Long-term Proton Pump Inhibitors Research Articles

Long-term proton pump inhibitor use and the incidence of gastric cancer: A systematic review and meta-analysis

Background: There are controverted whether the long-term use of proton pump inhibitors (PPI) will increase the risk of gastric cancer. We performed a meta-analysis to assess the risk of gastric cancer in PPI users compared with non-PPI users. Methods: The main inclusion criteria were original studies reporting the incidence of gastric cancer in PPI users compared with non-PPI users. Key outcomes were the risk ratios (RR) for gastric cancer in association with PPI users or non-PPI users. Results: We analyzed data from 8 studies, comprising more than 927,684 patients. The risk of gastric cancer in PPI users was significantly higher than in non-PPI users [RR= 2.10, 95% CI (1.17-3.97)]. The risk of gastric cancer was similar between the 2 groups when the duration was ≤1 year [RR= 2.18, 95% CI (0.66-7.11)]. While the risk of gastric cancer for PPI users was higher than in non-PPI users when the duration was between 1-3 years, ≥1 year, ≥3 years and ≥5 years. The risk of non-cardiac gastric cancer for PPI users was higher than for non-PPI users [RR= 2.66, 95% CI (1.66 -4.27)], and the risk of non-cardiac gastric cancer for PPI users was higher than for non-PPI users when the duration ≥1 year [RR= 1.99, 95% CI (1.03-3.83)], but the risk for cardiac gastric cancer was similar between the 2 groups [RR= 1.86, 95% CI (0.71-4.89)]. Conclusions: We found the long-term use of PPI (duration ≥1 year) was significantly associated with a higher risk of non-cardiac gastric cancer.

Physicians' Perceptions of Proton Pump Inhibitor Risks and Recommendations to Discontinue: A National Survey.

To provide contemporary estimates of internists' perceptions of adverse effects associated with proton pump inhibitors (PPIs) and self-reported clinical use. We invited 799 internists, including specialists and postgraduate trainees, to complete an online survey. Topics included perceptions of PPI adverse effects (AEs) and effectiveness for upper gastrointestinal bleeding (UGIB) prevention, changes in prescribing, and management recommendations for patients using PPIs for gastroesophageal reflux disease or UGIB prevention. We used logistic regression to identify factors associated with appropriate PPI continuation in the scenario of a patient at high risk for UGIB. Among 437 respondents (55% response rate), 10% were trainees and 72% specialized in general medicine, 70% were somewhat/very concerned about PPI AEs, and 76% had somewhat/very much changed their prescribing. A majority believed PPIs increase the risk for 6 of 12 AEs queried. Fifty-two percent perceived PPIs to be somewhat/very effective for UGIB prevention. In a gastroesophageal reflux disease scenario in which PPI can be safely discontinued, 86% appropriately recommended PPI discontinuation. However, in a high-risk UGIB prevention scenario in which long-term PPI use is recommended, 79% inappropriately recommended discontinuation. In this latter scenario, perceived effectiveness for bleeding prevention was strongly associated with continuing PPI (odds ratio 7.68, P < 0.001 for moderately; odds ratio 17.3, P < 0.001 for very effective). Other covariates, including concern about PPI AEs, had no significant association. Most internists believe PPIs cause multiple AEs and recommend discontinuation even in patients at high risk for UGIB. Future interventions should focus on ensuring that PPIs are prescribed appropriately according to individual risks and benefits.

New Developments in the Diagnosis and Management of Gastroesophageal Reflux.

To examine recent key developments in the pathophysiology, diagnosis, and treatment of gastroesophageal reflux disease (GERD). Newer research has suggested cytokine-mediated inflammation may play a role in the physiology of GERD, implying that the underlying mechanism may not be entirely related to chemical damage due to acid. Aided by novel technologies, diagnostic testing is also moving toward elucidating individual mechanisms and better defining specific GERD phenotypes with the goal of providing directed therapy. This is especially important in current times given the increase in coverage of adverse events reportedly linked to long-term proton pump inhibitor use. As patients are looking for potential alternatives, we highlight the key recent updates in pathophysiology and understanding of GERD and current medical and endoscopic/surgical options and explore the exciting treatments in the pipeline.

