Vonoprazan in Management of Refractory Gastroesophageal Reflux Disease: An Indian Expert Group Consensus Statements.

Background/Aims: Approximately 20-40% of patients with gastroesophageal reflux disease (GERD) are refractory to proton pump inhibitor (PPI) treatment. The acid-inhibitory effect of vonoprazan, a novel potassium-competitive acid blocker (P-CAB), is significantly greater when compared to the effect of PPIs. We investigated the efficacy of vonoprazan treatment for PPI-refractory GERD and factors associated with P-CAB non-response. Methods: We enrolled 277 GERD patients receiving continuous PPI therapy. Subjects completed a self-report questionnaire including the frequency scale for the symptoms of GERD (FSSG). Patients with PPI-refractory GERD received 20 mg of vonoprazan once daily for 8 weeks. After that, subjects completed the same questionnaire, and the results were used to identify P-CAB responders and non-responders. Results: Twenty-eight patients were identified as P-CAB responders and 26 were non-responders. Vonoprazan treatment significantly decreased scores of FSSG, nighttime symptom, and Athens Insomnia Scale. Multivariate analysis demonstrated co-existing functional dyspepsia (FD; OR 4.94) and the presence of sleep disturbances (OR 4.34) was associated with P-CAB non-response, whereas alcohol consumption was inversely associated. Conclusions: Vonoprazan treatment might be appropriate as a promising new strategy for PPI-refractory GERD. Co-existing FD, sleep disturbances, and alcohol abstinence were significantly associated with P-CAB non-response. Other therapeutic options should be considered in patients with these factors.

Potassium competitive acid blockers (PCABs) are superior to proton pump inhibitors (PPIs) for healing of Los Angeles (LA) class C/D erosive esophagitis and are approved for nonerosive gastroesophageal reflux disease (GERD) given their efficacy measured by heartburn-free days. However, they are more expensive than PPIs. We estimated the cost-effectiveness of PCABs compared with PPIs for the management of GERD. A decision tree was constructed for the base case of a patient with GERD. We tested scenarios in which nonerosive reflux disease, LA A/B, or LA C/D esophagitis was present, comparing PCABs with PPIs as first-line therapy, including step up therapy and/or class switching if symptoms persisted. Using publicly available cost estimates, quality-adjusted life years (QALYs) were compared using a willingness-to-pay threshold of $100,000/QALY from a societal perspective at 6 months. The cost of PCABs for GERD was $3,240 more than PPIs, with an incremental cost-effectiveness ratio of $144,208/QALY. When evaluating GERD phenotypes separately, the incremental cost-effectiveness ratio was consistently over our willingness-to-pay threshold. One-way analyses showed the most influential parameters were PCAB cost and efficacy for heartburn-free days. Probabilistic sensitivity analysis favored PPIs 71.7% out of 100,000 iterations. Reducing one-week costs to below $91 would make PCABs a cost effective first-line strategy across all GERD phenotypes. Despite PCAB efficacy, PPIs are a cost-effective strategy for GERD treatment, and can be positioned ahead of PCAB escalation on this basis. Reducing PCAB costs or accepting a higher willingness-to-pay threshold would influence this finding, although PCABs may be favored in some current situations as evidenced by probabilistic sensitivity results.

Persistent Reflux Symptoms in the Proton Pump Inhibitor Era: The Changing Face of Gastroesophageal Reflux Disease

IntroductionThe first drug selected for treatment of gastro-oesophageal reflux disease (GERD) and prevention of the recurrence is a proton pump inhibitor (PPI), but recently, a potassium-competitive acid blocker (P-CAB) was...

