Upper Gastrointestinal Ulcers Research Articles

S2247 Gastric Irritation Noted in Patients Using New Tablet-Based Colonoscopy Preparation

Introduction: In November 2020, the FDA approved a novel colonoscopy preparation, a tablet-based bowel prep containing poorly absorbed sulfate salts. This case series includes 3 patients undergoing upper and lower endoscopy who were found to have gastric irritation thought to be caused by this bowel preparation. Case Description/Methods: A 35-year-old male with gastroesophageal reflux presented with 5-day history of hematochezia and abdominal pain. He underwent colonoscopy which showed internal hemorrhoids and esophogastroduodenoscopy (EGD) showed ulceration of the stomach body (Figure, top left). Biopsies showed focal active gastritis and superficial erosion without H. pylori organisms. The patient started daily PPI and 3 months later repeat EGD showed normal mucosa both visually and pathologically. A 59-year-old female endorsed abdominal bloating and heartburn after completing treatment for H. pylori 1-month prior. She underwent EGD with colonoscopy (for screening). EGD showed multiple diminutive round erythematous spots in the stomach antrum with pinpoint foci of dark heme suggestive of hemorrhagic gastritis (Figure, top right). Biopsies showed moderate inactive chronic inflammation without H. pylori organisms. A 70-year-old female requested endoscopy as she had a personal history of remote H. pylori infection and her father had gastric cancer. On EGD, there were superficial erosions in the lesser curve of the stomach (Figure, bottom 3). Biopsies were obtained and showed gastric mucosa with reactive epithelial changes without evidence of H. pylori infection. Discussion: The preparation consists of 24 tablets total, each taken with 16 ounces of water. The ingredients include magnesium sulfate, potassium chloride, and sodium sulfate. The sulfate salts are responsible for the osmotic and therefore laxative effects of the medication. Potassium chloride is included to avoid diarrhea induced hypokalemia. Potassium chloride is a mucosal irritant that has been reported to cause upper gastrointestinal ulcers and erosions. In each case, gastric irritation was an unexpected finding in a patient without significant risk factors for developing gastric ulcers. The common factor among them all is the same tablet-based preparation used for colonoscopy. Noted was a similar pattern of ulceration in the gastric antrum and body noted in these patients, which was in a pattern of the tablets resting on the greater curve of the stomach. While gastric ulceration may be asymptomatic, it may lead to diagnostic confusion and further unnecessary workup.Figure 1.: Colonoscopy images.

Medication-Wide Association Study Using Electronic Health Record Data of Prescription Medication Exposure and Multifetal Pregnancies: Retrospective Study.

BackgroundMedication-wide association studies (MWAS) have been applied to assess the risk of individual prescription use and a wide range of health outcomes, including cancer, acute myocardial infarction, acute liver failure, acute renal failure, and upper gastrointestinal ulcers. Current literature on the use of preconception and periconception medication and its association with the risk of multiple gestation pregnancies (eg, monozygotic and dizygotic) is largely based on assisted reproductive technology (ART) cohorts. However, among non-ART pregnancies, it is unknown whether other medications increase the risk of multifetal pregnancies.ObjectiveThis study aimed to investigate the risk of multiple gestational births (eg, twins and triplets) following preconception and periconception exposure to prescription medications in patients who delivered at Penn Medicine.MethodsWe used electronic health record data between 2010 and 2017 on patients who delivered babies at Penn Medicine, a health care system in the Greater Philadelphia area. We explored 3 logistic regression models: model 1 (no adjustment); model 2 (adjustment for maternal age); and model 3—our final logistic regression model (adjustment for maternal age, ART use, and infertility diagnosis). In all models, multiple births (MBs) were our outcome of interest (binary outcome), and each medication was assessed separately as a binary variable. To assess our MWAS model performance, we defined ART medications as our gold standard, given that these medications are known to increase the risk of MB.ResultsOf the 63,334 distinct deliveries in our cohort, only 1877 pregnancies (2.96%) were prescribed any medication during the preconception and first trimester period. Of the 123 medications prescribed, we found 26 (21.1%) medications associated with MB (using nominal P values) and 10 (8.1%) medications associated with MB (using Bonferroni adjustment) in fully adjusted model 3. We found that our model 3 algorithm had an accuracy of 85% (using nominal P values) and 89% (using Bonferroni-adjusted P values).ConclusionsOur work demonstrates the opportunities in applying the MWAS approach with electronic health record data to explore associations between preconception and periconception medication exposure and the risk of MB while identifying novel candidate medications for further study. Overall, we found 3 novel medications linked with MB that could be explored in further work; this demonstrates the potential of our method to be used for hypothesis generation.