The effects of a multispecies synbiotic on microbiome-related side effects of long-term proton pump inhibitor use: A pilot study

Side effects of proton pump inhibitors (PPI) can be linked to the changes in the intestinal microbiome that occur during therapy, especially in long-term users. Therefore, the microbiome might also be a key player in the reduction of PPI side effects. We tested the effects of a three-month intervention with a multispecies synbiotic on intestinal inflammation, gut barrier function, microbiome composition, routine laboratory parameters and quality of life in patients with long-term PPI therapy. Thirty-six patients received a daily dose of a multispecies synbiotic for three months and were clinically observed without intervention for another three months. After intervention 17% of patients reached normal calprotectin levels; the overall reduction did not reach statistical significance (−18.8 ng/mg; 95%CI: −50.5; 12.9, p = 0.2). Elevated zonulin levels could be significantly reduced (−46.3 ng/mg; 95%CI: −71.4; −21.2; p < 0.001). The abundance of Stomatobaculum in the microbiome was reduced and Bacillus increased during the intervention. Furthermore, albumin, alkaline phosphatase and thrombocyte count were significantly increased and aspartate transaminase was significantly decreased during intervention. Gastrointestinal quality of life showed significant improvements. In conclusion, microbiome-related side effects of long-term PPI use can be substantially reduced by synbiotic intervention. Further studies are warranted to optimize dosage and duration of the intervention.

Optimizing Prescribing and Deprescribing of Proton Pump Inhibitors

Prescribing of proton pump inhibitors (PPIs) has markedly increased since their inception more than 30 years ago. The increase is related to inappropriate and long-term prescribing of PPIs, associated with a lack of education and unclear prescribing and deprescribing guidelines. The implementation of prescribing stewardship programs influences the reduction and inappropriate use of this medication. The purpose of this review is to address the gaps that exist regarding the use of PPIs along with determining methods for deprescribing. Guidelines and stewardship programs, along with education, are needed to reduce the adverse health effects of long-term PPI therapy.

Deleterious effect of proton pump inhibitors on the disease course of cirrhosis.

Proton pump inhibitors(PPIs) are widely prescribed to patients with liver cirrhosis. We hypothesized that long-standing PPI use is associated with spontaneous bacterial peritonitis(SBP) and accelerated development of disease-specific complications and liver-related death. A 5-year follow-up observational cohort study assessed the impact of long-standing PPI use on the clinical course of cirrhosis in a large referral patient cohort. Three hundred fifty patients with cirrhosis (alcohol:69.1%, Child-Pugh stage A/B/C:206/108/36) were assigned to two groups: regular PPI users (n=196) and nonusers (n=154). Occurrence of SBP, decompensation events (ascites, hepatic encephalopathy and variceal bleeding), and liver-related death were assessed. Regular PPI use was associated with an increased cumulative probability of SBP compared to nonusers [55% vs. 24.8%, hazard ratio(HR):4.25; P=0.05], in patients without previous SBP episode (n=84). A similar association was found between regular PPI use and decompensation events. The risk of the development of a first decompensation was higher in regular PPI users compared with nonusers, in patients with compensated clinical stage at enrollment (HR: 2.81, P= 0.008, n=146). The risk of liver-related death was also significantly increased among regular PPI users (P<0.001). In multivariate Cox-regression analysis, regular PPI use (HR:2.81, P=0.003) and MELD score (HR:1.21, P<0.001) was an independent predictor of mortality. In the present follow-up cohort study, long-term PPI use was associated with the development of SBP and a progressive disease course in patients with cirrhosis that may have been caused by enhanced pathologic bacterial translocation, accelerated development of bacterial translocation-dependent disease-specific complications, and liver-related death.

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.

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). 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 ≥7days 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. During a median follow-up period of 1.2years (interquartile range, 0.2-3.2years), the initial CDI occurrence differed significantly between matched cohorts of patients taking PPIs and H2RAs [PPIs vs H2RAs, 88/31095 person years vs 47/32836 person years; HR, 2.22; 95% confidence interval (CI) 1.29-3.96; P=0.005]. Almost 50% of all events occurred within 1year 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]. 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.

