Randomised clinical trial: 3-year interim analysis results of the VISION trial to evaluate the long-term safety of vonoprazan as maintenance treatment in patients with erosive oesophagitis.

BACKGROUND: VISION is a randomised, phase 4, open-label, parallel-group, multicentre study conducted in 33 centres in Japan. The aim of this study was to assess the long-term safety of vonoprazan for maintenance treatment of healed erosive oesophagitis versus lansoprazole. METHODS: Patients with endoscopically diagnosed erosive oesophagitis were randomised 2:1 to once-daily vonoprazan 20 mg or lansoprazole 30 mg, for a 4- to 8-week healing phase. Patients with endoscopically confirmed healing entered a 260-week maintenance phase with a once-daily starting dose of vonoprazan 10 mg or lansoprazole 15 mg. Primary endpoint was change in gastric mucosal histopathology. RESULTS: Of 208 patients (vonoprazan, n = 139; lansoprazole, n = 69) entering the healing phase, 202 entered the maintenance phase (vonoprazan, n = 135; lansoprazole, n = 67). At 3 years, 109 vonoprazan-treated and 58 lansoprazole-treated patients remained on treatment. Histopathological evaluation of gastric mucosa showed that hyperplasia of parietal, foveolar and G cells was more common with vonoprazan than lansoprazole at week 156 of the maintenance phase. There was no marked increase in the occurrence of parietal, foveolar and G cell hyperplasia among patients in the vonoprazan group from week 48 to week 156. Histopathological evaluation of the gastric mucosa also showed no neoplastic changes in either group. No new safety issues were identified. CONCLUSIONS: In this interim analysis of VISION, no new safety concerns were identified in Japanese patients with healed erosive oesophagitis receiving vonoprazan or lansoprazole as maintenance treatment for 3 years. (CT.gov identifier: NCT02679508; JapicCTI-163153; Japan Registry of Clinical Trials: jRCTs031180040).

Proton Pump Inhibitors Are Associated with Increased Risk of Psoriasis: A Nationwide Nested Case-Control Study.

BACKGROUND: Proton pump inhibitors (PPIs) are among the most widely used drugs. Little is known about the association between PPI use and risk of psoriasis. OBJECTIVE: To investigate the association between PPI use and subsequent psoriasis risk. METHODS: We included participants from the Taiwan National Health Insurance Research Database. Patients with PPI use and an incidence of psoriasis (n = 5,756) were assigned to the case cohort and 1:1 matched to controls. PPI use was defined as >30 cumulative defined daily doses (cDDDs); PPI nonuse was defined as ≤30 cDDDs. Logistic regression was used for the analyses. RESULTS: There was a significant association between PPI use and psoriasis risk. The confounder-adjusted odd ratios (95% confidence interval [CI]) were 1.52 (1.31-1.76) and 1.54 (1.22-1.93) for patients with 120-365 cDDDs and >365 cDDDs, respectively, compared with PPI nonusers. Stratified analyses based on PPI type showed that exposure to lansoprazole (OR, 1.25; 95% CI, 1.11-1.41) was associated with subsequent psoriasis risk. CONCLUSIONS: PPI use might be associated with an increased risk of developing psoriasis or as an epiphenomenon. Further prospective studies are needed to elucidate the association and underlying mechanisms.

Effect of ilaprazole on the healing of endoscopic submucosal dissection-induced gastric ulcer: randomized-controlled, multicenter study.

BACKGROUND: The optimal treatment regimen or the duration of treatment for an endoscopic submucosal dissection (ESD)-induced gastric ulcer has not been established. The aim of this study was to assess the efficacy of novel proton-pump inhibitor, ilaprazole, for the treatment of ESD-induced gastric ulcer. METHODS: This was a prospective, open-label, randomized multicenter study. Between June 2015 and March 2018, a total of 176 patients (178 lesions) who underwent ESD for a gastric neoplasm were randomly allocated to receive the oral proton-pump inhibitor ilaprazole 20 mg or rabeprazole 20 mg daily for 8 weeks. The primary outcome was the ulcer healing rate at 4 and 8 weeks. RESULTS: A total of 155 (157 lesions) and 154 patients (156 lesions) were included in the modified intention-to-treat (mITT) and per-protocol analyses, respectively. There was no significant difference in the ulcer healing rate (ilaprazole vs. rabeprazole, 97.4% vs. 97.0 p = 0.78 at 4 weeks, 100% vs. 100%, p = 0.95 at 8 weeks in the mITT analysis) or stage of ulcer (scar stage, 25.6% vs. 17.7%, p = 0.25 at 4 weeks, 92.3% vs. 88.6%, p = 0.59 at 8 weeks in the mITT analysis) between the treatment groups. The quality of ulcer healing was not significantly different between the two groups. No independent predictive factor for higher-quality ulcer healing was found in the multivariate analysis. CONCLUSIONS: According to this trial, ilaprazole and rabeprazole showed no significant difference in the healing of artificial gastric ulcers. Most of the ulcers achieved complete healing within 4-8 weeks. TRIAL REGISTRATION: ClinicalTrial.gov NCT02638584.

