresistant strains): vonoprazan triple therapy 84.7%, dual therapy 78.5%, vs lansoprazole triple therapy 78.8% (both noninferior; difference 5.9%; 95% confidence interval [CI], -0.8 to 12.6; P < .001; difference -0.3%; 95% CI, -7.4 to 6.8; P = .007, respectively). Eradication rates in clarithromycin-resistant infections: vonoprazan triple therapy 65.8%, dual therapy 69.6%, vs lansoprazole triple therapy 31.9% (both superior; difference 33.9%; 95% CI, 17.7-48.1; P < .001; difference 37.7%; 95% CI, 20.5-52.6; P < .001, respectively). In all patients, vonoprazan triple and dual therapy were superior to lansoprazole triple therapy (80.8% and 77.2%, respectively, vs 68.5%, difference 12.3%; 95% CI, 5.7-18.8; P < .001; difference 8.7%; 95% CI, 1.9-15.4; P = .013). Overall frequency of treatment-emergent adverse events was similar between vonoprazan and lansoprazole regimens (P > .05)., Conclusion: Both vonoprazan-based regimens were superior to proton pump inhibitor-based triple therapy in clarithromycin-resistant strains and in the overall study population., Clinicaltrials: gov; NCT04167670., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Fecal microbiota transplantation (FMT) is used commonly for treatment of Clostridioides difficile infections (CDIs), although prospective safety data are limited and real-world FMT practice and outcomes are not well described. The FMT National Registry was designed to assess FMT methods and both safety and effectiveness outcomes from North American FMT providers., Methods: Patients undergoing FMT in clinical practices across North America were eligible. Participating investigators enter de-identified data into an online platform, including FMT protocol, baseline patient characteristics, CDI cure and recurrence, and short and long-term safety outcomes., Results: Of the first 259 participants enrolled at 20 sites, 222 had completed short-term follow-up at 1 month and 123 had follow-up to 6 months; 171 (66%) were female. All FMTs were done for CDI and 249 (96%) used an unknown donor (eg, stool bank). One-month cure occurred in 200 patients (90%); of these, 197 (98%) received only 1 FMT. Among 112 patients with initial cure who were followed to 6 months, 4 (4%) had CDI recurrence. Severe symptoms reported within 1-month of FMT included diarrhea (n = 5 [2%]) and abdominal pain (n = 4 [2%]); 3 patients (1%) had hospitalizations possibly related to FMT. At 6 months, new diagnoses of irritable bowel syndrome were made in 2 patients (1%) and inflammatory bowel disease in 2 patients (1%)., Conclusions: This prospective real-world study demonstrated high effectiveness of FMT for CDI with a good safety profile. Assessment of new conditions at long-term follow-up is planned as this registry grows and will be important for determining the full safety profile of FMT., (Copyright © 2021. Published by Elsevier Inc.)

Background & Aims: Scoring systems are suboptimal for determining risk in patients with upper gastrointestinal bleeding (UGIB); these might be improved by a machine learning model. We used machine learning to develop a model to calculate the risk of hospital-based intervention or death in patients with UGIB and compared its performance with other scoring systems., Methods: We analyzed data collected from consecutive unselected patients with UGIB from medical centers in 4 countries (the United States, Scotland, England, and Denmark; n = 1958) from March 2014 through March 2015. We used the data to derive and internally validate a gradient-boosting machine learning model to identify patients who met a composite endpoint of hospital-based intervention (transfusion or hemostatic intervention) or death within 30 days. We compared the performance of the machine learning prediction model with validated pre-endoscopic clinical risk scoring systems (the Glasgow-Blatchford score [GBS], admission Rockall score, and AIMS65). We externally validated the machine learning model using data from 2 Asia-Pacific sites (Singapore and New Zealand; n = 399). Performance was measured by area under receiver operating characteristic curve (AUC) analysis., Results: The machine learning model identified patients who met the composite endpoint with an AUC of 0.91 in the internal validation set; the clinical scoring systems identified patients who met the composite endpoint with AUC values of 0.88 for the GBS (P = .001), 0.73 for Rockall score (P < .001), and 0.78 for AIMS65 score (P < .001). In the external validation cohort, the machine learning model identified patients who met the composite endpoint with an AUC of 0.90, the GBS with an AUC of 0.87 (P = .004), the Rockall score with an AUC of 0.66 (P < .001), and the AIMS65 with an AUC of 0.64 (P < .001). At cutoff scores at which the