Introduction

The Deutsche Gastroenterologie, Verdauungs-und Stoffwechselkrankheiten (DGVS) guideline, issued in March 2023 in Germany, recommends limiting PPI therapy to 4-8 weeks’ duration with aim of reducing unnecessary long-term use and potential adverse events, where an appropriate long-term indication is absent. Doses of long-term PPI should be regularly reviewed with the aim of prescribing minimum effective dose.

Aims & Methods

This study aims to assess the impact of targeted educational intervention using a General Practitioner (GP) alerting system at the point of prescription on recent PPI deprescribing guidelines. The study also sorts to identify patient prescribed PPIs while observing PPI prescription patterns pre and post guideline release.

A 12-month non-interventional real-world study was carried out leveraging GP alerting messages in the electronic medical record (EMR) containing non-commercial short messages on latest guidance, recommendations, and peer-reviewed publications around PPI deprescribing in the management of Gastroesophageal reflux disease (GORD) and upper GI conditions. Baseline for this study was January to March 2023.
This study spans 54% of primary care practices in Germany with anonymised prescription data of GPs in 2400 private GP practices equipped with a GP information system. Data analysis was conducted in patients with ICD codes for uncomplicated reflux and diagnosed GORD to determine impact of this intervention on PPI prescription by comparing prescription numbers in terms of pack sizes, diagnosis codes and number of GPs reached monthly.

Results

Over the 12 months period, an average of 333 and 65 GPs were reached monthly for diagnosed GORD and uncomplicated reflux respectively. While there was variation in number of GPs reached monthly, analysis revealed a statistical significant difference in high numbers of PPI prescriptions without indicated diagnosis; mean difference of 15 GPs against those with diagnosis code (95%Cl: 9.7-20.10; P<0.001) for uncomplicated reflux and 47 GPs for diagnosed GORD (95%Cl: 19.7-74.3; P<0.0017). The ratio of patients with an ICD code per GP reached ranged from 0.34 to 0.47 for uncomplicated reflux and diagnosed GORD indicating that less than half of the patients per physician had documented diagnosis justifying PPI use. This highlights significant gap in guideline adherence. However, for diagnosed GORD, percentage of patients with diagnosis rose by approximately 10% from Q1 to Q4.
An analysis of the data also showed consistent large pack sizes being prescribed for both uncomplicated Reflux (ICD12) and Diagnosed GORD (ICD K21.0 and K21.9). For uncomplicated reflux, it was found that 86% of prescriptions after the intervention were for >3 months while uncomplicated reflux rose to 100%. This is consistent with the findings of Plehhova 2023¹, which found that between 2020 to 2021, more than 60% of PPI prescriptions were for > 3 months and Rückert-Eheberg 2022 which described high proportions of off-label use in Bavaria². This study also found that patients with diagnosed GORD and with uncomplicated reflux were often prescribed doses larger than 20mg, both before and after the messaging intervention.

Conclusion

Findings from this study suggest that a significant proportion of PPI prescriptions do not align with current guideline recommendations. This emphasises the need for continuous and multidimensional improvement strategies and interventions on alignment of prescribing practice with guidelines, particularly in high-pressure primary care settings.

References

^1. Plehhova K, Haering M, Wray J, Coyle C, Ibáñez E, Kostev K. Prescribing Patterns of Proton Pump Inhibitors in Germany: A Retrospective Study Including 472 146 Patients. J Prim Care Community Health. 2023 Jan-Dec;14:21501319231221002. doi: 10.1177/21501319231221002. PMID: 38142444; PMCID: PMC10749518.

²Rückert-Eheberg IM, Nolde M, Ahn N, Tauscher M, Gerlach R, Güntner F, Günter A, Meisinger C, Linseisen J, Amann U, Baumeister SE. Who gets prescriptions for proton pump inhibitors and why? A drug-utilization study with claims data in Bavaria, Germany, 2010-2018. Eur J Clin Pharmacol. 2022 Apr;78(4):657-667. doi: 10.1007/s00228-021-03257-z. Epub 2021 Dec 8. PMID: 34877614; PMCID: PMC8927002.