Long-term Proton Pump Inhibitor Administration Caused Physiological and Microbiota Changes in Rats

Proton pump inhibitors (PPIs) are used for the long-term treatment of gastroesophageal disorders and the non-prescription medicines for acid reflux. However, there is growing concerns about PPI misuse, overuse and abuse. This study aimed to develop an animal model to examine the effects of long-term use of PPI in vivo. Twenty one Wistar rats were given omeprazole orally or intravenously for 30 days, and caerulein as a positive control. After euthanization, the serum and stool were collected to perform MS-based quantitative analysis of metabolites. We carried out 16S-based profiling of fecal microbiota, assessed the expression of bile acid metabolism regulators and examined the immunopathological characteristics of bile ducts. After long-term PPI exposure, the fecal microbial profile was altered and showed similarity to those observed in high-fat diet studies. The concentrations of several metabolites were also changed in various specimens. Surprisingly, morphological changes were observed in the bile duct, including ductal epithelial proliferation, micropapillary growth of biliary epithelium, focal bile duct stricture formation and bile duct obstruction. These are characteristics of precancerous lesions of bile duct. FXR and RXRα expressions were significantly reduced, which were similar to that observed in cholangiocarcinoma in TCGA and Oncomine databases. We established a novel animal model to examine the effects of long-term use of omeprazole. The gut microbes and metabolic change are consequences of long-term PPI exposure. And the results showed the environment in vivo tends to a high-fat diet. More importantly, we observed biliary epithelial hyperplasia, which is an indicator of a high-fat diet.

Proton Pump Inhibitor Use, Hypergastrinemia, and Gastric Carcinoids-What Is the Relationship?

Neuroendocrine tumors (NETs) throughout the body are the focus of much current interest. Most occur in the gastrointestinal tract and have shown a major increase in incidence over the past 30 years, roughly paralleling the world-wide increase in the use of proton pump inhibitor (PPI) drugs. The greatest rise has occurred in gastric carcinoids (g-NETs) arising from enterochromaffin-like (ECL) cells. These tumors are long known to occur in auto-immune chronic atrophic gastritis (CAG) and Zollinger-Ellison syndrome (ZES), with or without multiple endocrine neoplasia type-1 (MEN-1), but the incidences of these conditions do not appear to have increased over the same time period. Common to these disease states is persistent hypergastrinemia, generally accepted as causing g-NETs in CAG and ZES, and postulated as having similar tumorigenic effects in PPI users. In efforts to study the increase in their occurrence, g-NETs have been classified in a number of discussed ways into different grades that differ in their incidence and apparent pathogenesis. Based on a large amount of experimental data, tumorigenesis is mediated by gastrin’s effects on the CCK2R-receptor on ECL-cells that in turn leads to hyperplasia, dysplasia, and finally neoplasia. However, in all three conditions, the extent of response of ECL-cells to gastrin is modified by a number of genetic influences and other underlying risk factors, and by the duration of exposure to the hormonal influence. Data relating to trophic effects of hypergastrinemia due to PPI use in humans are reviewed and, in an attached Appendix A, all 11 reports of g-NETs that occurred in long-term PPI users in the absence of CAG or ZES are summarized. Mention of additional suspected cases reported elsewhere are also listed. Furthermore, the risk in humans may be affected by the presence of underlying conditions or genetic factors, including their PPI-metabolizer phenotype, with slow metabolizers likely at increased risk. Other problems in estimating the true incidence of g-NETs are discussed, relating to non-reporting of small tumors and failure of the Surveillance, Epidemiology, and End Results Program (SEER) and other databases, to capture small tumors or those not accorded a T1 rating. Overall, it appears likely that the true incidence of g-NETs may be seriously underestimated: the possibility that hypergastrinemia also affects tumorigenesis in additional gastrointestinal sites or in tumors in other organ systems is briefly examined. Overall, the risk of developing a g-NET appears greatest in patients who are more than 10 years on drug and on higher doses: those affected by chronic H. pylori gastritis and/or consequent gastric atrophy may also be at increased risk. While the overall risk of g-NETs induced by PPI therapy is undoubtedly low, it is real: this necessitates caution in using PPI therapy for long periods of time, particularly when initiated in young subjects.

Systematic review with meta-analysis: the risks of proton pump inhibitors during pregnancy.

