Short-term Proton Pump Inhibitor Research Articles

The impact of proton pump inhibitors on brain health based on cross-sectional findings from the Rhineland Study

Reports linking proton pump inhibitors (PPIs) with cognition and dementia show conflicting results, with limited evidence on underlying biological mechanisms. However, existing studies did not investigate brain microstructure, which could provide valuable insights into early structural changes indicative of cognitive decline. Analyses were based on cross-sectional baseline data from the Rhineland Study (n = 7,465; mean age 55.3 ± 13.7 years, range 30–95 years, 56.5% women). Using multivariate linear regression, we investigated associations between PPI use and cognition and brain macro- and microstructural measures (fractional anisotropy (FA) and mean diffusivity (MD) as measures of white matter integrity). Analyses were stratified by short-term (< 3 years) and long-term (≥ 3 years) PPI use, with additional age stratification (< 65 years; ≥65 years) for cognitive outcomes. PPI users, especially younger individuals, showed poorer global cognition and working memory. Notably, younger long-term users had worse total memory. PPI use was not associated with brain volume or FA, but both short-term and long-term users showed higher MD in cognitive-related brain regions. Our findings indicate that prolonged PPI use, particularly in younger long-term users, is associated with poorer cognitive performance. Moreover, PPI users showed higher MD, indicating potential white matter integrity disruptions. Further research is needed to ascertain causality and underlying mechanisms behind PPI-related cognitive decline.

Characterization of intestine-specific TRPM6 knockout C57BL/6J mice: effects of short-term omeprazole treatment.

The transient receptor potential melastatin type 6 (TRPM6) is a divalent cation channel pivotal for gatekeeping Mg2+ balance. Disturbance in Mg2+ balance has been associated with the chronic use of proton pump inhibitors (PPIs) such as omeprazole. In this study, we investigated if TRPM6 plays a role in mediating the effects of short-term (4days) omeprazole treatment on intestinal Mg2+ malabsorption using intestine-specific TRPM6 knockout (Vill1-TRPM6-/-) mice. To do this, forty-eight adult male C57BL/6J mice (50% TRPM6fl/fl and 50% Vill1-TRPM6-/-) were characterized, and the distal colon of these mice was subjected to RNA sequencing. Moreover, these mice were exposed to 20mg/kg bodyweight omeprazole or placebo for 4days. Vill1-TRPM6-/- mice had a significantly lower 25Mg2+ absorption compared to control TRPM6fl/fl mice, accompanied by lower Mg2+ serum levels, and urinary Mg2+ excretion. Furthermore, renal Slc41a3, Trpm6, and Trpm7 gene expressions were higher in these animals, indicating a compensatory mechanism via the kidney. RNA sequencing of the distal colon revealed a downregulation of the Mn2+ transporter Slc30a10. However, no changes in Mn2+ serum, urine, and feces levels were observed. Moreover, 4days omeprazole treatment did not affect Mg2+ homeostasis as no changes in serum 25Mg2+ and total Mg2+ were seen. In conclusion, we demonstrate here for the first time that Vill1-TRPM6-/- mice have a lower Mg2+ absorption in the intestines. Moreover, short-term omeprazole treatment does not alter Mg2+ absorption in both Vill1-TRPM6-/- and TRPM6fl/fl mice. This suggests that TRPM6-mediated Mg2+ absorption in the intestines is not affected by short-term PPI administration.

Short-term usage of proton pump inhibitors during admission was associated with increased risk of rehospitalization in critically ill patients with myocardial infarction: a cohort study.

