Association between Acid-Lowering Agents, Metformin, and Vitamin B12 among Boston-Area Puerto Ricans.

BACKGROUND: Vitamin B12 involves several physiological functions, and malabsorption is reported with medication use. OBJECTIVES: Studies have reported an inverse association between the use of metformin or acid-lowering agents (ALAs), such as proton pump inhibitors, histamine 2 receptor antagonists, and blood vitamin B12 concentration, because of malabsorption. The concomitant use of these medications is underreported. We sought to examine these associations in a cohort of Boston-area Puerto Rican adults. METHODS: This analysis was conducted within the Boston Puerto Rican Health Study (BPRHS), an ongoing longitudinal cohort that enrolled 1499 Puerto Rican adults aged 45-75 y at baseline. Our study comprised 1428, 1155, and 782 participants at baseline, wave2 (2.2 y from baseline), and wave3 (6.2 y from baseline), respectively. Covariate-adjusted linear and logistic regression was used to examine the association between baseline medication use and vitamin B12 concentration or deficiency (vitamin B12 <148 pmol/L or methylmalonic acid >271 nmol/L), and long-term medication use (continuous use for ∼6.2 y) and wave3 vitamin B12 concentration and deficiency. Sensitivity analyses were done to examine these associations in vitamin B12 supplement users. RESULTS: At baseline, we observed an association between metformin use (ß = -0.069; P = 0.03) and concomitant ALA and metformin use (ß = -0.112; P = 0.02) and vitamin B12 concentration, but not a deficiency. We did not observe associations between ALA, proton pump inhibitors, or histamine 2 receptor antagonists, individually, with vitamin B12 concentration or deficiency. CONCLUSIONS: These results suggest an inverse relationship between metformin, concomitant ALA, metformin use, and serum vitamin B12 concentration.

The Association of Proton Pump Inhibitors and QT Interval Prolongation in Critically Ill Patients.

INTRODUCTION: Drug-induced QT interval prolongation has been reported to be related to life-threatening polymorphic ventricular tachycardia (torsade de pointes). Proton pump inhibitors (PPIs) are prescribed widely for hospitalized patients; the QT interval prolongation and torsade de pointes caused by PPIs were reported. We conducted a study to determine the association between PPI treatment and QT interval prolongation in critically ill patients. METHODS: This study included patients with electrocardiography (ECG) reports from the Medical Information Mart for Intensive Care III database (MIMIC-III). Patients younger than 18 years, missing baseline laboratories and with QT interval prolongation before intensive care unit (ICU) admission were excluded. The end point was the diagnosis of QT interval prolongation reported by ECG. RESULTS: This study included 24,512 ICU patients. Of them, 11,327 patients were treated with PPIs, 4181 with histamine 2 receptor antagonists (H2RAs) and 6351 without acid suppression therapy (non-AST); the incidence of QT interval prolongation were 8.5%, 3.3% and 3.4% respectively. After adjustment for demographics, electrolytes, comorbidities and medications, PPIs were associated a higher risk of QT interval prolongation compared with H2RAs (OR 1.66, 95% CI 1.36 - 2.03) and non-AST (OR 1.54, 95% CI 1.31 - 1.82), while there was not significant difference between H2RAs and non-AST (OR 0.93, 95% CI 0.73 - 1.17). In the propensity score matching population, the results were consistent. Pantoprazole (OR 2.14, 95% CI 1.52 - 3.03) and lansoprazole (OR 1.80, 95% CI: 1.18 - 2.76) showed a higher QT prolongation risk than omeprazole. Several drugs caused higher QT prolongation risk when used in combination with PPIs. CONCLUSION: In ICU patients, the association between PPI prescription and increased risk of QT interval prolongation was independent of known QT-prolonging factors; pantoprazole and lansoprazole had a higher risk compared with omeprazole. The combination of PPIs and other QT-prolonging drugs should be avoided.

Maintenance Proton Pump Inhibitor Use Associated with Increased All-Cause and Cause-Specific Mortality in Sweden.