Disclosure

All authors disclose that they are employees of Reckitt Benckiser (UK and Germany)

Introduction

Fecal calprotectin (FC) is a key non-invasive biomarker used to monitor inflammatory bowel disease (IBD). Despite its clear clinical value, patient adherence to the test remains suboptimal, mainly due to reluctance related to stool collection. The objective of the ACCALMI study was to compare the acceptability of a new stool collection device, similar to the one used for fecal immunochemical tests (FIT), with a standard stool container, and to evaluate its impact on patient compliance.

Aims & Methods

In this prospective, single-center study, 156 patients with an established diagnosis of IBD and who had been prescribed an FC test as part of their routine care, were randomly assigned to either the standard container group or the alternative device group (Procise Stool Collection Device™), which includes a collection tube with a thin spiral-shaped probe facilitating stool collection. Acceptability was assessed using a 4-category ordinal scale (from "poor" to "very good") and a visual analog scale (VAS, from 0 to 10). Analyses were conducted in both per-protocol and intention-to-treat (ITT) populations, with missing data handled using the maximum bias method. Factors associated with improved FC acceptability, and compliance with FC testing, were analyzed.

Results

The alternative collection device significantly improved acceptability as measured by the ordinal scale (odds ratio [OR] 2.69; p < 0.001). In the alternative group, acceptability ratings were significantly higher with only 1.4% versus 7.0% rating it as ‘poor’, 12.5% versus 46.6% as ‘average’, 66.7% versus 40.8% as ‘good’, and 19.4% versus 5.6% as ‘very good’. Measured using the VAS, the average acceptability was 7.9/10 in the group using the alternative device compared to 6.1/10 in the standard group, with a significant difference of 30.4% (95% CI [19.7 - 44.7%], p < 0.001), although it did not reach the threshold of 30% that was set a priori. The ITT analysis led to the same conclusions. Among the patients who had already undergone FC testing and were randomized to the "alternative device" group, 55% indicated a preference for the alternative device, compared to 7.2% for the conventional device, while 37.7% found them similar. Embarrassment and discomfort associated with the standard container were alleviated by the alternative device. A long home-to-hospital distance (> 50 km) and the use of the alternative device were the only factors associated with better acceptability in the multivariate analysis. Compliance was similar between both groups and remarkably high (92%).

Conclusion

The ACCALMI study demonstrated that the alternative stool collection device, similar to the one used in FIT for colorectal cancer screening, is more accepted by IBD patients than the standard container, thus improving the acceptability of FC testing. These findings support the integration of patient-centered innovations in diagnostic and follow-up testing to improve the monitoring of IBD.

Disclosure

Acknowledgments: Collaboration with Biosynex®.

Introduction

Barrett Esophagus (BE) is a pre-cancerous esophageal condition caused by chronic uncontrolled gastro-esophageal reflux disease (GERD). The goal of Proton Pump Inhibitors (PPIs) therapy in BE patients is to effectively achieve symptoms control. However, BE patient tend to be asymptomatic or to under-report acid-related symptoms. Furthermore, previous evidence in Literature showed that optimal control of esophageal acid exposure, as objectively assessed by an on-therapy 24h pH-impedance monitoring (24h MII-pH) is able to decrease COX-2 expression in esophageal biopsy of BE patients [1]. In spite of that, to date, current guidelines [2] suggest the use of a standard dose once daily PPI for chemoprevention in BE patients and do not advise for evaluating the effectiveness of therapy, by means of an on-therapy 24h MII-pH.

Aims & Methods

This is a prospective study involving consecutive BE patients referred to our tertiary center. The diagnosis of non-dysplastic BE was confirmed in all patients through endoscopic and histological assessment by a single experienced endoscopist. After the endoscopy, patients were prescribed therapy with full dose PPIs (either esomeprazole or pantoprazole 40 mg b.i.d.). After one month of PPI therapy, a high-resolution manometry (HRM) and on-therapy 24h MII-pH were performed. GERD refractory patients without BE matched for age, gender and therapy (drug and dose) were used as controls. Data are expressed as mean±SD.