Previous studies showed that long-term use of proton pump inhibitors (PPIs) was associated with cardiovascular events. However, the impact of short-term PPI exposure on intensive care unit (ICU) patients with myocardial infarction (MI) remains largely unknown. This study aims to determine the precise correlation between short-term PPI usage during hospitalization and prognostic outcomes of ICU-admitted MI patients using Medical Information Mart for Intensive Care IV database (MIMIC-IV). Propensity score matching (PSM) was applied to adjust confounding factors. The primary study outcome was rehospitalization with mortality and length of stay as secondary outcomes. Binary logistic, multivariable Cox, and linear regression analyses were employed to estimate the impact of short-term PPI exposure on ICU-admitted MI patients. A total of 7249 patients were included, involving 3628 PPI users and 3621 non-PPI users. After PSM, 2687 pairs of patients were matched. The results demonstrated a significant association between PPI exposure and increased risk of rehospitalization for MI in both univariate and multivariate [odds ratio (OR) = 1.157, 95% confidence interval (CI) 1.020-1.313] analyses through logistic regression after PSM. Furthermore, this risk was also observed in patients using PPIs > 7days, despite decreased risk of all-cause mortality among these patients. It was also found that pantoprazole increased the risk of rehospitalization, whereas omeprazole did not. Short-term PPI usage during hospitalization was still associated with higher risk of rehospitalization for MI in ICU-admitted MI patients. Furthermore, omeprazole might be superior to pantoprazole regarding the risk of rehospitalization in ICU-admitted MI patients.

Amelioration of obsessive-compulsive disorder by intracellular acidification of cortical neurons with a proton pump inhibitor

Obsessive-compulsive disorder (OCD) is a highly prevalent neuropsychiatric disorder poorly controlled with pharmacological treatment because of the wide variation in symptom patterns. We analysed real-world data on adverse self-reports and insurance claims to identify a novel therapeutic target for OCD. We found that dopamine D2 receptor (D2R) agonists increased the incidence of OCD-like symptoms, which were suppressed by the concomitant use of proton pump inhibitors (PPIs). Further, OCD-like repetitive and habitual behaviours were observed in mice repeatedly injected with a D2R agonist, quinpirole. However, these abnormalities were suppressed by short-term PPI treatment. In quinpirole-treated mice, PPI inhibited pyramidal neuron hyperactivity in the lateral orbitofrontal cortex, a region where the P-type proton pump gene Atp4a is abundantly expressed. In primary cultured cortical neurons, short-term PPI treatment lowered intracellular pH and decreased firing activity, which was mimicked by Atp4a knockdown. Our findings show that inhibition of P-type proton pumps may be a novel therapeutic strategy for OCD.

Proton pump inhibitors induced fungal dysbiosis in patients with gastroesophageal reflux disease.

Gut mycobiota inhabits human gastrointestinal lumen and plays a role in human health and disease. We investigated the influence of proton pump inhibitors (PPIs) on gastric mucosal and fecal mycobiota in patients with gastroesophageal reflux diseases (GERD) by using Internal Transcribed Spacer 1 sequencing. A total of 65 participants were included, consisting of the healthy control (HC) group, GERD patients who did not use PPIs (nt-GERD), and GERD patients who used PPIs, which were further divided into short-term (s-PPI) and long-term PPI user (l-PPI) groups based on the duration of PPI use. The alpha diversity and beta diversity of gastric mucosal mycobiota in GERD patients with PPI use were significantly different from HCs, but there were no differences between s-PPI and l-PPI groups. LEfSe analysis identified Candida at the genus level as a biomarker for the s-PPI group when compared to the nt-GERD group. Meanwhile, Candida, Nothojafnea, Rhizodermea, Ambispora, and Saccharicola were more abundant in the l-PPI group than in the nt-GERD group. Furthermore, colonization of Candida in gastric mucosa was significantly increased after PPI treatment. However, there was no significant difference in Candida colonization between patients with endoscopic esophageal mucosal breaks and those without. There were significant differences in the fecal mycobiota composition between HCs and GERD patients regardless whether or not they used PPI. As compared to nt-GERD patient samples, there was a high abundance of Alternaria, Aspergillus, Mycenella, Exserohilum, and Clitopilus in the s-PPI group. In addition, there was a significantly higher abundance of Alternaria, Aspergillus, Podospora, Phallus, and Monographella in the l-PPI group than nt-GERD patients. In conclusion, our study indicates that dysbiosis of mycobiota was presented in GERD patients in both gastric mucosal and fecal mycobiota. PPI treatment may increase the colonization of Candida in the gastric mucosa in GERD patients.