Upper gastrointestinal ulcer in children: a clinical analysis of 173 cases

To study the clinical manifestations and gastroscopic characteristics of upper gastrointestinal ulcer in children. A retrospective analysis was performed for the children who underwent gastroscopy and were found to have upper gastrointestinal ulcer for the first time at the Endoscopy Center of Shengjing Hospital, China Medical University, from January 2011 to May 2021. According to the cause of the disease, they were divided into primary ulcer group (primary group; n=148) and secondary ulcer group (secondary group; n=25). The clinical data were compared between the two groups. A total of 173 children with upper gastrointestinal ulcer were enrolled, with a male/female ratio of 3.9:1. Compared with girls, boys had significantly higher proportions of duodenal ulcer and primary ulcer (P<0.05). Compared with the children aged below 6 years, the children aged 6-14 years had higher proportions of duodenal ulcer and primary ulcer and lower proportions of giant ulcer and multiple ulcers. Of the 148 children in the primary group, 95 (64.2%) had Helicobacter pylori infection. Abdominal pain was the most common clinical symptom and was observed in 101 children (68.2%). Duodenal ulcer was common and was observed in 115 children (77.7%), followed by gastric ulcer in 25 children (16.9%) and esophageal ulcer in 7 children (4.7%). Multiple ulcers were observed in 32 children (21.6%). Seventy children (47.3%) experienced complications, among which bleeding was the most common complication and was observed in 63 children (43.6%). Of the 25 children in the secondary group, abdominal pain was the most common clinical symptom and was observed in 9 children (36.0%), with a significantly lower incidence rate than the primary group (P<0.05); foreign body in the digestive tract was the most common cause of ulcer and was observed in 17 children (68%), followed by abdominal Henoch-Schönlein purpura in 5 children (20.0%) and Crohn's disease in 3 children (12.0%). The secondary group had a significantly higher proportion of multiple ulcer or giant ulcer than the primary group (P<0.05). Upper gastrointestinal ulcer is more common in boys than girls, and duodenal ulcer and primary ulcer are more common in boys. Children aged 6-14 years often have duodenal ulcer and primary ulcer, and giant ulcer and multiple ulcers are relatively uncommon. Primary ulcer in children has a variety of clinical manifestations, mainly abdominal pain, and duodenal ulcer is relatively common, with bleeding as the main complication. The clinical symptoms and endoscopic manifestations of secondary ulcer are closely associated with the primary causes, and it is more likely to induce huge ulcers and multiple ulcers.

Association of Diverticulitis with Prolonged Spondyloarthritis: An Analysis of the ASAS-COMOSPA International Cohort.

This study examined the relationship between spondyloarthritis (SpA) duration and gastrointestinal comorbidities other than inflammatory bowel disease (IBD). We evaluated the association between SpA duration and upper gastrointestinal ulcers, hepatitis B (HBV), hepatitis C (HCV) and diverticulitis using data from a large international cross-sectional study. Binary regression models were created, adjusted for age, sex, body mass index (BMI), smoking, alcohol, non-steroidal anti-inflammatory drugs (NSAIDs), disease-modifying anti-rheumatic drugs (DMARDs), biologics, steroids, IBD history and country. Subgroup analysis was performed by disease phenotype. The data of 3923 participants were analysed. The prevalence of gastrointestinal conditions were 10.7% upper gastrointestinal ulcers; 4.7% viral hepatitis and 1.5% diverticulitis. While SpA duration was not associated with upper gastrointestinal ulcers, HBV or HCV, longer SpA duration was significantly associated with diverticulitis (odds ratios (OR) = 1.18, 95% confidence interval (CI): 1.03–1.34), reflecting an 18% increase for every five years of SpA duration. Other significant associations with diverticulitis were age and high alcohol intake but not medication history. In subgroup analyses, the association was strongest with those with axial SpA. The reasons for this association of increased diverticulitis with disease duration in SpA, especially those with axial disease, are unclear but may reflect shared underlying gut inflammation. Diverticulitis should be considered, in addition to IBD, when SpA patients present with lower gastrointestinal symptoms.