BACKGROUND: Proton pump inhibitor (PPI) use has increased over the last decades and has been associated with multiple adverse events and potentially even overall survival. AIMS: We aimed to investigate the association between proton pump inhibitor maintenance use and all-cause and cause-specific mortality, addressing confounding by indication and duration of use. METHODS: This Swedish population-based cohort study included all adult (N = 935,236) PPI and histamine-2 receptor antagonist maintenance users (≥ 180 days use) during 2005-2014. Standardised mortality ratios (SMRs) and 95% confidence intervals were calculated for all-cause and cause-specific mortality comparing the risk among PPI/H2RA users to that of the Swedish background population, stratified by age, sex, calendar period, indication and duration of use. Multivariable Poisson regression models were used to compare PPI use to H2RA use, expressed as incidence rate ratios and 95% confidence intervals. RESULTS: PPI and histamine-2 receptor antagonist use were associated with an increased risk of all-cause mortality (SMR = 1.35; 1.34-1.36; SMR = 1.31; 1.27-1.36, respectively). The highest SMRs were found in the youngest age groups. In direct comparison, PPI use showed a higher mortality risk than histamine-2 receptor antagonist use (incidence rate ratios = 1.42; 1.38-1.46). PPIs were related to increased cancer (SMR = 1.21; 1.20-1.22), and cardiovascular mortality (SMR = 1.36; 1.35-1.37). Increased SMRs were observed for most indications. Longer duration of use was associated with a higher mortality among PPI users but not among histamine-2 receptor antagonist users. CONCLUSION: Maintenance PPI use was associated with an increased risk of all-cause and cause-specific mortality, and the risk increased with prolonged duration.

Assessment of the Relationship Between Gastric-Acid Suppressants and the Risk of Esophageal Adenocarcinoma: A Systematic Review and Meta-Analysis.

Background: Esophageal cancer is a cancerous tumor that develops in the esophagus. It is the 10th most common cancer and has a low survival rate. Esophageal adenocarcinoma (EAC) is increasing in incidence globally. Those with EAC are affected by Barrett's esophagus metaplasia, which is attributed to genetic predisposition and is more common in men. Studies suggest that gastric acid suppressants, like proton pump inhibitors and histamine-2 receptor antagonists, have anticancer properties and reduce EAC. However, other research has suggested that they are not cancer-protective, and the use of antisecretory drugs is a risk factor for developing EAC. Objective: This systematic review and meta-analysis investigated the properties and risk factors associated with using gastric acid suppressants in patients with EAC. Methods: This meta-analysis used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses checklist. Information from selected articles, including the lead author's name, year of publication, study setting, sample size, and gender, was extracted and recorded into an Excel (Microsoft, Redmond, Washington) form. Statistical data included odds ratio, hazard ratio, and/or risk ratio, with a 95% CI associated with patients with EAC and receiving gastric acid suppressants. Data were compared with individuals not receiving treatment. Publication bias was assessed using Begg's and Egger's tests. Statistical analyzes used Stata 14.0 (Stata LLC, College Station, Texas). Results: The initial electronic literature search retrieved 3761 titles/abstracts. Extensive screening selected 20 articles for analysis. Odds ratios associated with EAC in the individuals using gastric acid suppressants were 0.77 (95% CI, 0.49-1.22; P = 0.274) and 0.67 (95% CI, 0.39-1.29; P = 0.240) for proton pump inhibitors and 1.02 (95% CI, 0.44-2.36; P = 0.967) for histamine-2 receptor antagonists. Conclusions: The results found that gastric acid suppressants do not have a protective role in EAC and are not risk factors. Future studies of confounding variables and risk factors are needed to understand what affects EAC development.

Assessment of adherence to the national stress ulcer prophylaxis guidelines: A cross-sectional analysis.