Risk factors of active upper gastrointestinal bleeding in patients with COVID-19 infection and the effectiveness of PPI prophylaxis

BackgroundGastrointestinal (GI) bleeding is one of the most impactful complications in patients hospitalized from COVID-19 infection. Limited study has focused on patients with upper GI bleeding (UGIB). This study aimed to identify the risk factors of patients who were hospitalized from COVID-19 infection and developed UGIB as well as the effectiveness of proton pump inhibitor (PPI) prophylaxis in those patients.MethodsThis study was comprised of two phases. The first phase was the retrospective enrollment of patients who were admitted due to COVID-19 infection and developed UGIB between April and August 2021 to evaluate the associated factors of active UGIB. The second phase was a retrospective analysis after PPI prophylaxis protocol from September – October 2021 to assess the benefit of PPI use in those patients.ResultsOf 6,373 patients hospitalized, 43 patients (0.7%) had evidence of UGIB. The majority were male 28 (65.1%) with a mean age of 69.1 ± 11.8 years. Twenty-four of 43 patients (55.8%) needed mechanical ventilation, 35 patients (81.4%) received systemic corticosteroids, and 10 patients (23.3%) were taking anticoagulants for venous thromboembolic prophylaxis. Seven of 43 patients (16%) had active UGIB. There was no significant difference in the number of patients taking antiplatelets, anticoagulants, or steroids and the severity of COVID-19 infection between the two groups. An emergency endoscopy or endoscopic hemostasis were performed in 6/7 (85.7%) patients. The multivariate logistic regression analysis revealed two significant factors associated with active UGIB including higher of Glasgow-Blatchford score (GBS) per point (OR = 7.89; 95%CI 1.03–72.87; p = 0.04) and an absence of PPI use (OR 4.29; 95%CI 1.04–19.51; p = 0.04). After prescribing PPI as a prophylaxis, there was a slightly lower incidence of UGIB (0.6% vs 0.7%) in addition to an absence of active UGIB (0% vs 16%).ConclusionOur study demonstrated that the absence of PPI and higher GBS were significant risk factors for active UGIB which required therapeutic endoscopy in patients with COVID-19 infection. We suggest that short-term PPI prophylaxis should be prescribed in those patients once they need hospitalization regardless of the severity of COVID-19 infection to minimize the severity of UGIB.

Pantoprazole-Associated Thrombocytopenia: A Literature Review and Case Report

Proton-pump inhibitors (PPIs) are commonly utilized in the treatment of upper gastrointestinal bleeds (UGIBs) due to their ability to stabilize blood clot formation. PPIs have been shown to reduce rebleeding after endoscopic hemostasis and reduce signs of bleeding at index endoscopy. While PPIs are well-tolerated and commonly administered to patients suffering from acute UGIBs, significant adverse effects may occur. Patients have reported various mild systemic symptoms during short-term PPI use, including headache, rash, dizziness, nausea, abdominal pain, flatulence, constipation, and diarrhea. In general, serious side effects of PPIs tend to be mild during treatment periods under two weeks; however, as the treatment duration increases, side effects have been observed to increase in frequency and severity. PPI-induced thrombocytopenia is an exceedingly rarely reported adverse reaction that remains largely unstudied due to the dearth of patient cases. This adverse effect continues to be a diagnosis of exclusion, and there are no current evidence-based recommendations to approach this complication. Thrombocytopenia increases the risk of rebleeding and hemodynamic instability, which may be devastating to patients suffering from UGIBs. Here, we present a case of thrombocytopenia that began after the introduction of pantoprazole in the setting of a UGIB. The thrombocytopenia resolved promptly after cessation of the medication. We highlight this case to increase awareness of this rare finding given the lack of recommendations for short-term PPI-induced thrombocytopenia.

