Efficacy of Shugan Hewei formula combined with rabeprazole in refractory gastroesophageal reflux disease: randomized, double-blind, placebo-controlled trial

Abstract

Objectives

To assess the efficacy of the Chinese herbal medication Shugan Hewei formula (SHF) combined with rabeprazole in patients with refractory gastroesophageal reflux disease (rGERD).

Method

A total of 264 participants were randomly assigned to the treatment group (n = 132) receiving SHF granules (20 mg) combined with rabeprazole (10 mg) and the control group (n = 132) receiving placebo SHF granules (20 mg) combined with rabeprazole (20 mg). Both groups undergo 8 weeks of treatment and 2 weeks of follow-up.

Results

The treatment group showed higher total clinical symptom efficacy and lower total symptom scores compared to the control group. The treatment group was superior to the control group in reducing rGERD major symptom scores, including heartburn, retrosternal pain, regurgitation and belching, and acid regurgitation. Additionally, treatment group (Z = 8.169, P < 0.001) and control group (Z = 9.800, P < 0.001) treatments were all significantly attenuated esophageal inflammation, demonstrating comparable efficacy. Patients with esophagitis grade A decreased from 40.34% to 17.23%, and those with grade B decreased from 11.76% to 3.78% in the treatment group. The results of the SF-36 scale showed that combination therapy was more effective in improving role limitations due to physical health, vitality, general health, total somato-physical health, and psychiatric mental health.

Conclusion

Our study reveals that the combined treatment of SHF with rabeprazole is more efficacious in managing patients with rGERD when contrasted with sole rabeprazole treatment.

Introduction

Gastroesophageal reflux disease (GERD) is a comprehensive disease with reflux symptoms caused by reflux of gastric or duodenal contents into the esophagus or pharynx [1]. The current prevalence of GERD varies, ranging from 8 to 33%, and it is anticipated that this prevalence will continue to increase in the future [2]. The pharmaceutical approach to managing GERD focuses on reducing gastric acid secretion and preventing exposure of the esophagus to acid [3]. Proton pump inhibitors (PPIs) are the preferred medication for managing GERD as they can effectively decrease acid reflux [4, 5]. Nevertheless, it is essential to note that PPIs provide relief for only about half of individuals with reflux symptoms [5, 6]. The ineffectiveness of double-dose PPIs for more than 4 weeks of continuous treatment, coupled with symptoms such as retrosternal heartburn or regurgitation occurring at least 3 times per week, is often referred to as refractory GERD (rGERD), even though rGERD has never been distinctly defined [7,8,9]. The rGERD significantly affects the quality of life and places a substantial burden on healthcare resources, making it a prominent health concern [10]. Therefore, it is imperative to explore supplementary or alternative treatments to enhance treatment outcomes for individuals with rGERD.

Traditional Chinese medicine (TCM), known for its lower occurrence of adverse effects and demonstrated therapeutic benefits, has gained widespread acceptance and extensive research in many Asian countries. It has been widely applied for the treatment of GERD in China [11]. Various TCM improve symptoms in GERD patients. Modified Xiaochaihu Decoction, BanxiaXiexin Decoction, and Hewei Jiangni Decoction all relief symptoms in GERD patients [12,13,14]. In addition, the combination of TCM and traditional Western medicine may be a potentially effective strategy in the treatment of rGERD. Combined treatment of rikkunshito and rabeprazole significantly reduced mental component summary scores and improved acid-related dysmotility symptoms in female and elderly patients with non-erosive reflux disease refractory [15]. The combination of Sini Zuojin Decoction and traditional gastric medication shows superiority over traditional gastric medication alone, particularly in improving symptoms like heartburn, retrosternal chest pain, acid reflux, and regurgitation [16]. Consequently, exploring the combination of TCM and Western medicine treatment holds significant importance in enhancing the therapeutic outcomes for patients with rGERD.

In the present study, we explored the efficacy of SHF combined with rabeprazole in the treatment of rGERD. We found that SHF combined with rabeprazole was more efficacious than rabeprazole alone in improving the symptoms and enhancing the quality of life of patients with rGERD. The efficacy and safety of SHF combined with rabeprazole in the treatment of rGERD are significant, suggesting that it could be used as a combination of traditional Chinese and Western medicine for the treatment of rGERD.

Methods

Study design

This clinical trial was conducted in strict accordance with the Declaration of Helsinki (Edinburgh 2000 version) and relevant Chinese clinical trial research norms and regulations. The study protocol received approval from the Ethics Committee of Yueyang Hospital of Integrative Medicine affiliated with Shanghai University of Traditional Chinese Medicine (Ethics No. 2013-060). The written informed consent was obtained from all participating patients. The subjects for this study were sourced from outpatients and inpatients at Yueyang Hospital of Integrative Medicine affiliated with Shanghai University of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, and Shuguang Hospital of Shanghai University of Traditional Chinese Medicine. All participating investigators received standardized training in accordance with standard operating procedures (SOP) for clinicians. The study followed the principles of center-stratified paired randomized grouping. Case collection began in April 2014 and ended in March 2016.