Potassium-competitive acid blockers (PCABs), a new class of potent and sustained acid-suppressing drugs, have emerged as an alternative to proton pump inhibitors (PPIs) for gastroesophageal reflux disease (GERD) management. However, the specific benefits of PCABs for nocturnal GERD symptoms remain unclear. This systematic review and meta-analysis aimed to evaluate the efficacy and safety of PCAB therapy compared with PPIs or placebo for managing nighttime heartburn and related symptoms in adults with GERD. We systematically searched the MEDLINE, EMBASE, and Cochrane CENTRAL databases from inception to August 8, 2024. We included randomized controlled trials (RCTs) that compared any PCAB (vonoprazan, tegoprazan, or fexuprazan) with either a PPI or placebo in adult GERD patients. The primary outcome was the proportion of patients with complete resolution of nighttime heartburn throughout the treatment period; the secondary outcome was the treatment-emergent adverse events (TEAEs). Meta-analyses were performed using random-effects models with risk ratios (RRs). Sensitivity analyses were used to assess the robustness of the results. Risk of bias was evaluated using the Cochrane RoB 2 tool. Three RCTs were included in the meta-analysis. PCABs significantly increased the likelihood of complete nighttime heartburn resolution compared with PPIs (RR2.29, 95% CI 1.36-3.87; p = 0.002), with no heterogeneity. Safety analysis of the three trials showed no significant difference in TEAE risk (RR0.88, 95% CI 0.53-1.45; p = 0.62). The findings were consistent across all sensitivity analyses. Our study results suggest that PCABs therapy may provide better nighttime heartburn resolution than PPIs.

Tu1105 Gastric Acid Output Suppression in Response to Proton Pump Inhibitor Therapy in Symptomatic Versus Asymptomatic GERD Patients: Results of a Prospective Study Measuring Control and Meal-Stimulated Gastric Acid Secretion

Nocturnal Gastroesophageal Reflux: Assessment and Clinical Implications

Background: Gastroesophageal reflux disease (GERD) is a frequent and debilitating complication of systemic sclerosis (SSc), primarily due to esophageal dysmotility and smooth muscle atrophy. Standard treatment with proton pump inhibitors (PPIs) often provides suboptimal symptom relief. Vonoprazan, a potassium-competitive acid blocker (P-CAB), offers more potent and sustained acid suppression. This study aimed to compare the efficacy and safety of vonoprazan versus standard-dose PPIs in the treatment of SSc-associated GERD. Methods: In a randomized controlled trial, 30 patients with SSc and symptomatic GERD were assigned to receive either vonoprazan 20 mg once daily or a standard-dose PPI for 8 weeks. Primary outcomes included changes in symptom severity scores and endoscopic mucosal healing. Secondary outcomes assessed quality-of-life (QoL) improvements and adverse events. Data were analyzed using independent t-tests and chi-square tests, with a significance threshold of p < 0.05. Results: Patients in the vonoprazan group experienced a significantly greater reduction in GERD symptom scores compared to those receiving PPIs (mean difference: 3.1; p = 0.02). Mucosal healing occurred in 80% of vonoprazan-treated patients versus 53% in the PPI group (OR: 3.5; 95% CI: 0.8–14.9; p = 0.09). QoL improvements were noted in both groups, with a significantly greater effect observed in the vonoprazan group (p = 0.04). Adverse events were mild and similar in both arms Conclusions: Vonoprazan provided superior symptom control and showed a favorable trend toward improved mucosal healing in patients with SSc-associated GERD compared to standard PPIs. These findings suggest vonoprazan may represent a more effective first-line treatment option in this challenging clinical population