The effect of gastric acid suppression on probiotic colonization in a double blinded randomized clinical trial.

Probiotics contain living microorganisms consumed for their putative benefits on the intestinal microbiota and general health and a concept is emerging to use probiotic as a therapeutic intervention to reduce proton pump inhibitors (PPIs) negative effects, but data is lacking. The use of PPIs can result in disordered gut microbiota, leading to a risk of enteric infections. PPIs are frequently prescribed in the general practice setting for gastroesophageal reflux disease (GERD), peptic ulcer disease, and related conditions. Despite the availability and widespread use of probiotics and acid-suppressing medications, the effect of PPIs-induced gastric acid suppression on the survival and colonization of probiotics bacterial species is currently unclear. We hypothesized that gastric acid suppression may improve intestinal colonization of probiotics bacterial species and probiotic intervention may have a potential role in mitigating untoward effects of PPI. In a randomized, double-blind, placebo-controlled study, healthy subjects were given either proton pump inhibitor (PPI, n=15) or placebo (n=15) over 6 weeks. All subjects then consumed multi-strain probiotics from weeks 2-6. Thirty participants (10 males, 20 females, age range: 18-56 years) were enrolled in the study. Shotgun metagenomic sequencing and untargeted metabolomics analyses were performed on stool samples collected at week 0, 2, and 6. Short term PPI treatment increased the microbial abundance of Streptococcaceae (p=0.004), Leuconostacaceae (p=0.001), and Pasteurellaceae (p=0.020) at family level and corresponding genus levels. The metabolomic analysis of the stools revealed a change in 10 metabolites where Gly Arg Val and phenylacetic acid were consistently increased compared to the baseline. Probiotic intervention inhibited PPI-induced microbial changes such as a decrease in Leuconostacaceae family (p=0.01) and led to an increase in metabolite 1H-Indole-4-carbaldehyde. Notably, PPI enhanced the colonization of certain probiotic bacterial species like Streptococcus thermophilus (p<0.05) along with other species present in the multi-strain probiotic. Acid suppression enhanced certain probiotic associated bacterial colonization and probiotics in turn suppressed PPI-mediated intestinal microbial alterations. Thus, probiotics in combination with PPI might be a beneficial strategy that allows probiotic colonization and suppress PPI-induced microbial perturbations. CLINICAL TRIALS. NCT03327051.

Duodenal Dysbiosis and Relation to the Efficacy of Proton Pump Inhibitors in Functional Dyspepsia.

Proton pump inhibitors (PPI) may improve symptoms in functional dyspepsia (FD) through duodenal eosinophil-reducing effects. However, the contribution of the microbiome to FD symptoms and its interaction with PPI remains elusive. Aseptic duodenal brushings and biopsies were performed before and after PPI intake (4 weeks Pantoprazole 40 mg daily, FD-starters and controls) or withdrawal (2 months, FD-stoppers) for 16S-rRNA sequencing. Between- and within-group changes in genera or diversity and associations with symptoms or duodenal factors were analyzed. In total, 30 controls, 28 FD-starters and 19 FD-stoppers were followed. Mucus-associated Porphyromonas was lower in FD-starters vs. controls and correlated with symptoms in FD and duodenal eosinophils in both groups, while Streptococcus correlated with eosinophils in controls. Although clinical and eosinophil-reducing effects of PPI therapy were unrelated to microbiota changes in FD-starters, increased Streptococcus was associated with duodenal PPI effects in controls and remained higher despite withdrawal of long-term PPI therapy in FD-stoppers. Thus, duodenal microbiome analysis demonstrated differential mucus-associated genera, with a potential role of Porphyromonas in FD pathophysiology. While beneficial effects of short-term PPI therapy were not associated with microbial changes in FD-starters, increased Streptococcus and its association with PPIeffects in controls suggest a role for duodenal dysbiosis after long-term PPI therapy.

