Publications by Year: 2024

2024

Shah ED, Curley MA, Patel A, Lo WK, Chan WW. Heartburn Relief is the Major Unmet Need for Drug Development in Gastroesophageal Reflux Disease: Threshold Value Analysis. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. Published online 2024. doi:10.1016/j.cgh.2024.01.049

BACKGROUND AND AIMS: Heartburn symptoms contribute to healthcare-seeking among patients with gastroesophageal reflux disease (GERD). Despite clinical guidance, management is often dictated by insurance restrictions. Several potassium-competitive acid blockers (PCAB) are under development as a new class of therapy. We performed economic analyses to align GERD drug development with the needs of gastroenterologists, insurers and patients in a value-based environment.

METHODS: A decision-analytic model was constructed to compare vonoprazan 20mg daily (an example of a potassium-competitive acid blocker[PCAB]), common over-the-counter or prescription proton pump inhibitor (PPI) regimens, and no treatment over a one-year time horizon. Clinical responses were evaluated based on the proportions of heartburn-free days in a recent phase 3 multicenter trial. Healthcare utilization for persistent reflux symptoms was derived from national observational studies compared to healthy controls. Costs and quality-adjusted life years [QALY] were reported.

RESULTS: Without insurance coverage for appropriate therapy, patients spend $4,443 and insurers spend $3,784 on average per year for inadequately treated GERD symptoms. Our model estimates that PCABs could save at least $3,000 in annual costs to patients and insurers, could generate QALY gains (+0.06/year), and could be cost-saving to insurers as a covered option at a price up to $8.57/pill, if these drugs are able to demonstrate similar effectiveness to PPIs in future trials evaluating heartburn relief and erosive esophagitis healing to regulators. Threshold prices reflect pricing after all pharmacy benefits manager rebates and discounts.

DISCUSSION: We demonstrate that aiming GERD-related drug development toward heartburn relief appears critical to align cost-effective incentives for industry and insurers with those of patients and gastroenterologists.

Muftah M, Barshop K, Redd WD, Goldin AH, Lo WK, Chan WW. Baseline Peripheral Eosinophil Count Independently Predicts Proton Pump Inhibitor Response in Eosinophilic Esophagitis. Journal of clinical gastroenterology. 2024;58(3):242-246. doi:10.1097/MCG.0000000000001845

GOALS: To assess the predictive value of baseline peripheral absolute eosinophil counts (AECs) for proton pump inhibitor (PPI) response in eosinophilic esophagitis (EoE).

BACKGROUND: PPI leads to histologic remission in  50% of EoE patients, although there are few distinguishing clinical features between PPI-responsive (PPI-r-EoE) and nonresponsive (PPI-nr-EoE) diseases. Peripheral eosinophilia is present in  50% of EoE cases and is associated with eosinophil density on esophageal biopsy and worse clinical outcomes. The association between peripheral eosinophilia and PPI-responsiveness in EoE remains unclear.

STUDY: This is a retrospective cohort study of adult EoE patients at a tertiary center between 2012 and 2016. All patients underwent twice daily PPI trials for ≥8 weeks followed by repeat esophageal biopsies and were classified as PPI-r-EoE or PPI-nr-EoE based on histologic response (<15 eosinophils/high power field). Baseline peripheral AEC was obtained within 1 month before index endoscopy. Analyses were performed using Fisher exact/Student t test (univariate) and logistic regression (multivariable).

RESULTS: One hundred eighty-three patients (91 PPI-nr-EoE and 92 PPI-r-EoE) were included. Mean peripheral AEC was higher among PPI-nr-EoE patients (0.41 vs 0.24 K/µL, P = 0.013). Baseline peripheral eosinophilia (>0.5 K/µL) was more prevalent among patients with PPI-nr-EoE (70.4% vs 45.5%, P = 0.023) and a history of food impaction (51.9% vs 23.7%, P = 0.0082). On multivariable analyses, peripheral eosinophilia remained an independent predictor for PPI response (adjacent odds ratio = 2.86, CI: 1.07-7.62, P = 0.036) and food impaction (adjacent odds ratio = 2.80, CI: 1.07-7.35, P = 0.037).