There have been safety concerns considering long-term proton pump inhibitor (PPI) use, also during pregnancy. To assess the risk of adverse neonatal outcomes associated with maternal intake of PPIs by means of systematic review and meta-analysis. The systematic search included PubMed, Web of Science, Cochrane Database and Embase (inception until June 2019). All studies reporting ≥1 adverse pregnancy outcome comparing PPI users to non-users. Histamine-2 receptor antagonists (H2RA) were also compared to both non-users and PPI users. Outcomes included congenital malformations, abortion, stillbirth, neonatal death, preterm birth, small for gestational age and low birth weight. Pooled odds ratios (OR) and 95% confidence intervals (CI) were obtained by random-effects modelling. PROSPERO study-protocol: CRD42018103320. In total, 26 observational studies (20 cohort, 6 case-control studies) were identified, of which 19 assessed PPIs and 12 H2RA. PPI use was associated with an increased risk of congenital malformations (OR1.28, 95% CI 1.09-1.52), especially in case-control studies (OR 2.04, 1.46-2.86). No associations were found between H2RA and congenital malformations. No significant associations were found between PPI use and abortions, stillbirth, neonatal death, preterm birth and low-birth weight, although H2RA use may be associated with an increased risk of preterm birth (OR 1.25, 95% CI 1.02-1.56). Although statistical heterogeneity and the risk of bias were overall low, clinical heterogeneity, information and selection bias may be present in the individual studies. This meta-analysis suggests an association between maternal PPI use and congenital malformations in humans, yet power was insufficient to assess specific malformations and drugs.

Erosive Esophagitis Portends a Benign Clinical Course in the Majority of Patients

Indefinite proton pump inhibitor (PPI) therapy and endoscopic evaluation for Barrett's esophagus is recommended for erosive esophagitis (EE). However, the clinical course of EE remains undefined. Adults with EE on esophagogastroduodenoscopy (EGD) were identified at Mayo Clinic Rochester between January 2003 and September 2005. Patients with repeat EGD performed after index endoscopy were included. Patients with a history of upper gastrointestinal surgery, esophageal cancer, achalasia, or Barrett's on initial EGD were excluded. Of 219 patients identified, 98 had LA grade A, 72 LA grade B, and 49 LA grade C esophagitis. Persistent EE was found in 27% on repeat endoscopy. No patients progressed to more severe grades of esophagitis. While discontinuation of PPI was associated with persistent esophagitis, long-term healing of esophagitis occurred in the majority of patients despite discontinuation of PPI. Grade A or B esophagitis and the absence of hiatal hernia were also independent predictors of esophagitis healing on multivariate analysis. The rate of Barrett's esophagus was similar among patients with LA grade A/B and C esophagitis on initial EGD (5% vs. 14%, p = 0.6). The majority of patients with EE demonstrated healing at follow-up endoscopy regardless of continued PPI use. A small proportion developed Barrett's esophagus, including those with LA grade A and B esophagitis, highlighting a potential role for repeat endoscopy in all grades of EE. A more conservative long-term PPI strategy may be reasonable in patients with LA grade A or B esophagitis in the absence of hiatal hernia.

Machine Learning Aided Diagnosis of Diseases Without Clinical Gold Standard: A New Score for Laryngopharyngeal Reflux Disease Based on pH Monitoring

Objective: Laryngopharyngeal Reflux Disease (LPRD) is prevalent and has a range of symptoms. However, diagnosing LPRD is difficult because of the lack of specific symptoms or clinical gold standard. An objective and reliable test, which does not rely on a perfect clinical gold standard, is required in clinical practice. Methods: 60 normal volunteers and 74 confirmed Laryngopharyngeal Reflux (LPR) patients were labelled based on the combined consideration of the reflux symptom index, reflux finding score, 24h oropharyngeal pH monitoring and results of anti-reflux treatment. 72 candidate features were extracted from pH recordings and the most efficient feature combination was detected using a stepwise wrapper method. The labelled data were combined with 1552 unlabelled data for feature selection and model training using semi-supervised learning. A latent class model method was used to assess the proposed model based on 64 additional validation data and an imperfect clinical reference test. Results: A new score (named W score), which significantly improved the sensitivity of the LPRD test (82.67% vs. 24.09%) and has a relatively high specificity (80.19%), was proposed. W score concurs with the complicated clinical test. Conclusion: W score which significantly improves LPRD diagnostic efficiency, can aid the clinical diagnosis of LPRD. W score provides an objective, efficient, and reliable indicator for the application of anti-reflux treatment in clinical practice. Significance: More LPRD patients can benefit from anti-reflux treatment in clinical practice and fewer patients may suffer from, for example, the side effects of unnecessary long-term Proton Pump Inhibitors (PPI) treatments.