Background: Clinical guidelines support the use of stress ulcer prophylaxis (SUP) in patients at risk of gastrointestinal (GI) bleeding such as those with coagulopathy, renal replacement therapy, and mechanical ventilation. Despite the observed benefits of SUP, its overuse has been highly associated with serious adverse effects. Objective: To assess the adherence to the national SUP guidelines in a tertiary hospital in Saudi Arabia. Methods: A cross-sectional study was conducted using electronic health records at King Fahad Specialist Hospital (KFSH), Buraydah, Saudi Arabia. We collected the data from January 1st to December 31st, 2020. Adult patients aged 18 and older who received SUP prescriptions were included. Descriptive analysis was performed to assess the adherence to the guidelines and to explore the factors associated with SUP use in a hospital-based setting. Results: A total of 424 patients were enrolled in this study. The median age of patients was 55.2 years old. Only 54% of patients were candidates for SUP. Internal medicine and surgery wards ranked the highest in prescribing SUP at 34.2% and 30.4%, respectively. The most common major criterion to start SUP was the concomitant use of two or more of these medications (anticoagulants, aspirin, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and antidepressants) followed by using NSAIDs or corticosteroids by older adult patients aged (≥65 years) or have GI bleeding history at 43.2% and 21.5%, respectively. Conclusion: The observed overuse of anti-ulcer drugs (AUD) indicates a need for greater adherence to SUP guidelines. Areas of improvement can be implemented to ensure appropriate adherence to SUP guidelines to control the costs and avoid unnecessary anti-ulcer-related adverse effects.

Acid Suppression Medications During Hospitalization as a Risk Factor for Recurrence of Clostridioides difficile Infection: Systematic Review and Meta-analysis.

BACKGROUND: Studies have had conflicting results regarding the influence of acid-suppression medications (ASMs) during hospitalization on the recurrence of Clostridioides difficile infection (CDI). METHODS: A systematic review and meta-analysis investigating the association between recurrent CDI and ASM use in inpatients was performed. Relevant literature was identified using Medline, Google Scholar, and Web of Science. All human studies were considered regardless of publication date. Case-control and cohort studies and clinical trials were included if they contained the necessary information to calculate appropriate statistics related to the objective of this study. Review articles, meta-analyses, and commentaries were excluded; however, their references were searched to identify any studies missed. The random-effects model was selected since significant heterogeneity in study design was identified. To evaluate the sensitivity of the analysis various subgroup analyses were performed. RESULTS: Our search identified 9 studies involving 5668 patients of whom 1003 (17.7%) developed recurrent CDI. Patients on ASM were 64% more likely to develop recurrent CDI than patients not on ASM (OR, 1.64; 95% CI, 1.13-2.38; P = .009; I2 = 79.54%). Proton pump inhibitor (PPI) use was associated with an 84% increased risk of recurrent CDI versus no ASM (OR, 1.84; 95% CI, 1.18-2.85; P = .007; I2 = 83.4%). CONCLUSIONS: ASM use during hospitalization was associated with a 64% increase in recurrent CDI. The association was greater with PPI use. Due to significant heterogeneity in the analyses, additional studies are essential to further elucidate iatrogenic effects of ASM. Unnecessary PPI use should be discontinued.

Proton Pump Inhibitors Inhibit PHOSPHO1 Activity and Matrix Mineralisation In Vitro.

Proton pump inhibitors (PPIs) have been associated with an increased risk of fragility fractures in pharmaco-epidemiological studies. The mechanism is unclear, but it has been speculated that by neutralising gastric acid, they may reduce intestinal calcium absorption, causing secondary hyperparathyroidism and bone loss. Here we investigated that hypothesis that the skeletal effects of PPI might be mediated by inhibitory effects on the bone-specific phosphatase PHOSPHO1. We found that the all PPIs tested inhibited the activity of PHOSPHO1 with IC50 ranging between 0.73 µM for esomeprazole to 19.27 µM for pantoprazole. In contrast, these PPIs did not inhibit TNAP activity. We also found that mineralisation of bone matrix in primary osteoblast cultures was inhibited by several PPIs in a concentration dependent manner. In contrast, the histamine-2 receptor antagonists (H2RA) nizatidine, famotidine, cimetidine and ranitidine had no inhibitory effects on PHOSPHO1 activity. Our experiments show for the first time that PPIs inhibit PHOSPHO1 activity and matrix mineralisation in vitro revealing a potential mechanism by which these widely used drugs are associated with the risk of fractures.