Results

Twenty-five BE patients (16 M, 49±18 years) were enrolled. Fourteen BE patients showed a pathological 24h MII-pH compared to only 4 patients with refractory GERD (56 vs 16%; p=0.001). In both populations, the gastric acid exposure time was sub-optimally controlled by PPI therapy (44±24% vs 50±26% in BE and GERD patients; p=NS). In BE patients, however, total and upright esophageal Acid Exposure Time (AET) were significantly higher and reached pathological values as compared to refractory GERD patients (8.4±11.1% vs 2±3% and 6±6.5% vs 1.7±2.1%, both p<0.01). Total distal and acid refluxes were not significantly different between the two groups (52±30 vs 38±22 and 32±29 vs 21±16, p=NS). Nonetheless, when comparing the duration of the longest reflux episode, BE patients showed significantly longer reflux episodes compared to refractory GERD (33.7±41.4 vs 8.3±12.4 minutes, p=0.02) and more ineffective esophageal swallows at HRM (49±42% vs18±25%; p=0.006).

Conclusion

In our hands, more than half of asymptomatic BE patients show persistently abnormal AET despite PPI therapy. This could be explained by prolonged reflux episodes and a worsened esophageal clearance and motility compared to GERD patients, despite the similar gastric acid exposure time and number of acid refluxes. In BE patients, we found a consistent risk of underestimating the esophageal acid burden by simply relying on patients’ symptoms. Although, further larger studies are needed to validate our results, an on-therapy 24h MII-pH could guide the choice of the most adequate acid-suppressive therapy, by objectively measuring AET values.

References

1- de Bortoli N, Martinucci I, Piaggi P, et al. Randomised clinical trial: twice daily esomeprazole 40 mg vs. pantoprazole 40 mg in Barrett's oesophagus for 1 year. Aliment Pharmacol Ther. 2011;33(9):1019-1027. doi:10.1111/j.1365-2036.2011.04616.x
2- Weusten BLAM, Bisschops R, Dinis-Ribeiro M, et al. Diagnosis and management of Barrett esophagus: European Society of Gastrointestinal Endoscopy (ESGE) Guideline. Endoscopy. 2023;55(12):1124-1146. doi:10.1055/a-2176-2440

Introduction

Eosinophilic Esophagitis (EoE) is a chronic immune antigen-mediated inflammatory disease, characterised by esophageal dysfunction and eosinophilic infiltration. The pharmacological treatments aim to achieve clinical, endoscopic and histological remission. Recently, a new budesonide orodispersible tablet (BOT) has become available, showing in the registration trials great efficacy compared to placebo in inducing clinical, endoscopic and histological disease remission. Only few real-life data are available in EoE setting.

Aims & Methods

This is a multicentre, prospective, observational study, aimed to evaluate in clinical practice (real-life setting) the safety profile and the clinical, endoscopic and histological effectiveness of BOT in EoE patients. Patients diagnosed with EoE, aged ≥ 18 years, treated with BOT 1mg bid as induction treatment for 12 weeks were enrolled. Clinical, demographic and medication data were collected at baseline. BOT treatment outcomes were evaluated after 12 weeks, considering EoE Endoscopic Reference Score (EREFS) for endoscopic appearance, and peak eosinophilic infiltration for histological assessment. Moreover, the Dysphagia Symptom Questionnaire (DSQ) and Health-Related Quality of Life (HRQoL) were also collected in order to evaluate clinical response.

Results

One-hundred and fifty-two patients (121 male; mean age 35) treated with BOT were enrolled, in 8 Italian Centres and 1 Israelian Centre. The most frequent symptoms at diagnosis were dysphagia (N=119, 78%) and food bolus impaction (N=106, 70%). Allergic comorbidities were present in 105 (69%) of patients. 129 patients were previously treated with PPI, with a positive histological response only in 42 (33%). After 12 weeks of treatment, endoscopic remission was achieved in 54% of patients, with a reduction of the mean EREFS score from 3.1±2 to 1.3±1.1 (p<0.0001). Histological remission was obtained in 91% of patients, with a mean peak of 33.3±29.9 of eosinophils/high power field (HPF) at the baseline vs 3.1±11.3 (p<0.0001). The DSQ shows a significant reduction from 20.3±23.5 vs 4.8±9.6 (p=0.001). HRQoL questionnaire score passed from 119.6±41.8 to 140±40.6 (p=0.02), which demonstrates an improvement in quality of life. Main data are resumed in Table 1. Side effects occurred in 22 out of 151 patients (15.6%), but only four of them needed to stop the treatment with BOT.