POST-VAGOTOMY GASTROPARESIS – A CASE REPORT

We present Mr M.A. a 27 year old Nigerian of the Yoruba tribe who has been having recurrent dyspeptic symptoms for 5 years but not previously endoscopically evaluated for peptic ulcer disease who now presented with six days history of abdominal pain which was initially epigastric but later became generalized associated with four episodes of vomiting and a day history of abdominal distension and fever. He was acutely ill-looking and dehydrated. The Abdomen was moderately distended, does not move with respiration, generalized tenderness with guarding and rebound tenderness, intra-abdominal organs were difficult to palpate due to the guarding. Bowel sound was absent. Examination of the other systems was not remarkable. A provisional diagnosis of Generalized peritonitis likely secondary to perforated peptic ulcer was made. He had an emergency exploratory laparotomy under general anaesthesia. He was commenced on intravenous fluids and parenteral proton pump inhibitor(PPI) and antibiotics. Intra-op findings include 2 liters of bilious peritoneal fluid, Multiple fibrous adhesions, a 2.5cm x 2cm gastric perforation at the anterior wall of the antrum and a grossly normal bowel. The surgical operation performed was a Graham Omental patch closure of the gastric defect with Bilateral Truncal Vagotomy and Peritoneal lavage. Post-operative state was satisfactory and he was later discharged. He presented at the gastroenterology out-patient clinic eight months later with complaints of early satiety, feeling of indigestion and episodes of vomiting. Vomitus is usually offensive / foul smelling and contains undigested or partially digested stale food substances. Abdominal examination revealed a positive succussion splash. Other clinical examination findings were not remarkable. A Provisional Diagnosis of suspected Gastric outlet obstruction probably secondary to a chronic duodenal ulcer was made. Endoscopy findings revealed copious fluid and food debris in the stomach cavity which had an offensive smell with remnants of partially digested stale food substances seen. There was poor peristaltic activity and the stomach was poorly distensible. There were multiple areas of mucosa erosions seen in the gastric cardia and corpus. No corporal or antral lesion seen. The pyloric ring was normal and the duodenum was normal. Diagnosis- (1) Endoscopic features of Gastroparesis likely secondary to previous Bilateral Truncal Vagotomy. No evidence of mechanical obstruction of the Gastric outlet. (2) Gastric Cardia and Corporal mucosa lesions likely secondary to Stasis Gastritis. Histology of biopsy specimens showed acute on chronic non-specific gastritis and acute duodenitis. He was commenced on empirical first line Helicobacter pylori eradication triple therapy (PPI, Amoxycillin and Clarithromycin) and a prokinetic drug (Domperidone). He had made significant clinical improvement with resolution of the symptoms by the time he was seen in the clinic three weeks later. He was tolerating oral food intake adequately and he had no new complaints. He was counselled on dietary modification and placed on long term prokinetic agent (Domperidone) and long-term PPI therapy with regular clinic follow-up. The initial management of post-vagotomy gastroparesis should be conservative as many symptoms resolve with time, this occurs possibly because the enteric nervous system is able to adapt to the loss of vagal input. Modification of dietary habits, such as regular intake of small meals, and use of prokinetic drugs bring about symptomatic relief in most patients.

Long-term use of proton-pump inhibitors: whole-of-population patterns in Australia 2013-2016.

