Effectiveness of PCAB vs. high-dose PPI in refractory GERD

Clinical Research 6 min 645

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Created On: 03/03/2026

Gastroesophageal reflux disease (GERD) is a chronic ailment marked by the reflux of gastric contents into the esophagus, resulting in persistent symptoms and reduced quality of life.

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Key take away

PCAB therapy demonstrates superior symptom control compared with double-dose PPI therapy in refractory GERD. The benefit is most significant in those with pathological abnormal acid exposure.

Background

Gastroesophageal reflux disease (GERD) is a chronic ailment marked by the reflux of gastric contents into the esophagus, resulting in persistent symptoms and reduced quality of life. A substantial proportion of patients continue to experience symptoms despite optimized proton pump inhibitor (PPI) therapy, a condition recognized as refractory GERD. PPIs suppress gastric acid secretion but have limitations related to delayed onset, short plasma half-life, and dependence on acid activation. Potassium-competitive acid blockers (PCABs) directly and reversibly inhibit the gastric H⁺/K⁺-ATPase, providing rapid, sustained, and meal-independent gastric acid inhibition. However, comparative clinical evidence evaluating PCABs against intensified PPI regimens in refractory GERD, particularly in patients with objectively confirmed abnormal acid exposure time (AET), remains limited.

Objective

The study aimed to compare the clinical efficacy of PCAB therapy with double split doses of PPI therapy in patients with refractory GERD according to esophageal AET.

Method

1. Study Design

This retrospective, consecutive, controlled case series was conducted at The Catholic University of Korea, St. Vincent’s Hospital. Patients were enrolled consecutively in a real-world clinical practice setting. Treatment allocation was assessed by clinical decision-making instead of randomization.

2. Study Population

A total of 63 consecutive patients with persistent, refractory symptoms were included. All participants had remained symptomatic despite more than 8 weeks of standard-dose PPI therapy. Patients were excluded if they had:

Esophageal achalasia
Eosinophilic esophagitis
Esophageal ulcers
Los Angeles classification grade B or higher erosive esophagitis
Incomplete diagnostic evaluation
Esophageal AET <1%
Loss to follow-up

3. Treatment Protocol

Volunteers received one of the following regimens for 2 weeks:

Rabeprazole 20 mg (double split dose)
Tegoprazan 50 mg (double split dose)

Mean age was 62.6±10.8 years in the PPI group and 58.1±13.4 years in the PCAB group.

4. Comprehensive Esophageal Evaluation

All patients underwent a standardized diagnostic workup including:

(a) Esophagogastroduodenoscopy (EGD)

Upper endoscopy was performed within 2 weeks prior to ambulatory reflux monitoring to assess mucosal pathology and exclude structural disease.

(b) High-resolution esophageal manometry

Manometry was conducted to:

Identify esophageal motility disorders
Precisely localize the lower esophageal sphincter (LES)

(c) Ambulatory 24-hour esophageal pH monitoring

Catheter-based pH monitoring (Digitrapper system) was performed. The pH probe was positioned 5 cm above the squamocolumnar junction using a standard transoral placement technique. Data were examined separately for each 24-hour recording period. The worst day was selected for diagnostic classification. Results were processed using ManoView ESO Software (Medtronic Inc.).

5. Assessment of Abnormal Acid Exposure

Total 24-hour esophageal acid exposure (%) was described as the proportion of monitoring time with pH <4.0. Esophageal AET—the percentage of time pH remained below 4—was the primary reproducible metric and predictor of therapeutic response. AET is considered the most reproducible parameter for quantifying esophageal acid burden and predicting response to acid-suppressive therapy or anti-reflux surgery.

AET ≥4% on 24-hour ambulatory pH monitoring was termed as pathological acid reflux. Symptom index (SI) was computed as the percentage of reflux-associated symptoms relative to total reported symptoms and was considered positive at ≥50%. Symptom association probability (SAP), reflecting the likelihood that symptom–reflux correlation occurred by chance, was deemed positive at ≥95%.

6. Symptom Assessment and Treatment Response

Symptom severity was determined via a visual analog scale (VAS) ranging from:

0 = No symptoms
10 = Worst possible symptoms

VAS scores were recorded before and after the 2-week treatment period. A treatment response was considered positive if there was more than 50% reduction in the VAS symptom severity score after therapy.