machine learning model and GBS identified patients who met the composite endpoint with 100% sensitivity, the specificity values were 26% with the machine learning model versus 12% with GBS (P < .001)., Conclusions: We developed a machine learning model that identifies patients with UGIB who met a composite endpoint of hospital-based intervention or death within 30 days with a greater AUC and higher levels of specificity, at 100% sensitivity, than validated clinical risk scoring systems. This model could increase identification of low-risk patients who can be safely discharged from the emergency department for outpatient management., (Copyright © 2020 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Bowel preparation is defined as adequate if it is sufficient for identification of polyps greater than 5 mm. However, adequate preparation has not been quantified. We performed a prospective observational study to provide an objective definition of adequate preparation, based on the Boston Bowel Prep Scale (BBPS, which consists of 0-3 points for each of 3 colon segments)., Methods: We collected data from 438 men who underwent screening or surveillance colonoscopies and then repeat colonoscopy examinations within 60 days by a different blinded endoscopist (1161 colon segments total) at the West Haven Veterans Affairs Medical Center from January 2014 to February 2015. Missed polyps were defined as those detected on the second examination of patients with the best possible bowel preparation (colon segment BBPS score of 3) on the second examination. The primary outcome was the proportion of colon segments with adenomas larger than 5 mm that were missed in the first examination. We postulated that the miss rate was noninferior for segments with BBPS scores of 2 vs those with BBPS scores of 3 (noninferiority margin, <5%). Our secondary hypotheses were that miss rates were higher in segments with BBPS scores of 1 vs those with scores of 3 or of 2., Results: The adjusted proportion with missed adenomas greater than 5 mm was noninferior for segments with BBPS scores of 2 (5.2%) vs those with BBPS scores of 3 (5.6%) (a difference of -0.4%; 95% confidence interval [CI], -2.9% to 2.2%). Of study subjects, 347 (79.2%) had BBPS scores of 2 or greater in all segments on the initial examination. A higher proportion of segments with BBPS scores of 1 had missed adenomas larger than 5 mm (15.9%) than segments with BBPS scores of 3 (5.6%) (a difference of 10.3%; 95% CI, 2.7%-17.9%) or 2 (5.2%) (a difference of 10.7%; 95% CI, 3.2%-18.1%). Screening and surveillance intervals based solely on the findings at the first examination would have been incorrect for 16.3% of patients with BBPS scores of 3 in all segments, for 15.3% with BBPS scores of 2 or 3 in all segments, and for 43.5% of patients with a BBPS score of 1 in 1 or more segments., Conclusions: Patients with BBPS scores of 2 or 3 for all colon segments have adequate bowel preparation for the detection of adenomas larger than 5 mm and should return for screening or surveillance colonoscopy at standard guideline-recommended intervals. Colon segments with a BBPS score of 1 have a significantly higher rate of missed adenomas larger than 5 mm than segments with scores of 2 or 3. This finding supports a recommendation for early repeat colonoscopic evaluation in patients with a BBPS score of 0 or 1 in any colon segment., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The community of microorganisms within the human gut (or microbiota) is critical to health and functions with a level of complexity comparable to that of an organ system. Alterations of this ecology (or dysbiosis) have been implicated in a number of disease states, and the prototypical example is Clostridium difficile infection (CDI). Fecal microbiota transplantation (FMT) has been demonstrated to durably alter the gut microbiota of the recipient and has shown efficacy in the treatment of patients with recurrent CDI. There is hope that FMT may eventually prove beneficial for the treatment of other diseases associated with alterations in gut microbiota, such as inflammatory bowel disease, irritable bowel syndrome, and metabolic syndrome, to name a few. Although the basic principles that underlie the mechanisms by which FMT shows therapeutic efficacy in CDI are becoming apparent, further research is needed to understand the possible role of FMT in these other conditions. Although relatively simple to perform, questions regarding both short-term and long-term safety as well as the complex and rapidly evolving regulatory landscape has limited widespread use. Future work will focus on establishing best practices and more robust safety data than exist currently, as well as refining FMT beyond current "whole-stool" transplants to increase safety and tolerability. Encapsulated formulations, full-spectrum stool-based products, and defined microbial consortia are all in the immediate future., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: The cardiometabolic risk cluster metabolic syndrome (MS) includes ≥3 of elevated fasting glucose, hypertension, elevated triglycerides, reduced high-density lipoprotein cholesterol (HDL-c), and increased waist circumference. Each can be affected by physical activity and diet. Our objective was to determine whether determine whether baseline physical activity and/or diet behavior impact MS in the course of a large pharmaceutical trial., Materials/methods: This was an observational study from NAVIGATOR, a double-blind, randomized (nateglinide, valsartan, both, or placebo), controlled trial between 2002 and 2004. We studied data from persons (n=9306) with impaired glucose tolerance and cardiovascular disease (CVD) or CVD risk factors; 7118 with pedometer data were included in this analysis. Physical activity was assessed with 7-day pedometer records; diet behavior was self-reported on a 6-item survey. An MS score (MSSc) was calculated using the sum of each MS component, centered around the Adult Treatment Panel III threshold, and standardized according to sample standard deviation. Excepting HDL-c, assessed at baseline and year 3, MS components were assessed yearly. Follow-up averaged 6 years., Results: For every 2000-step increase in average daily steps, there was an associated reduction in average MSSc of 0.29 (95% CI (-)0.33 to (-)0.25). For each diet behavior endorsed, there was an associated reduction in average MSSc of 0.05 (95% CI (-)0.08 to (-)0.01). Accounting for the effects of pedometer steps and diet behavior together had minimal impact on parameter estimates with no significant interaction. Relations were independent of age, sex, race, region, smoking, family history of diabetes, and use of nateglinide, valsartan, aspirin, antihypertensive, and lipid-lowering agent., Conclusions: Baseline physical activity and diet behavior were associated independently with reductions in MSSc such that increased attention to these lifestyle elements provides cardiometabolic benefits. Thus, given the potential to impact outcomes, assessment of physical activity and diet should be performed in pharmacologic trials targeting cardiometabolic risk., (Published by Elsevier Inc.)

Objective: To compare the efficacy of a regimen combining mental practice (MP) with overground training (OT) with the efficacy of a regimen consisting of OT only on gait velocity and lower extremity motor outcomes in individuals with chronic (>12mo postinjury), incomplete spinal cord injury (SCI)., Design: Randomized, controlled, single-blinded study., Setting: Outpatient rehabilitation laboratories., Participants: Subjects with chronic, incomplete SCI (N=18)., Interventions: Subjects were randomly assigned to receive (1) OT only, occurring 3d/wk for 8 weeks; or (2) OT augmented by MP (MP + OT), during which randomly assigned subjects listened to an MP audio recording directly after OT sessions., Main Outcome Measures: Subjects were administered a test of gait velocity as well as the Tinetti Performance Oriented Mobility Assessment, Spinal Cord Injury Independence Measure, and Satisfaction With Life Scale on 2 occasions before intervention, 1 week after intervention, and 12 weeks after intervention., Results: A significant increase in gait velocity was exhibited across subjects at both 1 week posttherapy (P=.005) and at 12 weeks posttherapy (P=.006). However, no differences were seen in intervention response at either 1 or 12 weeks postintervention among subjects in the MP + OT group versus the OT-only group., Conclusions: OT was associated with significant gains in gait velocity, and these gains were not augmented by further addition of MP., (Copyright © 2014 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Capsule endoscopy improves the diagnostic yield in patients with obscure gastrointestinal (GI) bleeding, but whether it improves outcomes is uncertain., Methods: Patients with obscure GI bleeding and negative upper endoscopy, colonoscopy, and push enteroscopy were randomly assigned to capsule endoscopy or dedicated small bowel contrast radiography. Patients returned at 1, 2, 3, 6, 9, and 12 months for follow-up visits and to check hemoglobin level. The primary endpoint was further bleeding., Results: The predefined sample size of 136 patients (54 overt bleeding, 82 occult bleeding) was enrolled. Diagnostic yield was 20 (30%) with capsule vs 5 (7%) with radiography (difference = 23%; 95% CI: 11%-36%). Further bleeding with capsule versus radiography occurred in 20 (30%) versus 17 (24%) (difference, 6%; 95% confidence interval [CI], -9% to 21%), subsequent diagnostic or therapeutic interventions for bleeding were performed in 17 (26%) versus 15 (21%) (difference, 4%; 95% CI, -10% to 19%), subsequent hospitalizations for bleeding were required in 8 (12%) versus 4 (6%) (difference, 6%; 95% CI, -3% to 16%), and subsequent blood transfusions were given in 5 (8%) versus 4 (6%) (difference, 2%; 95% CI, -7% to 10%). Further bleeding was more common in patients presenting with overt bleeding than in those with occult bleeding (21/54 [39%] vs 16/82 [20%]; difference, 19%; 95% CI, 4% to 35%)., Conclusions: The significant improvement in diagnostic yield with capsule endoscopy may not translate into improved outcomes in a population with obscure GI bleeding. Most patients do well whether or not abnormalities are identified, and additional diagnostic or therapeutic interventions may be required whether or not capsule endoscopy identifies a source of bleeding., (Copyright 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objectives: To assess the efficacy of cyclooxygenase-2 selective inhibitors (coxibs) in osteoarthritis (OA) and their gastrointestinal, cardiovascular, renovascular, and hepatic side effects compared with traditional nonsteroidal antiinflammatory drugs (NSAIDs) and acetaminophen., Methods: Bibliographic database searches for randomized controlled trials, meta-analyses, and literature reviews., Results: Coxibs are comparable to traditional NSAIDs, providing moderate benefit for OA patients in pain and function versus placebo. NSAIDs, including coxibs, are superior to acetaminophen for OA, particularly in patients with moderate to severe pain. Coxibs decrease gastroduodenal ulcers (74% relative risk reduction) and ulcer complications (61% reduction) versus traditional NSAIDs. Meta-analysis of randomized trials indicates that coxibs increase the risk of myocardial infarctions approximately twofold versus placebo and versus naproxen, but do not increase the risk versus nonnaproxen NSAIDs. NSAIDs, including coxibs, commonly cause fluid retention and increase blood pressure and uncommonly induce congestive heart failure or significant renal dysfunction; risk factors include advanced age, hypertension, and heart or kidney disease. NSAIDs are a rare cause of clinical hepatotoxicity (<1 liver-related death per 100,000 NSAID users in clinical studies). Increased rates of aminotransferase elevations occur with rofecoxib (2%) and high-dose lumiracoxib (3%), and postmarketing cases of clinical liver injury with lumiracoxib have been reported recently., Conclusions: Coxibs are as effective as traditional NSAIDs and superior to acetaminophen for the treatment of OA. Coxibs cause fewer gastrointestinal complications than traditional NSAIDs. Coxibs increase cardiovascular risk versus placebo and naproxen-but probably not versus nonnaproxen NSAIDs. Blood pressure commonly increases after initiation of selective or nonselective NSAIDs, especially in hypertensive patients.

Background & Aims: Nonsteroidal anti-inflammatory drugs (NSAIDs) cause lower gastrointestinal (GI) clinical events such as bleeding. Cyclo-oxygenase (COX)-2 selective inhibitors decrease upper GI events, but no prospective trial has prespecified assessment of lower GI clinical events., Methods: Patients >or=50 years old with osteoarthritis or rheumatoid arthritis were randomly assigned to etoricoxib (60 or 90 mg qd) or diclofenac (150 mg qd). Lower GI clinical events, confirmed by a blinded adjudication committee, included perforation or obstruction requiring hospitalization or bleeding (gross or occult rectal bleeding without upper GI cause associated with hypotension, orthostatic changes in heart rate [>20 beats per minute] or blood pressure [>20 mmHg systolic or >10 mmHg diastolic], hemoglobin drop >or=2 g/dl, or transfusion; or observed active bleeding or stigmata of hemorrhage)., Results: We enrolled 34,701 patients with mean duration of therapy of 18 months. Rates were 0.32 and 0.38 lower GI clinical events per 100 patient-years for etoricoxib and diclofenac (hazard ratio [HR] = 0.84; 95% confidence interval [CI], 0.63-1.13). Bleeding was the most common event (rates of 0.19 and 0.23 per 100 patient-years, respectively). Multivariable analysis revealed significant risk factors to be prior lower GI event (HR = 4.06; 95% CI, 2.93-5.62) and age >or=65 years (HR = 1.98; 95% CI, 1.45-2.71)., Conclusions: A statistically significant decrease in lower GI clinical events was not seen with the COX-2 selective inhibitor etoricoxib versus the traditional NSAID diclofenac. The risk of a lower GI clinical event with NSAID use seems to be constant over time, and the major risk factors are a prior lower GI event and older age.