Gastroesophageal reflux disease (GERD) affects 6-20% of the population globally, with lower prevalence in Asia and higher rates in Western countries. The disorder, diagnosed across multiple specialties, manifests through a spectrum of symptoms-ranging from classic heartburn and regurgitation to atypical and extra-esophageal presentations. Management often becomes fragmented as patients consult various providers. This review aims to comprehensively evaluate gastroesophageal reflux disease management, from lifestyle modifications and pharmacotherapy to diagnostic pathways and surgical interventions. This review performed a narrative review of current definitions, pathophysiology, symptomatology, diagnostic strategies, and therapeutic options. Sources include major practice guidelines (American, Japanese, British), clinical trials, and emerging technologies spanning medical, endoscopic, and surgical modalities. gastroesophageal reflux disease diagnostics start with symptom-based clinical evaluation. Empirical therapy includes lifestyle changes such as weight loss, dietary modifications, head-of-bed elevation, and timing of meals. A standard 8-week course of proton pump inhibitors is more effective than H₂-receptor antagonists; high-potency proton pump inhibitors or twice-daily dosing may be warranted in refractory cases. Potassium-competitive acid blockers (e.g., vonoprazan) offer alternative acid suppression. Diagnostic testing-upper endoscopy, impedance‑pH monitoring, barium studies, and manometry-is indicated in treatment failures, alarm features, or when considering surgical/endoscopic intervention. Surgically, laparoscopic or robotic fundoplication remains the gold standard for patients with inadequate response to medical therapy or long-term proton pump inhibitor use. Magnetic sphincter augmentation presents as a minimally invasive alternative. Endoscopic therapies (e.g., Stretta, transoral incisionless fundoplication 2.0) show promise, yet lack long-term data and are typically reserved for select patients. gastroesophageal reflux disease is a heterogeneous, multifaceted disease requiring a tailored approach. Initial management prioritizes lifestyle measures and empiric acid suppression. Diagnostic evaluation refines treatment in non-responders or complicated cases. Effective long-term control may require surgery or endoscopic intervention, particularly for patients with refractory symptoms, hiatal hernia, or concerns over chronic proton pump inhibitor use. Further research is needed to establish long-term efficacy and optimal patient selection for advanced therapies.

Potassium-competitive acid blockers (PCABs), such as vonoprazan, provide more rapid, potent and prolonged acid suppression than proton pump inhibitors (PPIs), and as such may offer advantages in the treatment of GERD and other acid-related disorders. PPI-related adverse effects, including enteric infection, pneumonia, and micronutrient deficiencies, have been attributed primarily to gastric acid suppression [1], which raises concerns that treatment-emergent adverse events (TEAEs) could be more profound with PCAB use. The current study by Howden et al. [2] found that vonoprazan is well-tolerated, with a safety profile comparable to PPIs. This is based on an assessment of TEAEs across 14 clinical trials of vonoprazan compared with lansoprazole, esomeprazole or placebo, in addition to post-marketing data from 2014–2023. While the short-term safety of vonoprazan seems supported, the study's mean exposure duration of 142 days (20 weeks/5 months) and maximum duration of 260 weeks (5 years) may offer an incomplete assessment of the longer-term safety profile. Notably, several PPI-associated TEAEs can only be fully evaluated after chronic exposure, including bone fracture, vitamin B12 deficiency and gastric malignancy. Bone fracture has been associated with PPI use of at least 7 years, but not less than 6 years [3]; thus, the duration of vonoprazan exposure in this analysis may not be sufficient to detect an increased incidence of fractures. The associated mechanism may be due to calcium and magnesium malabsorption, which occurs over 5–10 years [4]. Additionally, while the impact of PPI on bone mineral density is controversial, the timing of osteoporosis development in women can exceed 10 years [5]. Vitamin B12 can take 3–5 years to deplete in the body, usually presenting with no or minimal symptoms in the short term and can take additional years to decades to manifest clinically as glossitis, anaemia or neuropsychiatric dysfunction [6], though the association between chronic PPI use and dementia remains controversial [7]. Gastric malignancy often arises as a subacute process, with a median time to progression of 6.1 years from nondysplastic gastric intestinal metaplasia to adenocarcinoma [8]. Risk of gastric cancer increased with cumulative PPI dose as well as longer duration of therapy (> 3 years) [9], though this association was inconsistent across studies and may involve various mechanisms, including H. pylori infection and alterations in GI microbiota [10]. Of note, other serious adverse events that were identified as potentially related to vonoprazan use by investigators included acute cholangitis, diverticulitis, malignancies, acute thyroiditis, atrial fibrillation and transient loss of consciousness. Additional evaluation is needed to determine the frequency, causality and potential mechanisms of action. Despite the concerns associated with chronic use, PPIs remain a mainstay of treatment for numerous GI conditions because, ultimately, the absolute risk is low, causality is debated, and few therapeutic alternatives exist. While there is not yet sufficient data on long-term PCAB use to draw the same conclusions, we believe that PCABs likely have a role in the treatment of acid-related conditions, particularly those in which PPIs have failed, and that future evaluations of real-world clinical application will clarify the longer-term harms and benefits that may presently remain underappreciated. Stephanie Owyang: conceptualization, writing – original draft, writing – review and editing. Wai-Kit Lo: conceptualization, writing – review and editing, supervision. This article is linked to Howden et al paper. To view this article, visit https://doi.org/10.1111/apt.18458. Data sharing not applicable to this article as no datasets were generated or analysed during the current study.