Background:Proton-pump inhibitors (PPIs) are among the most prescribed medicines worldwide and concern about their long-term use is growing. We used dispensing claims for every person in Australia dispensed publicly subsidized PPIs between 2013 and 2016 to determine the incidence and prevalence of PPI use and to examine the patterns and durations of PPI treatment among individuals continuing treatment beyond the guideline-recommended maximum 12 weeks.Methods:We estimated annual prevalence and incidence per 100 people and duration of treatment for every Australian dispensed publicly subsidized PPIs between 2013 and 2016. We examined patterns of PPI treatment in three patient subgroups using PPIs for more than 12 weeks duration; people receiving maintenance, long-term continuous or long-term intermittent treatment. We calculated the proportion in each subgroup stepping down from higher to lower PPI strengths, stepping up from lower to higher PPI strength and discontinuing treatment.Results:PPIs were dispensed to 4,388,586 people; 60% were women; median age at initiation was 52 years [interquartile range (IQR): 36–65]. Standard and high strength PPIs accounted for 95% of dispensings. Annual incidence and prevalence were 3.9/100 and 12.5/100, respectively, in 2016 and highest among individuals over 65 years (prevalence range: 33–43/100). Most people (67%) stopped treatment after one dispensing; while 25%, 6% and 10% continued on maintenance, long-term continuous and long-term intermittent treatment, respectively. Median duration of treatment in people continuing treatment was 501 days (IQR: 180–not reached) for maintenance treated individuals and ‘not reached’ for long-term treated individuals. We observed 35%, 20% and 47% of people stepping down from higher to lower treatment strengths on maintenance, long-term continuous and long-term intermittent treatment, respectively.Conclusions:Longer-term treatment with higher strength PPIs is common. Targeted regulation of PPI prescribing may improve the uptake of lower strength formulations and reduce both harms and costs associated with long-term PPI treatment.

Long-term proton pump inhibitor usage and the association with pancreatic cancer in Sweden

BackgroundThe long-term safety of proton pump inhibitors (PPIs) is increasingly questioned. The aim of our study was to assess the risk of pancreatic cancer among long-term PPI users in Sweden.MethodsThis population-based nationwide Swedish cohort study including 796,492 adult long-term PPI users has been used to calculate the standardized incidence rate ratios (SIRs) and 95% confidence intervals (CI) for pancreatic cancer, stratifying by indications of use, age, sex, and duration of use. The risk among all 20,210 long-term H2-receptor antagonist users was assessed as comparison.ResultsPancreatic cancer was found in 1733 long-term PPI users, and 25 H2-receptor antagonist users. For PPI users, the risk of pancreatic cancer was increased overall (SIRs = 2.22; 95% CI 2.12–2.32) and in all subgroup analyses, with the highest risk among PPI-users younger than 40 years (SIR = 8.90, 95% CI 4.26–16.37), and among individuals with a history of Helicobacter pylori (SIR = 2.99, 95% CI 2.54–3.49). After the first year after enrolment (during which PPI use may be because of early symptoms of pancreatic cancer), the risk remained increased over time, with SIR = 1.57 (95% CI 1.38–1.76) after 5 years. No associations were found for H2-receptor antagonists (SIR = 1.02, 95% CI 0.66–1.51).ConclusionsThis large study showed an increased risk of pancreatic cancer in long-term users of PPIs in Sweden, in particular among the youngest users.

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.

Exacerbation of gastroesophageal reflux symptoms after discontinuation of proton pump inhibitors is not associated with increased esophageal acid exposure.

Discontinuation of long-term proton pump inhibitors (PPIs) on patients with reflux symptoms can be challenging, as symptoms often exacerbate after stopping. The mechanism remains unknown. Our aim was to evaluate the impact of stopping long-term PPIs on patients with heartburn, and its association with esophageal acid exposure. Patients with heartburn on long-term PPIs underwent symptom questionnaire, high-resolution manometry, and 24h ambulatory impedance-pH studies, following a 7-day PPIs discontinuation. We investigated the association between exacerbation of symptoms and findings on ambulatory reflux studies. We studied 37 patients. After stopping PPIs, 27 patients (73%) had exacerbation of heartburn. Esophageal acid exposure time% (AET) in patients with exacerbation of heartburn was not significantly higher than in patients without (3.5% [1.3-9.7] vs 2.5% [1.3-8.7], NS). Fourteen of 27 patients with exacerbation had physiological AET (<4%) as compared with 6 of 10 patients with physiological AET (NS). All questioned symptoms (heartburn, regurgitation, epigastric discomfort/pain, bloating/belch) worsened after stopping PPIs (NS). Exacerbation of heartburn after discontinuation of PPIs does not appear to be due to increased esophageal acid exposure.

Insights into Effects/Risks of Chronic Hypergastrinemia and Lifelong PPI Treatment in Man Based on Studies of Patients with Zollinger-Ellison Syndrome.

