PPI-resistant Gastroesophageal Reflux Disease Research Articles

Treatment Response With Potassium-competitive Acid Blockers Based on Clinical Phenotypes of Gastroesophageal Reflux Disease: A Systematic Literature Review and Meta-analysis.

Gastroesophageal reflux disease (GERD) is typically managed based on the clinical phenotype. We evaluated the efficacy and safety of potassium-competitive acid blockers (PCABs) in patients with various clinical GERD phenotypes. Core databases were searched for studies comparing PCABs and proton pump inhibitors (PPIs) in clinical GERD phenotypes of erosive reflux disease (ERD), non-erosive reflux disease (NERD), PPI-resistant GERD and night-time heartburn. Additional analysis was performed based on disease severity and drug dosage, and pooled efficacy was calculated. In 9 randomized controlled trials (RCTs) evaluating the initial treatment of ERD, the risk ratio for healing with PCABs versus PPIs was 1.09 (95% CI, 1.04-1.13) at 2 weeks and 1.03 (95% CI, 1.00-1.07) at 8 weeks, respectively. PCABs exhibited a significant increase in both initial and sustained healing of ERD compared to PPIs in RCTs, driven particularly in severe ERD (Los Angeles grade C/D). In 3 NERD RCTs, PCAB was superior to placebo in proportion of days without heartburn. Observational studies on PPI-resistant symptomatic GERD reported symptom frequency improvement in 86.3% of patients, while 90.7% showed improvement in PPIresistant ERD across 5 observational studies. Two RCTs for night-time heartburn had different endpoints, limiting meta-analysis. Pronounced hypergastrinemia was observed in patients treated with PCABs. Compared to PPIs, PCABs have superior efficacy and faster therapeutic effect in the initial and maintenance therapy of ERD, particularly severe ERD. While PCABs may be an alternative treatment option in NERD and PPI-resistant GERD, findings were inconclusive in patients with night-time heartburn.

Potassium-competitive acid blockers and acid-related disorders.

Potassium-competitive acid blockers (PCABs) represent a new class of compounds for the treatment of acid-related disorders. Recent FDA approval of the PCAB vonoprazan for erosive esophagitis has started an important new approach to acid-related disorders. Compared to conventional proton pump inhibitors (PPIs), PCABs provide more rapid, potent, and sustained suppression of gastric acid with faster and more durable symptom relief. Studies have demonstrated the efficacy of PCABs for erosive esophagitis, nonerosive reflux disease, and peptic ulcer disease including H. pylori. However, the PCAB vonoprazan was only approved in the US as part of combination therapy for eradication of H. pylori. Clinical trials have now demonstrated noninferiority of vonoprazan to lansoprazole for treatment of erosive esophagitis, particularly noting superiority of vonoprazan in patients with severe esophagitis resulting in FDA approval of vonoprazan for treatment of erosive esophagitis. Emerging data suggests a possible utility of vonoprazan for PPI-resistant gastroesophageal reflux disease (GERD) and on-demand therapy for nonerosive reflux disease. Vonoprazan is generally well tolerated but long-term safety data is not well established. The PCAB vonoprazan is a newly FDA approved treatment option for erosive esophagitis. Its possible role in PPI-resistant GERD and nonerosive reflux disease warrants further investigation.

A systematic review and meta-analysis of the efficacy of vonoprazan for proton pump inhibitor-resistant gastroesophageal reflux disease.

Up to 40% of gastroesophageal reflux disease (GERD) patients experience inadequate symptom relief with a proton pump inhibitor (PPI), termed PPI-resistant or refractory GERD. Vonoprazan, a potassium-competitive acid blocker, has better efficacy than PPI in suppressing gastric acid secretion. This meta-analysis summarizes the efficacy and safety of vonoprazan for treating PPI-resistant GERD (both erosive esophagitis [EE] and non-erosive reflux disease [NERD]). Four electronic databases (Medline, Embase, SCOPUS, and CENTRAL) were searched for studies indexed until August 1, 2023. Both observational studies and clinical trials assessing the efficacy and safety of vonoprazan in PPI-resistant GERD were included. Efficacy outcomes included healing and maintenance rates of EE and improvement of the Frequency Scale for Symptoms of GERD (FSSG) scores. Serious adverse events (SAEs) were considered a safety outcome. The modified Newcastle-Ottawa Scale (NOS) was used to assess study quality. Twelve studies were included in this meta-analysis. Healing rates of PPI-resistant EE with vonoprazan 20mg were 91.7% (95% CI 86.8-94.8%) and 88.5% (95% CI 69.7-96.2%) at weeks 4 and 8, respectively. For healed PPI-resistant EE, the overall maintenance rates with vonoprazan 10mg were 82.6% (95% 61.2-95.0%) at week 8, 86.0% (95% CI 72.1-94.7%) at week 24, and 93.8% (95% CI 69.8-99.8%) at week 48. FSSG scores were improved in 74.6% (95% CI 65.8-81.7%) and 51.9% (95% CI 37.8-65.7%) of patients at weeks 4 and 8. Overall, no SAE was reported. Vonoprazan demonstrated high efficacy in the healing and maintenance of PPI-resistant EE and moderate efficacy for the improvement of FSSG score. Vonoprazan was well tolerated in PPI-resistant GERD patients.

