Low-dose Proton Pump Inhibitors Research Articles

Reduction of Upper Gastrointestinal Bleeding Risk With Proton Pump Inhibitor Therapy in Asian Patients With Atrial Fibrillation Receiving Direct Oral Anticoagulant: A Nationwide Population-based Cohort Study

Background & AimsIn patients with atrial fibrillation (AF) receiving direct oral anticoagulant (DOAC), upper gastrointestinal bleeding (UGIB) is a serious complication. There are limited data on the benefit of preventive proton pump inhibitor (PPI) use to reduce the risk of UGIB in DOAC users. MethodsWe included patients with AF receiving DOAC from 2015 to 2020 based on the Korean Health Insurance Review and Assessment database. The propensity score (PS) weighting method was used to compare patients with PPI use and those without PPI use. The primary outcome was hospitalization for UGIB. Weighted hazard ratios (HR) and corresponding 95% confidence intervals (CI) were evaluated using the Cox proportional hazards regression model. ResultsA total of 165,624 patients were included (mean age: 72±11 years; mean CHA2DS2-VASc score: 4.3±1.8; mean HAS-BLED score: 3.3±1.2). Among them, 99,868 and 65,756 were in the non-PPI group and PPI group, respectively. During a median follow-up of 1.5 years, the PPI group was associated with lower risks of hospitalization for UGIB and UGIB requiring RBC transfusion than non-PPI group [weighted HR (95% CI): 0.825 (0.761-0.894) and 0.798 (0.717-0.887), respectively, both p<0.001]. The benefits of PPI on the risk of hospitalization for UGIB were greater in those with older age (≥75 years), higher HAS-BLED score (≥3), prior UGIB history, and concomitant use of antiplatelet agent (all p-for-interaction<0.1). Low-dose PPI was consistently associated with a lower risk of significant UGIB [adjusted HR: 0.564 (0.504-0.631), p<0.001]. ConclusionsIn this large Asian cohort of patients with AF on DOAC, PPI co-therapy is beneficial for reducing the risk of hospitalization for UGIB, particularly in high-risk patients.

High-dose proton pump inhibitors are associated with hospitalisation in bronchiectasis exacerbation.

BACKGROUND Bronchiectasis is a common respiratory disease complicated by periodic exacerbations. The association with different degrees of gastric acid suppression has not been well studied.METHODS A retrospective cohort study of 350 patients was conducted to investigate the association of different gastric acid suppressants with bronchiectasis exacerbation that required hospitalisation. Components of FACED (FEV1% predicted, age, chronic colonisation by Pseudomonas aeruginosa, radiological extent of the disease, and dyspnoea) were adjusted in multivariate analysis.RESULTS Among patients with exacerbation of bronchiectasis, 52 (14.9%) required hospitalisation. Prescription of a high-dose of proton pump inhibitors (PPI) was associated with increased risk of bronchiectasis exacerbation requiring hospitalisation (adjusted OR 2.77, 95% CI 1.01-7.59; P = 0.05). There was no significant association with use of a histamine-2 receptor antagonist (H2RA) (OR 1.28, 95% CI 0.32-5.06) or low-dose PPI (OR 1.47, 95% CI 0.42-5.13). Nonetheless, patients prescribed a high dose of PPI required a significantly longer hospital stay for exacerbation (13.1 ± 1.4 days) than patients not prescribed a gastric acid suppressant (8.2 ± 2.6 days) or those on a low dose PPI (8.3 ± 1.3 days) and H2RA (6.50 ± 1.50 days).CONCLUSIONS Risk of bronchiectasis exacerbation requiring hospitalisation was increased among high-dose PPI users, but not those prescribed an H2RA or low-dose PPI.

High vs Low Dose Proton Pump Inhibitor (PPI) related Mortality in Hospitalized Coronavirus Disease-19 (COVID-19): A Retrospective Cohort Study

Introduction: The role of proton pump inhibitor (PPI) in Coronavirus Disease-19 (COVID-19) is still debatable. PPI is commonly used to prevent or treat upper gastrointestinal bleeding and/or dyspeptic symptoms. However, previous studies showed that PPI may lead to adverse outcomes in COVID-19 patients, thus the dose of PPI may play an important role. This study aimed to compare the risk of mortality between high vs low dose PPI in hospitalized COVID-19 patients.&#x0D; Methods: We performed retrospective cohort study from two COVID-19 referral centers in Jakarta between June 2021 and September 2021. We included hospitalized COVID-19 patients, moderate-critically ill cases, who had been given intravenous PPI for more than 7 days. We defined high dose PPI for omeprazole &gt;40 mg/day or pantoprazole &gt;40 mg/day, and low dose PPI for omeprazole ≤40 mg/day or pantoprazole ≤40 mg/day.&#x0D; Results: Of the total 365 patients (median age[Q1–Q3] 55 [45–64] years old), 216 subjects were given high dose PPI. Subjects with high dose PPI had a significantly higher mortality rate than the low dose PPI according to bivariate analysis (54.2% vs 26.1%; p&lt;0.001), but quite similar length of stay (median[Q1–Q3] 12.5 [9–16] vs 13 [9–18] days). After conducting a multivariate analysis to control the confounders, we found that high dose PPI still led to higher mortality (aOR 3.04; 95%CI 1.22–7.60; p=0.017).&#x0D; Conclusion: High dose PPI may increase risk of mortality in hospitalized COVID-19 patients.