Chronic Course, Weaning, and Awareness of Patients With Reflux Toward Proton Pump Inhibitor Therapy

To assess the feasibility of middle-term proton pump inhibitor (PPI) weaning in patients with laryngopharyngeal reflux (LPR) and evaluate patient awareness of PPI adverse events. We conducted a cross-sectional study of 100 LPR patients treated with an association of diet, PPIs, and alginate. Patients were followed from September 2016 to May 2020. At the end of the initial 3-to-6 months therapeutic period, LPR patients were weaned from PPIs and instructed to respect diet and stress management over the long-term. The 3-year symptom recurrence rate, PPI use, and patient awareness of PPI adverse events were assessed. Sixty-seven patients completed the evaluation. Twenty-seven patients (40.3%) reported a chronic course of LPR-symptoms, requiring chronic or occasional PPI use. LPR symptom recurrence occurred 1-to-2 or 3-to-5 times yearly in 8.9% and 20.9% of patients, respectively. Recurrences were managed by short-term diet, alginate, or PPI intake. The remaining patients (29.9%) did not report middle-term LPR recurrence. The 3-year weaning rate of occasional or chronic use of PPIs was 64.2%. Among participants, 26.8% were aware of PPI-related adverse events, most frequently through physicians (33%), online sources (17%), and friends or family (17%). Nonresponder patients were significantly more aware of PPI adverse events than responders (P=0.029). PPI-attributed adverse events occurred in 29.8% of patients. Sixty-four percent of LPR patients treated with PPIs were weaned at 3-year posttreatment time. Different forms of LPR may exist regarding symptom relief, recurrences, and chronic course.

S1341 Risk of Acute Interstitial Nephritis in Patients on Acute Proton Pump Inhibitor Therapy

INTRODUCTION: Proton pump inhibitors (PPIs) are commonly prescribed medications. Studies suggest a link between PPI and acute interstitial nephritis (AIN), however data is limited. Our primary aim was to evaluate the prevalence of AIN in patients on short-term PPI therapy. Our secondary aim was to compare the risk of AIN in patients on PPI compared to H2-receptor blockers and compare adverse events (AE) . METHODS: We performed a retrospective analysis in the IBM Explorys database 5 (1999-2020), a pooled, national, de-identified clinical database of over 72 million unique patients from 26 health care networks and 300 hospitals across the United States. Patient populations were identified using SNOMED and ICD codes. PPI included were esomeprazole, omeprazole, pantoprazole and lansoprazole. The development of AIN was evaluated within 8 weeks of PPI initiation. Patients on medications commonly implicated in AIN which included NSAIDs, antibiotics, loops diuretic, H2-blockers, rifampin, and allopurinol were excluded from the study if prescribed within 30 days of initiation of PPI. Additionally, patients with systemic lupus erythematous, sarcoidosis, granulomatosis with polyangiitis, and Sjogren’s disease were also excluded from the study. The control group was defined as patients on H2 blockers with the above exclusion criteria. AE were defined as ICU admission within 7 days, hemodialysis within 2 weeks, new chronic kidney disease within 6 months of diagnosis of AIN, and new end stage renal disease within 1 year for PPI group and control group. Prevalence was reported for each PPI. Odds ratio with 95% CI were calculated for risk of AIN for each PPI compared to control group. Chi-squared test was used to compare the risk of AEs in the combined PPI group vs H2-blockers. RESULTS: Acute PPI-induced AIN comprised 0.56% (n = 1410) of total AIN patients. Prevalence of AIN in esomeprazole and omeprazole was 6 (per 10,000), pantoprazole was 18 (per 10,000) and lansoprazole was 4 (per 10,000). Pantoprazole was the only PPI associated with an increased risk of AIN (OR 1.66, 95% CI 1.51-1.84). There was no difference between risk of CKD and ESRD between PPI and control. Patients in PPI group were more likely to be senior, female, have Medicare insurance, hypertension, hyperlipidemia and heart failure. CONCLUSION: Our study shows that AIN is a rare side effect of acute PPI therapy. Pantoprazole should be used with caution perhaps in patients with underlying CKD however this needs to be validated in future studies.Figure 1Figure 2Table 1

Effect of Acid Suppressants on the Risk of COVID-19: A Propensity Score-Matched Study Using UK Biobank

Effect of Acid Suppressants on the Risk of COVID-19: A Propensity Score-Matched Study Using UK Biobank

Problems Associated with Deprescribing of Proton Pump Inhibitors.

