Real-world outcomes associated with vonoprazan-based versus proton pump inhibitor-based therapy for Helicobacter pylori infection in Japan.

Background: Japanese guidelines recommend triple therapy with vonoprazan or a proton pump inhibitor (PPI) in combination with antibiotics to treat Helicobacter pylori (H. pylori) infection. While studies have shown improved eradication rates and reduced costs with vonoprazan versus PPIs, there is little data describing healthcare resource use (HCRU) and treatment patterns. Objectives: To compare patients treated with a vonoprazan-based or PPI-based regimen for H. pylori infection in Japan in terms of their characteristics, HCRU, healthcare costs, clinical outcomes, and treatment patterns. Design: Retrospective matched cohort. Methods: We used data from the Japan Medical Data Center claims database (July 2014-January 2020) to identify adult patients with H. pylori infection and a first observed use of vonoprazan or a PPI in 2015 or later (index date). Patients prescribed a vonoprazan-based or a PPI-based regimen were matched 1:1 using propensity score matching. HCRU, healthcare costs, diagnostic tests, a proxy for H. pylori eradication (i.e. no triple therapy with amoxicillin in combination with metronidazole or clarithromycin >30 days after the index date), and second-line treatment were described during the 12-month follow-up period. Results: Among 25,389 matched pairs, vonoprazan-treated patients had fewer all-cause and H. pylori-related inpatient stays and outpatient visits than PPI-treated patients, resulting in lower all-cause healthcare costs [185,378 Japanese yen (JPY) versus 230,876 JPY, p < 0.001]. Over 80% of patients received a post-treatment test for H. pylori. Fewer vonoprazan-treated than PPI-treated patients subsequently received an additional triple regimen for H. pylori infection (7.1% versus 20.0%, p < 0.001) or a prescription for vonoprazan or a PPI as monotherapy (12.4% versus 26.4%, p < 0.001) between 31 days and 12 months after the index date. Conclusion: Patients with H. pylori infection who were treated with vonoprazan-based therapy had lower rates of subsequent H. pylori treatment, lower overall and H. pylori-related HCRU, and lower healthcare costs than patients treated with PPI-based therapy.

Physiologically-based pharmacokinetic modelling to predict intragastric rifabutin concentrations in the treatment of Helicobacter pylori infection.

BACKGROUND: Sustained intragastric antibiotic exposure is important for Helicobacter pylori eradication, yet little is known about gastric pharmacology of commonly used H. pylori regimens. For rifabutin, differing intragastric concentrations based on dosing regimen may account for differences in reported eradication rates. AIM: To compare intragastric rifabutin concentrations between low-dose rifabutin (50 mg three time daily; as in RHB-105) and generically dosed rifabutin 150 mg once daily, 150 mg twice daily, and 300 mg once daily using a validated Physiologically-based pharmacokinetic (PBPK) model. METHODS: We obtained plasma pharmacokinetic data from the RHB-105 clinical development programs and used it to develop and validate a whole-body PBPK model using PK-SIM software. We modified the existing rifabutin model to include the impact of omeprazole on gastric pH and emptying time. Modelled intragastric rifabutin exposure was expressed as the time that each regimen maintained its concentration ≥MIC90 . RESULTS: Rifabutin 50 mg three times daily achieved significantly longer times with intragastric concentration above MIC90 (22.3 ± 1.1 h) than 150 mg once daily (8.3 ± 1.7 h), 150 mg twice daily (16.3 ± 2.3 h), or 300 mg once daily (8.5 ± 1.9 h) while providing the lowest mean maximal plasma concentration and mean area under the plasma concentration-time curve of all regimens studied. CONCLUSIONS: PBPK modelling showed rifabutin 50 mg three times daily had higher intragastric exposure times than 150 mg once daily or twice daily, or 300 mg once daily. This low-dose rifabutin regimen provides the highest potential for H. pylori eradication while minimising systemic rifabutin exposure.

A translational pharmacokinetic/pharmacodynamic approach supports optimal vonoprazan dosing for erosive oesophagitis and Helicobacter pylori infection.