Effects of high-dose versus low-dose proton pump inhibitors for treatment of gastrointestinal ulcer bleeding: a meta-analysis of randomized controlled trials.

BackgroundWe performed a meta-analysis to compare the effects of high-dose (80 mg/day) versus low-dose (40 mg/day) proton pump inhibitors (PPIs) on gastrointestinal ulcer bleeding.MethodsWe retrieved studies of randomized controlled trials of PPIs administered according to different schedules for the treatment of gastrointestinal ulcer bleeding from Medline, Embase, Web of Science, Clinical Trials, and the Cochrane Database in April 2020.ResultsNine randomized controlled trials including 2329 patients were included in this meta-analysis. There were no significant differences in the incidences of re-bleeding, operation intervention, postoperative mortality, and length of hospital stay between the low-dose and high-dose groups. However, the blood transfusion volume was significantly higher in the high-dose group.ConclusionCompared with low-does PPIs, high-dose PPIs had no effect on the incidence of re-bleeding, operation intervention, or postoperative mortality, and did not reduce hospital stay in patients treated with endoscopic hemostasis for gastrointestinal bleeding.

Effectiveness of PPI treatment and guideline adherence in 236 patients with eosinophilic oesophagitis-Results from the population-based DanEoE cohort shows a low complication rate.

BackgroundProton pump inhibitors (PPIs) are often the first drug of choice in the treatment of eosinophilic oesophagitis (EoE), and in Denmark 8 weeks of high‐dose PPI therapy is recommended as first‐line treatment followed by rebiopsying, reflecting international recommendations.AimsTo assess the population‐based effectiveness of PPIs in the treatment of EoE and evaluate whether patients were treated and followed according to the regional guideline.MethodsThis is a retrospective, registry‐based, DanEoE cohort study of 236 adult EoE patients diagnosed between 2007 and 2017 in the North Denmark Region. After patient file revision, the EoE diagnosis was defined according to the AGREE 2 consensus. Symptomatic PPI response was defined as complete symptom resolution and histological remission (<15 eosinophils per high‐power field).ResultsPPI treatment was initiated in 92% of the EoE patients. High‐ and low‐dose PPIs were prescribed in 55% and 45% of the cases, respectively. When treated with high‐dose PPIs, 68% of the patients were completely symptom‐free, and 49% were in histological remission. In 39% of high‐dose PPI‐treated patients, the symptomatic and histological responses were conflicting. While treated with PPIs, complications were rare, with <5% strictures in responders and <10% in non‐responders. Rebiopsying was done in 67% of the EoE patients started on PPIs.ConclusionsHigh‐dose PPI treatment was effective in half of the EoE patients started on PPIs, but conflicting symptomatic and histological PPI responses were common. Complications were rare when PPIs were started. One‐third of the patients were not rebiopsied as recommended.

Proton-pump inhibitor use and risk of community-acquired pneumonia in congenital heart disease patients

BackgroundAdults with congenital heart disease (CHD) are at elevated risk of hospitalization for community-acquired pneumonia (CAP). Proton-pump inhibitors (PPIs) have been shown to be a risk factor for CAP in adult and pediatric general populations. This study explored the association between PPI use and subsequent CAP hospitalizations in the adult CHD population. MethodsUsing the Danish National Patient Registry, we performed a nested case-control study of adults with CHD who had been admitted to the hospital for CAP between 1996 and 2017. The timing and dose of PPI were evaluated in the year preceding the CAP admission. Logistic regression measured the impact of timing and dose of PPI on the subsequent CAP admission. ResultsIn total, 618 adult CHD patients were admitted for CAP during the study period. The adjusted odds ratio (OR) was 2.21 (95% confidence interval (CI) 1.66–2.94) for CAP in current PPI users compared with non-users. The OR amongst current PPI users was further elevated for males, those older than 65 years old and those with severe/univentricular CHD [3.59 (95% CI 2.33–5.52), 2.30 (95% CI 1.55–3.41), 2.35 (95% CI 1.13–4.87)], respectively. Segmenting by dose, the OR for CAP patients taking low-dose and high-dose PPI was 2.11 (95% CI 1.38–3.22) and 2.29 (95% CI 1.60–3.26), respectively. ConclusionsAdults with CHD prescribed a PPI are at elevated risk of hospitalization for CAP in the following 90 days. The risk for CAP admission is further increased for those prescribed high-dose PPIs, males, those older than 65 years of age, and those with severe/univentricular CHD.