Acute necrotizing pancreatitis as a fatal complication following DC Bead transcatheter arterial chemoembolization for hepatocellular carcinoma: A case report and review of the literature.

Transcatheter arterial chemoembolization (TACE) is one of the most effective palliative measures for patients with inoperable hepatocellular carcinoma (HCC). Acute pancreatitis is a rare but well-known complication following TACE. We herein present the case of a patient with HCC who developed fatal complications (acute necrotizing pancreatitis and upper gastrointestinal ulcers) after TACE with DC Beads. The patient was diagnosed with HCC in segments 4 and 8, measuring ~70 mm in greatest diameter, and he was treated by TACE. Hepatic arteriography revealed replacement of the origin of the right hepatic artery to the superior mesenteric artery, while the left hepatic artery originated from the celiac artery. After selection of the segmental arterial branches feeding the tumor, 2 ml of 100-300-µm-sized DC Beads loaded with 150 mg epirubicin were injected through the microcatheter. The patient complained of abdominal pain after the TACE procedure. Upper gastrointestinal endoscopy revealed longitudinal ulcers from the esophagus to the duodenum, and contrast-enhanced computed tomography revealed swelling of the pancreas and focal areas of low density in the pancreatic body, suggesting necrosis. The patient developed respiratory insufficiency, renal failure and sepsis, and finally succumbed to the complications 54 days after the procedure, despite general management of the acute pancreatitis. An autopsy revealed that the main cause of the patient's death was extensive pancreatic necrosis due to a gastroduodenal artery embolism after TACE with DC Beads. Therefore, it is crucial for treating physicians to be aware of this complication following TACE with DC Beads, particularly in patients with anatomical variations.

Do misoprostol, H2-receptor antagonists, or proton pump inhibitors used for at least 12 weeks prevent upper gastrointestinal ulcers in patients requiring chronic NSAID use?

Do misoprostol, H2-receptor antagonists, or proton pump inhibitors used for at least 12 weeks prevent upper gastrointestinal ulcers in patients requiring chronic NSAID use?

Gastroprotective efficacy and safety of single-tablet ibuprofen/famotidine vs ibuprofen in older persons

Objectives: A combination tablet of ibuprofen 800 mg and famotidine 26.6 mg given three times daily is effective for the treatment of rheumatoid arthritis and osteoarthritis and decreases the risk of developing upper gastrointestinal (GI) ulcers. This analysis evaluated the gastroprotective efficacy and safety of the single-tablet combination of ibuprofen/famotidine compared with ibuprofen alone on the basis of age and the presence of one or more risk factors for development of upper GI ulcer. Methods: Pooled data from the 24-week, randomized, double-blind, parallel-group REDUCE-1 and REDUCE-2 trials were used. Endoscopies were performed in patients aged 40–80 years. The proportion of patients who developed ≥1 upper GI ulcer during treatment with ibuprofen/famotidine versus ibuprofen alone stratified on the basis of age (<60 or ≥60 years) was evaluated. Further, analyses were performed on additional risk factors for ulcer development. Results: Gastroprotective efficacy of the combination was not affected by age. Pooled results demonstrated statistically significantly fewer upper GI (10.0 vs 19.5%, p < 0.0001), gastric (8.9 vs 16.8%, p = 0.0004), and duodenal ulcers (1.1 vs 5.4%, p < 0.0001) in patients <60 years treated with ibuprofen/famotidine versus ibuprofen alone compared with 12.9 vs 26.6% (p = 0.0002), 11.9 vs 23.4% (p = 0.0011), and 1.0 vs 4.5% (p = 0.0096), respectively, in patients ≥60 years. The ibuprofen/famotidine combination provided nearly 51 and 59% reduction in the risk of developing a GI ulcer in patients <60 years and ≥60 of age, respectively. Efficacy was maintained in the presence of additional risk factors, as well. Conclusions: These results indicate that the fixed-combination of ibuprofen/famotidine provides gastroprotection in those of older age, with or without additional risk factors for the development of upper GI ulcers, as compared with ibuprofen alone. US National Institutes of Health registry, http://www.clinicaltrials.gov, NCT00450658 and NCT00450216.