BACKGROUND: Treatment of acid-related disorders relies on gastric acid suppression. The percentage of time intragastric pH is >4 (pH >4 holding time ratio [HTR]) is important for healing erosive oesophagitis; and the pH >6 HTR is critical for eradication of Helicobacter pylori infection, as bacterial replication is active and antibiotic effectiveness is optimised. Vonoprazan, a potassium-competitive acid blocker approved in the USA and other countries, suppresses gastric acid secretion in a predictable, rapid and consistent manner, extended over prolonged periods. AIM: To explore the relationship between vonoprazan exposure and pH HTR through a pharmacokinetic/pharmacodynamic (PK/PD) model. METHODS: We pooled data from Phase 1 studies with intragastric pH measurements. Pharmacokinetic profiles were predicted for study participants using an existing population pharmacokinetic model. Pharmacokinetic and pharmacodynamic data were merged, and three direct-link PK/PD models were derived and used to simulate pH HTRs with between-participant variability for pH >4, >5 and >6, for vonoprazan doses of 20 mg once and twice daily. RESULTS: We used data from five Phase 1 studies to derive the PK/PD model. These included 245 participants (95.1% male, 50.6% Japanese and 49.4% non-Asian). Pre-dose, the mean pH >4 HTR was 6.4%, pH >5 3.2% and pH >6 1.2%. After 7 days of dosing, simulations predicted pH >4 HTRs of 89.7% and 98.1%, and pH >6 HTRs of 53.1% and 75.3%, for vonoprazan 20 mg once and twice daily, respectively. CONCLUSIONS: Vonoprazan 20 mg once- and twice-daily dosing demonstrated high, dose-dependent, 24-hour intragastric acid control in this PK/PD model, supporting clinical efficacy data in patients with acid-related disorders.

Erythromycin Improves the Quality of Esophagogastroduodenoscopy in Upper Gastrointestinal Bleeding: A Network Meta-Analysis.

BACKGROUND/AIM: Upper gastrointestinal bleeding (UGIB) usually requires esophagogastroduodenoscopy (EGD) for diagnostic and-potentially-therapeutic purposes. However, blood within the gastric lumen may hinder the procedure. Administration of prokinetics like erythromycin has shown efficacy. This network meta-analysis investigates the efficacy of this intervention prior to EGD. METHODS: We performed a systematic literature search of Embase, PubMed/Medline, and other databases through March 8, 2022 to include randomized controlled trials (RCTs) comparing prokinetic use in EGD for UGIB. We used the DerSimonian-Laird approach to pool data and compare outcomes including need for repeat endoscopy and blood transfusion. Pooled prevalence of proportional outcomes, 95% confidence interval (CI), and p-values were calculated. RESULTS: We included eight RCTs with four distinct intervention groups (erythromycin, placebo to erythromycin, nasogastric (NG) lavage and NG lavage + erythromycin) published between 2002 and 2020 with a total of 721 patients (mean age 60.0 ± 3.1 years; 73.2% male). The need for second look endoscopy was significantly lower with erythromycin than placebo (relative risk: 0.42, CI 0.22-0.83, p = 0.01). Using the frequentist approach, the combination of NG lavage and erythromycin (92.2) was rated highest, followed by erythromycin alone (73.1) for higher rates of empty stomach. Erythromycin was rated highest for lower need for packed red blood cell transfusion (72.8) as well as mean endoscopy duration (66.0). CONCLUSION: Erythromycin improved visualization at EGD, reduced requirements for blood transfusion and repeat EGD, and shortened hospital stay. The combination of erythromycin and NG lavage showed reduced mortality.

Rates of Antimicrobial Resistance in Helicobacter pylori Isolates From Clinical Trial Patients Across the US and Europe.