High- versus low-dose proton pump inhibitors post endoscopic hemostasis in hemodialysis cases with peptic ulcer bleeding.

Post-endoscopic hemostasis treatment is not adequately addressed in high-risk patients on regular hemodialysis (HD) with emergency peptic ulcer bleeding. This study aimed to compare post-endoscopic high- versus low-dose proton pump inhibitors (PPIs) for peptic ulcer bleeding in patients undergoing regular HD. This prospective study comprised 200 patients on regular hemodialysis having emergency peptic ulcer bleeding confirmed at endoscopy and managed with endoscopic hemostasis. Half of the patients received high-dose intensive regimen and the other half received the standard regimen. Patients who were suspected to have recurrent bleeding underwent a second endoscopy for bleeding control. The primary outcome measure was rate of recurrent bleeding during period of hospitalization that was detected through second endoscopy. Rebleeding occurred in 32 patients ; 15 in the High-Dose Cohort and 17 in the Low-Dose Control (p = 0.700). No significant differences between the two dose cohorts regarding the time of rebleeding (p = 0.243), endoscopic hemostasis mode (p = 1.000), and need for surgery (p = 0.306). The highdose regimen Inhospital mortality in high-dose group was 9.0% compared to 8.0% in the low-dose group (p = 0.800). Apart from the pre-hemostatic Forrest classification of ulcers, there were no significant differences between patients with re-bleeding ulcers (n=32) and those with non-rebleeding (n=168). Rebleeding was more common in class Ia, i.e. spurting bleeders (p < 0.001). Endoscopic hemostasis followed by the standard low-dose PPI regimen of 40 mg daily IV boluses is safe and effective option for bleeding peptic ulcers in the high-risk patients under regular hemodialysis.

Low-dose PPI to prevent bleeding after ESD: A multicenter randomized controlled study

BackgroundAlthough proton pump inhibitors (PPIs) are widely used in the prevention of gastric bleeding caused by endoscopic submucosal dissection (ESD), there is no consensus on the optimal regimen for these patients. Therefore, we aim to investigate whether intermittent use of low-dose PPI is sufficient to prevent post-ESD bleeding. MethodsThis multicenter, non-inferiority, randomized controlled trial was conducted at 9 hospitals in China. Consecutive eligible patients with a diagnosis of gastric mucosal lesions after ESD treatment were randomly assigned (1:1) to receive either intermittent low-dose or continuous high-dose PPIs treatment. After three days, all patients administered orally esomeprazole 40 mg once a day for 8 weeks. The primary endpoint was post-ESD bleeding within 7 days. Analysis was done according to the intention-to-treat principle with the non-inferiority margin (Δ) of 5%. Results526 consecutive patients were assessed for eligibility from 30 September 2017 to 30 July 2019, of whom 414 were randomly assigned to low-dose (n = 209) or high-dose (n = 205) esomeprazole treatment group without dropouts within7 days. The total post-ESD bleeding is occurred in 13 (6.2 %, 95 % CI 3.3–9.6) of 209 within 7 days in the intermittent low-dose group, and 12 (5.9 %, 95 % CI 2.9–9.3) of 205 in the continuous high-dose group. The absolute risk reduction (ARR) was 0.4 % (−4.2, 4.9). One month after ESD, There are 44 patients (21.1 %, 95 % CI 15.8, 26.8) and 39 patients (19.0 % 95 % CI 13.7, 24.4) in scar stage respectively in low-dose group and high-dose group (P = 0.875).The hospital costs in the low-dose PPI group was lower than high -dose group (P = 0.005). ConclusionThe intermittent use of low-dose PPIs is sufficient to prevent post-ESD bleeding. It might be applied in clinical practice to prevent post-ESD bleeding and reduce the costs related to PPIs.

Systematic review and network meta-analysis: efficacy of drugs for functional dyspepsia.