One-year safety of ibuprofen/famotidine fixed combination versus ibuprofen alone: pooled analyses of two 24-week randomized, double-blind trials and a follow-on extension

Objective:To evaluate the safety of the fixed combination of ibuprofen and famotidine compared with ibuprofen alone from two 24-week, multicenter, double-blind trials designed to evaluate the comparative incidence of endoscopically documented upper gastrointestinal ulcers and a 28-week double-blind extension study.Research design and methods:Safety was analyzed by pooling data from the two double-blind trials and the follow-on study. Safety was assessed by monitoring the incidence, causality, and severity of adverse events (AEs).Results:In the pivotal efficacy and safety trials, discontinuation rates due to any cause and dyspepsia were significantly lower for the ibuprofen/famotidine combination versus ibuprofen alone. Other than dyspepsia, gastrointestinal and cardiovascular AEs of special interest were similar. Events judged to be treatment related were significantly lower with the ibuprofen/famotidine combination (20.6% vs. 25%). In the safety extension population, there were no differences in the discontinuation rates and the reporting of AEs or serious AEs (SAEs) between the two groups. Gastrointestinal-related events were similar between the groups. Incidence of cardiovascular-related AEs of special interest were 11% (ibuprofen/famotidine) and 2% (ibuprofen) (p = 0.06), possibly due to a higher number of rheumatoid arthritis patients in the combination group. Of these, 80% were reports of hypertension (8% ibuprofen/famotidine vs. 2% ibuprofen). Three cases of hypertension in the ibuprofen/famotidine group were considered treatment related. The probability of a cardiovascular event decreased during days 112–167 of treatment and remained low with continued treatment.Conclusions:One-year safety data from two pivotal trials and a long-term extension study indicate that the ibuprofen/famotidine combination demonstrates a favorable gastrointestinal safety profile and more patients continued on therapy compared to ibuprofen alone. No new safety signals have been identified. These data offer additional evidence supporting a new therapeutic option to improve gastrointestinal safety and adherence for patients who require long-term ibuprofen.

Risk of Upper Gastrointestinal Ulcers in Patients With Osteoarthritis Receiving Single-Tablet Ibuprofen/Famotidine Versus Ibuprofen Alone: Pooled Efficacy and Safety Analyses of Two Randomized, Double-Blind, Comparison Trials

Background: Although anti-inflammatory doses of ibuprofen are very effective in treating the signs and symptoms of osteoarthritis (OA), they come with an increased risk for gastrointestinal damage which can limit their use and decrease patient adherence to therapy. Objective: Assess the efficacy and safety of an ibuprofen/famotidine fixed-dose tablet for reducing the risk of upper gastrointestinal (UGI) ulcers compared with ibuprofen alone in OA patients. Methods: Osteoarthritis patients from previously completed randomized, double-blind, comparison registration trials (REDUCE-1 and 2) which included a broad pain patient population, were pooled and analyzed for (1) the risk of endoscopically identified UGI ulcers over 24 weeks and (2) comparative pre-specified treatment emergent adverse events (TEAEs). The primary outcomes were the comparative incidence of UGI, gastric, and duodenal ulcers and TEAEs in (1) the total OA population, (2) those aged ≥ 60 years, and (3) those on low dose aspirin. A total of 776 patients were randomized (safety population), and 713 were evaluable as the study population. Results: Upper gastrointestinal ulcer risk was statistically significantly reduced with the fixed dose tablet compared with ibuprofen alone by 44% in the overall population, 55% in those aged > 60 years and 65% in those on low dose aspirin. Individually, gastric and duodenal ulcers were also significantly reduced in all groups analyzed. Adverse events of special interest were generally similar between the 2 groups, with the exception of dyspepsia. Relative risk reduction for dyspepsia in the overall population was 40% and 55% in those aged ≥ 60 years. Patients not receiving low dose aspirin had a 49% relative risk reduction in dyspepsia. Conclusion: The fixed combination of ibuprofen/famotidine significantly reduced the risk for endoscopically documented gastrointestinal ulcers in OA patients and produced clinically meaningful reductions in patient reported dyspepsia compared with the ibuprofen alone.