Gastroesophageal reflux disease (GERD) and Helicobacter pylori (H. pylori) infection are different disease states that are united by the core role of acid suppression in their management. In GERD, proton pump inhibitors (PPIs) have long been standard therapy based on abundant positive clinical trial data supporting their efficacy and safety. In H. pylori, PPIs are also a critical element of therapy in combination with 1 or more antibiotics to achieve and maintain a pH that maximizes the efficacy of therapy. Despite the considerable clinical success and widespread use of PPIs, room remains for agents with differentiated pharmacokinetic and pharmacodynamic profiles. The potassium-competitive acid blockers (PCABs) are mechanistically distinct from PPIs but are acid-stable and do not require activation of the proton pump by coadministration of food. In pharmacodynamic studies, these agents have shown greater durations of acid suppression above the critical threshold of pH 4 (for GERD) and pH 6 (for H. pylori), which have been shown to optimize therapeutic efficacy in these settings. These results have translated in clinical studies to similar and, in some cases, improved outcomes relative to PPIs in these disease states. This review summarizes current knowledge on the physiology of acid secretion, pathophysiology and management of GERD and H. pylori, and key characteristics and clinical trial data for PPIs and PCABs.

Introduction: The comparative effectiveness of potassium-competitive acid blocker (PCABs) and proton pump inhibitors (PPIs) in preventing upper gastrointestinal bleeding (UGIB) in cirrhotic patients remains unclear. Although PPIs are commonly used for acid suppression, concerns exist about their potential risks, including infections and hepatic encephalopathy. This study compares the incidence of UGIB following initiation of PCAB versus PPI therapy in patients with cirrhosis. Methods: We performed a retrospective cohort study using TriNetX Research Network, a federated database of de-identified electronic health records. Data were collected from 134 healthcare organizations in 14 different countries. Adult patients (≥18 years) with a diagnosis of cirrhosis between January 1, 2016, and December 31, 2024, who were prescribed either PCAB or PPI, were identified. Patients with a history of UGIB within 6 months prior to drug initiation were excluded. Patients with PCAB exposure were also excluded if they had received a PPI within 6 months of PCAB initiation. Propensity score matching (1:1) was adjusted for demographic characteristics and known risk factors of UGIB. Kaplan-Meier survival analysis and univariate Cox proportional hazards models were used to assess the incidence of UGIB within 90 days of therapy initiation. The secondary outcomes included rebleeding, need for endoscopic intervention, and mortality. Results: A total of 790,065 adults with cirrhosis and 137,843,348 without were analyzed. Before propensity score matching (PSM), PCAB users were older and had higher rates of diabetes, dialysis, and anticoagulant/antiplatelet use, but lower rates of varices, alcohol use, and NSAID exposure (all P <0.001). After 1:1 PSM, 58 patients per group were matched. Within 90 days, UGIB incidence was significantly lower with PCABs than PPIs (OR 0.490; 95% CI, 0.261–0.921; P = 0.024). While endoscopic intervention rates were similar (P = 0.079), the PCAB group had significantly lower rebleeding rates (P = 0.010) and inpatient mortality (OR 0.294; 95% CI, 0.156–0.552; P < 0.001). Conclusion: PCAB use was associated with significantly lower odds of UGIB compared to PPI use. PCAB users also had lower rates of rebleeding and inpatient mortality, suggesting a safer bleeding profile in patients with Cirrhosis. These findings support re-evaluating acid suppression strategies in cirrhotic patients at high risk for bleeding.