Conclusion

This study confirms the effectiveness of the treatment with BOT in the induction of EoE remission in a real-life setting, either considering clinical, endoscopic and histologic outcomes. Our data also showed a good safety profile, with a few patients requiring drug interruption. Further investigations are necessary to evaluate BOT effectiveness in the long-term period.

References

• Miehlke S et al.; International EOS-2 Study Group. Budesonide orodispersible tablets for induction of remission in patients with active eosinophilic oesophagitis: A 6-week open-label trial of the EOS-2 Programme. United European Gastroenterol J. 2022 Apr;10(3):330-343. doi: 10.1002/ueg2.12220.

• Laserna-Mendieta EJ et al, EUREOS and EoE CONNECT research group: Swallowed topical corticosteroids for eosinophilic esophagitis: Utilization and real-world efficacy from the EoE CONNECT registry. United European Gastroenterol J. 2024 Jan 29. doi: 10.1002/ueg2.12533. Epub ahead of print. PMID: 38284792.

Disclosure

Prof. Savarino: Individual Scientific Consultant for Dr. Falk

Introduction

Proton-pump inhibitors (PPIs) are the most prescribed first-line treatment for eosinophilic esophagitis (EoE). However, only around half of patients respond histologically to a double dosage of PPI (1). Pharmacogenetics of PPIs is largely known to depend on CYP2C19 haplotypes (2). Previous studies in EoE have shown promising results to predict PPI response by analyzing genetic variations in CYP2C19 and STAT6 genes, while other single nucleotide variations (SNPs) could play also a role (3).

Aims & Methods

The study aims to analyze the effect of 60 previously described SNPs associated with the response to PPIs in EoE or other diseases, or related to EoE genetics. Those SNPs were genotyped using an Open Array platform on DNA obtained from peripheral blood. Inclusion criteria were patients diagnosed with EoE according to clinical guidelines and treated with PPIs. Exclusion criteria were: response not evaluated under double or higher PPI doses, lack of histopathologic response assessment or unresponsiveness to PPIs before 8 weeks of treatment length. Patients were recruited in 4 Spanish referral hospitals and demographical and clinical data were obtained retrospectively. Patients were classified as non-responders (peak of eosinophils ≥15 per high power field, hpf) or responders (<15 eos/hpf). Chi-square or Fisher’s exact test were used for statistical comparisons. Statistical significance was established for p<0.05.

Results

Overall, 505 patients (75% male and 15% <18 years-old at PPI onset, mean age 34.5 ± 14.9 years) were included; 48% responded to double o higher PPI doses. Omeprazole was the most common PPI (57%). Seventeen percent of patients presented mixed or stricturing EoE phenotypes.
Regarding clinical variables, sex and age did not influence PPI effectiveness. In concordance with previous studies, a lower response rate was found in patients with mixed/structuring compared with inflammatory phenotypes (27% vs 52%, p<0.001). Treatments length over 10 weeks achieved higher effectiveness (p=0.028). Using omeprazole and rabeprazole trended to produce higher effectiveness (p=0.067).
Two SNPs were found to be associated with response to double or higher PPI doses: CYP3A5 rs776746 (p=0.013, intermediate phenotype associating to a lower response rate of 35%, and being present in 14% of patients) and KCNJ2 rs312691 (recessive model, p=0.006, this variant increasing response up to 69%, and being present in 8% of patients).
Since phenotype had a great influence in response to PPIs, patients’ genotypes were analyzed according to this variable. The 2 aforementioned variants had no effect on mixed/stricturing phenotypes, while statistical significance was kept for CYP3A5 rs776746 and KCNJ2 rs312691 in patients with inflammatory phenotypes (p=0.007 and p=0.005, respectively). For patients with mixed/stricturing phenotypes, the presence of variants in chr14 rs7144958 (dominant model), STAT6 rs3024974 (recessive model) or being a CYP2C19 rapid/ultrarapid metabolizer (frequency of 18%, 19% and 28% in this type of patients, respectively) produced a trend to unresponsiveness to PPI (93%, p=0.097; 92% p=0.100; and 86%, p=0.094, respectively).
On the other hand, when sub-groups were created according to PPI drug, the use of esomeprazole in patients carrying the CYP3A5 rs776746 variant further reduced the response rate to only 19% (p=0.072).