CONCLUSIONS: Baseline peripheral eosinophilia independently predicts PPI nonresponse and food impaction in EoE patients. Peripheral AEC may help therapy selection in EoE and prevent delays in achieving histologic remission.

Muftah M, Goldin AH, Barshop K, et al. Twice Daily PPI Induces Higher Remission Rate in Eosinophilic Esophagitis Than Once Daily Regimen Regardless of Total Daily Dose. The American journal of gastroenterology. Published online 2024. doi:10.14309/ajg.0000000000002712

BACKGROUND: The optimal proton pump inhibitor (PPI) regimen for eosinophilic esophagitis (EoE) is unclear. We compared histologic response rates of different dosing combinations.

METHODS: 305 newly-diagnosed EoE patients received standard (omeprazole 20mg daily), once-daily moderate (40mg daily), twice-daily moderate (20mg twice daily), or high (40mg twice daily) dose PPI for ≥8 weeks.

RESULTS: 42.3% achieved histologic response to PPI, with higher rates for twice-daily (moderate:52.8%/high:54.3%) than once-daily (standard:11.8%/moderate:10%) dosing (p<0.0001). On multivariable analysis, twice-daily moderate (aOR:6.75, CI:2.53-18.0,p=0.0008) and high (aOR:12.8, CI:4.69-34.8,p<0.0001) doses independently predicted histologic response.

CONCLUSION: Twice-daily PPI is associated with higher EoE histologic response rates than once-daily regimen.

Shah ED, Ahuja NK, Brenner DM, et al. Optimizing the Management Algorithm for Adults With Functional Constipation Failing a Fiber/Laxative Trial in General Gastroenterology: Cost-Effectiveness and Cost-Minimization Analysis. The American journal of gastroenterology. 2024;119(2):342-352. doi:10.14309/ajg.0000000000002515

INTRODUCTION: Anorectal function testing is traditionally relegated to subspecialty centers. Yet, it is an office-based procedure that appears capable of triaging care for the many patients with Rome IV functional constipation that fail empiric over-the-counter therapy in general gastroenterology, as an alternative to empirical prescription drugs. We aimed to evaluate cost-effectiveness of routine anorectal function testing in this specific population.

METHODS: We performed a cost-effectiveness analysis from the patient perspective and a cost-minimization analysis from the insurer perspective to compare 3 strategies: (i) empiric prescription drugs followed by pelvic floor physical therapy (PFPT) for drug failure, (ii) empiric PFPT followed by prescription drugs for PFPT failure, or (iii) care directed by up-front anorectal function testing. Model inputs were derived from systematic reviews of prospective clinical trials, national cost data sets, and observational cohort studies of the impact of chronic constipation on health outcomes, healthcare costs, and work productivity.

RESULTS: The most cost-effective strategy was upfront anorectal function testing to triage patients to appropriate therapy, in which the subset of patients without anal hypocontractility on anorectal manometry and with a balloon expulsion time of at least 6.5 seconds would be referred to PFPT. In sensitivity analysis, empiric PFPT was more cost effective than empiric prescription drugs except for situations in which the primary goal of treatment was to increase bowel movement frequency. If adopted, gastroenterologists would refer ∼17 patients per year to PFPT, supporting feasibility.

DISCUSSION: Anorectal function testing seems to be an emergent technology to optimize cost-effective outcomes, overcoming testing costs by phenotyping care.

Krause AJ, Kaizer AM, Carlson DA, et al. Validated Clinical Score to Predict Gastroesophageal Reflux in Patients with Chronic Laryngeal Symptoms: COuGH RefluX. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. Published online 2024. doi:10.1016/j.cgh.2024.01.021

BACKGROUND & AIMS: Discerning whether laryngeal symptoms result from gastroesophageal reflux is clinically challenging and a reliable tool to stratify patients is needed. We aimed to develop and validate a model to predict likelihood of gastroesophageal reflux disease (GERD) among patients with chronic laryngeal symptoms.