INTRODUCTION: Guidelines recommend that proton pump inhibitor-based triple regimens with clarithromycin not be used for Helicobacter pylori infection in areas where clarithromycin resistance is ≥15%, or in patients with prior macrolide use. Up-to-date information on local resistance patterns is limited, especially in the US. Here, we report resistance rates to antibiotics commonly used to treat H. pylori from a large study conducted in the US and Europe (pHalcon-HP). METHODS: Gastric mucosal biopsies were collected from adult participants with H. pylori infection during screening. Minimum inhibitory concentrations were determined via agar dilution for clarithromycin, amoxicillin, and metronidazole, with breakpoints ≥1 µg/mL, >0.125 µg/mL, and >8 µg/mL, respectively. Resistance rates were obtained for the US and Europe, and also for US subregions and participating European countries. RESULTS: Resistance rates were established in isolates from 907 participants. Overall, 22.2% were resistant to clarithromycin, 1.2% to amoxicillin, and 69.2% to metronidazole. Resistance in the US and Europe was similar; metronidazole resistance was the most prevalent (50%-79%) and amoxicillin the least (≤5%). In all subregions, ≥15% of isolates were resistant to clarithromycin, except the UK (0/8 isolates). Among clarithromycin-resistant isolates, 75% were also metronidazole-resistant. Two US isolates were resistant to clarithromycin and amoxicillin; one of these was also metronidazole-resistant. DISCUSSION: The resistance rates observed in this study argue against the continued empiric use of proton pump inhibitor-based triple therapy containing clarithromycin, per treatment guidelines, and highlight the need for antibiotic resistance surveillance and novel treatment strategies for H. pylori infection in the US and Europe.

Second exam of right colon improves adenoma detection rate: Systematic review and meta-analysis of randomized controlled trials.

Background and study aims A second examination of the right colon, either as a second forward view (SFV) or as retroflexion (RF) in the cecum, can increase adenoma detection rate (ADR) in the right colon. In this meta-analysis, we have evaluated the role of a second examination of the right colon in improving ADR. Methods We reviewed several databases to identify randomized controlled trials that compared right colon SFV with no SFV, and RCTs that compared SFV with RF in the right colon, and reported data on ADR. Our outcomes of interest were ADR and polyp detection rate (PDR) with SFV vs no SFV, right colon and total withdrawal times, and additional ADR and PDR with SFV vs RF. For categorical variables, we calculated pooled risk ratios (RRs) with 95 % confidence intervals (CIs); for continuous variables, we calculated standardized mean difference (SMD) with 95 % CI. Data were analyzed using random effects model. Results We included six studies with 3901 patients. Comparing SFV with no SFV, right colon ADR and PDR were significantly higher in the SFV group: ADR (RR [95 % CI] 1.39 [1.22,1.58]) and PDR (RR [95 % CI] 1.47 [1.30, 1.65]). We found no significant difference in right colon withdrawal time (SMD [95 % CI] 1.54 [-0.20,3.28]) or total withdrawal time (SMD (95 % CI) 0.37 [-0.39,1.13]) with and without SFV. We found no significant difference in additional ADR between SFV and RF. Conclusions SFV of the right colon significantly increases right-sided and overall ADR.

Patient journey in erosive oesophagitis: real-world perspectives from US physicians and patients.

OBJECTIVE: Management of erosive oesophagitis (EE) remains suboptimal, with many patients experiencing incomplete healing, ongoing symptoms, and relapse despite proton pump inhibitor (PPI) treatment. The Study of Acid-Related Disorders investigated patient burden of individuals with EE in a real-world setting. DESIGN: US gastroenterologists (GIs) or family physicians (FPs)/general practitioners (GPs) treating patients with EE completed a physician survey and enrolled up to four patients with EE for a patient survey, with prespecified data extracted from medical records. RESULTS: 102 GIs and 149 FPs/GPs completed the survey; data were available for 73 patients (mean age at diagnosis, 45.4 years). Omeprazole was healthcare professional (HCP)-preferred first-line treatment (60.8% GIs; 56.4% FPs/GPs), and pantoprazole preferred second line (29.4% and 32.9%, respectively). Price and insurance coverage (both 55.5% HCPs) and familiarity (47.9%) key drivers for omeprazole; insurance coverage (52.0%), price (50.0%), familiarity (48.0%), initial symptom relief (46.0%), and safety (44.0%) key drivers for pantoprazole. Only 49.3% patients took medication as instructed all the time; 56.8% independently increased medication frequency some of the time. Despite treatment, 57.5% patients experienced heartburn and 30.1% regurgitation; heartburn was the most bothersome symptom. 58.9% patients believed that their symptoms could be better controlled; only 28.3% HCPs were very satisfied with current treatment options. 83.6% patients wanted long-lasting treatment options. Fast symptom relief for patients was a top priority for 66.1% HCPs, while 56.6% would welcome alternatives to PPIs. CONCLUSION: This real-world multicentre study highlights the need for new, rapidly acting treatments in EE that reduce symptom burden, offer durable healing and provide symptom control.