Predictive Factors for Endoscopic Hemostasis in Patients with Upper Gastrointestinal Bleeding

Predictive Factors for Endoscopic Hemostasis in Patients with Upper Gastrointestinal Bleeding

Predictive factors for intractability to endoscopic hemostasis in the treatment of bleeding gastroduodenal peptic ulcers in Japanese patients.

Background/AimsDespite improvements in endoscopic hemostasis and pharmacological therapies, upper gastrointestinal (UGI) ulcers repeatedly bleed in 10% to 20% of patients, and those without early endoscopic reintervention or definitive surgery might be at a high risk for mortality. This study aimed to identify the risk factors for intractability to initial endoscopic hemostasis.MethodsWe analyzed intractability among 428 patients who underwent emergency endoscopy for bleeding UGI ulcers within 24 hours of arrival at the hospital.ResultsDurable hemostasis was achieved in 354 patients by using initial endoscopic procedures. Sixty-nine patients with Forrest types Ia, Ib, IIa, and IIb at the second-look endoscopy were considered intractable to the initial endoscopic hemostasis. Multivariate analysis indicated that age ≥70 years (odds ratio [OR], 2.06; 95% confidence interval [CI], 1.07 to 4.03), shock on admission (OR, 5.26; 95% CI, 2.43 to 11.6), hemoglobin <8.0 mg/dL (OR, 2.80; 95% CI, 1.39 to 5.91), serum albumin <3.3 g/dL (OR, 2.23; 95% CI, 1.07 to 4.89), exposed vessels with a diameter of ≥2 mm on the bottom of ulcers (OR, 4.38; 95% CI, 1.25 to 7.01), and Forrest type Ia and Ib (OR, 2.21; 95% CI, 1.33 to 3.00) predicted intractable endoscopic hemostasis.ConclusionsVarious factors contribute to intractable endoscopic hemostasis. Careful observation after endoscopic hemostasis is important for patients at a high risk for incomplete hemostasis.

The efficacy of rebamipide add-on therapy in arthritic patients with COX-2 selective inhibitor-related gastrointestinal events: a prospective, randomized, open-label blinded-endpoint pilot study by the GLORIA study group

Objective We aimed to confirm the effect of combined treatment with celecoxib and rebamipide would be more effective than celecoxib alone for prevention of upper gastrointestinal (GI) events.Methods Patients with rheumatoid arthritis, osteoarthritis, and low back pain were enrolled in this study. Patients were randomized to two groups: a monotherapy group (100 mg celecoxib twice daily) and a combination therapy group (add on100 mg of rebamipide three times a day). The GI mucosal injury was evaluated by endoscopic examination before treatment and at 3 months. The primary endpoint was to evaluate the preventive effect of the combination therapy group for GI events, endoscopic upper GI ulcers and intolerable GI symptoms, compared with the monotherapy group.Results Seventy-five patients were enrolled. Sixty-five patients were analyzed (16 males, 49 females; mean age: 67 ± 13 years). The prevalence of upper GI events, five of endoscopic GI ulcers and one of intolerable GI symptoms, were 6/34 (17.6 %) in the monotherapy group and 0/31 in the combination therapy group, p = 0.0252.Conclusions The combination therapy group was more effective than the monotherapy group for prevention of upper GI events in this study. Rebamipide might be a candidate for an option to prevent COX-2 selective inhibitor-induced upper GI events.

Cyclo‐oxygenase‐2 inhibitors or nonselective NSAIDs plus gastroprotective agents: what to prescribe in daily clinical practice?