The status of proton pump inhibitor use: a prescription survey of 45 hospitals in China.

BACKGROUND: proton pump inhibitors (PPI) have been widely used in the clinic but inappropriate prescribing has also increased dramatically. OBJECTIVE: to describe the prescribing patterns and assess the appropriateness of the prescribed PPI use in 45 hospitals in China. MATERIALS AND METHODS: PPI prescriptions for non-hospitalized patients were collected from hospitals in Beijing, Chengdu, Guangzhou and Hangzhou of China over a 40-day period in 2016. These data were analyzed using the prescription number, proportion and economic indicators (defined daily dose system [DDD], defined daily cost [DDC] and drug utilization index [DUI]). The evaluation criteria of PPI use was based on Martindale: The Complete Drug Reference, New Materia Medica and drug instructions. RESULTS: in total, 357,687 prescriptions using oral PPI and 38,216 prescriptions using injectable PPI were assessed. The average age of PPI users was 53 years. The most commonly used oral PPI was rabeprazole, while the most common injectable PPI was pantoprazole. The DDD of oral rabeprazole and DDC of injectable rabeprazole were the highest. Meanwhile, only the DUI values of oral rabeprazole, lansoprazole and ilaprazole were less than 1.0. The clinical diagnosis of some users included well identified risky comorbidities such as kidney disease (2.9%). Furthermore, between 32.6% and 56.8% of the PPI prescriptions were used for inappropriate indications. CONCLUSION: this survey demonstrated that PPI use was accompanied by unapproved indications and excessive dosages. Comprehensive measures are urgently needed to improve PPI use and reduce unnecessary drug costs.

Proton Pump Inhibitors Decrease Phlebotomy Need in HFE Hemochromatosis: Double-Blind Randomized Placebo-Controlled Trial.

Phlebotomy constitutes the established treatment for HFE-related hemochromatosis. Retrospective studies have suggested proton pump inhibitors (PPIs) reduce the need for phlebotomy in this population. We conducted a randomized controlled trial to prove this. Thirty p.C282Y homozygous patients were randomly allocated to PPI (pantoprazole 40 mg/day) or placebo for 12 months. Phlebotomies were performed when serum ferritin was > 100 µg/L. Phlebotomy need turned out to be significantly lower in patients taking PPI (P = .0052). PPI treatment significantly reduces the need for phlebotomies in p.C282Y homozygous patients. In view of the known long-term safety profile of PPI, they can be a valuable addition to standard therapy. Clinicaltrials.gov: NCT01524757.

Helicobacter pylori eradication with bismuth quadruple therapy leads to dysbiosis of gut microbiota with an increased relative abundance of Proteobacteria and decreased relative abundances of Bacteroidetes and Actinobacteria.

BACKGROUND: Bismuth quadruple therapy is the treatment of choice for the first-line therapy of Helicobacter pylori infection in areas of high clarithromycin resistance. Currently, the impact of the promising treatment on gut microbiota remains unclear. AIM: To investigate the short-term and long-term impacts of bismuth quadruple therapy on gut microbiota. METHODS: Adult patients with H. pylori-related gastritis were treated with 14-day bismuth quadruple therapy. Fecal samples were collected before treatment at week 2, week 8, and week 48. Nucleic acid extraction from fecal samples was performed. The V3-V4 region of the bacterial 16S rRNA gene was amplified by polymerase chain reaction and sequenced with the MiSeq followed by data analysis using Qiime pipeline. RESULTS: Eleven patients received complete follow-up. Before treatment, the most abundant phyla were Firmicutes (45.3%), Bacteroidetes (24.3%), Proteobacteria (9.9%), and Actinobacteria (5.0%). At the end of bismuth therapy, the relative abundances of Bacteroidetes and Actinobacteria decreased to 0.5% (P < .001) and 1.3% (P = .038), respectively. Additionally, the relative abundance of Verrucomicrobia also decreased from 3.2% to 1.11E-3% (P = .034). In contrast, the relative abundances of Proteobacteria and Cyanobacteria increased (P < .001 and P = .003, respectively). At week 8, the relative abundances of all phyla restored to the levels at baseline. The relative abundances of all phyla at week 48 also did not significantly differ from those at baseline. During eradication therapy, 6 patients (55%) reported at least 1 adverse event. The relative abundance of phylum Proteobacteria in patients with adverse effects was more than that in patients without adverse effects (68.7% ± 8.8% vs 43.4% ± 25.5%; P = .048). CONCLUSIONS: Bismuth quadruple therapy for H. pylori eradication can lead to short-term dysbiosis of gut microbiota. The increase in Proteobacteria in gut microbiota may attribute to the development of adverse effects during bismuth quadruple therapy.