Prophylactic acid suppressants in children in the intensive care unit: a systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Critically ill children are at risk of stress-induced gastrointestinal ulceration. Acid suppressants are frequently used in intensive care units even though there is uncertainty about the benefits and harms. With this systematic review, we aimed to assess patient-important benefits and harms of stress ulcer prophylaxis (SUP) in children in intensive care. METHODS: We conducted the review according to the PRISMA statement, the Cochrane Handbook, and GRADE, using conventional meta-analysis and trial sequential analysis (TSA). We included randomised clinical trials comparing SUP with histamine-2-receptor antagonists or proton pump inhibitors vs placebo/no prophylaxis in children admitted for intensive care. Primary outcomes were all-cause mortality and overt gastrointestinal bleeding. Secondary outcomes were serious adverse events, hospital-acquired pneumonia, Clostridium difficile enteritis, myocardial ischemia, acute kidney injury and quality of life. RESULTS: We included a total of seven trials (n = 504) with eight trial comparisons. We found no statistically significant difference in all-cause mortality (relative risk (RR) 1.43, 95% confidence interval (CI) 0.86-2.37), overt gastrointestinal bleeding (RR 0.75, 95% CI 0.42-1.35) or hospital-acquired pneumonia (RR 1.18, 95% CI 0.77-1.82) between SUP vs placebo/no prophylaxis. No trials reported on remaining secondary outcomes. TSA was unable to draw firm conclusions for all outcomes and certainty of evidence for all outcomes was "very low." CONCLUSIONS: We found no difference in all-cause mortality, overt gastrointestinal bleeding or hospital-acquired pneumonia in children in intensive care receiving acid suppressants compared with placebo/no prophylaxis. However, the quantity and quality of evidence was very low with no firm evidence for benefit or harm.

Acid-suppressive agents and survival outcomes in patients with cancer: a systematic review and meta-analysis.

BACKGROUND: Patients with cancer often receive acid-suppressive agents (ASAs) to treat common gastroesophageal reflux and peptic ulcer diseases. Our systematic review addresses the association between ASAs and survival outcomes in these patients. METHODS: We searched MEDLINE, EMBASE, and Cochrane until December 2019, including randomized controlled trials (RCTs), quasi-RCTs, and observational studies concerning ASAs that reported progression-free survival (PFS) and/or overall survival (OS). We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) using the random-effects model, and assessed heterogeneity with I2 statistic. RESULTS: We included 45,626 patients from 7 RCTs and 18 observational studies, including esophageal/gastric, colorectal, pancreatic, lung, breast, prostate, kidney, and other cancers. Five studies showed that ASAs in lung cancer patients received tyrosine kinase inhibitors (TKIs) had significantly worse PFS (HR 1.64, 95% CI 1.14 - 2.37, I2 = 57%) and OS (HR 1.13, 95% CI 1.05 - 1.21, I2 = 0%) than nonusers. Each of five studies found no significant association between ASAs and OS in esophageal/gastric (HR 0.91, 95% CI 0.77 - 1.09, I2 = 32%) or colorectal cancer patients (HR 1.33, 95% CI 0.96- 1.85, I2 = 0%). ASAs were not significantly associated with an OS in patients with kidney cancer (HR 1.04, 95% CI 0.96 - 1.13, I2 = 28%). CONCLUSIONS: Meta-analysis showed that ASAs significantly associated with an increased mortality risk in lung cancer patients treated TKIs, but not in patients with esophageal/gastric, colorectal, or kidney cancer. Until further studies confirm these results, caution should be used when administering ASAs and TKIs to patients with lung cancer.