Two strategies for prevention of upper gastrointestinal (UGI) events for nonselective nonsteroidal anti-inflammatory drug (nsNSAID) users are replacement of the nsNSAID by a cyclo-oxygenase-2-selective inhibitor (coxib) or co-prescription of a gastroprotective agent (GPA). To identify whether and in whom either of these strategies should be preferred in daily practice. A nested case-control study was conducted using three European primary care databases. We selected a cohort including all naive nsNSAID+GPA (≥80% GPA adherence) and coxib users (without GPA use) aged ≥50 years. Cases with an UGI event (i.e. symptomatic UGI ulcer or bleeding) were matched to cohort members without an UGI event on age, sex and number of individual UGI risk factors (i.e. UGI event history, age ≥65 years, concomitant use of anticoagulants, antiplatelets, or glucocorticoids) and calendar time. Conditional logistic regression analysis was used to calculate odds ratios (ORs) with 95% CI, while adjusting for potential confounders. Within the NSAID cohort (n = 617,220), 398 UGI cases were identified. The risk of UGI events was equivalent for coxib and nsNSAID+GPA (≥80% adherence) users (OR: 1.02; 95%CI: 0.77-1.37). In concurrent glucocorticoid users, the risk of UGI events was significantly elevated for nsNSAID+GPA (≥80% adherence) compared with coxib users (OR: 9.01; 95%CI: 1.61-50.50). The risk of UGI events was similar in nsNSAID+GPA (≥80% adherence) and coxibs users. In patients concurrently using glucocorticoids, a significant increase in the risk of UGI events for nsNSAID+GPA users was observed and coxibs should be preferred.

Sodium Alginate Inhibits Methotrexate-Induced Gastrointestinal Mucositis in Rats

Gastrointestinal mucositis is one of the most prevalent side effects of chemotherapy. Methotrexate is a pro-oxidant compound that depletes dihydrofolate pools and is widely used in the treatment of leukemia and other malignancies. Through its effects on normal tissues with high rates of proliferation, methotrexate treatment leads to gastrointestinal mucositis. In rats, methotrexate-induced gastrointestinal mucositis is histologically characterized by crypt loss, callus fusion and atrophy, capillary dilatation, and infiltration of mixed inflammatory cells. The water-soluble dietary fiber sodium alginate (AL-Na) is derived from seaweed and has demonstrated muco-protective and hemostatic effects on upper gastrointestinal ulcers. In the present study, we evaluated the effects of AL-Na on methotrexate-induced small intestinal mucositis in rats. Animals were subcutaneously administered methotrexate at a dosage of 2.5 mg/kg once daily for 3 d. Rats were treated with single oral doses of AL-Na 30 min before and 6 h after methotrexate administration. On the 4th day, small intestines were removed and weighed. Subsequently, tissues were stained with hematoxylin-eosin and bromodeoxyuridine. AL-Na significantly prevented methotrexate-induced small intestinal mucositis. Moreover, AL-Na prevented decreases in red blood cell numbers, hemoglobin levels, and hematocrit levels. These results suggest the potential of AL-Na as a therapy for methotrexate-induced small intestinal mucositis.

52 Evaluation of Proton Pump Inhibitor Infusions in Patients With Suspected Upper Gastrointestinal Tract Bleeding in the Emergency Department

Study Objectives: Proton pump inhibitor infusions initiated after therapeutic endoscopy reduce the incidence of re-bleeding and the need for blood transfusions in patients with upper gastrointestinal ulcers. The role of proton pump inhibitor infusions prior to endoscopy is not well defined but may benefit high risk patients. The Blatchford Score may be used to predict patients at high risk who will require endoscopic intervention. The primary objective of this study was to evaluate proton pump inhibitor infusion use in the emergency department (ED).

Incidence of Peptic Ulcer Bleeding in the US Pediatric Population

The aim of the present study was to determine the incidence of peptic ulcer bleeding (PUB) in pediatric patients. A hospital inpatient database, Premier Perspective, and an insurance claims database, MarketScan, were analyzed to estimate upper and lower limits for the annual incidence of PUB in the US pediatric population. Using data from the Premier Perspective database and database-specific projection methodology, the total number of cases of hospitalization of pediatric patients for PUB in the United States in 2008 was estimated to be between 378 and 652. This translated to an incidence of 0.5 to 0.9/100,000 individuals in the pediatric population. Using data from the MarketScan database, the incidence of PUB in the insured pediatric population was estimated to be 4.4/100,000 individuals. Overall, 17.4% of insured pediatric patients diagnosed as having any upper gastrointestinal ulcer in 2008 were reported to have developed PUB. The estimated incidence of PUB in the US pediatric population in 2008 ranged from 0.5 to 4.4/100,000 individuals. The total number of cases of PUB in pediatric patients in the United States each year was thus estimated to be between 378 and 3250. Such estimates provide a likely lower and upper limit for the total number of cases of the condition annually.