Proton pump inhibitors (PPIs) are recommended as a first-line treatment for gastroesophageal reflux disease (GERD) and other acid related disorders. In recent years, concerns have been raised about the increasing prevalence of patients on long-term PPI therapy and inappropriate PPI use. It is well known that short-term PPI therapy is generally well tolerated and safe; however, their extensive long-term use is a major global issue. One of these long-standing concerns is PPI-induced gastrin elevation secondary to hypoacidity. Hypergastrinemia is believed to play a role in rebound hyperacidity when PPIs are discontinued resulting in induced dyspeptic symptoms that might result in the reinstitution of therapy. Gastrin exerts tropic effects in the stomach, especially on enterochromaffin-like (ECL) cells, and concerns have also been raised regarding the potential progression to dysplasia or tumor formation following long-term therapy. It is well known that a substantial number of patients on long-term PPI therapy can discontinue PPIs without recurrence of symptoms in deprescribing trials. What is unknown is how sustainable deprescribing should be undertaken in practice and how effective it is in terms of reducing long-term outcomes like adverse drug events, morbidity and mortality. Moreover, there is no clear consensus on when and how deprescribing strategies should be attempted in practice. This review sought to summarize the harms and benefits of long-term PPI therapy with special focus on gastrin elevation and its relation to deprescribing studies and future interventions that may improve PPI use.

Short-Term Proton Pump Inhibitor Use and Hepatic Encephalopathy Risk in Patients with Decompensated Cirrhosis.

Objective: A window period of approximately 3–6 months is usually adopted in studies that evaluate hepatic encephalopathy (HE) risk in proton pump inhibitor (PPI) users. However, HE risk after short-term PPI exposure remains unclear. We explored the effect of short-term PPI exposure using a case-crossover study design. Design: Records of patients with decompensated cirrhosis who had received an HE diagnosis were retrieved from the National Health Insurance Research Database. PPI use rates were compared for case and control with window periods of 7, 14, and 28 days. The adjusted self-matched odds ratio (OR) and 95% confidence interval (CI) from a conditional logistic regression model were used to determine the association between PPI use and HE risk. Results: Overall, 13 195 patients were analyzed. The adjusted OR for HE risk after PPI exposure was 3.13 (95% CI = 2.33–4.20) for the 7-day window, 4.77 (95% CI = 3.81–5.98) for the 14-day window, and 5.60 (95% CI = 4.63–6.78) for the 28-day window. All PPI categories, except omeprazole and pantoprazole, were associated with an increased HE risk. Irrespective of other precipitating factors, such as recent gastrointestinal bleeding or infection, PPI significantly increased HE risk. Conclusion: Short-term PPI use is significantly associated with HE in patients with decompensated cirrhosis. Physicians should use PPI in these patients for appropriate indications, and carefully monitor signs of HE even after short-term exposure. Owing to the limitations of retrospective design in the current study, further study is warranted to confirm our findings.

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.

Effects of Proton Pump Inhibitors on the Gastrointestinal Microbiota in Gastroesophageal Reflux Disease