Functional dyspepsia (FD) is a relapsing and remitting condition affecting between 5% and 10% of people. Efficacious therapies are available, but their relative efficacy is unknown. To perform a systematic review with network meta-analysis to resolve this uncertainty. We searched the medical literature through July 2020 for randomised controlled trials (RCTs) assessing efficacy of drugs for adults with FD, compared with each other, or placebo. Trials reported a dichotomous assessment of symptom status after completion of therapy. We pooled data using a random effects model. Efficacy was reported as a pooled relative risk (RR) of remaining symptomatic with a 95% confidence interval (CI) to summarise efficacy of each comparison tested. Relative ranking was assessed with surface under the cumulative ranking curve (SUCRA) probabilities. We identified 71 eligible RCTs (19243 participants). Tricyclic antidepressants (TCAs) were ranked second for efficacy (RR of remaining symptomatic=0.71; 95% CI 0.58-0.87, SUCRA 0.87), and first when only low risk of bias trials were included. Most RCTs that used TCAs recruited patients who were refractory to other drugs included in the network. Although sulpiride or levosulpiride were ranked first for efficacy (RR=0.49; 95% CI 0.36-0.69, SUCRA 0.99), trial quality was low and only 86 patients received active therapy. TCAs were more likely to cause adverse events than placebo. TCAs, histamine-2 receptor antagonists, standard- and low-dose proton pump inhibitors, sulpiride or levosulpiride, itopride and acotiamide were all more efficacious than placebo for FD.

Proton pump inhibitors for chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a common and progressive disease characterised by chronic cough, airflow limitation and recurrent exacerbations. Since COPD exacerbations are linked to rising mortality and reduced quality of life, the condition poses a substantial burden on individuals, society and the healthcare system. Effective management of COPD exacerbations that includes treatment of related conditions in people with COPD is thus recognised as a relevant clinical question and an important research topic. Gastroesophageal reflux disease (GERD) is a known comorbidity of COPD, and pulmonary microaspiration of gastric acid is thought to be a possible cause of COPD exacerbations. Therefore, reducing gastric acid secretion may lead to a reduction in COPD exacerbations. Proton pump inhibitors (PPIs) are one of the most commonly prescribed medications and are recommended as first-line therapy for people with GERD because of their inhibitory effects on gastric acid secretion. Treatment with PPIs may present a viable treatment option for people with COPD. To evaluate the efficacy and safety of PPI administration for people with COPD, focusing on COPD-specific outcomes. We searched the Cochrane Airways Register of Trials and conventional clinical trial registers from inception to 22 May 2020. We also screened bibliographies of relevant studies. Parallel-group and cluster-randomised controlled trials (RCTs) that compared oral PPIs versus placebo, usual care or low-dose PPIs in adults with COPD were eligible for inclusion. We excluded cross-over RCTs, as well as studies with a duration of less than two months. Two independent review authors screened search results, selected studies for inclusion, extracted study characteristics and outcome data, and assessed risk of bias according to standard Cochrane methodology. We resolved discrepancies by involving a third review author. Primary outcomes of interest were COPD exacerbations, pneumonia and other serious adverse events. Secondary outcomes were quality of life, lung function test indices, acute respiratory infections and disease-specific adverse events. We extracted data on these outcome measures and entered into them into Review Manager software for analysis. The search identified 99 records, and we included one multicentre RCT that randomised 103 adults with COPD. The 12-month RCT compared an oral PPI (lansoprazole) and usual care versus usual care alone. It was conducted at one tertiary care hospital and three secondary care hospitals in Japan. This study recruited participants with a mean age of 75 years, and excluded people with symptoms or history of GERD. No placebo was used in the usual care arm. Among the primary and secondary outcomes of this review, the study only reported data on COPD exacerbations and acute respiratory infections (the common cold). As we only included one study, we could not conduct a meta-analysis. The included study reported that 12 of the 50 people on lansoprazole had at least one exacerbation over a year, compared to 26 out of 50 on usual care (risk ratio 0.46, 95% CI 0.26 to 0.81). The frequency of COPD exacerbations per person in a year was also lower in the PPI plus usual care group than in the usual care alone group（0.34 ± 0.72 vs 1.18 ± 1.40; P < 0.001). The number of people with at least one cold over the year was similar in both groups: 26 people on lansoprazole and 27 people in the usual care group. We judged the evidence to be of low to very low certainty, according to GRADE criteria. The study reported no data on pneumonia and other serious adverse events, quality of life, lung function test indices or disease-specific adverse events. The risk of bias was largely low or unclear for the majority of domains, though the performance bias was a high risk, as the study was not blinded. Evidence identified by this review is insufficient to determine whether treatment with PPIs is a potential option for COPD. The sample size of the included trial is small, and the evidence is low to very low-certainty. The efficacy and safety profile of PPIs for people with COPD remains uncertain. Future large-scale, high-quality studies are warranted, which investigate major clinical outcomes such as COPD exacerbation rate, serious adverse events and quality of life.

Practice Advisory on the Appropriate Use of NSAIDs in Primary Care.