Per-Oral Endoscopic Myotomy-Induced Gastroesophageal Reflux Disease and Review of the Efficacy of Proton Pump Inhibitors as a Management Strategy: Review of the Literature.

Per-oral endoscopic myotomy (POEM) is a minimally invasive procedure that is very effective in the treatment of achalasia, a rare esophageal motility disorder. POEM has become the first-line treatment for achalasia, with high success rates reported in the literature. However, a known complication of POEM is gastroesophageal reflux disease (GERD). The exact cause and risk factors of post-POEM GERD are not fully understood; however, a number of factors have played a role in its development. The management of post-POEM GERD is mainly by conservative measures, such as lifestyle changes and medications, like proton pump inhibitors (PPI), which are often the first-line method of treatment. However, surgical procedures, such as fundoplication, may be necessary in some patients. This literature review will discuss the effectiveness of the use of PPIs as a management strategy for post-POEM GERD, the factors that lead to PPI-resistant GERD, and other management strategies utilized in these cases.

New technology minimally invasive for the treatment of gastro-esophageal reflux disease: LINX

: Gastroesophageal reflux disease (GERD) is a common disorder worldwide (10–30% of adults); lifestyle modifications and PPI therapy (the gold-standard medical treatment for GERD) work in many patients with GERD but in 30–40% of them symptoms persist. Anti-reflux surgery is indicated, with moderate level of evidence, in PPI-resistant GERD patients and with low level of evidence in erosive GERD patients on long term PPI treatment. LINX Reflux Management System (Torax Medical, Maple Grove, MN) is a device for magnetic sphincter augmentation (MSA) and is gaining interest as a valuable surgical alternative approach in patients with GERD, compared to laparoscopic Nissen fundoplication (LNF) which is nowadays the gold-standard surgical technique. In this brief review of current literature in order to compare LINX to the gold-standard surgical procedure for GERD, we analyzed two reviews and three meta-analyses. Each Authors confirmed the efficacy and safety of both techniques. LINX seems to have shorter operative time, shorter length of stay and fewer complications of gas and bloating, if compared to standard surgical procedure. In all analyzed studies the presence of hiatal hernia (HH) larger than 3 cm was often an exclusion criterion for LINX. No RCTs are currently available in literature in order to compare LNF vs. LINX and future researches are needed.

New endoscopic treatment methods for PPI-resistant GERD

Introduction. Gastroesophageal reflux disease (GERD) is a common disease with the highest prevalence in North America. Up to 40% of patients report persistent gastroesophageal reflux disease (GERD) symptoms despite proton pump inhibitor (PPI) therapy. Aim. The aim of this article is to complete discuss the GERD characterized by heartburn and/or regurgitation symptoms. Material and methods. We discuss here the evidence for medical therapy for PPI nonresponsive GERD. Analysis of the literature. GERD may present with a variety of other symptoms, including water brash, chest pain or discomfort, dysphagia, belching, epigastric pain, nausea, and bloating. In addition, patients may experience extraesophageal symptoms like cough, hoarseness, throat clearing, throat pain or burning, wheezing, and sleep disturbances. Conclusion. There has been an increase in GERD prevalence. GERD is one of the most common gastrointestinal disorders managed by gastroenterologists and primary care physicians.

Efficacy of vonoprazan for initial and maintenance therapy in reflux esophagitis, nonerosive esophagitis, and proton pump inhibitor-resistant gastroesophageal reflux disease.