Empirical treatment of outpatients with gastroesophageal reflux disease with proton pump inhibitors: A survey of Chinese patients (the ENLIGHT Study).

BACKGROUND AND AIM: Empirical proton pump inhibitor (PPI) treatment is recommended as a diagnostic indicator for gastroesophageal reflux disease (GERD) and as a therapy for symptomatic control, with responses generally seen within 4 weeks. However, there are no real-world data assessing the effectiveness of short-term empirical treatment with PPIs in patients with GERD in China. METHODS: The ENLIGHT study was a multicenter, prospective, observational study conducted in China. The primary outcome was the overall response rate after 4 weeks' empirical treatment with PPIs. Adult patients aged between 18 and 65 years of age, with a gastroesophageal reflux disease questionnaire score of ≥ 8, prescribed empirical PPI treatment by their physicians and with no planned endoscopy were eligible to participate. Statistical analyses were primarily descriptive. RESULTS: Overall, 987 patients were eligible to participate and were included in the full analysis set (FAS); 707 patients were included in the per protocol set. In the FAS, esomeprazole was received by 57.1% of patients and was the most commonly used PPI. After 4-week treatment, 71.1% (95% confidence interval [CI], 67.9% to 74.2%) of patients were considered responders to PPI. The response rate at the end of 2-week PPI treatment reached 57.0% (95% CI, 52.5% to 61.7%). The median time to response was 13 days (95% CI, 12 to 15). Response rates at 2 and 4 weeks of the per protocol set were similar to those of the FAS. CONCLUSIONS: Short-term empirical PPI treatment can provide an effective relief of GERD symptoms in most Chinese patients in real-world practice.

Gender differences in the presentation of dysphonia related to laryngopharyngeal reflux disease: a case-control study.

OBJECTIVE: To investigate the voice quality impairments in patients with laryngopharyngeal reflux (LPR) according to the gender. DESIGN: Controlled multi-center study. MATERIALS AND METHODS: 80 LPR patients (40 males and 40 females) with reflux finding score (RFS) > 7 and reflux symptom index (RSI) > 13 were included and clinically compared according to gender. To be considered as LPR patients, subjects responded to an empiric therapeutic trial based on pantoprazole intake and diet recommendations for 3 months or had positive pH/Impedance metry. Voice Handicap Index (VHI); Short Form Healthy Survey 36 (SF36), blinded Grade, Roughness, Breathiness, Asthenia, Strain and Instability (GRBASI); aerodynamic and acoustic measurements were assessed in all patients and compared with 80 healthy controls (40 males and 40 females) according to gender. RESULTS: The most common reasons for the consultation were, respectively, globus sensation in males (22.5%) and dysphonia (27.5%) in female who complained more of breathing difficulties and choking episodes related to LPR than males (p = 0.024). From a quality of life standpoint, female had increased significant impact of LPR disease on vitality and mental health than male. Compared to healthy subjects, both LPR male and female patients had stronger values of G, R, B, S, I, VHI, percent jitter, percent shimmer, and soft palate index than controls. In addition, LPR female had stronger values of lowest fundamental frequency and all aerodynamic measurements than controls. CONCLUSION: As showed in many other laryngeal conditions, voice quality of female could be more impaired by LPR than male. Some anatomical, histological and functional factors can be suspected and need additional future researches.

[Features of exchange of calcium saliva in patients with gastroesophageal reflux disease].