Stress-Related Gastrointestinal Bleeding in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Retrospective Observational Study.

BACKGROUND/OBJECTIVE: Stress-related mucosal bleeding (SRMB) occurs in approximately 2-4% of critically ill patients. Patients with aneurysmal subarachnoid hemorrhage (aSAH) have a (diffuse) space-occupying lesion, are critically ill, often require mechanical ventilation, and frequently receive anticoagulation or antiplatelet therapy after aneurysm embolization, all of which may be risk factors for SRMB. However, no studies have evaluated SRMB in patients with aSAH. Aims of the study were to determine the incidence of SRMB in aSAH patients, evaluate the effect of acid suppression on SRMB, and identify specific risk factors for SRMB. METHODS: This was a multicenter, retrospective, observational study conducted across 17 centers. Each center reviewed up to 50 of the most recent cases of aSAH. Patients with length of stay (LOS) < 48 h or active GI bleeding on admission were excluded. Variables related to demographics, aSAH severity, gastrointestinal (GI) bleeding, provision of SRMB prophylaxis, adverse events, intensive care unit (ICU), and hospital LOS were collected for the first 21 days of admission or until hospital discharge, whichever came first. Descriptive statistics were used to analyze the data. A multivariate logistic regression modeling was utilized to examine the relationship between specific risk factors and the incidence of clinically important GI bleeding in patients with aSAH. RESULTS: A total of 627 patients were included. The overall incidence of clinically important GI bleeding was 4.9%. Of the patients with clinically important GI bleeding, 19 (61%) received pharmacologic prophylaxis prior to evidence of GI bleeding, while 12 (39%) were not on pharmacologic prophylaxis at the onset of GI bleeding. Patients who received an acid suppressant agent were less likely to experience GI bleeding than patients who did not receive pharmacologic prophylaxis prior to evidence of bleeding (OR 0.39, 95% CI 0.18-0.83). The multivariate regression analysis identified any instance of elevated intracranial pressure, creatinine clearance < 60 ml/min and the incidence of cerebral vasospasm as specific risk factors associated with GI bleeding. Cerebral vasospasm has not previously been described as a risk for GI bleeding (OR 2.5 95% CI 1.09-5.79). CONCLUSIONS: Clinically important GI bleeding occurred in 4.9% of patients with aSAH, similar to the general critical care population. Risk factors associated with GI bleeding were prolonged mechanical ventilation (> 48 h), creatinine clearance < 60 ml/min, presence of coagulopathy, elevation of intracranial pressure, and cerebral vasospasm. Further prospective research is needed to confirm this observation within this patient population.

A Retrospective Cohort Analysis of the Use of Enteral Nutrition Plus Pharmacologic Prophylaxis or Enteral Nutrition Alone.

Background: Due to the risk of development of stress ulcers in intensive care unit (ICU) patients, pharmacologic prophylaxis is often utilized. However, some literature describes the use of enteral nutrition instead as stress ulcer prophylaxis. Methods: The purpose of this study is to determine if enteral nutrition is similar to pharmacologic stress ulcer prophylaxis (SUP) with enteral nutrition for reduction of gastrointestinal (GI) bleeding, perforation, or ulceration in ICU patients. This was a retrospective, single-center cohort study that took place at an academic medical center. Adult ICU patients receiving enteral nutrition who had a risk factor for stress-related mucosal damage were included. The primary outcome was the incidence of GI bleeding, perforation, or ulcer formation. Results: Overall, 167 patients were included in the study, 147 in the pharmacologic prophylaxis plus EN group (PPEN) and 20 in the enteral therapy only (EN) group. Of 167 patients included, 22 patients (21 in the PPEN group and 1 in the EN group) developed a primary outcome of GI bleeding, perforation, or ulceration (14.3% vs 5%, P = .4781). Patients in the PPEN group had a higher incidence of pneumonia (42.2% vs 15%, P = .0194), but no difference was seen between groups when patients with pneumonia present on admission were excluded (20.6% vs 10.5%, P = .5254). Conclusion: In this small cohort of patients, enteral nutrition alone is as effective as pharmacologic therapy in addition to enteral nutrition for the reduction of stress-related GI bleeding, perforation, and ulceration.