The use of proton pump inhibitors (PPIs) over the last 30 years has rapidly increased both in the United States and worldwide. PPIs are not only very widely used both for approved indications (peptic ulcer disease, gastroesophageal reflux disease (GERD), Helicobacter pylori eradication regimens, stress ulcer prevention), but are also one of the most frequently off-label used drugs (25–70% of total). An increasing number of patients with moderate to advanced gastroesophageal reflux disease are remaining on PPI indefinitely. Whereas numerous studies show PPIs remain effective and safe, most of these studies are <5 years of duration and little data exist for >10 years of treatment. Recently, based primarily on observational/epidemiological studies, there have been an increasing number of reports raising issues about safety and side-effects with very long-term chronic treatment. Some of these safety issues are related to the possible long-term effects of chronic hypergastrinemia, which occurs in all patients taking chronic PPIs, others are related to the hypo-/achlorhydria that frequently occurs with chronic PPI treatment, and in others the mechanisms are unclear. These issues have raised considerable controversy in large part because of lack of long-term PPI treatment data (>10–20 years). Zollinger–Ellison syndrome (ZES) is caused by ectopic secretion of gastrin from a neuroendocrine tumor resulting in severe acid hypersecretion requiring life-long antisecretory treatment with PPIs, which are the drugs of choice. Because in <30% of patients with ZES, a long-term cure is not possible, these patients have life-long hypergastrinemia and require life-long treatment with PPIs. Therefore, ZES patients have been proposed as a good model of the long-term effects of hypergastrinemia in man as well as the effects/side-effects of very long-term PPI treatment. In this article, the insights from studies on ZES into these controversial issues with pertinence to chronic PPI use in non-ZES patients is reviewed, primarily concentrating on data from the prospective long-term studies of ZES patients at NIH.

Successful deprescribing of unnecessary proton pump inhibitors in a primary care clinic

ObjectiveThe objective of this study was to determine the rate of successful deprescribing of unnecessary proton pump inhibitors (PPIs) after implementation of a clinical pharmacist– managed program that included detailed tapering instructions, patient education, and follow-up. SettingThe setting was a family medicine clinic in St. Paul, MN, in an underserved community. Practice descriptionEligible patients were taking a long-term PPI for gastroesophageal reflux disease without esophagitis, or without a clear indication. Each morning, the clinical pharmacist generated a report in the electronic medical record that identified patients with appointments who were currently prescribed a PPI. After chart review, the pharmacist determined if patients were candidates for PPI deprescribing. If so, a focused visit with these patients was conducted. Practice innovationA unique pharmacist-managed PPI tapering schedule was developed and implemented to deprescribe unnecessary PPI therapy in a family medicine clinic. EvaluationEligible patients were seen by the pharmacist and initiated on a PPI taper. After 8 weeks, the patients who were initiated on a PPI taper were evaluated to determine if they successfully discontinued the PPI completely, decreased the dose or frequency, or were unsuccessful at tapering the PPI. ResultsOf the patients assessed (N = 126), 60% were excluded, 19% were unable to be seen, and 21% were willing to attempt the taper and discontinue their PPI. Of the 22 patients who initiated PPI deprescribing, 19 (86%) successfully discontinued their PPI completely, 2 (9%) decreased the dose or frequency, and 1 (5%) was unable to decrease or discontinue their PPI. This success rate of PPI discontinuation was higher than that in previous studies in primary care settings (31%-66%). ConclusionDeprescribing long-term PPI therapy can be successful in a family medicine clinic when implementing a clinical pharmacist–managed program that includes detailed tapering instructions, patient education, and follow-up.

Patient and Provider Perspectives on Deprescribing Proton Pump Inhibitors.

The aim of the current study is to describe proton pump inhibitor (PPI) prescribing trends in an older adult population and elucidate perspectives regarding PPI deprescribing. A retrospective chart review and a prospective cross-sectional analysis of provider and patient surveys were conducted. The retrospective chart review identified 107 patients age ≥65 who were prescribed PPI therapy. Nineteen patients on PPI therapy and 74 providers completed surveys regarding their perspectives on PPI deprescribing. PPI therapy was potentially inappropriate for 66% of patients based on dose, duration, and/or indication. Provider barriers to deprescribing included fear of outcomes, access to documentation, and uncertainty of current guidelines. This study illustrates the prevalence of long-term PPI use in geriatric patients without associated clinical indications, as well as perceived barriers to deprescribing. Long-term PPI use is associated with significant side effects; therefore, successful deprescribing must address these perceived barriers. [Journal of Gerontological Nursing, 45(10), 9-17.].