OBJECTIVE: Introduction: The pathogenesis of gastroesophageal reflux disease (GERD) is a topical issue of modern gastroenterology. There are a number of scientific papers on changes in the qualitative and quantitative composition of saliva, which triggers a cascade of biochemical reactions, the consequence of which is the destruction of the resistance of the mucous membrane of the esophagus. Calcium is a macro element that provides the normal functioning of cells. Parathormone also regulates the metabolism of calcium in the body. The aim: To study the level of calcium of saliva in patients with GERD before and after 6 months after treatment, to investigate the correlation with the concentration of parathyroid hormone. PATIENTS AND METHODS: Materials and methods: The samples of saliva of patients with GERD before and after treatment are analyzed. The content of calcium in saliva was determined by photometric method. To test the level of parathyroid hormone, the Intact-PTH ELISA test was used. The treatment was carried out with pantoprazole doses of 40 mg per day. Normal values of electrolyte levels in human saliva are set on 10 virtually healthy volunteers. Data processing was carried out using Microsoft Excel. Correlations were calculated using the Pearson method. RESULTS: Results: 25 samples of saliva have been analyzed: 15 patients with GERD and 10 healthy individuals. Concentration of parathormonone in plasma was consistent with normal values. The concentration of calcium saliva for practically healthy individuals was 2.48 ± 0.07 mmol / L, in patients with GERD before treatment 1.92 ± 0.16 mmol / L, after treatment 2.04 ± 0.07 mmol / L. The correlation coefficient between the level of calcium salivation in patients with GERD and the plasma parathyroid hormone concentration before treatment was 0.21, after treatment 0.73. CONCLUSION: Conclusions: The concentration of calcium is statistically significantly reduced in patients with GERD by 22.5% and increased by 10% after treatment. There is a high correlation between the concentration of calcium after treatment and the level of plasma parathyroid hormone.

Lansoprazole use and tuberculosis incidence in the United Kingdom Clinical Practice Research Datalink: A population based cohort.

BACKGROUND: Recent in vitro and animal studies have found the proton pump inhibitor (PPI) lansoprazole to be highly active against Mycobacterium tuberculosis. Omeprazole and pantoprazole have no activity. There is no evidence that, in clinical practice, lansoprazole can treat or prevent incident tuberculosis (TB) disease. METHODS AND FINDINGS: We studied a cohort of new users of lansoprazole, omeprazole, or pantoprazole from the United Kingdom Clinical Practice Research Datalink to determine whether lansoprazole users have a lower incidence of TB disease than omeprazole or pantoprazole users. Negative control outcomes of myocardial infarction (MI) and herpes zoster were also studied. Multivariable Cox proportional hazards regression was used to adjust for potential confounding by a wide range of factors. We identified 527,364 lansoprazole initiators and 923,500 omeprazole or pantoprazole initiators. Lansoprazole users had a lower rate of TB disease (n = 86; 10.0 cases per 100,000 person years; 95% confidence interval 8.1-12.4) than omeprazole or pantoprazole users (n = 193; 15.3 cases per 100,000 person years; 95% confidence interval 13.3-17.7), with an adjusted hazard ratio (HR) of 0.68 (0.52-0.89). No association was found with MI (adjusted HR 1.04; 95% confidence interval 1.00-1.08) or herpes zoster (adjusted HR 1.03; 95% confidence interval 1.00-1.06). Limitations of this study are that we could not determine whether TB disease was due to reactivation of latent infection or a result of recent transmission, nor could we determine whether lansoprazole would have a beneficial effect if given to people presenting with TB disease. CONCLUSIONS: In this study, use of the commonly prescribed and cheaply available PPI lansoprazole was associated with reduced incidence of TB disease. Given the serious problem of drug resistance and the adverse side effect profiles of many TB drugs, further investigation of lansoprazole as a potential antituberculosis agent is warranted.

A Randomized Controlled Trial Shows that both 14-Day Hybrid and Bismuth Quadruple Therapies Cure Most Patients with Helicobacter pylori Infection in Populations with Moderate Antibiotic Resistance.

