Gastroesophageal reflux (GERD) symptoms occur when stomach contents flow back and cause symptoms or complications [1]. Defined as heartburn and/or acid reflux at least once a week, the prevalence is lowest in East Asia (2.5%–9.4%) and highest in West Asia (12.5%–27.6%) [1,2]. The highest population-based prevalence was reported in Europe at 23.7% and in the United States at 28.8% [2,3]. Unlike in the West, the frequency of GERD is low in Asia. This is because the maximum gastric acid secretion is low, and the lower esophageal sphincter pressure is known to be higher than in Westerners [4]. In addition, there are fewer obese patients, low-fat diet intake, and lower incidence of Helicobacter pylori infection. However, the incidence of GERD is expected to steadily increase owing to the westernization of diet, an increase in the elderly population, and an increase in interest in health in East Asia. In particular, with age, the function of the upper and lower esophageal sphincters, which anatomically prevent reflux, gradually decreases, thereby increasing the possibility of reflux. Lastly, it is believed that the number of diagnoses is increasing as the number of upper gastrointestinal endoscopies, a diagnostic test, increases due to it being performed as a basic test in health checkups.

GERD is a disease with long-lasting relapses and an increased frequency of esophageal complications, and is not selflimiting. GERD is known to reduce the quality of life more than any other disease due to its chronic nature. GERD is mainly treated conservatively to reduce reflux in the esophagus by suppressing gastric acid secretion. Double split doses can be administered if the response to a standard dose of proton pump inhibitor (PPI) is insufficient. Previously, many patients with GERD symptoms such as epigastric pain, heartburn, and regurgitation do not respond to conventional PPI therapy, which has been referred to as “refractory GERD.” The recent Lyon Consensus 2.0 (2024) refined this definition, characterizing refractory GERD as symptoms persisting despite optimized PPI therapy, with symptoms linked to documented pathological acid exposure [5].

Potassium-competitive acid blockers (PCABs) accumulate in high concentrations in secretory canaliculi. As PCABs are not prodrugs that need to be activated in the body, have their own pharmacological activity, and directly block H⁺/K⁺ ATPase in a reversible manner, they do not require an acidic environment for activation. Unlike PPIs, PCABs are unaffected by acid secretion. Second, PCABs require a short time to reach their peak blood concentrations. Third, PCABs have a long action time and can be administered regardless of meals [6]. Therefore, gastric acidity can be stably maintained. In patients with insufficient suppression due to various reasons or refractory symptoms, switching from PPIs to PCABs is thought to effectively suppress acid secretion and ameliorate reflux-related symptoms. In this study, we aimed to classify the pathophysiology of refractory symptoms through examinations (esophagogastroduodenoscopy, esophageal manometry, and 24-hour ambulatory pH meter) and compare the efficacy of double split dose PPIs and PCABs. We also analyzed the effects of drugs according to abnormal esophageal acid exposure times (AETs).

A total of 84 patients were enrolled in this study. Among these, 63 cases were analyzed after excluding patients with esophageal achalasia (1), incomplete examination (3), AETs of less than 1% (14), and patients who were lost to follow-up (3) (Fig. 1, Table 1). All participating patients were encouraged to quit smoking and drinking, and were educated on changing their eating habits (avoiding overeating).

Of the enrolled patients, 33 (52.4%) received a double split dose of PPIs. Patients with abnormal acid exposure (AET >4.0%, 18 patients) were diagnosed with nonerosive reflux disease (NERD). The total positive response rate was 63.6% (21/33). Among 18 patients with abnormal AET results, the positive response rate was 50.0% (9/18). In the PCAB group (n=30), the total positive response rate was 80.0% (24/30) (p=0.15) (Fig. 2). There were 19 patients with abnormal AET in this group, with a positive response rate of 84.2% (16/19). When comparing only cases with abnormal AET, the response rate in the PCAB group was significantly higher than that in the PPI double split dose group (p=0.02) (Fig. 2). There were no significant differences between the PCAB and PPI groups in patients without abnormal AET.

The diagnostic approach to managing GERD requires comprehensive evaluation, as criteria vary across different tests and may differ from initial clinical impressions. The Lyon Consensus emphasizes examination including esophageal impedance, manometry, histopathology, and psychometry to achieve an accurate diagnosis [11]. Refractory GERD has various pathophysiologies and disease groups, with most patients having NERD, reflux hypersensitivity, or functional heartburn. However, conditions that are not GERD, such as achalasia or eosinophilic esophagitis, may present with similar symptoms. Despite the expansion of available PPIs, approximately 40% of patients with GERD experience symptoms that are refractory to standard PPI therapy [12]. Most refractory GERD is not characterized by symptoms that cannot be completely controlled, but rather by chronic relapsing symptoms. Therefore, before treatment, patients should understand the disease itself and implement lifestyle modifications (control of abdominal obesity) while managing symptom thresholds.