Proton pump inhibitors (PPIs) have been the first line treatment for gastroesophageal reflux disease (GERD). The aim of this study was to evaluate the efficacy of vonoprazan (VPZ), a potassium-competitive acid blocker for reflux esophagitis (RE), nonerosive reflux disease (NERD), and PPI-resistant GERD patients.An open-label, single-center, observational study in our hospital was performed from August 2016 to August 2017. All patients diagnosed with GERD were asked to self-report a questionnaire of frequency scale for the symptoms of GERD (FSSG) and rate their degree of satisfaction with the treatment of GERD during outpatient visit. A total of 200 (RE 47, NERD 49, PPI-resistant GERD 104) patients were included in the present study. The primary endpoint was the change of FSSG and the proportion of degree of satisfaction with the treatment at the end of the initial therapy. A percentage of improvement (improvement rate) and resolution (resolution rate) at the end of the initial therapy were evaluated. Secondary endpoint included the proportion of patients with symptomatic relapse in the 24-week maintenance phase.FSSG and the degree of satisfaction were significantly improved after the initial therapy in every group. Improvement and resolution rate after the initial therapy were 83.0% and 67.0% in RE, 66.7% and 60.4% in NERD, and 76.0% and 60.4% in PPI-resistant group. There was no significance between after the initial therapy and 24 weeks in improvement and resolution rate. Thirty-two of the total 48 patients did not take VPZ at 24 weeks. Total FSSG score in each group was 1.67 ± 1.97, 2.71 ± 4.91, and 4.0 ± 4.93. The nonrelapse rate at 24 weeks in each group was 66.7%, 60.0%, and 50.0%. The resolution rate at 24 weeks in each group was 38.9%, 45.0%, and 30.0%.The VPZ therapy is effective for initial and maintenance therapy and improves heartburn and patient's satisfaction significantly in all 3 groups. Among patients who stopped taking VPZ during the maintenance period, 42.0% of RE and NERD group and 30% of PPI-resistant group experience complete remission from GERD at 24 weeks by introduction of VPZ.

Efficacy of Vonoprazan for Gastroesophageal Reflux Symptoms in Patients with Proton Pump Inhibitor-resistant Non-erosive Reflux Disease.

Objective Clinically, patients with proton pomp inhibitor (PPI)-resistant gastroesophageal reflux disease (GERD) are very challenging to treat. The aim of this study was to determine the rates of symptom relief and adverse events among PPI-resistant GERD patients that changed their therapy from a PPI to vonoprazan. Methods Patients with severe gastroesophageal reflux symptoms (total GERD-Q score ≥8) without endoscopic findings of mucosal breaks who changed their medication from a PPI to vonoprazan during a 12-week period from 2015 to 2016 at 2 hospitals were selected. The primary outcome was the self-reported relief of gastroesophageal reflux symptoms. The odds ratio (OR) for the improvement of symptoms was calculated based on an exact binomial distribution using a matched-pair analysis. The secondary outcome was the GERD-Q score and adverse events. Results Twenty-six patients (6 men) with a mean age of 67.5 years were analyzed. After the therapy was changed from a PPI to vonoprazan, 18 patients (69.2%) reported an improvement, 6 (23.1%) reported no change, and 2 (7.7%) reported an exacerbation of symptoms. A change in therapy was significantly associated with improved self-reported symptoms (OR 9.0, p<0.001). The mean total GERD-Q score during vonoprazan treatment was significantly lower than that during PPI therapy (11.96 vs. 8.92). There were no significant differences in the incidence of adverse events between the therapies. Conclusion Changing the medication from a PPI to vonoprazan was significantly associated with an improvement in gastroesophageal reflux symptoms. Vonoprazan is one of the most promising treatment options for patients with PPI-resistant GERD.

Vonoprazan: A Novel and Potent Alternative in theTreatment of Acid-Related Diseases.

Although proton pump inhibitors (PPIs) have been used widely, acid-related diseases are still associated with a huge burden on the health care system. Recently, the efficacy and safety of a new acid suppressant named vonoprazan in the treatment of acid-related diseases have been evaluated by a series of studies. As a novel potassium-competitive acid blocker, vonoprazan may provide reversible acid suppression by preventing K+ from binding to gastric H+/K+-ATPase. It has been clinically used for the short-term treatment of gastroesophageal reflux disease (GERD), peptic ulcer disease and Helicobacter pylori (H. pylori) infection in Japan. The healing rate of GERD and gastric ulcers by vonoprazan is more than 95 and 90%, respectively; also, it is effective in curing PPI-resistant GERD. It increases H. pylori eradication rate to more than 88% as part of both first-line and second-line therapy. It is also effective in the eradication of clarithromycin-resistant H. pylori strains. All of these short-term studies show vonoprazan is safe and well-tolerated. As a safe and effective acid inhibitor, vonoprazan might be a novel alternative in the treatment of acid-related diseases.