Hybrid therapy is a novel two-step treatment achieving a high eradication rate for Helicobacter pylori infection. Currently, whether this new therapy achieves a higher eradication rate than bismuth quadruple therapy remains an unanswered question. The aim of this prospective, randomized comparative study was to investigate the efficacies of 14-day hybrid therapy and bismuth quadruple therapy in the treatment of H. pylori infection. From July 2013 to June 2015, eligible H. pylori-infected subjects were randomly assigned to receive either 14-day bismuth quadruple therapy (pantoprazole, bismuth subcitrate, tetracycline, and metronidazole for 14 days) or 14-day hybrid therapy (a 7-day dual therapy with pantoprazole plus amoxicillin, followed by a 7-day quadruple therapy with pantoprazole plus amoxicillin, clarithromycin, and metronidazole). H. pylori status was examined 6 weeks after the end of treatment. Three hundred thirty H. pylori-infected participants were randomized to receive 14-day bismuth quadruple therapy (n = 164) or 14-day hybrid therapy (n = 166). The eradication rates by intention-to-treat analysis were similar: 93.9% versus 92.8%, respectively (95% confidence interval [CI], -4.3% to 5.4%; P = 0.68). Per-protocol analysis yielded similar results (96.7% versus 94.9%, respectively; P = 0.44). However, bismuth quadruple therapy had a higher frequency of adverse events than hybrid therapy (55.5% versus 15.7%, respectively; 95% CI, 30.4% to 49.2%; P < 0.001). The two treatments exhibited comparable drug adherence (93.9% versus 97%, respectively). The resistance rates of antibiotics were: clarithromycin, 16.7% of patients; amoxicillin, 1.3%; metronidazole, 25%; and tetracycline, 0%. In the bismuth quadruple therapy group, the eradication rate of metronidazole-resistant strains was lower than that of metronidazole-susceptible strains (70.0% versus 96.4%, respectively; P = 0.04). In the hybrid therapy group, no significant impact of clarithromycin or metronidazole resistance on eradication rates was identified. Both 14-day hybrid and bismuth quadruple therapies cure most patients with H. pylori infection in populations with moderate antibiotic resistance. However, the 14-day hybrid therapy has fewer adverse effects than the bismuth quadruple therapy. (This study has been registered at ClinicalTrials.gov under identifier NCT02541864.).

Sitagliptin plus pantoprazole can restore but not maintain insulin independence after clinical islet transplantation: results of a pilot study.

AIMS: Resuming insulin use due to waning function is common after islet transplantation. Animal studies suggest that gastrointestinal hormones, including gastrin and incretins may increase ß-cell mass. We tested the hypothesis that pantoprazole plus sitagliptin, would restore insulin independence in islet transplant recipients with early graft insufficiency and determined whether this would persist after a 3-month washout. METHODS: Single-centre, uncontrolled, open label study of sitagliptin 100 mg daily plus pantoprazole 40 mg twice daily for 6 months. RESULTS: After 6 months of treatment, two of eight participants (25%) achieved the primary endpoint, defined as HbA1C < 42 mmol/mol (6%), fasting plasma glucose < 7.0 mmol, C-peptide > 0.5 nmol and no insulin use. There was a significant reduction in mean insulin dose, but no change in HbA1C or weight. There were no changes in the acute insulin response to arginine, the mixed meal tolerance test or blinded continuous glucose monitoring. After the washout, no participants met the primary endpoint and HbA1C increased from 45 ± 8 mmol/mol (6.3 ± 0.7%) to 51 ± 6 mmol/mol (6.8 ± 0.6%) (P < 0.05). Two participants had mild-moderate transient gastrointestinal side effects. There were no episodes of hypoglycaemia. CONCLUSIONS: Sitagliptin plus pantoprazole is well tolerated and safe and may restore insulin independence in some islet transplant recipients with early graft insufficiency, but this was not sustained when treatment was withdrawn. A larger, controlled trial is required to confirm the effectiveness of this combination to achieve insulin independence and to confidently exclude any persistent benefit for graft function. (Clinical Trials Registry No.: NCT00768651).

Association Between Proton Pump Inhibitors and Microscopic Colitis.

OBJECTIVE: Microscopic colitis (MC) is a chronic inflammatory disease of the colon that is characterized by chronic, watery, nonbloody diarrhea. Concern regarding a potential association between proton-pump inhibitors (PPIs) and MC has recently emerged. We sought to systematically review and summarize the evidence for the potential association between PPIs and MC. DATA SOURCES: We systematically searched EMBASE, MEDLINE, Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Google Scholar using the terms proton-pump inhibitors (omeprazole, lansoprazole, dexlansoprazole, rabeprazole, pantoprazole, or esomeprazole), microscopic colitis, collagenous colitis, and lymphocytic colitis. STUDY SELECTION: Full-text, English-language reports of case reports/series, observational studies, experimental studies, and systematic reviews/meta-analyses published between January 2000 to August 2016 were included. Bibliographies from pertinent publications were reviewed for additional references. Outcome was defined as the development of biopsy-confirmed MC. DATA EXTRACTION/SYNTHESIS: A total of 19 publications were identified: 5 case control studies and 14 case reports/series (encompassing a total of 32 cases). All studies were limited by small sample sizes. Risk of MC by dose or specific PPI agent was not investigated in any of the studies. A review of the current body of evidence reveals a possible association between PPIs and MC. CONCLUSIONS: There is a need for large observational studies of high quality to examine the differential effect of specific PPIs and whether the magnitude of association is dose dependent. Given their widespread use, clinicians should routinely question whether patients are receiving unnecessary treatment with PPIs and discontinue therapy where appropriate.