Cyclo-oxygenase (COX)-2 selective and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs) are important in managing acute and chronic pain secondary to inflammation. As a greater understanding of the risks of gastrointestinal (GI), cardiovascular (CV) and renal events with NSAIDs use has emerged, guidelines have evolved to reflect differences in risks among NSAIDs. Updated guidelines have yet to reflect new evidence from recent trials which showed similar CV event rates with celecoxib compared to naproxen and ibuprofen, and significantly better GI tolerability for celecoxib. This practice advisory paper aims to present consensus statements and associated guidance regarding appropriate NSAID use based on a review of current evidence by a multidisciplinary group of expert clinicians. This paper is especially intended to guide primary care practitioners within Asia in the appropriate use of NSAIDs in primary care. Following a literature review, group members used a modified Delphi consensus process to determine agreement with selected recommendations. Agreement with a statement by 75% of total voting members was defined a priori as consensus. For low GI risk patients, any nonselective NSAID plus proton pump inhibitor (PPI) or celecoxib alone is acceptable treatment when CV risk is low; for high CV risk patients, low-dose celecoxib or naproxen plus PPI is appropriate. For high GI risk patients, celecoxib plus PPI is acceptable for low CV risk patients; low-dose celecoxib plus PPI is appropriate for high CV risk patients, with the alternative to avoid NSAIDs and consider opioids instead. Appropriate NSAID prescription assumes that the patient has normal renal function at commencement, with ongoing monitoring recommended. In conclusion, appropriate NSAID use requires consideration of all risks.

Chemoprevention of esophageal adenocarcinoma.

Esophageal adenocarcinoma (EAC) is a major cause of cancer-related death, particularly in Western populations, and is rapidly rising in Asian populations at this time. Virtually all EACs develop from the precursor lesion Barrett’s esophagus (BE), which is the most significant risk factor for EAC. However, the rates of progression from BE to EAC are low and patients with BE are asymptomatic. Thus, any strategy for EAC prevention must carry a low risk of harm in order to be clinically useful. Since current EAC-screening and BE-surveillance methods carry some procedural risk and are burdensome, there is an opportunity for chemoprevention, i.e. medications or dietary factors that may prevent BE from progressing to EAC. A variety of candidate chemoprevention therapies have been assessed to date. Proton-pump inhibitors (PPIs) are the best studied and have modest EAC-chemoprevention efficacy in BE patients, with a recent randomized trial showing that high-dose PPI may be more effective than low-dose PPI. Aspirin and other non-steroidal anti-inflammatory drugs have moderate quality observational and randomized-trial evidence for preventing progression of BE to EAC, but their risks for harm have precluded their routine clinical use. Other therapies (statins, metformin, female sex hormones) generally do not have strong evidence to support their use in EAC chemoprevention. Although progress has been made in this field, there is still a need for more effective and safe chemoprevention therapies for EAC.

Consumption of medicines used for gastric acid-related disorders in Australia and South Korea: a cross-country comparison

The study's aim was to compare the use of proton pump inhibitors (PPIs), histamine 2-receptor antagonists (H2RAs) and mucoprotective medicines (MPs) used for gastric acid-related disorders (GARD) in Australia and South Korea (Korea) from 2004 to 2017. Prescription data for PPIs, H2RAs and MPs for Australian outpatients were extracted from the Australian Statistics on Medicines annual reports, with dose-specific and expenditure data obtained from Medicare. Similar data were obtained from Korean National Health Insurance Service claims data. We analysed the volume and expenditure of medicines use annually using the defined daily dose per 1,000 population per day. We calculated which medicines accounted for 90% of use and estimated the proportions of use for low- and high-dose PPIs. While total utilisation for GARD medicines increased over time in both countries, patterns of use differed. Overall, use was somewhat higher in Australia but increased more rapidly in Korea. PPIs were used more extensively in Australia, while more MPs and H2RAs were used in Korea. Expenditure and use of low-dose PPIs is escalating in Korea. There were substantial differences in the use of GARD medicines in Australia and Korea over 14years. Both countries face similar challenges to promote rational medicines use and contain medical care costs. The discrepant prescribing patterns can be attributed to differences in healthcare systems, pharmaceutical policies and demographics. This study provides a baseline to influence more rational use of these medicines. It provides insight into medicines policies for other countries that face similar challenges.

Efficacy of Low Dose Proton Pump Inhibitor-Based Therapy to Eradicate Helicobacter pylori in Patients with Subtotal Gastrectomy.