Proton pump inhibitors (PPIs) are commonly used to lessen symptoms in patients with gastroesophageal reflux disease (GERD). However, the effects of PPI therapy on the gastrointestinal microbiota in GERD patients remain unclear. We examined the association between the PPI usage and the microbiota present in gastric mucosal and fecal samples from GERD patients and healthy controls (HCs) using 16S rRNA gene sequencing. GERD patients taking PPIs were further divided into short-term and long-term PPI user groups. We showed that PPI administration lowered the relative bacterial diversity of the gastric microbiota in GERD patients. Compared to the non-PPI-user and HC groups, higher abundances of Planococcaceae, Oxalobacteraceae, and Sphingomonadaceae were found in the gastric microbiota from the PPI-user group. In addition, the Methylophilus genus was more highly abundant in the long-term PPI user group than in the short-term PPI-user group. Despite the absence of differences in alpha diversity, there were significant differences in the fecal bacterial composition of between GERD patients taking PPIs and those not taking PPIs. There was a higher abundance of Streptococcaceae, Veillonellaceae, Acidaminococcaceae, Micrococcaceae, and Flavobacteriaceae present in the fecal microbiota from the PPI-user group than those from the non-PPI-user and HC groups. Additionally, a significantly higher abundance of Ruminococcus was found in GERD patients on long-term PPI medication than that on short-term PPI medication. Our study indicates that PPI administration in patients with GERD has a significant effect on the abundance and structure of the gastric mucosal microbiota but only on the composition of the fecal microbiota.

Sustained efficacy following resolution of frequent heartburn with an over-the-counter regimen of esomeprazole 20\xa0mg or placebo for 14\xa0days: two randomized trials

BackgroundA two-week course of therapy with an over-the-counter proton-pump inhibitor (PPI) is recommended for frequent heartburn. Limited research has been conducted on the sustained efficacy of short-term PPI therapy after treatment cessation. Esomeprazole 20 mg was evaluated in the seven-day follow-up period after the two-week treatment period using pooled data from two identical randomized, double-blind, placebo-controlled studies.MethodsAdults without confirmed diagnoses of gastroesophageal reflux disease experiencing heartburn at least two days/week in the past four weeks were eligible. Subjects received treatment with esomeprazole 20 mg or placebo once daily for 14 days. Heartburn episodes were documented using daily diaries. Missing data during the two-week treatment period were assumed to be days with heartburn. The proportion of subjects with heartburn resolution while on treatment and during the seven days of follow-up was assessed. Predictors of resolution during this post-treatment period were evaluated using a stepwise logistic regression model.ResultsAll subjects in the pooled analysis set who reported diary data for at least three follow-up days were analyzed (N = 584). This cut-off was used to ensure that sufficient data were collected for these analyses. Greater run-in heartburn frequency was a significant negative predictor of heartburn resolution during follow-up (P < 0.001). Among the on-treatment efficacy variables, the best predictor of resolution during follow-up was resolution during the last seven days of treatment (odds ratio: 3.81 [95% confidence interval: 2.40, 6.05; P < 0.0001]).ConclusionsLower baseline heartburn frequency and heartburn resolution during the last seven days of treatment were associated with a greater likelihood of heartburn resolution during the seven-day follow-up.Trial registrationRegistered at ClinicalTrials.gov June 11, 2011: NCT01370525; NCT01370538.

Adverse Events of Proton Pump Inhibitors: Potential Mechanisms.

We aimed at summarizing current evidence about mechanisms for potentially harmful effects of Proton Pump Inhibitors (PPIs). A Pubmed search was performed, and 207 studies concerning the relationship between use of PPIs and cardiovascular diseases, kidney impairment, nutritional disorders, fractures, infections, functional decline, and mortality were selected and reviewed. PPIs may cause potentially harmful effects by several mechanisms, including endothelial dysfunction, hypomagnesemia, drug interactions, reduced absorption of selected nutrients, increased gastric microbiota and small intestine bacterial overgrowth, reduced immune response, tubular-interstitial inflammation, increased bone turnover, accumulation of amyloid in the brain. Clinical and epidemiologic evidence is not consistent in regard to some negative outcomes during PPI treatment. Data from randomized clinical trials seem to deny most of them, but they are usually designed to investigate efficacy of drugs in ideal conditions and are not powered enough to detect adverse events. Besides being at special risk of experiencing negative outcomes during long-term treatment with PPIs, older and complex patients treated with polypharmacy regimens are persistently excluded from randomized clinical trials. Thus, large observational studies involving real-world patients should be considered as an important informative source about potential risks related to PPIs. Current evidence suggests that use of PPIs may be associated with negative outcomes by eliciting several different pathophysiologic mechanisms. While short-term PPIs could be considered effective and safe in adult patients with acid-related disorders, their long-term and often inappropriate use in patients carrying vulnerability to adverse events and/or high risk of drug-interactions should be avoided.