Comparative risk of Clostridium difficile infection between proton pump inhibitors and histamine-2 receptor antagonists: A 15-year hospital cohort study using a common data model.

BACKGROUNDS AND AIM: There are potential concerns regarding infectious complications including Clostridium difficile infections (CDIs) among patients taking gastric acid suppressants. Furthermore, it is speculated that the stronger acid suppression by proton pump inhibitors (PPIs) potentially enhance infectious complications. This study aimed to compare the risk of CDI between PPIs and histamine-2 receptor antagonists (H2RAs). METHODS: Using the long-term database of the Kangdong Sacred Heart Hospital, converted to the Observational Medical Outcomes Partnership Common Data Model, we identified outpatients treated with PPIs and H2RAs for ≥ 7 days from January 1, 2004 through December 31, 2018. We conducted Cox regression analysis to examine the hazard ratio (HR) of CDI after propensity score matching. RESULTS: During a median follow-up period of 1.2 years (interquartile range, 0.2-3.2 years), the initial CDI occurrence differed significantly between matched cohorts of patients taking PPIs and H2RAs [PPIs vs H2RAs, 88/31 095 person years vs 47/32 836 person years; HR, 2.22; 95% confidence interval (CI) 1.29-3.96; P = 0.005]. Almost 50% of all events occurred within 1 year of drug exposure. The risk of CDIs was significantly greater among groups receiving PPIs or H2RAs than in matched controls (PPIs vs control: HR, 2.65; 95% CI 1.28-5.79; P = 0.011; and H2RAs vs control: HR 2.43; 95% CI 1.09-5.68; P = 0.034]. CONCLUSION: In long-term hospital cohort, outpatient-based PPIs were associated with greater risk of CDI than H2RAs. It is necessary to be cautioned about complication of CDI in patients taking long-term PPI therapy.

Impact of concomitant acid suppressive therapy on pazopanib efficacy and dose reductions in patients with metastatic renal cell carcinoma.

PURPOSE: The aim of this study was to investigate the impact of acid suppressive therapy on clinical efficacy and safety of pazopanib in patients with metastatic renal cell carcinoma (mRCC). METHODS: A single-center retrospective study was carried out. Charts of mRCC patients who received pazopanib as first-line treatment were reviewed and concomitant use of proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) was studied. Two groups of patients were identified, namely patients receiving PPI/H2RA and patients without acid suppressive therapy. Both groups were compared with regard to progression free survival (PFS), overall survival (OS), tumor response, and time to dose reduction of pazopanib. RESULTS: Ninety-one patients were included. Median PFS was 8 months in the PPI/H2RA group vs. 7 months in the no PPI/H2RA group (hazard ratio (HR) 0.76 (95% confidence interval (CI) 0.42-1.35)), p = 0.35. Median OS was 27 months in the PPI/H2RA group vs. 23 months in the no PPI/H2RA group (HR 0.87 (95% CI 0.46-1.66)), p = 0.68. Mean tumor response was 17% (95% CI 8-25%) in the PPI/H2RA group vs. 11% (95% CI 0-21%) in the no PPI/H2RA group, p = 0.52. Median time to first dose reduction was 9 months in both subgroups (HR 1.25 (95% CI 0.65-2.39)), p = 0.51. Median time to second dose (< 600 mg) reduction was 17 months in the PPI/H2RA group vs. 7 months in the no PPI/H2RA group (HR 0.26 (95% CI 0.07-0.89)), p = 0.03. CONCLUSION: In this limited patient series, no evidence of a negative impact of PPI/H2RA on clinical outcome and time to first dose reduction was observed. These results suggest that PPI/H2RA might be considered, when there is a clinical need, in patients treated with pazopanib for mRCC. However, a prospective study is warranted to confirm these results.