A clinical evaluation must be conducted before diagnosing a patient with refractory GERD. In this study, we first assessed medication compliance. When compliance was confirmed to be adequate, the PPI dose was doubled. Upper gastrointestinal endoscopy was performed to exclude alternative esophageal or gastric etiologies such as drug-induced esophagitis, eosinophilic esophagitis, or esophageal involvement in autoimmune diseases. For patients who demonstrated no improvement despite double split doses of PPI and had no evidence of alternative diagnoses, we performed 24-hour esophageal pH-impedance test and esophageal manometry. These procedures helped us diagnose conditions such as esophageal motility disease, nocturnal acid breakthrough, NERD, reflux hypersensitivity, and functional heartburn. The 24-hour ambulatory esophageal pH and impedance tests offer increased diagnostic sensitivity for GERD compared with the 24-hour ambulatory esophageal pH test alone. Esophageal manometry provides valuable information for discriminating patients with motor disorders (e.g., achalasia) who require stronger anti-reflux therapy.

In reflux monitoring tests, AET and reflux episodes are key indicators of reflux severity. Esophageal AET, which is the fraction of time that the pH decreases to below 4, is the most reproducible measurement and is used to predict responses to drug treatment and anti-reflux surgery. The Lyon Consensus on the criteria for diagnosing GERD suggests that an esophageal AET value of less than 4% indicates normal physiological reflux, whereas values of 6% or greater represent pathological acid reflux. Values between 4%–6% were considered borderline and required additional clinical context for interpretation. To establish a standard for the normal level of esophageal AET in Asians, a meta-analysis including 19 studies of healthy Asian subjects was conducted, and the upper normal limit of esophageal AET in Asians calculated was 3.2% (95% confidence interval 2.7%–3.9%) [4]. Therefore, an esophageal AET value of 4% or more was proposed as the standard for abnormal acid reflux in Asians. However, although this value exceeded the normal physiological range, further research is required to determine whether it constitutes the definitive threshold for pathological reflux that causes clinically significant GERD symptoms. In this study, we excluded patients with an AET<1% from our analysis because their symptoms were likely attributable to reflux sensitivity or functional disorders rather than to true acid reflux. What is noteworthy in the results of this study is that even in the cases without abnormal acid exposure, a significant proportion of patients with refractory symptoms benefited from potent acid suppression therapy. Although SI or SAP are theoretically valuable for establishing reflux-symptom relationships, the practical application of these measures presents challenges, and many patients experience persistent pharyngeal sensations throughout the day, making accurate measurement of SI or SAP difficult. In future, more reliable biomarkers or treatment guidelines that can predict additional aspects are needed.

For optimal dosing in PPI treatment, it is necessary to understand the pharmacological action and inherent limitations of PPIs [13,14]. First, PPIs have a relatively short plasma half-life of 60–90 minutes. Therefore, the administration of PPIs twice daily may be insufficient to suppress gastric acid reflux at night. Second, PPIs are prodrugs that require acidic conditions and depend on food intake for their activation. Third, the onset of the PPI effects is slow; therefore, rapid results cannot be expected because it takes time to achieve maximum efficacy. PCABs have been developed as a new class of acid inhibitors to overcome these limitations. In a previous clinical trial, 8 weeks of administration of the PCAB vonoprazan was not inferior to PPI [15]. However, comparative efficacy data between PPIs and PCABs in patients with refractory GERD remain limited due to the restricted global commercial availability of PCABs. As PCABs are expected to replace PPIs as the next generation of acid suppressants, they should be considered as a therapeutic option for patients with refractory symptoms.

In this study, the effects of 2 weeks of PCAB in patients with refractory symptoms were superior to those of high-dose PPI, particularly in patients with abnormal AETs. PPIs are affected by genetic polymorphisms in cytochrome 2C19 and are easily inactivated under acidic conditions. Compared to PPIs, PCABs bind continuously to the proton pump in parietal cells to reduce gastric acid secretion without having to be activated by gastric acid [16,17]. For these reasons, PCAB can be a new treatment for patients with PPI-resistant GERD. The Seoul Consen-sus now includes PCABs as an option for the initial treatment of GERD. Similarly, the Japanese Society of Gastroenterology (JSGE) approved PCABs for both initial and maintenance treatment of reflux esophagitis in their 2015 practice guidelines and further expanded their recommendations to include initial treatment and long-term maintenance of mild GERD in 2021 [18,19]. Today, as the number of patients with GERD continues to increase, we hope that PCABs will grow further as drugs that dramatically reduce pain in patients with GERD.

However, this study has several limitations. First, we excluded patients with borderline acid exposure time (AET 1%–4%) from our analysis, which may limit the generalizability of our findings to this clinically relevant subgroup. Second, the relatively small sample size (n=63) and single-center retrospective design conducted in an Asian population may limit generalizability across different ethnic groups and healthcare settings. Although the large effect size in patients with abnormal AET suggests clinical relevance, larger multicenter randomized controlled trials are needed to definitively establish the superiority of PCAB over double dose PPI in the overall population. Third, the short 2-week evaluation period may not capture long-term therapeutic sustainability, and the lack of post-treatment AET monitoring limits our understanding of the mechanistic differences between treatments. Finally, we did not analyze the treatment effects according to specific symptom types or perform comprehensive adverse event monitoring, which would have provided additional clinical insights.

In patients with refractory GERD symptoms, PCAB therapy demonstrated an efficacy comparable to that of double split doses of PPIs in the overall population. However, PCAB showed statistically significant superiority in patients with an abnormal acid exposure time, suggesting that PCABs should be considered an effective therapeutic option for refractory GERD, particularly in patients with pathological acid reflux.