Introduction: Acid suppression with proton pump inhibitors (PPI) is linked with infections and poor outcomes in cirrhosis. Potassium competitive acid blockers (PCAB) have been introduced as alternatives. We aimed to compare PCABs vs PPIs in predicting outcomes in cirrhosis. Methods: Using TriNetX, we created a cohort of cirrhosis patients using validated ICD-9/10 codes between Jan 2018 to Dec 2024 who were started on PPI or PCAB (vonoprazan) after cirrhosis diagnosis. Demographics, comorbidities, cirrhosis severity labs closest to the index PPI/vonoprazan prescription dates were chosen. To address the differences in baseline characteristics between the 2 groups, we extracted demographic variables such as age, sex, race, and ethnicity, comorbidities and concurrent medication use within 2 years before the index date. The laboratory tests analyzed in this study included MELD-Na labs and blood counts; closest labs from the index date were selected. Primary outcome was 6-month post-index date mortality, while infections and all-cause hospitalizations were secondary outcomes. One-year outcomes were also evaluated. Univariate analysis performed and crude estimate of odds ratio of outcomes were reported. Adjusted hazard ratios (AHRs) with 95% confidence intervals (CIs) and P values were calculated using Cox proportional hazards regression models for all outcomes. Kaplan-Meier curves for outcomes were created. Results: Overall, 19,273 cirrhosis patients (63.9 ± 13.8 yrs, 66% men) were included. Most (89%, n = 17.285) were on PPI while the rest (11% n = 1988) were on vonoprazan. The median follow up was 180 (IQR 117 days). PPI users were older, and more male. PCAB users had higher cardiovascular disorders and GERD. Cirrhosis variables showed lower alcohol, higher HE with lactulose and rifaximin, and SBP with higher propranolol in PPI gp. Lower platelets, worse MELD score variables were seen in PPI but albumin was higher than PCABs. Cox proportional hazards shows lower rate of all outcomes at 6 and 12 months with vonoprazan versus PPIs which remained significant on adjusted comparisons. Kaplan Meier curves showed significant separation between vonoprazan and PPIs for all outcomes. Conclusion: In patients with cirrhosis there was a lower risk of infections, all-cause hospitalizations, and trend towards lower death at 6- and 12-months post-medication initiation date with vonoprazan compared to PPIs despite controlling for demographics, cirrhosis severity, and comorbid conditions. PCAB use in cirrhosis could be considered instead of PPIs.

Potassium-competitive acid blockers (P-CABs) are newly introduced gastrointestinal protectants, but their interaction with clopidogrel remains uncharacterized. Proton pump inhibitors (PPIs) are often coprescribed with clopidogrel, despite potential pharmacodynamic interactions. This study evaluated the effectiveness and safety of P-CAB and PPI coadministered with clopidogrel in patients with ischemic stroke. This population-based, longitudinal, retrospective cohort study used the Korean National Health Insurance Service database, covering 51.4 million individuals (≈97% of the Korean population) from 2016 to 2022. Patients with incident ischemic stroke were identified using predefined criteria. Propensity score matching compared the 6-month incidence of major adverse cardiovascular events (including myocardial infarction, stroke recurrence, and all-cause mortality) and gastrointestinal bleeding among 3 cohorts: clopidogrel alone, clopidogrel+P-CAB, and clopidogrel+PPI. Between 2017 and 2021, 40 752 of 65 180 patients with incident stroke (62.5%) received clopidogrel. A total of 6680 patients (16.4%) formed the clopidogrel-alone cohort, 578 (1.4%) the clopidogrel+P-CAB cohort, and 8806 (21.6%) the clopidogrel+PPI cohort. During the follow-up period, stroke recurred in 268 patients (4.0%) receiving clopidogrel alone, 26 patients (4.5%) receiving clopidogrel+P-CAB, and 431 patients (4.9%) receiving clopidogrel+PPI. After propensity score matching, the clopidogrel+P-CAB cohort showed a higher risk of major adverse cardiovascular events (hazard ratio [HR], 2.40 [95% CI, 1.18-4.85]) and stroke recurrence (HR, 2.64 [95% CI, 1.27-5.47]) than the clopidogrel-alone cohort. The clopidogrel+PPI cohort also had an increased risk of major adverse cardiovascular events (HR, 1.38 [95% CI, 1.17-1.63]) and stroke recurrence (HR, 1.41 [95% CI, 1.20-1.67]) relative to clopidogrel alone. Among PPIs, esomeprazole was associated with a higher risk of major adverse cardiovascular events (HR, 1.46 [95% CI, 1.10-1.92]) and stroke recurrence (HR, 1.50 [95% CI, 1.13-2.00]). Gastrointestinal bleeding did not differ significantly among the clopidogrel-alone, clopidogrel+P-CAB, and clopidogrel+PPI cohorts. Concomitant use of P-CABs or PPIs with clopidogrel was associated with an increased risk of ischemic events in patients with stroke. P-CABs or PPIs should, therefore, be prescribed cautiously for patients with stroke treated with clopidogrel.