Conclusion

We have identified two SNPs affecting the response to double or higher doses of PPI in EoE patients with inflammatory phenotype and three SNPs that may decrease PPI effectiveness in patients with mixed or stricturing phenotypes.

References

1. Laserna-Mendieta EJ, Casabona S, Guagnozzi D, et al. Efficacy of Proton Pump Inhibitor Therapy for Eosinophilic Oesophagitis in 630 Patients: Results from the EoE Connect Registry. Aliment Pharmacol Ther 2020, 52:798–807.
2. Lima JJ, Thomas CD, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing. Clin Pharmacol Ther 2021, 109:1417–1423.
3. Rodriguez-Alcolado L, Navarro P, Arias-Gonzalez L, et al. Proton-Pump Inhibitors in Eosinophilic Esophagitis: A Review Focused on the Role of Pharmacogenetics. Pharmaceutics 2024, 16:487.

Introduction

The available evidence on the epidemiology of acute pancreatitis (AP) is primarily based on older studies conducted in other countries, limiting its applicability to local settings. This study aims to provide updated data on the clinical characteristics and outcomes of patients with AP in our region thereby improving understanding and management of the disease.

Aims & Methods

A retrospective analysis was conducted on a prospective database comprising a cohort of 526 patients with acute pancreatitis (AP), consecutively included between March 2017 and June 2019 at a tertiary care hospital. Systematic laboratory testing was performed at admission and again at 48 hours. Clinical management followed standard practice guidelines, including routine abdominal ultrasound after admission and abdominal CT scan in cases of diagnostic uncertainty, clinical deterioration, or lack of improvement. Diagnosis and classification were based on the revised 2012 Atlanta classification.

Results

The most frequent etiology of AP in our setting was biliary lithiasis (65.9%), followed by idiopathic (15.4%) and alcohol-related causes (8.4%). Severe AP accounted for 9% of cases, while 14.3% were classified as moderately severe. Up to 20.2% of patients developed local complications; however, only 4.9% presented with pancreatic necrosis. SIRS was observed in 18.7% of patients at admission, decreasing to 8.7% at 48 hours. Only 3.7% of patients required ICU admission (Table 1). Factors such as smoking, ERCP, antibiotic therapy, acute cholangitis, and SIRS showed significant differences across different etiological groups.

Conclusion

Acute pancreatitis (AP) is a common condition that imposes a significant healthcare burden. Determining the etiology of AP at admission is important not only from an epidemiological standpoint but also due to its profound implications for patient prognosis.
Contrary to what has been reported in the literature, the second most frequent cause of AP in our cohort was idiopathic, surpassing alcohol-related cases. In line with other studies, we observed significant differences between biliary and alcohol-related etiologies regarding smoking habits, development of acute cholangitis, need for ERCP, and use of antibiotic therapy. Patients with alcohol-related AP were significantly more likely to present with SIRS at admission. However, we did not find statistically significant differences in other key clinical outcomes, although patients with alcohol-related AP appeared to have a higher, but not statistically significant, risk of developing local complications, pancreatic necrosis, and SIRS at 48 hours.
This study highlights the importance of tailoring management strategies according to etiology to optimize clinical outcomes.

References

1. Wang, G. J., Gao, C. F., Wei, D., Wang, C., & Ding, S. Q. (2009). Acute pancreatitis: etiology and common pathogenesis. World journal of gastroenterology, 15(12), 1427–1430.
2. Petrov, M. S., & Yadav, D. (2019). Global epidemiology and holistic prevention of pancreatitis. Nature reviews. Gastroenterology & hepatology, 16(3), 175–184.
3. Iannuzzi, J. P., King, J. A., Leong, J. H., Quan, J., Windsor, J. W., Tanyingoh, D., Coward, S., Forbes, N., Heitman, S. J., Shaheen, A. A., Swain, M., Buie, M., Underwood, F. E., & Kaplan, G. G. (2022). Global Incidence of Acute Pancreatitis Is Increasing Over Time: A Systematic Review and Meta-Analysis. Gastroenterology, 162(1), 122–134.