Prophylactic use of acid suppressants in adult acutely ill hospitalised patients: A systematic review with meta-analysis and trial sequential analysis.

BACKGROUND: Acutely ill patients are at risk of stress-related gastrointestinal (GI) bleeding and prophylactic acid suppressants are frequently used. In this systematic review, we assessed the effects of stress ulcer prophylaxis (SUP) with proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs) versus placebo or no prophylaxis in acutely ill hospitalised patients. METHODS: We conducted the review according to the PRISMA statement, the Cochrane Handbook and GRADE, using conventional meta-analysis and trial sequential analysis (TSA). The primary outcomes were all-cause mortality, clinically important GI bleeding and serious adverse events (SAEs). The primary analyses included overall low risk of bias trials. RESULTS: We included 65 comparisons from 62 trials (n = 9713); 43 comparisons were from intensive care units. Only three trials (n = 3596) had overall low risk of bias. We did not find an effect on all-cause mortality (RR 1.03, 95% CI 0.94 to 1.14; TSA-adjusted CI 0.90 to 1.18; high certainty). The rate of clinically important GI bleeding was lower with SUP (RR 0.62, 95% CI 0.43 to 0.89; TSA-adjusted CI 0.14 to 2.81; moderate certainty). We did not find a difference in pneumonia rates (moderate certainty). Effects on SAEs, Clostridium difficile enteritis, myocardial ischaemia and health-related quality of life (HRQoL) were inconclusive due to sparse data. Analyses of all trials regardless of risk of bias were consistent with the primary analyses. CONCLUSIONS: We did not observe a difference in all-cause mortality or pneumonia with SUP. The incidence of clinically important GI bleeding was reduced with SUP, whereas any effects on SAEs, myocardial ischaemia, Clostridium difficile enteritis and HRQoL were inconclusive. STUDY REGISTRATION: PROSPERO registration number CRD42017055676; published study protocol: Marker, et al 2017 in Systematic Reviews.

Stress ulcer prophylaxis with proton pump inhibitors or histamine 2 receptor antagonists in critically ill adults - a meta-analysis of randomized controlled trials with trial sequential analysis.

BACKGROUND: Proton pump inhibitors (PPI) and histamine 2 receptor antagonists (H2RA) have been widely used as stress ulcer prophylaxis (SUP) in critically ill patients, however, its efficacy and safety remain unclear. This study aimed to assess the effect of SUP on clinical outcomes in critically ill adults. METHODS: Literature search was conducted in PubMed, EMBASE, Web of Science, and the Cochrane database of clinical trials for randomized controlled trials (RCTs) that investigated SUP, with PPI or H2RA, versus placebo or no prophylaxis in critically ill patients from database inception through 1 June 2019. Study selection, data extraction and quality assessment were performed in duplicate. The primary outcomes were clinically important gastrointestinal (GI) bleeding and overt GI bleeding. Conventional meta-analysis with random-effects model and trial sequential analysis (TSA) were performed. RESULTS: Twenty-nine RCTs were identified, of which four RCTs were judged as low risk of bias. Overall, SUP could reduce the incident of clinically important GI bleeding [relative risk (RR) = 0.58; 95% confidence intervals (CI): 0.42-0.81] and overt GI bleeding (RR = 0.48; 95% CI: 0.36-0.63), these results were confirmed by the sub-analysis of trials with low risk of bias, TSA indicated a firm evidence on its beneficial effects on the overt GI bleeding (TSA-adjusted CI: 0.31-0.75), but lack of sufficient evidence on the clinically important GI bleeding (TSA-adjusted CI: 0.23-1.51). Among patients who received enteral nutrition (EN), SUP was associated with a decreased risk of clinically important GI bleeding (RR = 0.61; 95% CI: 0.44-0.85; TSA-adjusted CI: 0.16-2.38) and overt GI bleeding (RR = 0.64; 95% CI: 0.42-0.96; TSA-adjusted CI: 0.12-3.35), but these benefits disappeared after adjustment with TSA. Among patients who did not receive EN, SUP had only benefits in reducing the risk of overt GI bleeding (RR = 0.37; 95% CI: 0.25-0.55; TSA-adjusted CI: 0.22-0.63), but not the clinically important GI bleeding (RR = 0.27; 95% CI: 0.04-2.09). CONCLUSIONS: SUP has benefits on the overt GI bleeding in critically ill patients who did not receive EN, however, its benefits on clinically important GI bleeding still needs more evidence to confirm.