Proton pump inhibitor (PPI)-based therapy is standard to eradicate Helicobacter pylori (H. pylori). Gastric acidity is lowered after gastrectomy because of bile reflux and impaired mechanism of acid secretion. Therefore, low-dose PPI may be effective for H. pylori eradication in the remnant stomach after gastrectomy. In this study, we compared the efficacy of low-dose PPI with standard double-dose PPI to eradicate H. pylori in patients who underwent subtotal gastrectomy. A total of 145 patients who were treated for eradication after gastrectomy was analyzed. They were treated with PPI-based triple regimen (PPI, clarithromycin and amoxicillin) for 14 days. We compared the eradication rate in the low-dose PPI group (lansoprazole 15 mg once daily) with that in the standard double-dose PPI group (lansoprazole 30 mg twice daily). The H. pylori eradication rate was 79.1% in the low-dose PPI group and 85.3% in the standard double-dose group; the difference was not significant statistically (p = 0.357). In the multivariate analysis, low-dose PPI (odds ratio (OR) = 1.79, 95% confidence interval (CI), 0.68–4.69) was not associated with eradication failure, while Billroth II anastomosis (OR = 4.45, 85% CI, 1.23–16.2) was significantly associated with eradication failure. Low-dose PPI-based triple regimen was as effective as standard double-dose PPI-based regimen for H. pylori eradication in patients with subtotal gastrectomy. Further study is needed to confirm the effect of low-dose PPI on H. pylori eradication in patients with gastrectomy.

Proton pump inhibitors and hypomagnesemia: A meta-analysis of observational studies.

Previous meta-analyses have suggested that there might be an association between the use of proton pump inhibitors (PPIs) and the development of hypomagnesemia, although the conclusions were no definitive. To provide an update on this topic, we performed a meta-analysis of all observational studies that examined the association between the use of PPIs and the development of hypomagnesemia. A literature search was conducted in MEDLINE, Scopus and Cochrane Central Register of Controlled Trials (January 1970 to June 2018) to identify observational studies that examined the association between the use of PPIs and the incidence and prevalence of hypomagnesemia. In the absence of randomized controlled trials, we focused primarily on observational studies, including cross-sectional, case-control, retrospective, and prospective cohort studies. There was no limitation on sample size or study duration. Random-effect models meta-analyses were used to compute pooled unadjusted and adjusted odds ratios (ORs) for binary variables. Sixteen observational studies were identified, including 13 cross-sectional studies, 2 case-control studies, and 1 cohort study, with a total of 131,507 patients. The pooled percentage of PPI users was 43.6% (95% confidence interval [CI] 25.0%, 64.0%). Among PPI users, 19.4% (95% CI 13.8%, 26.5%) had hypomagnesemia compared to 13.5% (95% CI 7.9%, 22.2%) among nonusers. By meta-analysis, PPI use was significantly associated with hypomagnesemia, with a pooled unadjusted OR of 1.83 (95% CI 1.26, 2.67; P = .002) and a pooled adjusted OR of 1.71 (95% CI 1.33, 2.19; P < .001). In subgroup analyses, high-dose PPI use was associated with higher odds for hypomagnesemia relative to low-dose PPI use (pooled adjusted OR 2.13; 95% CI 1.26, 3.59; P = .005). Our findings are in support of the results of the previous meta-analyses. Furthermore, we found a dose-response between the PPI use and development of hypomagnesemia.

Higher dose but not low dose proton pump inhibitors are associated with increased risk of subsequent hip fractures after first hip fracture: A nationwide observational cohort study

AimTo examine the association of proton pump inhibitor (PPI) use with subsequent hip fracture incidence in hip fracture patients, accounting for gender, age, PPI doses, PPI initiation before or after first fracture, and year from first fracture in which the first subsequent fracture occurred. MethodsData from 31,668 Austrian patients ≥50 years with the first hip fracture between July 2008 and December 2010 were analyzed retrospectively. After exclusion of patients on anti-osteoporotic medication, incidence of subsequent hip fractures was compared between users and non-users of PPIs using regression models. ResultsIn general, use of PPIs among hip fracture patients was associated with increased risk for subsequent hip fracture (OR 1.58, 95%-CI 1.25–2.00), in particular in men, in the age group of 70–84 years, and when PPIs were initiated before the first fracture. Low PPI doses of ≤90 cumulative DDDs and ≤0.25 DDDs/day, however, were not linked to elevated subsequent fracture risk, especially among female patients. Subsequent hip fracture incidence was elevated within the first year after first fracture in female and male PPI users (OR 1.75, 95%-CI 1.28–2.38) and dropped in women but not in men in the second year. ConclusionsLow-dose PPI use is not associated with increased risk of subsequent hip fractures, especially in women. Patients thus get most benefit of short-term PPI use after a hip fracture that has previously been linked to lowered mortality if low doses are not exceeded. Varying risk profiles for the time of subsequent hip fracture could have implications for risk group-specific follow-up care.