The gastric mucosa maintains structural integrity and function despite continuous exposure to noxious factors, including 0.1 mol/L HCl and pepsin, that are capable of digesting tissue. Under normal conditions, mucosal integrity is maintained by defense mechanisms, which include preepithelial factors (mucus-bicarbonate-phospholipid "barrier"), an epithelial "barrier" (surface epithelial cells connected by tight junctions and generating bicarbonate, mucus, phospholipids, trefoil peptides, prostaglandins (PGs), and heat shock proteins), continuous cell renewal accomplished by proliferation of progenitor cells (regulated by growth factors, PGE(2) and survivin), continuous blood flow through mucosal microvessels, an endothelial "barrier," sensory innervation, and generation of PGs and nitric oxide. Mucosal injury may occur when noxious factors "overwhelm" an intact mucosal defense or when the mucosal defense is impaired. We review basic components of gastric mucosal defense and discuss conditions in which mucosal injury is directly related to impairment in mucosal defense, focusing on disorders with important clinical sequelae: nonsteroidal anti-inflammatory drug (NSAID)-associated injury, which is primarily related to inhibition of cyclooxygenase (COX)-mediated PG synthesis, and stress-related mucosal disease (SRMD), which occurs with local ischemia. The annual incidence of NSAID-associated upper gastrointestinal (GI) complications such as bleeding is approximately 1%-1.5%; and reductions in these complications have been demonstrated with misoprostol, proton pump inhibitors (PPIs) (only documented in high-risk patients), and COX-2 selective inhibitors. Clinically significant bleeding from SRMD is relatively uncommon with modern intensive care. Pharmacologic therapy with antisecretory drugs may be used in high-risk patients (eg, mechanical ventilation >or=48 hours), although the absolute risk reduction is small, and a decrease in mortality is not documented.

Background & Aims: Intravenous bolus plus infusion proton pump inhibitor (PPI) therapy is recommended for patients with bleeding ulcers and higher risk stigmata. If frequent oral dosing of PPIs provided similar antisecretory effect, this might be preferred based on ease and cost., Methods: Patients presenting with overt bleeding due to ulcers had intragastric pH probes placed after endoscopy and baseline pH recorded. They were randomly assigned to intravenous lansoprazole (90-mg bolus followed by 9-mg/h infusion) or oral lansoprazole (120-mg bolus followed by 30 mg every 3 hours). pH was recorded for 24 hours., Results: Intragastric pH was > 6 for 67.8% of the study period with intravenous PPI (n = 32) and 64.8% with oral PPI (n = 34): difference, 3.0%; 95% confidence interval (CI): -9.2% to 15.2%. Intragastric pH was > 6 for > 60% of the study period in 22 (68.8%) patients receiving intravenous and 22 (64.7%) patients receiving oral PPI: difference, 4.0%; 95% CI: -18.7% to 26.8%. At 1 hour, mean pHs for intravenous vs oral were 5.3 +/- 0.4 vs 3.3 +/- 0.4, respectively (difference, 2.0; 95% CI: 0.8-3.1; P = .001). At > or = 1.5 hours, 95% CIs of the differences for all hourly mean pHs included zero. Mean pH rose above 6 after 2-3 hours of intravenous PPI and 3-4 hours of oral PPI., Conclusions: Frequent oral PPI may be able to replace the currently recommended intravenous bolus plus infusion PPI therapy in patients with bleeding ulcers, although the possibility that intravenous PPIs are superior cannot be definitively excluded given our relatively wide confidence intervals. Intravenous PPI provides more rapid increase in pH, reaching mean pH of 6 approximately 1 hour sooner than oral PPI.