Introduction

5-HT3 receptor antagonists are a second line treatment for irritable bowel syndrome with predominant diarrhoea (IBS-D), but there is no evidence on their efficacy for functional diarrhoea (FDr) (Savarino, 2022). Randomized controlled trials show that ondansetron seems to be effective in treating IBS symptoms (Garsed 2014, Gunn 2023), but real-life data are lacking.

Aims & Methods

Our aim was to study the clinical response to ondansetron in patients with IBS-D or FDr in a real-life setting. A retrospective analysis on consecutive patients (December 2014 – February 2024) meeting criteria for IBS-D or FDr according to Rome III criteria was conducted in a single Neurogastroenterology outpatient clinic. Only patients prescribed with ondansetron were included. A standardized template was used to collect clinical data and patient-reported response to treatment. Ondansetron was prescribed at initial dosage of 4mg 1 tablet every other day with the possibility of increasing the dosage up to 6 tablets/daily. Clinical response was defined as (i) an improvement in the number of bowel movements per day vs baseline and (ii) firmer stool consistency (Bristol stool form types 3 and 4, ‘normal’).

Results

Ninety-four patients (female 68.1%, mean age 45 ±15 years old) were included. Among them, 77 (82%) were diagnosed with IBS-D and 17 (18%) with FDr. The mean follow-up duration was 19.1 months (SD±16.71). Seventy patients (74.5%) achieved a clinical response to ondansetron. Response was maintained with ondansetron at a mean dosage of 2.5 tablets/daily (SD±1.5) for a mean follow-up duration of 23.5±17 months. There was no significant difference between the number of IBS-D and FDr patients who responded to ondansetron (table 1). Patients with IBS-D reported a significantly higher improvement in abdominal pain vs baseline (p<0.01, table 1). Twenty-four patients (25.5%) did not respond to ondansetron. Adverse events were significantly higher in non-responders compared to responders (p=0.02, table 1).

Table 1. Main characteristics of responders and non-responders at baseline and post-treatment

Conclusion

This is the first real-life study assessing the response to ondansetron in IBS-D or FDr patients showing long-term reduction in the frequency of bowel movements, improvement in faecal consistency, and reduction in abdominal pain. Our data suggest that ondansetron can be used in FDr patients.

References

1. Savarino E, Zingone F, Barberio B, Marasco G, Akyuz F, Akpinar H, Barboi O, Bodini G, Bor S, Chiarioni G, Cristian G, Corsetti M, Di Sabatino A, Dimitriu AM, Drug V, Dumitrascu DL, Ford AC, Hauser G, Nakov R, Patel N, Pohl D, Sfarti C, Serra J, Simrén M, Suciu A, Tack J, Toruner M, Walters J, Cremon C, Barbara G. Functional bowel disorders with diarrhoea: Clinical guidelines of the United European Gastroenterology and European Society for Neurogastroenterology and Motility. United European Gastroenterol J. 2022 Jul;10(6):556-584.
2. Garsed K, Chernova J, Hastings M, Lam C, Marciani L, Singh G, Henry A, Hall I, Whorwell P, Spiller R. A randomised trial of ondansetron for the treatment of irritable bowel syndrome with diarrhoea. Gut. 2014 Oct;63(10):1617-25.
3. Gunn D, Topan R, Barnard L, Fried R, Holloway I, Brindle R, Corsetti M, Scott M, Farmer A, Kapur K, Sanders D, Eugenicos M, Trudgill N, Whorwell P, Mclaughlin J, Akbar A, Houghton L, Dinning PG, Aziz Q, Ford AC, Farrin AJ, Spiller R. Randomised, placebo-controlled trial and meta-analysis show benefit of ondansetron for irritable bowel syndrome with diarrhoea: The TRITON trial. Aliment Pharmacol Ther. 2023 Jun;57(11):1258-1271.