Esophageal mucosal integrity improves after laparoscopic antireflux surgery in children with gastroesophageal reflux disease

BackgroundEsophageal intraluminal baseline impedance reflects the conductivity of the esophageal mucosa and may be an instrument for in vivo evaluation of mucosal integrity in children with gastroesophageal reflux disease (GERD). Laparoscopic antireflux surgery (LARS) is a well-established treatment option for children with proton pump inhibitory (PPI) therapy resistant GERD. The effect of LARS in children on baseline impedance has not been studied in detail. The aim of this study was to evaluate the effect of LARS on baseline impedance in children with GERD.MethodsThis is a prospective, multicenter, nationwide cohort study (Dutch national trial registry: NTR2934) including 25 patients [12 males, median age 6 (range 2–18) years] with PPI-resistant GERD scheduled to undergo LARS. Twenty-four hour multichannel intraluminal impedance pH monitoring (MII-pH monitoring) was performed before and 3 months after LARS. Baseline impedance was evaluated during consecutive 2-h intervals in the 24-h tracings.ResultsLARS reduced acid exposure time from 8.5 % (6.0–16.2 %) to 0.8 % (0.2–2.8 %), p < 0.001. Distal baseline impedance increased after LARS from 2445 Ω (1147–3277 Ω) to 3792 Ω (3087–4700 Ω), p < 0.001. Preoperative baseline impedance strongly correlated with acid exposure time (r −0.76, p < 0.001); however, no association between symptomatic outcome and baseline impedance was identified.ConclusionsLARS significantly increased baseline impedance likely reflecting recovery of mucosal integrity. As the change in baseline impedance was not associated with the clinical outcome of LARS, other factors besides mucosal integrity may contribute to symptom perception in children with GERD.

Evidence-based clinical practice guidelines for gastroesophageal reflux disease 2015.

As an increase in gastroesophageal reflux disease (GERD) has been reported in Japan, and public interest in GERD has been increasing, the Japanese Society of Gastroenterology published the Evidence-based Clinical Practice Guidelines for GERD (1st edition) in 2009. Six years have passed since its publication, and there have been a large number of reports in Japan concerning the epidemiology, pathophysiology, treatment, and Barrett's esophagus during this period. By incorporating the contents of these reports, the guidelines were completely revised, and a new edition was published in October 2015. The revised edition consists of eight items: epidemiology, pathophysiology, diagnosis, internal treatment, surgical treatment, esophagitis after surgery of the upper gastrointestinal tract, extraesophageal symptoms, and Barrett's esophagus. This paper summarizes these guidelines, particularly the parts related to the treatment for GERD. In the present revision, aggressive proton pump inhibitor (PPI) maintenance therapy is recommended for severe erosive GERD, and on-demand therapy or continuous maintenance therapy is recommended for mild erosive GERD or PPI-responsive non-erosive GERD. Moreover, PPI-resistant GERD (insufficient symptomatic improvement and/or esophageal mucosal break persisting despite the administration of PPI at a standard dose for 8weeks) is defined, and a standard-dose PPI twice a day, change in PPI, change in the PPI timing of dosing, addition of a prokinetic drug, addition of rikkunshito (traditional Japanese herbal medicine), and addition of histamine H2-receptor antagonist are recommended for its treatment. If no improvement is observed even after these treatments, pathophysiological evaluation with esophageal impedance-pH monitoring or esophageal manometry at an expert facility for diseases of the esophagus is recommended.

Protease-Activated Receptor-2 Up-Regulates Transient Receptor Potential Vanilloid 4 Function in Mouse Esophageal Keratinocyte.

The reflux of pancreatic-duodenal fluids is implicated in the pathophysiology of proton-pump inhibitor-resistant gastroesophageal reflux disease (GERD). Protease-activated receptor-2 (PAR-2) is activated by proteases, the pancreatic enzyme, trypsin, and the activated PAR-2 enhances transient receptor potential vanilloid 4 (TRPV4) function in neurons. TRPV4 stimulates ATP exocytosis in conjunction with the vesicular nucleotide transporter, which mediates mechano-transduction and vagal stimulation. The aim of the present study was to verify whether the activated PAR-2 up-regulates TRPV4 function in mouse esophageal keratinocytes, which may link to the pathophysiology in PPI-resistant GERD. TRPV4 and PAR-2 expressions were detected by RT-PCR, immunostaining, and western blotting in mouse esophageal keratinocytes. The functional response of TRPV4 to esophageal keratinocytes was analyzed using a Ca(2+) imaging system. Cellular ATP release was examined by luciferase-luciferin reaction. TRPV4 phosphorylation was studied by immunoprecipitation and western blotting. PAR-2 and TRPV4 mRNAs and proteins were expressed in esophageal keratinocytes. Pre-treatment with trypsin significantly increased the responses to TRPV4 activator in esophageal keratinocytes, probably via the phosphorylation of serine residue of TRPV4 by protein kinase C and resulted in cellular ATP release from the cells. Activated PAR-2 with trypsin exposure up-regulated TRPV4 function and increased ATP release in mouse esophageal keratinocytes. This mechanism might be related to the pathophysiology of GERD, especially non-erosive GERD.