Background & Aims: We assessed the risk of ulcers with low-dose aspirin and the interaction of low-dose aspirin with a COX-2 selective inhibitor in a double-blind trial that compared placebo, low-dose aspirin, rofecoxib + low-dose aspirin, and ibuprofen., Methods: Osteoarthritis patients > or =50 years of age without ulcers or erosive esophagitis at baseline endoscopy were assigned randomly to placebo, enteric-coated aspirin 81 mg/day, rofecoxib 25 mg combined with aspirin 81 mg/day, or ibuprofen 800 mg 3 times a day. Repeat endoscopies were performed at 6 and 12 weeks., Results: The 12-week cumulative incidence of ulcers was placebo (N = 381) 5.8%, aspirin (N = 387) 7.3%, rofecoxib combined with aspirin (N = 377) 16.1%, and ibuprofen (N = 374) 17.1% (P < 0.001 for rofecoxib combined with aspirin and for ibuprofen vs. each of placebo and aspirin). Over 12 weeks, mean increases in the number of erosions were placebo 0.17, aspirin 0.85 (P = 0.002 vs. placebo), rofecoxib combined with aspirin 1.67, and ibuprofen 1.91 (both P < 0.001 vs. aspirin and placebo)., Conclusions: Low-dose aspirin alone did not significantly increase ulcer incidence. Addition of a cyclooxygenase-2 (COX-2) selective inhibitor to low-dose aspirin increased ulcer incidence, to a rate not significantly less than a nonselective nonsteroidal anti-inflammatory drug (NSAID) alone. Determining the relative impact of COX-2 selective inhibitors and nonselective NSAIDs on gastrointestinal mucosal injury in low-dose aspirin users will require further study.

Background & Aims: Cyclooxygenase 2 (COX-2)-specific inhibitors (coxibs) decrease gastrointestinal (GI) events in controlled trials, but results in clinical practice are unknown. We assessed GI-related resource use and costs in patients switching from chronic nonsteroidal anti-inflammatory drug (NSAID) therapy to chronic coxib therapy and in patients starting chronic NSAID therapy vs. chronic coxib therapy in a U.S. administrative claims database of >8 million lives., Methods: "Switchers" (n = 2246) were assessed in the 12-month periods before and after switching from chronic NSAID therapy to coxib therapy. "New NSAID" (n = 25,989) and "new coxib" (n = 2125) groups were assessed for the 12-month periods before and after the initial prescription. Proportions of patients with GI resource use (odds ratio [OR] adjusted for relevant covariates) and costs were compared., Results: The adjusted OR for any GI resource use (coxib vs. NSAID period) among switchers was 0.86 (0.74-0.99). The decrease was due to less GI cotherapy (OR = 0.82 [0.69-0.97]). Costs were not significantly lower after switching to coxibs (mean difference, -$19; 95% CI: -$139, $55), although after adding NSAID/coxib costs, the total cost in the coxib period was significantly higher (mean increase, $377; $271, $488). Adjusted OR for GI resource use for new-coxib vs. new-NSAID was 1.04 (0.92-1.16), but GI costs were significantly lower in new-NSAID patients., Conclusions: Patients switching from chronic NSAID therapy to chronic coxib therapy had a slight decrease in the proportion using GI-related resources but not in GI costs. When NSAID/coxib drug costs were included, costs were significantly less with NSAIDs than with coxibs. The potential GI-related cost savings suggested in coxib clinical trials may not be fully realized in "real-world" settings.

Background & Aims: Epidemiologic studies suggest nonsteroidal anti-inflammatory drugs (NSAIDs) increase the risk for lower gastrointestinal (GI) clinical events, but data from prospective trials are lacking. Cyclooxygenase (COX)-2-selective inhibitors decrease upper GI clinical events but the effect on lower GI events has not been determined. We performed a post hoc analysis of serious lower GI clinical events with a nonselective NSAID and a COX-2-selective agent in a prospective, double-blind, randomized GI outcomes trial., Methods: A total of 8076 rheumatoid arthritis patients 50 years or older (or 40 years or older on corticosteroid therapy) expected to require NSAIDs for 1 year or greater were randomly assigned to naproxen 500 mg twice daily or rofecoxib 50 mg daily. The rate of serious lower GI clinical events, defined as bleeding with a 2 g/dL drop in hemoglobin or hospitalization, or hospitalization for perforation, obstruction, ulceration, or diverticulitis, was determined., Results: The rate of serious lower GI events per 100 patient-years was 0.41 for rofecoxib and 0.89 for naproxen (relative risk, 0.46; 95% confidence interval [CI], 0.22-0.93; P = 0.032). Serious lower GI events accounted for 39.4% of all serious GI events (complicated upper GI event or lower GI event) among patients taking naproxen and 42.7% among those taking rofecoxib., Conclusions: Serious lower GI events occurred at a rate of 0.9% per year in rheumatoid arthritis patients taking the nonselective NSAID naproxen, accounting for nearly 40% of the serious GI events that developed in these patients. Serious lower GI events were 54% lower with the use of the selective COX-2 inhibitor rofecoxib.