Efficacy and Pharmacokinetics of Glecaprevir and Pibrentasvir With Concurrent Use of Acid-Reducing Agents in Patients With Chronic HCV Infection

Proton pump inhibitors (PPIs) are commonly prescribed to treat acid-related disorders. Some direct-acting antiviral regimens for chronic hepatitis C virus (HCV) infection have reduced efficacy in patients taking concomitant acid-reducing agents, including PPIs, due to interactions between drugs. We analyzed data from 9 multicenter, phase 2 and 3 trials to determine the efficacy and pharmacokinetics of an HCV therapeutic regimen comprising glecaprevir and pibrentasvir (glecaprevir/pibrentasvir) in patients taking concomitant acid-reducing agents. We analyzed data from 2369 patients infected with HCV genotypes 1-6 and compensated liver disease treated with an all-oral regimen of glecaprevir/pibrentasvir for 8-16 weeks. We compared efficacy and pharmacokinetics among patients receiving at least 1 dose of an acid-reducing agent (a PPI, an H2 blocker, or antacid). High-dose PPI was defined as daily dose greater than 20 mg omeprazole dose equivalent. The objectives were to evaluate rate of sustained virologic response 12 weeks post-treatment (SVR12) and to assess steady-state glecaprevir and pibrentasvir exposures in patients on acid-reducing agents. Of the 401 patients (17%) who reported use of acid-reducing agents, 263 took PPIs (11%; 109 patients took a high-dose PPI and 154 patients took a low-dose PPI). Rates of SVR12 were 97.0% among patients who used acid-reducing agents and 97.5% among those not using acid-reducing agents (P= .6). An SVR12 was achieved in 96.3% taking a high-dose PPI and 97.4% taking a low-dose PPI, with no virologic failures in those receiving a high-dose PPI (P= .7). Glecaprevir, but not pibrentasvir, bioavailability was affected; its exposure decreased by 41% in patients taking a high-dose PPI. In an analysis of data from 9 clinical trials, we observed a high rate of SVR12 (approximately 97%) among patients treated with glecaprevir/pibrentasvir for HCV infection-even among patients taking concomitant ARA or high-dose PPI. This was despite decreased glecaprevir exposures in patients when on high-dose PPIs. ClinicalTrials.gov numbers, NCT02243280 (SURVEYOR-I), NCT02243293 (SURVEYOR-II), NCT02604017 (ENDURANCE-1), NCT02640482 (ENDURANCE-2), NCT02640157 (ENDURANCE-3), NCT02636595 (ENDURANCE-4), NCT02642432 (EXPEDITION-1), NCT02651194 (EXPEDITION-4), NCT02446717 (MAGELLAN-I).

Esomeprazole and aspirin in Barrett's oesophagus (AspECT): a randomised factorial trial

SummaryBackgroundOesophageal adenocarcinoma is the sixth most common cause of cancer death worldwide and Barrett's oesophagus is the biggest risk factor. We aimed to evaluate the efficacy of high-dose esomeprazole proton-pump inhibitor (PPI) and aspirin for improving outcomes in patients with Barrett's oesophagus.MethodsThe Aspirin and Esomeprazole Chemoprevention in Barrett's metaplasia Trial had a 2 × 2 factorial design and was done at 84 centres in the UK and one in Canada. Patients with Barrett's oesophagus of 1 cm or more were randomised 1:1:1:1 using a computer-generated schedule held in a central trials unit to receive high-dose (40 mg twice-daily) or low-dose (20 mg once-daily) PPI, with or without aspirin (300 mg per day in the UK, 325 mg per day in Canada) for at least 8 years, in an unblinded manner. Reporting pathologists were masked to treatment allocation. The primary composite endpoint was time to all-cause mortality, oesophageal adenocarcinoma, or high-grade dysplasia, which was analysed with accelerated failure time modelling adjusted for minimisation factors (age, Barrett's oesophagus length, intestinal metaplasia) in all patients in the intention-to-treat population. This trial is registered with EudraCT, number 2004-003836-77.FindingsBetween March 10, 2005, and March 1, 2009, 2557 patients were recruited. 705 patients were assigned to low-dose PPI and no aspirin, 704 to high-dose PPI and no aspirin, 571 to low-dose PPI and aspirin, and 577 to high-dose PPI and aspirin. Median follow-up and treatment duration was 8·9 years (IQR 8·2–9·8), and we collected 20 095 follow-up years and 99·9% of planned data. 313 primary events occurred. High-dose PPI (139 events in 1270 patients) was superior to low-dose PPI (174 events in 1265 patients; time ratio [TR] 1·27, 95% CI 1·01–1·58, p=0·038). Aspirin (127 events in 1138 patients) was not significantly better than no aspirin (154 events in 1142 patients; TR 1·24, 0·98–1·57, p=0·068). If patients using non-steroidal anti-inflammatory drugs were censored at the time of first use, aspirin was significantly better than no aspirin (TR 1·29, 1·01–1·66, p=0·043; n=2236). Combining high-dose PPI with aspirin had the strongest effect compared with low-dose PPI without aspirin (TR 1·59, 1·14–2·23, p=0·0068). The numbers needed to treat were 34 for PPI and 43 for aspirin. Only 28 (1%) participants reported study-treatment-related serious adverse events.InterpretationHigh-dose PPI and aspirin chemoprevention therapy, especially in combination, significantly and safely improved outcomes in patients with Barrett's oesophagus.FundingCancer Research UK, AstraZeneca, Wellcome Trust, and Health Technology Assessment.