METHODS: This multicenter international study collected data from adults with chronic laryngeal symptoms that underwent objective testing (upper GI endoscopy and/or ambulatory reflux monitoring) between 3/2018-5/2023. The training phase identified a model with optimal receiver operating characteristic curves, and beta coefficients informed a weighted model. The validation phase assessed performance characteristics of the weighted model.

RESULTS: 856 adults, 304 in training cohort and 552 in the validation cohort, were included. In the training phase the optimal predictive model [AUC 0.68 (95% CI 0.62, 0.74)] - the COuGH RefluX score - consisted of Cough, Overweight/obesity, Globus, Hiatal Hernia, Regurgitation, and male seX with a lower threshold of 2.5 and upper threshold of 5.0 to predict proven GERD. In the validation phase, the COuGH RefluX score had an AUC of 0.67 (0.62, 0.71) with 79% sensitivity and 81% specificity for proven GERD.

CONCLUSIONS: The externally validated COuGH RefluX score is a clinically practical model to predict likelihood of proven GERD. The score classifies most patients with chronic laryngeal symptoms as low/high likelihood of proven GERD, with only 38% remaining as indeterminate. Thus, the COuGH RefluX score can guide diagnostic strategies and reduce inappropriate proton pump inhibitor use or testing for patients referred for evaluation of chronic laryngeal symptoms.

INTRODUCTION: Adenoma per colonoscopy (APC) has recently been proposed as a quality measure for colonoscopy. We evaluated the impact of a novel AI system, compared to standard HD colonoscopy, for APC measurement.

METHODS: This was a U.S. based, multi-center, prospective randomized trial examining a novel AI detection system (EW10-EC02) that enables a real-time colorectal polyp detection enabled with the colonoscope (CAD-EYE™). Eligible average risk subjects (≥45 years) undergoing screening or surveillance colonoscopy were randomized to undergo either CAD-EYE-assisted colonoscopy (CAC) or conventional colonoscopy (CC). Modified Intention-to-treat (mITT) analysis was performed for all patients that completed colonoscopy with primary outcome of APC. Secondary outcomes included positive predictive value (PPV, total number of adenomas divided by total polyps removed) and adenoma detection rate (ADR).

RESULTS: In mITT analysis, of 1031 subjects (age: 59.1+/-9.8; 49.9% male), 510 underwent CAC vs. 523 underwent CC with no significant differences in age, gender, ethnicity, or colonoscopy indication between the 2 groups. CAC led to a significantly higher APC compared to CC: 0.99± 1.6 vs. 0.85±1.5, p=0.02, Incidence Rate Ratio 1.17 (1.03-1.33, p=0.02) with no significant difference in the withdrawal time: 11.28±4.59 min vs. 10.8±4.81 min; p=0.11 between the 2 groups. Difference in PPV of a polyp being an adenoma among CAC and CC was less than 10% threshold established: 48.6% vs 54%, 95% CI -9.56%, -1.48%. There were no significant differences in ADR (46.9% vs. 42.8%), advanced adenoma (6.5% vs. 6.3%), sessile serrated lesion detection rate (12.9% vs. 10.1%) and polyp detection rate (63.9% vs 59.3%) between the 2 groups. There was a higher polyp per colonoscopy with CAC compared to CC: 1.68 ± 2.1 vs. 1.33 ± 1.8 (incidence rate ratio 1.27; 1.15-1.4; p<0.01).

CONCLUSION: Use of a novel AI detection system showed to a significantly higher number of adenomas per colonoscopy compared to conventional HD colonoscopy without any increase in colonoscopy withdrawal time, thus supporting use of AI-assisted colonoscopy to improve colonoscopy quality. (Clinicaltrials.gov NCT04979962).