Nonsteroidal anti-inflammatory drugs (NSAIDs), which include aspirin, are among the most frequently prescribed medications worldwide. The main factor limiting use of NSAIDs is concern about their gastrointestinal (GI) side effects. The purpose of this article is to review the incidence, pathophysiology, and risk factors of GI side effects associated with NSAID therapy. Upper GI symptoms, such as dyspepsia, occur in 15% to 60% of NSAID users, twice as often as in individuals not taking NSAIDs. The prevalence of gastric or duodenal ulcers in patients taking NSAIDs regularly is approximately 15% to 30%. The annual incidence of NSAID-related clinical upper GI events (complicated and symptomatic ulcers) is approximately 2.5% to 4.5%, with the annual incidence of serious complications (severe bleeding, perforation, and obstruction) about 1% to 1.5%. A history of ulcer or GI complications, advanced age, concomitant anticoagulation therapy or corticosteroid use, and high-dose or multiple NSAID therapy are associated with an increased risk of GI events during NSAID therapy. The cyclooxygenase (COX)-2 specific inhibitors (coxibs) have been developed in order to improve the GI safety and tolerability profile of therapy with NSAIDs. In numerous clinical trials, coxibs have been shown to have efficacy similar to that of nonselective NSAIDs, but are associated with significantly fewer endoscopic ulcers. In addition, 2 large outcome trials indicated that coxibs can also reduce the incidence of clinically important GI events., (Copyright 2002, Elsevier Science (USA). All rights reserved.)

Background & Aims: Epidemiologic data indicate that the risk of nonsteroidal anti-inflammatory drug (NSAID)-related gastrointestinal (GI) clinical events varies based on patients' clinical characteristics. The authors determined risk factors for NSAID-related clinical upper GI events and the event rates, absolute risk reductions, and numbers needed to treat for individual risk factors for a nonselective NSAID and a selective cyclooxygenase 2 inhibitor in a double-blind outcomes trial., Methods: Eight thousand seventy-six rheumatoid arthritis patients aged >or=50 years (or >or=40 on corticosteroid therapy) were randomly assigned to rofecoxib 50 mg daily or naproxen 500 mg twice daily for a median of 9 months. The development of clinical upper GI events (bleeding, perforation, obstruction, and symptomatic ulcer identified on clinically indicated work-up) was assessed., Results: Significant risk factors included prior upper GI events, age >or=65, and severe rheumatoid arthritis (RR, 2.3-3.9). Patients administered naproxen who had prior upper GI complications or who were aged >or=75 years had 18.84 or 14.46 events per 100 patient-years, and the risk of events remained constant over time. The reduction in events with rofecoxib was similar in high- and low-risk subgroups (RR, 0.31-0.68). The number needed to treat with rofecoxib instead of naproxen to avert 1 GI event was 10-12 in highest risk patients (prior event, age >or=75 years, or severe rheumatoid arthritis), 17-33 in patients with other risk factors, and 42-106 in low-risk patients., Conclusions: NSAID-related GI events increase dramatically with risk factors such as prior events or older age. Ten to twelve high-risk patients need to be treated with a protective strategy such as the selective cyclooxygenase 2 inhibitor, rofecoxib, to avert a clinical GI event.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are probably the most common cause of gastroduodenal injury in the United States today. Approximately half of patients who regularly take NSAIDs have gastric erosions, and 15%-30% have ulcers when they are examined endoscopically. However, the incidence of clinical gastrointestinal (GI) events caused by NSAIDs is much lower. Clinical upper GI events may occur in 3%-4.5% of patients taking NSAIDs, and serious complicated events develop in approximately 1.5%. However, the risk varies widely in relationship to clinical features such as history of ulcers or GI events, age, concomitant anticoagulant or steroid use, and NSAID dose. This review discusses the risks of clinical GI disease in NSAID users, the predictors of increased risk, and strategies for prevention of NSAID-associated GI disease.