Vonoprazan Triple and Dual Therapy for Helicobacter pylori Infection in the United States and Europe: Randomized Clinical Trial.

BACKGROUND & AIMS: Novel, effective treatments for Helicobacter pylori infection are needed. This study evaluated the efficacy of vonoprazan, a potassium-competitive acid blocker, vs standard treatment on H pylori eradication in the United States and Europe. METHODS: In a randomized, controlled, phase 3 trial, treatment-naïve adults with H pylori infection were randomized 1:1:1 to open-label vonoprazan dual therapy (20 mg vonoprazan twice daily; 1 g amoxicillin 3 times daily), or double-blind triple therapy twice a day (vonoprazan 20 mg or lansoprazole 30 mg; amoxicillin 1 g; clarithromycin 500 mg) for 14 days. The primary outcome was noninferiority in eradication rates in patients without clarithromycin- and amoxicillin-resistant strains (noninferiority margin = 10%). Secondary outcomes assessed superiority in eradication rates in clarithromycin-resistant infections, and in all patients. RESULTS: A total of 1046 patients were randomized. Primary outcome eradication rates (nonresistant strains): vonoprazan triple therapy 84.7%, dual therapy 78.5%, vs lansoprazole triple therapy 78.8% (both noninferior; difference 5.9%; 95% confidence interval [CI], -0.8 to 12.6; P < .001; difference -0.3%; 95% CI, -7.4 to 6.8; P = .007, respectively). Eradication rates in clarithromycin-resistant infections: vonoprazan triple therapy 65.8%, dual therapy 69.6%, vs lansoprazole triple therapy 31.9% (both superior; difference 33.9%; 95% CI, 17.7-48.1; P < .001; difference 37.7%; 95% CI, 20.5-52.6; P < .001, respectively). In all patients, vonoprazan triple and dual therapy were superior to lansoprazole triple therapy (80.8% and 77.2%, respectively, vs 68.5%, difference 12.3%; 95% CI, 5.7-18.8; P < .001; difference 8.7%; 95% CI, 1.9-15.4; P = .013). Overall frequency of treatment-emergent adverse events was similar between vonoprazan and lansoprazole regimens (P > .05). CONCLUSION: Both vonoprazan-based regimens were superior to proton pump inhibitor-based triple therapy in clarithromycin-resistant strains and in the overall study population. CLINICALTRIALS: gov; NCT04167670.

Pharmacodynamics and Pharmacokinetics of the Potassium-Competitive Acid Blocker Vonoprazan and the Proton Pump Inhibitor Lansoprazole in US Subjects.

INTRODUCTION: We assessed pharmacodynamics and pharmacokinetics of a potassium-competitive acid blocker and proton pump inhibitor in US subjects. METHODS: Healthy adults were randomized to 7-day periods of vonoprazan 20 mg once daily followed by lansoprazole 30 mg once daily or the reverse order, separated by ≥ 7 days of washout. RESULTS: Vonoprazan (N = 40) had higher proportions of 24-hour periods with intragastric pH > 4 than lansoprazole (N = 41,38) on day 1 (62.4% vs 22.6%, P < 0.0001) and day 7 (87.8% vs 42.3%, P < 0.0001). Separation in pH started ∼2.5 hours after the first dose. DISCUSSION: Vonoprazan provided more rapid and potent inhibition of intragastric acidity than lansoprazole in US subjects.

Metal versus plastic stents in the management of benign biliary strictures: systematic review and meta-analysis of randomized controlled trials.