Muftah M, Hartnett DA, Flanagan R, et al. Allergic phenotype identified on allergen testing is associated with proton pump inhibitor nonresponse in eosinophilic esophagitis. Journal of gastroenterology and hepatology. Published online 2024. doi:10.1111/jgh.16469

BACKGROUND AND AIM: Food/environmental allergens have been associated with eosinophilic esophagitis (EoE); however, the correlation between allergy profiles and disease responsiveness to proton pump inhibitor (PPI) therapy remains unclear. We aimed to assess the association between food/environmental allergies identified on allergen testing and histologic response to PPI in patients with treatment-naive EoE.

METHODS: Adults with newly diagnosed EoE who underwent formal testing for food/environmental allergies at a tertiary center were included. All patients underwent twice-daily PPI for 8 weeks with subsequent repeat endoscopy and biopsy to assess histologic response. Patients with <15 eosinophils/hpf on post-PPI mucosal biopsies were classified as responders (PPI-r-EoE), while those with ≥15 eosinophils/hpf were nonresponders (PPI-nr-EoE).

RESULTS: Sixty-one patients met inclusion criteria (21 PPI-r-EoE vs 40 PPI-nr-EoE). Demographic, clinical, and endoscopic finding variables were similar between groups. Positive food allergen test was more prevalent among PPI-nr-EoE patients (82.5% vs 42.9%, P = 0.003). On multivariable analysis, positive food allergen testing remained an independent predictor for PPI nonresponse (aOR 0.15, CI: 0.04-0.58, P = 0.0006). Positive environmental allergen testing was highly prevalent, with no significant differences between groups (77.5% vs 95.2%, P = 0.14). However, higher number of positive environmental allergens (23.3% [≥5 allergens] vs 73.3% [<5 allergens], P = 0.003) and specific aeroallergens correlated with PPI-nr-EoE.

CONCLUSION: Positive food allergy testing and increased environmental allergens predicted lower likelihood of histologic response to PPI in EoE. Our findings support an allergic phenotype of EoE that may less likely respond to PPI therapy. Formal allergen testing may play a role in therapy selection and tailored management in EoE.

Lodhia NA, Hiramoto B, Horton L, Goldin AH, Thompson CC, Chan WW. Obesity Is Associated with Altered Rectal Sensitivity in Chronic Constipation. Digestive diseases and sciences. Published online 2024. doi:10.1007/s10620-023-08246-z

BACKGROUND: Defecation dysfunction may contribute to chronic constipation (CC), but the impact of obesity on anorectal physiology in CC remains unclear. We aimed to evaluate the relationship between obesity and anorectal function on physiologic testing in patients presenting with CC.

METHODS: This was a retrospective cohort study of consecutive adults who underwent high resolution anorectal manometry (HRAM) at a tertiary center for CC. Patient demographics, clinical history, surgical/obstetric history, medications, and HRAM results were reviewed. Patients were classified into obese (BMI > 30 kg/m2) vs non-obese (BMI < 30 kg/m2) groups at the time of HRAM. Fisher-exact/student t-test for univariate analyses and general linear regression for multivariable analysis were performed.

RESULTS: 383 adults (mean 50.3 years; 85.8% female) with CC were included. On HRAM, patients with obesity had lower anal sphincter resting tone (37.3 vs 48.5 mmHg, p = 0.005) and maximum squeeze pressure (104.8 mmHg vs 120.0 mmHg, p = 0.043). No significant differences in dyssynergia (61% vs 53%, p = 0.294) and failed balloon expulsion (18% vs 25%, p = 0.381) were found between obese and non-obese groups. On balloon distention testing, the maximum tolerated (163.5 vs 147.6 mL, p = 0.042) and urge sensation (113.9 vs 103.7 mL, p = 0.048) volumes were significantly increased among patients with obesity. After adjusting for potential confounders, obesity remained independently associated with increased maximum tolerated volume (β-coefficient 13.7, p = 0.049).

CONCLUSION: Obesity was independently associated with altered rectal sensitivity among patients with CC. Altered rectal sensation may play an important role in CC among patients with obesity. Anorectal physiology testing should be considered to understand the pathophysiology and guide management.