HZT-501 (DUEXIS®; ibuprofen 800 mg/famotidine 26.6 mg) gastrointestinal protection in the treatment of the signs and symptoms of rheumatoid arthritis and osteoarthritis

Arthritis affects nearly 50 million people in the USA and, with the aging of the population, the prevalence is expected to rise. While NSAIDs are very effective in relieving pain associated with osteoarthritis (OA) and rheumatoid arthritis (RA), they are associated with side effects, including gastrointestinal (GI) toxicity, which may manifest as dyspepsia, ulcers and/or bleeding. A number of approaches have been employed in an effort to either completely avoid or reduce the risk of GI toxicities associated with NSAID use. Two new products combining an NSAID with a gastroprotective agent have recently been approved and other agents are in the pipeline. Patient adherence to prescribed gastroprotective therapy is known to be poor, often resulting in an increased risk of GI events in patients taking NSAIDs. These newer combination products may fulfill an important need for many patients who need to receive NSAIDs for the pain of OA and RA, but who are also at risk of upper GI events. This article reviews preclinical and clinical results for a new fixed-dose combination of ibuprofen and famotidine, DUEXIS® (HZT-501), which has recently been approved in the USA for the relief of signs and symptoms of RA and OA and to decrease the risk of developing upper GI ulcers.

Long Term Safety of an NSAID With Built-in Gastroprotection for Treatment of Pain and Inflammation Related to Oa and RA: Comparative Results From Blinded and Open Label One Year Safety Trials of a Single-Tablet Combination of Ibuprofen-Famotidine

Background: Little is known about the upper gastrointestinal (UGI) protective effect of gastroprotective agents (GPAs) in COX-2-specific inhibitors (coxib)-users. Objectives: To study the association between GPA adherence and UGI complications among coxib-users. Methods: We used primary care data from the United Kingdom's (UK) General Practice Research Database , the Dutch (NL) Integrated Primary Care Information database, and the Italian (IT) Health Search/Thales Database. A case-control study was conducted within a cohort of coxib+GPA users aged ≥ 50 yrs. Episodes of coxib use were defined as a period of coxib use with gaps between subsequent prescriptions that were no longer than 100% of the duration of the previous coxib prescription. Patients could have more than one episode of coxib use during follow-up, but only if at least a 180-days NSAID-free period was present prior to the start of each episode. Cases with UGI complications (UGI bleeding and diagnosed symptomatic UGI ulcers) during or within 60 days after coxib use were matched to controls on age, gender, database, and calendar time. Adherence to GPAs was calculated over the most recent episode of coxib use prior to the index date as the proportion of coxib treatment days covered (PDC) by a GPA prescription. Adherence was expressed as a continuous variable as well as categorical (low (PDC 80%)). Adjusted odds ratios (OR) with 95% confidence intervals (95%CI) were calculated using conditional logistic regression. Results: 98,940 coxib episodes were counted in the coxib user cohort (UK: 52,698; NL: 7,201, IT: 39,041). In 16,442 (16.6%) of the eligible coxib episodes a GPA was prescribed (UK: 21.2%; NL: 13.4%, IT: 11.0%). Of the GPA users, 7.2% had low adherence (PDC 80%). Overall, mean pooled adherence was 0.76±0.30 (UK: 0.79±0.29; NL: 0.85±0.27; IT: 0.66±0.30). Only 18% used coxibs >90 days. In those patients, mean adherence dropped to 0.65 ± 0.34. Within the coxib+GPA users, we identified 74 cases with an UGI complication (30 UGI bleedings and 44 (un)complicated UGI ulcers). Mean adherence (PDC) to GPA was 0.72±0.32 for UGI complication cases compared to 0.78±0.30 for controls. Among low adherers, the risk was 1.97 (95%CI 0.84-4.60) for all UGI complications, compared with high adherers. For every 10% decrease in adherence, the risk of all UGI complications increased by 9% (OR: 1.09, 95%CI: 1.001.18). Conclusions: The risk of UGI complications increased by 9% in all coxib users ≥ 50 years for every 10% decrease in adherence of GPAs. Patients benefit from GPAs in addition to coxibs to lower their increased risk of UGI complications.