Benign biliary strictures (BBS) are usually treated with endoscopic retrograde cholangiopancreatography (ERCP) with the placement of multiple plastic stents (MPS) or a covered self-expandable metal stent (CSEMS). In this meta-analysis, we compared the efficacy and safety of MPS and CSEMS in the management of BBS. We reviewed several databases from inception to 28 April 2021 to identify RCTs that compared MPS with CSEMS in the management of BBS. Our outcomes of interest were stricture resolution, stricture recurrence, adverse events, stent migration and mean number of ERCPs to achieve stricture resolution. Data were analyzed using a random-effects model. We included eight RCTs with 524 patients. We found no significant difference in the rate of stricture resolution (risk ratio, 1.02; 95% CI, 0.96-1.10), stricture recurrence (risk ratio, 1.68; 95% CI, 0.72-3.88) or adverse events (risk ratio, 1.17; 95% CI, 0.73-1.87) between groups. Mean number of ERCPs was significantly lower in the CSEMS group (SMD, -1.99; 95% CI, -3.35 to -0.64). The rate of stent migration was significantly higher in the CSEMS group. CSEMS are comparable in efficacy and safety to MPS in the management of BBS but require fewer ERCPs to achieve stricture resolution.

Proton pump inhibitor treatment initiated prior to endoscopic diagnosis in upper gastrointestinal bleeding.

BACKGROUND: Upper gastrointestinal (GI) bleeding is a common reason for emergency hospital admission. Proton pump inhibitors (PPIs) reduce gastric acid production and are used to manage upper GI bleeding. However, there is conflicting evidence regarding the clinical efficacy of proton pump inhibitors initiated before endoscopy in people with upper gastrointestinal bleeding. OBJECTIVES: To assess the effects of PPI treatment initiated prior to endoscopy in people with acute upper GI bleeding. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Embase and CINAHL databases and major conference proceedings to October 2008, for the previous versions of this review, and in April 2018, October 2019, and 3 June 2021 for this update. We also contacted experts in the field and searched trial registries and references of trials for any additional trials. SELECTION CRITERIA: We selected randomised controlled trials (RCTs) that compared treatment with a PPI (oral or intravenous) versus control treatment with either placebo, histamine-2 receptor antagonist (H2RA) or no treatment, prior to endoscopy in hospitalised people with uninvestigated upper GI bleeding. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed study eligibility, extracted study data and assessed risk of bias. Outcomes assessed at 30 days were: mortality (our primary outcome), rebleeding, surgery, high-risk stigmata of recent haemorrhage (active bleeding, non-bleeding visible vessel or adherent clot) at index endoscopy, endoscopic haemostatic treatment at index endoscopy, time to discharge, blood transfusion requirements and adverse effects. We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included six RCTs comprising 2223 participants. No new studies have been published after the literature search performed in 2008 for the previous version of this review. Of the included studies, we considered one to be at low risk of bias, two to be at unclear risk of bias, and three at high risk of bias. Our meta-analyses suggest that pre-endoscopic PPI use may not reduce mortality (OR 1.14, 95% CI 0.76 to 1.70; 5 studies; low-certainty evidence), and may reduce rebleeding (OR 0.81, 95% CI 0.62 to 1.06; 5 studies; low-certainty evidence). In addition, pre-endoscopic PPI use may not reduce the need for surgery (OR 0.91, 95% CI 0.65 to 1.26; 6 studies; low-certainty evidence), and may not reduce the proportion of participants with high-risk stigmata of recent haemorrhage at index endoscopy (OR 0.80, 95% CI 0.52 to 1.21; 4 studies; low-certainty evidence). Pre-endoscopic PPI use likely reduces the need for endoscopic haemostatic treatment at index endoscopy (OR 0.68, 95% CI 0.50 to 0.93; 3 studies; moderate-certainty evidence). There were insufficient data to determine the effect of pre-endoscopic PPI use on blood transfusions (2 studies; meta-analysis not possible; very low-certainty evidence) and time to discharge (1 study; very low-certainty evidence). There was no substantial heterogeneity amongst trials in any analysis. AUTHORS' CONCLUSIONS: There is moderate-certainty evidence that PPI treatment initiated before endoscopy for upper GI bleeding likely reduces the requirement for endoscopic haemostatic treatment at index endoscopy. However, there is insufficient evidence to conclude whether pre-endoscopic PPI treatment increases, reduces or has no effect on other clinical outcomes, including mortality, rebleeding and need for surgery. Further well-designed RCTs that conform to current standards for endoscopic haemostatic treatment and appropriate co-interventions, and that ensure high-dose PPIs are only given to people who received endoscopic haemostatic treatment, regardless of initial randomisation, are warranted. However, as it may be unrealistic to achieve the optimal information size, pragmatic multicentre trials may provide valuable evidence on this topic.