The dramatic success of pharmacological acid suppression in healing peptic ulcers and managing patients with gastroesophageal reflux disease (GERD) has been reflected in the virtual abolition of elective surgery for ulcer disease, a reduction in nonsteroidal anti-inflammatory drug (NSAID)-associated gastropathy and the decision by most patients with reflux symptoms to continue medical therapy rather than undergo surgical intervention. However, a number of challenges remain in the management of acid-related disorders. These include management of patients with gastroesophageal symptoms who do not respond adequately to proton pump inhibitor (PPI) therapy, treatment of patients with nonvariceal upper gastrointestinal bleeding, prevention of stress-related mucosal bleeding, optimal treatment and prevention of NSAID-related gastrointestinal injury, and optimal combination of antisecretory and antibiotic therapy for the eradication of Helicobacter pylori infection. A number of new drugs are currently being investigated to provide a significant advance on current treatments. Some of them (namely potassium-competitive acid blockers (P-CABs) and CCK₂-receptor antagonists) have already reached clinical testing while some others (like the antigastrin vaccine, H₃-receptor ligands or gastrin-releasing peptide receptor antagonists) are still in preclinical development and need the proof of concept in human beings. Of the current approaches to reduce acid secretion, P-CABs and CCK₂-receptor antagonists hold the greatest promise, with several compounds already in clinical trials. Although the quick onset of action of P-CABs (i.e. a full effect from the first dose) is appealing, the results of phase II studies with one such agent (namely AZD0865) did not show any advantages over esomeprazole. Thanks to their limited efficacy and the development of tolerance it is unlikely that CCK₂ antagonists will be used alone as antisecretory compounds but, rather, their combination with PPIs will be attempted with the aim of reducing the long-term consequences of hypergastrinemia. While H₂-receptor antagonists (especially soluble or over-the-counter formulations) will become the ‘antacids of the third millennium’ and will be particularly useful for on-demand symptom relief, clinicians will continue to rely on PPIs to control acid secretion in GERD and other acid-related diseases. In this connection, several new PPI formulations have been developed and two novel drugs (namely ilaprazole and tenatoprazole) are being studied in humans. The recently introduced immediate-release (IR) omeprazole formulation (currently available only in the USA) quickly increases intragastric pH and, given at bedtime, seems to achieve a better control of nocturnal acidity. IR formulations of other PPIs (including the investigational ones) will probably be available in the future and will enlarge our therapeutic armamentarium. Amongst the novel PPIs, tenatoprazole appears to be a true advance in the acid suppression therapy. Its long half-life (the longest among the available compounds) and longer duration of antisecretory action, with no difference between day and night, will allow the drug to go beyond the intrinsic limitations of currently available PPIs. Thanks to its favorable pharmacokinetics, the sodium salt of S-tenatoprazole is being developed and the preliminary results indicate that this drug has the potential to address unmet clinical needs. Although some decades have elapsed since the introduction of effective and safe antisecretory drugs in clinical practice and their use has stood the test of time, the ongoing research will further provide the clinician with more effective means of controlling acid secretion.