Adherence to Gastroprotective Agents and the Risk of Upper Gastrointestinal Complications in Coxib Users

Background: Little is known about the upper gastrointestinal (UGI) protective effect of gastroprotective agents (GPAs) in COX-2-specific inhibitors (coxib)-users. Objectives: To study the association between GPA adherence and UGI complications among coxib-users. Methods: We used primary care data from the United Kingdom's (UK) General Practice Research Database , the Dutch (NL) Integrated Primary Care Information database, and the Italian (IT) Health Search/Thales Database. A case-control study was conducted within a cohort of coxib+GPA users aged ≥ 50 yrs. Episodes of coxib use were defined as a period of coxib use with gaps between subsequent prescriptions that were no longer than 100% of the duration of the previous coxib prescription. Patients could have more than one episode of coxib use during follow-up, but only if at least a 180-days NSAID-free period was present prior to the start of each episode. Cases with UGI complications (UGI bleeding and diagnosed symptomatic UGI ulcers) during or within 60 days after coxib use were matched to controls on age, gender, database, and calendar time. Adherence to GPAs was calculated over the most recent episode of coxib use prior to the index date as the proportion of coxib treatment days covered (PDC) by a GPA prescription. Adherence was expressed as a continuous variable as well as categorical (low (PDC 80%)). Adjusted odds ratios (OR) with 95% confidence intervals (95%CI) were calculated using conditional logistic regression. Results: 98,940 coxib episodes were counted in the coxib user cohort (UK: 52,698; NL: 7,201, IT: 39,041). In 16,442 (16.6%) of the eligible coxib episodes a GPA was prescribed (UK: 21.2%; NL: 13.4%, IT: 11.0%). Of the GPA users, 7.2% had low adherence (PDC 80%). Overall, mean pooled adherence was 0.76±0.30 (UK: 0.79±0.29; NL: 0.85±0.27; IT: 0.66±0.30). Only 18% used coxibs >90 days. In those patients, mean adherence dropped to 0.65 ± 0.34. Within the coxib+GPA users, we identified 74 cases with an UGI complication (30 UGI bleedings and 44 (un)complicated UGI ulcers). Mean adherence (PDC) to GPA was 0.72±0.32 for UGI complication cases compared to 0.78±0.30 for controls. Among low adherers, the risk was 1.97 (95%CI 0.84-4.60) for all UGI complications, compared with high adherers. For every 10% decrease in adherence, the risk of all UGI complications increased by 9% (OR: 1.09, 95%CI: 1.001.18). Conclusions: The risk of UGI complications increased by 9% in all coxib users ≥ 50 years for every 10% decrease in adherence of GPAs. Patients benefit from GPAs in addition to coxibs to lower their increased risk of UGI complications.

Preventing the gastrointestinal adverse effects of nonsteroidal anti-inflammatory drugs: From risk factor identification to risk factor intervention

Nonsteroidal anti-inflammatory drugs (NSAIDs) have huge prescription volumes, for two main reasons: the aging of the population is increasing the prevalence of diseases that respond to NSAIDs, such as osteoarthritis; and NSAIDs are highly effective drugs that contribute crucially to the management of many diseases. In France, the number of physician orders that include an NSAID is estimated at 25 to 30 million per year. Nevertheless, the use of NSAIDs is limited by adverse effects. The gastrointestinal tract is the main target of NSAID toxicity, and NSAID therapy is among the leading causes of bleeding from upper gastrointestinal ulcers. Adverse events targeting the lower gastrointestinal tract are also of concern, although they receive less attention. To effectively prevent NSAID toxicity, it must be recognized that the risk of adverse events can be diminished but not eliminated. Therefore, the risk/benefit ratio must be carefully evaluated at each prescription. A number of risk factors should be emphasized. Thus, the risk increases with age, and there is a sharp risk increase at 60 years of age. Other risk factors include a history of ulcers (most notably with bleeding), the use of high NSAID dosages, Helicobacter pylori infection, and the concomitant use of antiplatelet agents. Minimizing NSAID-related gastrointestinal toxicity requires a careful risk factor evaluation; selection of the most appropriate NSAID and NSAID dosage; and, in some patients, prophylactic gastroprotective therapy, for instance with a proton pump inhibitor. Gastrointestinal symptoms either have no value for predicting gastrointestinal events or occur too late to serve as alarm signals. The toxicity advantages of cyclooxygenase-2 inhibitors seem modest and do not eliminate the need for this rational prescription strategy.