Background & Aims: Prostaglandin production in the normal gastrointestinal tract, believed to be critical for mucosal integrity, is mediated by cyclooxygenase (COX)-1, whereas prostaglandin production at inflammatory sites seems to occur via induction of COX-2. We hypothesized that COX-2-specific inhibition with rofecoxib (25 mg once daily) in the treatment of patients with osteoarthritis would cause fewer gastroduodenal ulcers than an equally effective dose of ibuprofen (800 mg 3 times a day), a nonspecific COX inhibitor., Methods: A total of 742 osteoarthritis patients without ulcers on baseline endoscopy were randomly assigned to receive rofecoxib (25 or 50 mg once daily), ibuprofen (800 mg 3 times daily), or placebo. Endoscopy was repeated at 6, 12, and 24 weeks. At 16 weeks, by study design, 95% of the placebo group and 5% of the other groups were discontinued., Results: The cumulative incidence of gastroduodenal ulcers >/=3 mm with rofecoxib (25 or 50 mg once daily) was significantly (P < 0.001) lower than with ibuprofen and was statistically equivalent to placebo at week 12 (placebo, 9.9%; 25 mg rofecoxib, 4.1%; 50 mg rofecoxib, 7.3%; and ibuprofen, 27.7%). At 24 weeks, ulcer rates were 25 mg rofecoxib, 9. 6%; 50 mg rofecoxib, 14.7%; and ibuprofen, 45.8% (P < 0.001, ibuprofen vs. 25 and 50 mg rofecoxib)., Conclusions: Rofecoxib, at doses 2-4 times the dose demonstrated to relieve symptoms of osteoarthritis, caused significantly less gastroduodenal ulceration than ibuprofen, with ulcer rates comparable to placebo.

Background & Aims: Combining endoscopic sclerotherapy with ligation has been proposed to hasten variceal eradication. A randomized trial was performed comparing combination ligation plus sclerotherapy with ligation alone in patients with major bleeding from esophageal varices., Methods: Forty-one patients were randomly assigned to receive ligation or ligation plus 1 mL 1.5% tetradecyl injected just above each band. Treatment was repeated weekly until varices were eradicated. Repeat endoscopy was performed for rebleeding and every 3 months after eradication., Results: No significant differences were found between combined therapy and ligation in rebleeding (29% vs. 30%), blood transfused (3.1 +/- 1.1 vs. 2.0 +/- 0.8 U), hospital days (9.3 +/- 2.1 vs. 7.5 +/- 1.2), complications (29% vs. 10%), or deaths (14% vs. 15%) during a mean follow-up period of 28 weeks. Combined therapy required significantly more sessions to achieve eradication (4.9 +/- 0.6 vs. 2.7 +/- 0.4) and greater time per treatment session (18.3 +/- 1.7 vs. 13.3 +/- 0.5 minutes)., Conclusions: Combined ligation plus sclerotherapy does not reduce the number of treatment sessions required for variceal eradication as compared with ligation alone. Combined therapy lengthens the time required for treatment without improving efficacy or decreasing complications. Thus, combined ligation and sclerotherapy should not be used to treat patients with bleeding esophageal varices.

Background/aims: Antifungal therapy cures esophageal candidiasis in most patients with acquired immunodeficiency syndrome, but the subsequent course of these patients is not established. This study examines the natural history of esophageal candidiasis after successful treatment., Methods: Patients with endoscopic and clinical resolution of esophageal candidiasis after therapy were followed up prospectively with monthly clinical assessment and repeat endoscopy every 3 months or earlier if esophageal symptoms recurred or if the patient was to begin antifungal therapy for another reason., Results: Thirty-five patients met entry criteria; 21 agreed to enroll. The patients were followed up for a mean of 23 +/- 4 weeks after their initial posttreatment endoscopy. Nineteen patients (90%) had recurrent esophageal candidiasis at a mean of 11 +/- 2 weeks (range, 3-36 weeks). The 19 patients had 31 recurrences; 25 (81%) occurred < or = 10 weeks after documented cure of the prior episode of esophageal candidiasis. Twenty-two (71%) of the 31 recurrent episodes were symptomatic, and only 9 (29%) were associated with oral thrush. All symptomatic recurrences responded to treatment with fluconazole; 1 of 22 (5%) failed to show endoscopic resolution., Conclusions: Almost all patients with acquired immunodeficiency syndrome and successfully treated esophageal candidiasis develop a recurrence, usually within 2-3 months. Two thirds are symptomatic and one third are associated with oral thrush. Subsequent episodes of esophageal candidiasis respond well to oral therapy.