Result

1. Flow of Patients

2. Clinical Outcomes

The overall positive response rate was 63.6% (21/33) in the double-dose PPI group and 80.0% (24/30) in the PCAB group.
Among patients with abnormal esophageal AET (>4.0%), the response rate was 50.0% (9/18) with PPI therapy and 84.2% (16/19) with PCAB therapy, demonstrating statistically significant superiority of PCAB therapy (p=0.02).
No significant differences were noted between treatment groups in patients without abnormal AET (80% vs. 72.7%), as depicted in Figure 2:

Discussion

The diagnostic approach used in this study required a comprehensive clinical evaluation, as symptom presentation alone was insufficient to characterize refractory GERD. Patients with persistent symptoms demonstrated heterogeneous pathophysiological profiles, including nonerosive reflux disease (NERD), reflux hypersensitivity, and functional heartburn, while non-GERD conditions with overlapping symptoms were actively excluded through structured evaluation.

Before classifying patients as having refractory GERD, medication compliance was assessed. Following confirmation of medication adherence, the PPI dosage was escalated to twice the standard dose. Patients without symptomatic improvement underwent upper gastrointestinal endoscopy to eliminate alternative esophageal or gastric etiologies. In the absence of competing diagnoses, 24-hour esophageal pH-impedance monitoring and esophageal manometry were executed to further characterize functional heartburn, reflux patterns, NERD, esophageal motility disorders, nocturnal acid breakthrough, and reflux hypersensitivity. The combined use of pH-impedance testing and manometry improved diagnostic discrimination within this study population.

In reflux monitoring, AET served as the primary indicator of reflux severity. AET, defined as the proportion of time esophageal pH remained below 4, was used to stratify patients according to acid burden. Patients with AET <1% were excluded, as their symptoms were considered unlikely to be driven by true acid reflux. Notably, even among patients without clearly abnormal acid exposure, a meaningful proportion experienced symptomatic improvement with intensified acid suppression, suggesting clinical benefit beyond strict acid exposure thresholds.

Understanding the pharmacological limitations of PPIs was central to interpreting treatment response in this study. The short plasma half-life, food-dependent activation, and delayed onset of action of PPIs may contribute to inadequate acid suppression in refractory cases. PCABs were evaluated as an alternative due to their ability to provide continuous proton pump inhibition without requiring acid-dependent activation.

In this study, two weeks of PCAB use illustrated superior symptom control compared with high-dose PPI, particularly in those with abnormal AET. The continuous binding of PCABs to proton pumps provided more consistent acid suppression, which may explain the enhanced response observed in patients with pathological acid exposure.

Overall, PCAB therapy demonstrated efficacy comparable to double-dose PPI in the overall refractory GERD population, with statistically significant superiority in patients exhibiting abnormal AET, supporting its role as an effective therapeutic option in acid-driven refractory disease.

Limitations

Patients with borderline AET values (1%–4%) were excluded from the analysis, which may have limited the generalizability of the findings to this clinically relevant subgroup.
The study had a relatively small sample size (n=63) and a single-center retrospective design executed in an Asian population, which may have limited extrapolation to other ethnic groups and healthcare facilities.
Even though a large effect size was observed in those with abnormal AET, larger multicenter randomized controlled trials were required to definitively substantiate the superiority of PCABs over double-dose PPIs in the overall population.
The short 2-week treatment duration may not have adequately captured long-term therapy sustainability.
The absence of post-treatment AET monitoring limited the mechanistic interpretation of treatment-related acid suppression.
Treatment effects were not analyzed according to specific symptom subtypes, and comprehensive adverse event monitoring was not performed, which restricted additional clinical insight.

Clinical take-away

PCAB therapy achieved greater symptom improvement than double-dose PPI therapy in patients with refractory GERD and abnormal esophageal AET.

Source:

Korean Journal of Helicobacter and Upper Gastrointestinal Research

Link:

https://pmc.ncbi.nlm.nih.gov/articles/PMC12699069/

Article:

The Efficacy of Potassium-Competitive Acid Blocker Compared With Double Dose of Proton Pump Inhibitor in Patients With Refractory Gastro-Esophageal Reflux Disease: A Case-Control Study