Stress ulcer prophylaxis in the intensive care unit trial: detailed statistical analysis plan.

BACKGROUND: In this statistical analysis plan, we aim to provide details of the pre-defined statistical analyses of the Stress Ulcer Prophylaxis in the Intensive Care Unit (SUP-ICU) trial. The aim of the SUP-ICU trial is to assess benefits and harms of stress ulcer prophylaxis with a proton pump inhibitor in adult patients in the intensive care unit (ICU). METHODS: The SUP-ICU trial is an investigator-initiated, international, multicentre, randomised, blinded, parallel-group trial of intravenously pantoprazole 40 mg once daily vs. placebo in 3350 acutely ill adult ICU patients at risk of gastrointestinal bleeding. The primary outcome measure is 90-day mortality. Secondary outcomes include the proportion of patients with clinically important gastrointestinal bleeding, pneumonia, Clostridium difficile infection or myocardial ischaemia, days alive without life support, serious adverse reactions, 1-year mortality, and a health economic analysis. Two formal interim analyses will be performed. The statistical analyses will be conducted according to the outlined pre-defined statistical analysis plan. The primary analysis will be a logistic regression analysis adjusted for stratification variables comparing the two intervention groups in the intention-to-treat population. In a secondary analysis, we will additionally adjust the primary outcome for potential random differences in baseline characteristics. The conclusion will be based on the intention-to-treat population. CONCLUSION: Stress ulcer prophylaxis is standard of care in ICUs worldwide, but has never been tested in large high-quality randomised placebo-controlled trials. The SUP-ICU trial will provide important high-quality data on the balance between the benefits and harms of stress ulcer prophylaxis in adult critically ill patients.

Report: Impact of drug combination of clopidogrel and pantoprazole In the prognosis of patients with transient ischemic attack.

The study aimed to investigate the impact of clopidogrel combined with proton pump inhibitors (PPI) pantoprazole treatment on the prognosis of patients with transient ischemic attack (TIA). A total of 478 cases of TIA patients treated with clopidogrel were randomly assigned half to clopidogrel combined with pantoprazole treatment and the control groups (clopidogrel treatment alone) from January 2012 to January 20l4. The platelet aggregation before and after treatment and cerebrovascular events incidence within 90 days were compared and analyzed. Multivariate analysis was used to estimate the incidence of cerebrovascular events within 90 days. The platelet aggregation rate before treatment was 73.2±6.1% in the treatment group, 74.1±8.8% in the control group. The platelet aggregation rate after treatment was 38.1±10.7% in the treatment group, 36.8±9.7% in the control group. The platelet aggregation before and after treatments between the two groups had not significant difference (P>0.05). The incidence of cerebrovascular events within 90 days (11.7% in the treatment group, 9.6% in the control group) between the two groups had not significant difference (P>0.05). Multivariate analysis showed that the incidence of cerebrovascular events within 90 day was associated with hypertension (P=0.008), diabetes (P=0.000), hyperlipidemia (P=0.002) and ABCD2 score >3 points (P=0.000). Clopidogrel combined with pantoprazole treatment had no significant effect on the prognosis of TIA patients.

Pantoprazole or Placebo for Stress Ulcer Prophylaxis (POP-UP): Randomized Double-Blind Exploratory Study.

OBJECTIVES: Pantoprazole is frequently administered to critically ill patients for prophylaxis against gastrointestinal bleeding. However, comparison to placebo has been inadequately evaluated, and pantoprazole has the potential to cause harm. Our objective was to evaluate benefit or harm associated with pantoprazole administration. DESIGN: Prospective randomized double-blind parallel-group study. SETTING: University-affiliated mixed medical-surgical ICU. PATIENTS: Mechanically ventilated critically ill patients suitable for enteral nutrition. INTERVENTIONS: We randomly assigned patients to receive either daily IV placebo or pantoprazole. MEASUREMENTS AND MAIN RESULTS: Major outcomes were clinically significant gastrointestinal bleeding, infective ventilator-associated complication or pneumonia, and Clostridium difficile infection; minor outcomes included overt bleeding, hemoglobin concentration profiles, and mortality. None of the 214 patients randomized had an episode of clinically significant gastrointestinal bleeding, three patients met the criteria for either an infective ventilator-associated complication or pneumonia (placebo: 1 vs pantoprazole: 2), and one patient was diagnosed with Clostridium difficile infection (0 vs 1). Administration of pantoprazole was not associated with any difference in rates of overt bleeding (6 vs 3; p = 0.50) or daily hemoglobin concentrations when adjusted for transfusion rates of packed red cells (p = 0.66). Mortality was similar between groups (log-rank p = 0.33: adjusted hazard ratio for pantoprazole: 1.68 [95% CI, 0.97-2.90]; p = 0.06). CONCLUSIONS: We found no evidence of benefit or harm with the prophylactic administration of pantoprazole to mechanically ventilated critically ill patients anticipated to receive enteral nutrition. The practice of routine administration of acid-suppressive drugs to critically ill patients for stress ulcer prophylaxis warrants further evaluation.