A Population Pharmacokinetic Model of Vonoprazan: Evaluating the Effects of Race, Disease Status, and Other Covariates on Exposure.

Vonoprazan, a potassium-competitive acid blocker, is under investigation in the United States and Europe for the treatment of erosive esophagitis and Helicobacter pylori infection. Population pharmacokinetic (popPK) analysis allows the identification of factors that could affect drug exposure in population subgroups. Here, we report a popPK model based on pooled data sets of available pharmacokinetic (PK) studies in healthy volunteers and patients with gastroesophageal reflux disease, including erosive esophagitis, from Asia and Europe. This model was used to evaluate the impact of different covariates, including race and disease status, on vonoprazan exposure. We analyzed PK data from 746 patients and 410 healthy volunteers from 15 clinical trials using a nonlinear mixed-effects approach to develop the popPK model. Model development focused on characterizing and quantifying the effects of clinical covariates of race (Asian vs non-Asian) and disease status (gastroesophageal reflux disease vs healthy volunteers) on vonoprazan exposure. Identified clinical covariates included fed/fasting status, race, sex, disease status, weight, serum creatinine, and age. The impact of variations in these clinical covariates on exposure to vonoprazan was smaller than the effect of halving or doubling the dose. PK parameters were similar in Asian and non-Asian populations. Variations in weight, age, and race are not predicted to have a clinically relevant impact on vonoprazan exposure or safety and require no changes in vonoprazan dosing. The limited impact of race on exposure suggests that efficacy and safety data for vonoprazan in Asian populations are translatable to non-Asian populations.

Pitfalls of Physician-Directed Treatment of Helicobacter pylori: Results from Two Phase 3 Clinical Trials and Real-World Prescribing Data.

BACKGROUND: Helicobacter pylori (H. pylori) infects ~ 35% of Americans and can lead to serious sequelae if left untreated. Growing evidence indicates that clarithromycin-based therapies (CBT) are becoming increasingly ineffective for treating H. pylori infection. RHB-105 was approved by the US Food and Drug Administration in 2019 for the treatment of H. pylori infection in adults. AIMS: The primary aim of this study was to assess prescribing patterns and associated cure rates of physician-directed therapy for subjects with persistent H. pylori infection after participation in one of two Phase 3 clinical trials (ERADICATE Hp and ERADICATE Hp2). METHODS: We reviewed study reports to identify specific physician-directed regimens selected for subjects whose H. pylori infection was not eradicated. We also conducted a CYP2C19 genotype analysis of subjects who were prescribed CBT. Finally, we analyzed real-world H. pylori retail prescription data and compared these with to the physician-directed therapies in the clinical trials studies. RESULTS: Following ERADICATE Hp, CBT was prescribed for 27/31 (87%) subjects achieving a 59.3% cure rate. Following ERADICATE Hp2, CBT was prescribed for 48/94 (51%) subjects achieving a 60.4% cure rate. Rapid CYP2C19 metabolizers (2/11) had a cure rate of 18.2% with CBT. Real-world prescription data from IQVIA showed more than 80% of prescriptions for H. pylori infection were for CBT. CONCLUSIONS: Rates of CBT use persist despite sub-optimal eradication rates. Since RHB-105 does not contain clarithromycin, it can be prescribed first-line without concerns about clarithromycin resistance or CYP2C19 status. NCT03198507 & NCT01980095.