686 - Risk of Both upper and Lower Gastrointestinal Bleeding Associated with Low-Dose Acetylsalicylic Acid and Proton Pump Inhibitors Among Nearly 400,000 Individuals in Routine General Practice in the United Kingdom

686 - Risk of Both upper and Lower Gastrointestinal Bleeding Associated with Low-Dose Acetylsalicylic Acid and Proton Pump Inhibitors Among Nearly 400,000 Individuals in Routine General Practice in the United Kingdom

Proton pump inhibitors for functional dyspepsia.

Functional dyspepsia (FD or non-ulcer dyspepsia) is defined as continuous or frequently recurring epigastric pain or discomfort for which no organic cause can be found. Acid suppressive therapy, including proton pump inhibitors (PPIs), has been proposed as a therapeutic option in FD, but its efficacy remains controversial. While PPIs are generally considered safe and well tolerated, they have been associated with adverse events, especially in the long term. For this reason, decisions on whether to initiate or continue PPI therapy should be made based on an appropriate clinical indication. Therefore, we conducted a systematic review to evaluate whether PPI therapy provides symptomatic relief in FD. To determine the efficacy of proton pump inhibitors in the improvement of global symptoms of dyspepsia and quality of life compared to placebo, H2 receptor antagonists or prokinetics, in people with functional dyspepsia. We searched in the following electronic databases: the Cochrane Library (to May 2017), MEDLINE (OvidSP; to May 2017), Embase (OvidSP; to May 2017), and SIGLE grey literature (up to May 2017) and clinical trial registries; we handsearched abstracts from conferences up to May 2017. We screened non-systematic reviews, systematic reviews and guidelines to identify any additional trials. We contacted trialists to obtain missing information. All randomized controlled trials (RCTs) comparing any PPI with placebo, H2 receptor antagonists (H2RAs) or prokinetics for the treatment of FD of at least two weeks' duration. Participants were adults (aged 16 years or greater) with an adequate diagnosis of FD (any validated criteria such as Rome I, II, III or Lancet Working Group). Two review authors independently assessed eligibility and trial quality, and extracted data. We collected data on dyspeptic symptoms, quality of life and number of overall adverse events. Specific adverse events werebeyond the scope of this review. We identified 25 RCTs from 27 papers (with 8453 participants) studying the effect of PPIs versus placebo, H2RAs or prokinetics for improvement of global symptoms of dyspepsia and quality of life in people with FD. Low-dose PPIs had similar efficacy as standard-dose PPIs, therefore we combined these subgroups for the analysis. PPI was more effective than placebo at relieving overall dyspepsia symptoms in people with FD (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.82 to 0.94; participants = 6172; studies = 18; number needed to treat for an additional beneficial outcome (NNTB) 11; moderate quality evidence). PPIs may have little or no effect compared with H2RAs (RR 0.88, 95% CI 0.74 to 1.04; participants = 740; studies = 2; low quality evidence), and may be slightly more effective than prokinetics (RR 0.89, 95% CI 0.81 to 0.99; participants = 1033; studies = 5; NNTB 16; low quality evidence) at relieving overall dyspepsia symptoms in people with FD. PPIs plus prokinetics have probably little or no effect compared with PPIs alone at relieving overall dyspepsia symptoms (RR 0.85, 95% CI 0.68 to 1.08; participants = 407; studies = 2; moderate quality evidence).There was no difference when subgrouped by Helicobacter pylori status, country of origin, or presence of reflux or Rome III subtypes. There were no differences in the number of adverse events observed between PPIs and any of the other treatments. There were fewer adverse events in the combination of PPI plus prokinetics compared to prokinetics alone (RR 0.60, 95% CI 0.39 to 0.93; participants = 407; studies = 2; moderate quality evidence). There is evidence that PPIs are effective for the treatment of FD, independent of the dose and duration of treatment compared with placebo. PPIs may be slightly more effective than prokinetics for the treatment of FD; however, the evidence is scarce. The trials evaluating PPIs versus prokinetics are difficult to interpret as they are at risk of bias. Although the effect of these drugs seems to be small, the drugs are well tolerated.