Rifabutin Containing Triple Therapy and Rifabutin with Bismuth Containing Quadruple Therapy for Third-Line Treatment of Helicobacter pylori Infection: Two Pilot Studies.

AIM: To evaluate the therapeutic gain of the addition of bismuth to a rifabutin containing triple therapy with amoxicillin and pantoprazole at standard dosages for the treatment of third-line Helicobacter pylori infection after a preliminary susceptibility test. METHODS: Two separate groups of patients in two pilot studies which were carried out simultaneously. One group was treated with rifabutin 150 mg b.i.d., pantoprazole 20 mg b.i.d., and amoxicillin 1 g b.i.d. for 10 days and the other group with rifabutin 150 mg b.i.d., pantoprazole 20 mg b.i.d., amoxicillin 1 g b.i.d., and bismuth subcitrate 240 mg b.i.d. for 10 days. All patients underwent to culture and susceptibility testing prior to their inclusion in the study. A successful outcome was confirmed with an Urea Breath test performed 8 weeks after the end of treatment. A blood cell count was performed for all patients at the start and after 5 days of treatment since rifabutin has been shown to inhibit the growth of leucocytes. RESULTS: Twenty-nine patients were recruited in the pantoprazole, amoxicillin, rifabutin group and 30 in the pantoprazole, amoxicillin, rifabutin, and bismuth subcitrate group. All patients had a positive H. pylori culture and the susceptibility test used showed H. pylori sensitivity to rifabutin and amoxicillin. H. pylori eradication during follow-up was 18/27 (66.7%, 95% CI: 47.7-85.7%) in the pantoprazole, amoxicillin, rifabutin group and 28/29 (96.6%, 95% CI: 89.5-100.0%) in the pantoprazole, amoxicillin, rifabutin, and bismuth subcitrate group. Both treatments were well-tolerated with no reported side effects. Blood cell count remained normal in all patients. CONCLUSION: The addition of bismuth subcitrate to a triple therapy that includes proton pump inhibitors, amoxicillin, and rifabutin in patients who are treated for the third time for H. pylori infection resulted in a 30% therapeutic gain.

Association of Acute Gastroesophageal Reflux Disease With Esophageal Histologic Changes.

IMPORTANCE: The histologic changes associated with acute gastroesophageal reflux disease (GERD) have not been studied prospectively in humans. Recent studies in animals have challenged the traditional notion that reflux esophagitis develops when esophageal surface epithelial cells are exposed to lethal chemical injury from refluxed acid. OBJECTIVE: To evaluate histologic features of esophageal inflammation in acute GERD to study its pathogenesis. DESIGN, SETTING, AND PARTICIPANTS: Patients from the Dallas Veterans Affairs Medical Center who had reflux esophagitis successfully treated with proton pump inhibitors (PPIs) began 24-hour esophageal pH and impedance monitoring and esophagoscopy (including confocal laser endomicroscopy [CLE]) with biopsies from noneroded areas of distal esophagus at baseline (taking PPIs) and at 1 week and 2 weeks after stopping the PPI medication. Enrollment began May 2013 and follow-up ended July 2015. INTERVENTIONS: PPIs stopped for 2 weeks. MAIN OUTCOMES AND MEASURES: Twelve patients (men, 11; mean age, 57.6 year [SD, 13.1]) completed the study. Primary outcome was change in esophageal inflammation 2 weeks after stopping the PPI medication, determined by comparing lymphocyte, eosinophil, and neutrophil infiltrates (each scored on a 0-3 scale) in esophageal biopsies. Also evaluated were changes in epithelial basal cell and papillary hyperplasia, surface erosions, intercellular space width, endoscopic grade of esophagitis, esophageal acid exposure, and mucosal impedance (an index of mucosal integrity). RESULTS: At 1 week and 2 weeks after discontinuation of PPIs, biopsies showed significant increases in intraepithelial lymphocytes, which were predominantly T cells (median [range]: 0 (0-2) at baseline vs 1 (1-2) at both 1 week [P = .005] and 2 weeks [P = .002]); neutrophils and eosinophils were few or absent. Biopsies also showed widening of intercellular spaces (confirmed by CLE), and basal cell and papillary hyperplasia developed without surface erosions. Two weeks after stopping the PPI medication, esophageal acid exposure increased (median: 1.2% at baseline to 17.8% at 2 weeks; Δ, 16.2% [95% CI, 4.4%-26.5%], P = .005), mucosal impedance decreased (mean: 2671.3 Ω at baseline to 1508.4 Ω at 2 weeks; Δ, 1162.9 Ω [95% CI, 629.9-1695.9], P = .001), and all patients had evidence of esophagitis. CONCLUSIONS AND RELEVANCE: In this preliminary study of 12 patients with severe reflux esophagitis successfully treated with PPI therapy, stopping PPI medication was associated with T lymphocyte-predominant esophageal inflammation and basal cell and papillary hyperplasia without loss of surface cells. If replicated, these findings suggest that the pathogenesis of reflux esophagitis may be cytokine-mediated rather than the result of chemical injury. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01733810.