Proton pump inhibitor use and risk of hip fractures among community-dwelling persons with Alzheimer's disease-a nested case-control study.

Hip fractures are a major health concern among older persons with Alzheimer's disease, who usually use many concomitant drugs for several diseases. Evidence of the association between proton pump inhibitor use and risk of hip fracture is contradictory. To investigate whether the long-term use of proton pump inhibitor is associated with risk of hip fractures among community-dwelling persons with Alzheimer's disease. In this nested case-control study, the nationwide MEDALZ data were utilised. Community-dwelling persons with Alzheimer's disease who encountered incident hip fracture (N=4818; mean age 84.1) were included as cases. Four controls were matched for each case at the date of hip fracture (N=19235; mean age 84.0). The association between hip fracture and duration of current PPI use (ongoing use during 0-30days before the index date), and cumulative duration of use during 10years before was investigated with conditional logistic regression. Long-term or cumulative proton pump inhibitor use was not associated with an increased risk of hip fracture. Current proton pump inhibitor use was associated with an increased risk of hip fracture (adjusted OR 1.12, 95% CI 1.03-1.22). The risk was increased in short-term current use (<1year) (adjusted OR 1.23, 95% CI 1.10-1.37). The increased risk of hip fracture was evident only in short-term proton pump inhibitor use, but no association was found for long-term or cumulative use. Thus, our findings do not support previous assumptions that long-term proton pump inhibitor use would be associated with an increased risk of hip fractures.

Long-term Proton Pump Inhibitor Use in Primary Care Internal Medicine Resident Clinic

Introduction: Proton pump inhibitor (PPI) use is increasingly associated with nosocomial infections, including pneumonia, clostridium difficile and chronic diseases such as kidney disease and osteoporosis. The American Gastroenterological Association (AGA) recommends the dose of long-term PPIs should be periodically re-evaluated so that the lowest effective dose can be used, or a safer alternative can be used to manage the condition. Our aim is to evaluate and improve the appropriateness of PPIs used in our internal medicine resident clinic. Methods: The resident clinic at our tertiary care medical center is divided into five firms for primary care continuity. We performed a search on outpatient electronic health records for PPI orders on patients from all five firms of internal medicine resident clinic (5 attending providers and 60 residents). A sample size of 47 subjects was needed from each firm pre and post-intervention to achieve the significant power to detect a statistical difference between both groups. A pre-intervention retrospective chart review was performed on 47 patients from each firm to collect data on demographics, indications for PPI use, number of PPI tablets dispensed, refills offered, dosage and duration of treatment. Results: A detailed chart review of 201 patients was carried out. Mean age of our patient population was 53 years. Gastroesophageal reflux disease (GERD) was the most common indication (48%). Other indications were Barrett's esophagus (5.5%), peptic ulcer disease (2%), erosive gastritis (2%) while 17% did not have a clear indication. 75% of the patients were on PPI for greater than two months. EGD was performed in 24% (N=48) of the patients. A majority of the patients were on a 20mg once daily dose of PPI (44%). Most patients received three refills (28%, N=14) for their prescription with an average number of thirty tablets dispensed (47%, N= 94). Conclusion: Our study shows that 48% of our patients were prescribed PPIs for GERD, and none of the patients were treated with H2 receptor antagonists previously. 76% of our patient population on PPI had no documented EGD findings to support PPI use. Patients with uncomplicated GERD who respond to short-term PPIs should subsequently undergo attempts to stop or reduce them. The next step will be to develop and implement guidelines on appropriate PPI use in the ambulatory care setting and perform a post intervention data analysis to assess for outcomes.