Stress ulcer prophylaxis in critically ill children: Protocol for a systematic review.

BACKGROUND: Stress ulcer prophylaxis is the considered standard of care in many critically ill patients in the intensive care unit (ICU). Whether there is overall benefit or harm of stress ulcer prophylaxis in critically ill children is unknown. Accordingly, we aim to assess patient-important benefits and harms of stress ulcer prophylaxis versus placebo or no treatment in critically ill children in the ICU. METHODS/DESIGN: We will conduct a systematic review of randomized clinical trials with meta-analysis and trial sequential analysis and assess the use of proton pump inhibitors (PPIs) or histamine-2-receptor antagonists (H2RAs) versus placebo or no prophylaxis. We will systematically search the Cochrane Library, MEDLINE, EMBASE, Science Citation Index, BIOSIS, and Epistemonikos for relevant literature. We will follow the recommendations by the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. The risk of systematic errors (bias) and random errors will be assessed, and the overall quality of evidence will be evaluated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DISCUSSION: There is a need for an updated systematic review to summarize the benefits and harms of stress ulcer prophylaxis in critically ill children to inform practice and future research.

Stress Ulcer Prophylaxis in Neurocritical Care.

Stress ulcer prophylaxis (SUP) with acid-suppressive drug therapy is widely utilized in critically ill patients following neurologic injury for the prevention of clinically important stress-related gastrointestinal bleeding (CIB). Data supporting SUP, however, largely originates from studies conducted during an era where practices were vastly different than what is considered routine by today's standard. This is particularly true in neurocritical care patients. In fact, the routine provision of SUP has been challenged due to an increasing prevalence of adverse drug events with acid-suppressive therapy and the perception that CIB rates are sparse. This narrative review will discuss current controversies with SUP as they apply to neurocritical care patients. Specifically, the pathophysiology, prevalence, and risk factors for CIB along with the comparative efficacy, safety, and cost-effectiveness of acid-suppressive therapy will be described.

Gastric Acid Suppression Is Associated with an Increased Risk of Adverse Outcomes in Inflammatory Bowel Disease.

BACKGROUND: The intestinal microbiota may influence inflammatory bowel disease (IBD) activity. Histamine 2 receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) can alter the intestinal microbiota. The aim of this study was to assess the relationship between H2RAs, PPIs, and IBD-related outcomes. METHODS: We conducted a case-control study of IBD patients using the Veterans Health Affairs databases. Cases were defined by their first instance of an IBD-related hospitalization or surgery and the exposure of interest was H2RA or PPI use 30 days prior to the outcome. Incidence density ratios were calculated using conditional logistic regression. RESULTS: In a cohort of 58,459 patients with IBD, we found 4,887 cases and 9,761 controls with ulcerative colitis (UC) and 4,876 cases and 9,745 controls with Crohn disease (CD). Filled prescriptions for H2RAs were associated with an increased risk of IBD-related hospitalization or surgery in CD patients (adjusted incidence density ratio 1.18; 95% CI 1.03-1.34). A similar association was found for PPIs in UC patients (adjusted incidence density ratio 1.11; 95% CI 1.02-1.21) and CD patients (adjusted incidence density ratio 1.12; 95% CI 1.02-1.22). CONCLUSIONS: H2RAs and PPIs were associated with a modestly increased risk of IBD-related hospitalization or surgery.