Comparison of High Dose and Standard Dose Proton Pump Inhibitor before Endoscopy in Patients with Non-Portal Hypertension Bleeding.

Background: Gastrointestinal bleeding with non-portal hypertension bleeding (non-PHT) is the most common cause of gastrointestinal emergencies with high mortality rate. The majority of non-PHT patient stem from acid related disease. The practice guideline recommends using pre-endoscopic proton pump inhibitors (PPIs). However, the dose and route of PPIs administration were still unclear according to the Association for Gastroenterology. Objective: To compare the efficiency of PPIs between high dose and standard dose before endoscopy in patients suffering with gastrointestinal bleeding due to non-PHT. Material and Method: The present study was designed as a prospective, randomized controlled trial. The patients were randomly categorized into two groups, the first group received intravenous pantoprazole 80 mg bolus then continuously drip 8 mg per hour (high dose group) and the other group received intravenous pantoprazole 40 mg twice daily before endoscopy (standard dose group). Baseline characteristics, Blatchford score, endoscopic findings, morbidity, and other complications were recorded. Results: One hundred thirteen patients were recruited. Fifty-eight patients were in the high dose group and 55 patients in the standard dose group. Blatchford scores in the high dose group were slightly higher than the standard dose group but there was no statistically significant difference (12.49+3.29 and 12.38+4.06, respectively, p = 0.876). Twenty-two patients were high-risk for peptic ulcer bleeding from endoscopy. There were significantly less numbers of patient who were high-risk of peptic ulcer bleeding in the high dose group compared to the standard dose group (10 patients [17.24%] and 12 patients [21.82%], respectively, p = 0.025). There was no difference between the two groups in average time of hospital stay (3.03 and 2.89 days, respectively, p>0.05), mean unit of blood transfusion (1.79 and 1.63 units, respectively, p>0.05), and the complications after endoscopy such as recurrent bleeding (0 and 1 patient, respectively, p>0.05), recurrent bleeding and death (0 and 1 patient, respectively, p>0.05). The Blatchford score greater than 10, 11, and 12 showed high sensitivity of 100%, 95%, and 95% respectively with negative predictive values (NPV) of 100%, 97%, and 97% respectively, in predicting high-risk peptic ulcer bleeding. Conclusion: The high dose of PPIs administration before endoscopy reduced the chance of high-risk peptic ulcer bleeding compared to the standard dose. Both high dose and standard dose of PPIs did not affect the time of hospital stay, unit of blood transfusion, the complications after endoscopy, and mortality rate. Standard dose PPIs can be considered using in patients with Blatchford scores lower than 10. High dose PPIs would be beneficial in patients who have Blatchford scores between 10 and 12. For patients who have Blatchford scores greater than 12, high dose PPIs are recommended.

Potential Drug Interaction Between an Antiplatelet Agent and a Proton Pump Inhibitor.

Older adults frequently have multiple medical conditions and consequently receive multiple medications. Cardiovascular (CV) and gastrointestinal disorders are two conditions in seniors that often require both long-term antiplatelet therapy and medications for GI prophylaxis. Clopidogrel and pantoprazole are commonly used for these conditions; however, there are potential adverse consequences secondary to drug interactions. Both of these drugs are metabolized via the cytochrome P450 system, and there is a potential for drug interactions that may result in decreased effectiveness of clopidogrel and an increased risk of adverse CV outcomes. Pharmacists should be informed of these potential drug interactions and take appropriate actions to assure safe and effective patient care.