Mo1119 Detection of Reflux Mechanisms in PPI Non-Responder Patients: Post Prandial High Resolution Impedance Manometry (HRIM) Study

Background: In the last decade combined impedance-pH monitoring has become the gold standard for the detection of reflux episodes with several studies demonstrating its increased diagnostic yield in gastro-esophageal reflux disease (GERD). This is mainly due to the capability of impedance-pH to correlate symptoms to both acid and non-acid reflux episodes. However, despite its large use in clinical practice, limited data about its clinical usefulness for the management of GERD patients are present. AimM mean age 49; 14 ERD, 22 NERD and 12 NARD) reporting at least 3 symptoms during the impedance-pH monitoring were included. Fundoplication had a similar effect in all groups, as shown in the Figure. At 1 year, esophageal AET and number of total, acid and non-acid refluxes significantly decreased after surgery (in all cases, p<0.01), whereas mean lower esophageal pressure increased (p<0.05). The percentage of patients with resolved or markedly improved typical symptoms at 12 months after surgery was similar among the groups (ERD 93% vs. NERD 82% vs NARD 83%, p=ns). Quality of life similarly improved in all groups (p=ns). Finally, the percentage of failure or adverse events did not differ among the groups (ERD 21% vs. NERD 23% vs NARD 17%, p=ns). Conclusion: Our data show that laparoscopic fundoplication was a safe and effective procedure in relieving typical reflux symptoms in patients with NARD as well as in patients with ERD and NERD, thus markedly improving their quality of life. Therefore, impedance-pH monitoring facilitated a more focused therapeutical approach to patients with PPI-resistant GERD.

Mo1117 Patients With Non-Acid Reflux Disease and Those With Erosive and Non-Erosive Reflux Disease Have Similar Response to Anti-Reflux Surgical Therapy

Background: In the last decade combined impedance-pH monitoring has become the gold standard for the detection of reflux episodes with several studies demonstrating its increased diagnostic yield in gastro-esophageal reflux disease (GERD). This is mainly due to the capability of impedance-pH to correlate symptoms to both acid and non-acid reflux episodes. However, despite its large use in clinical practice, limited data about its clinical usefulness for the management of GERD patients are present. AimM mean age 49; 14 ERD, 22 NERD and 12 NARD) reporting at least 3 symptoms during the impedance-pH monitoring were included. Fundoplication had a similar effect in all groups, as shown in the Figure. At 1 year, esophageal AET and number of total, acid and non-acid refluxes significantly decreased after surgery (in all cases, p<0.01), whereas mean lower esophageal pressure increased (p<0.05). The percentage of patients with resolved or markedly improved typical symptoms at 12 months after surgery was similar among the groups (ERD 93% vs. NERD 82% vs NARD 83%, p=ns). Quality of life similarly improved in all groups (p=ns). Finally, the percentage of failure or adverse events did not differ among the groups (ERD 21% vs. NERD 23% vs NARD 17%, p=ns). Conclusion: Our data show that laparoscopic fundoplication was a safe and effective procedure in relieving typical reflux symptoms in patients with NARD as well as in patients with ERD and NERD, thus markedly improving their quality of life. Therefore, impedance-pH monitoring facilitated a more focused therapeutical approach to patients with PPI-resistant GERD.

M1926 A Prospective Trial to Investigate the Efficacy of Addition of Prokinetics to Proton Pump Inhibitor (PPI) for PPI-Resistant Gastroesophageal Reflux Disease (GERD) Using Symptom and Quality of Life Indexes

M1926 A Prospective Trial to Investigate the Efficacy of Addition of Prokinetics to Proton Pump Inhibitor (PPI) for PPI-Resistant Gastroesophageal Reflux Disease (GERD) Using Symptom and Quality of Life Indexes