Inclusion criteria: (1) This study included patients diagnosed with rGERD [Los Angeles (LA) Classification grade A–D] as confirmed by endoscopic examination. The patient exhibits typical symptoms related to rGERD, such as heartburn, acid reflux, burning sensation behind the sternum, belching, difficulty swallowing or throat discomfort, esophageal inflammation-related issues, like coughing during sleep or lying flat, and inflammation confirmed by endoscopy and biopsy from pathological examination after 8 weeks of PPI therapy. (2) Meeting the diagnostic criteria for TCM: referring to the consensus opinions of Chinese gastroesophageal reflux disease experts (2009 edition). (3) Those who have failed to take four or more consecutive weeks of standard-dose first-generation PPIs for GERD prior to this study. (4) Individuals aged 18 to 70 years, with no gender restrictions. (5) Patients who signed the informed consent.

Exclusion criteria: (1) Patients with the following medical conditions: peptic ulcer; gastrinoma; malignant lesions in the upper gastrointestinal tract; had a history of gastroesophageal and duodenal surgery; primary esophageal disorders (such as esophageal achalasia scleroderma, primary esophageal spasms); drug-induced esophagitis; individuals with psychiatric disorders. (2) Pregnant and lactating women. (3) Individuals with liver or kidney function abnormalities exceedingly twice the normal reference range for aspartate aminotransferase (AST), alanine aminotransferase (ALT), or creatinine are excluded. (4) Patients with possible esophageal functional diseases other than GERD were excluded using high-resolution esophageal manometry.

24-h esophageal pH monitoring

The 24-h esophageal pH monitoring was performed using an antimony pH catheter (Orion-Ohmega, the Netherlands). The sensor was positioned 5 cm above the lower esophageal sphincter and secured with tape on the nose and neck. Patients were told to keep their usual diets, avoiding acidic foods and alcohol, and not to take any medications that might interfere with the results.

To calculate the distal pH variables, the DeMeester score was employed, assessing the percentage of total time with pH < 4, the longest reflux event, the number of reflux events longer than 5 min, and the number of reflux episodes in 24 h. A DeMeester score > 14.72 indicated significant esophageal acid exposure. An elevated classification level of rGERD resulted in a higher DeMeester score (Supplementary Fig. 1).

SHF reagents and groupings

Granules of LHF and dummy SHF were sourced from Jiangyin Tianjiang Pharmaceutical Co., Ltd (Jiangsu, China). SHF included 12 Chinese herbs: Spinosa pedunculata, Magnolia officinalis, Coptis chinensis, Evodia rutaecarpa, ginger, Concha arcae, Inula japonica Thunb, radix bupleuri, Corydalis yanhusuo, Cyperus rotundus, Gardenia jasminoides, Fructus Aurantii, and Polygonatum sibiricum. The dummy SHF granules were formulated by cyclodextrin (90%), the SHF (5%), food colorants, and bitters using the same manufacturing procedure as the genuine therapeutic medication. The dummy SHF granules was essentially the same in appearance, size, color, dosage form, weight, taste and odor as the SHF granules. This study included two groups: the treatment group, which received treatment with SHF granules (20 mg) in combination with rabeprazole capsules (10 mg), and the control group, which received treatment with equal doses of dummy SHF (20 mg) and rabeprazole capsules (20 mg). In the treatment group, the SHF granules were reconstituted with 100 mL of warm water, and taken orally once a day in two divided doses. The SHF granules and rabeprazole capsules were taken more than 30 min apart each time. The control group received the same treatment regimen as the treatment group. The entire treatment lasted 8 weeks.

Variable assignment

(1) Center: Yueyang Hospital of Integrative Medicine affiliated with Shanghai University of Traditional Chinese Medicine was “1”; Shanghai University of Traditional Chinese Medicine was “2”; Shuguang Hospital of Shanghai University of Traditional Chinese Medicine was “3”. (2) Groups: Treatment group was “1”; Control group was “2”. (3) Gender: Male was “1”; Female was “2”. (4) Age: 18–44 years old was “1”; 45–59 years old was “2”; 60–70 years old was “3”. (5) Obesity level: Lean (BMI < 18.5) was “1”; Normal (BMI: 18.5–23.9) was “2”; Overweight (BMI: 23–24.9) was “3”; Obesity (BMI: 25–29.9) was “4”. (6) Course of disease (BC): Less than 1 year was “1”; 1–2 years was “2”; 2–3 years was “3”; More than 3 years was “4”.

Sample size estimation

Based on the clinical experience, the effective rate of GERD after 8 weeks of treatment with rabeprazole was 58.3%. The trial was planned to perform a superiority test of two independent sample proportions, employing a margin of 0.02, with an alpha risk of 0.05 and a beta risk of 0.20, while taking into account an anticipated attrition rate of about 20%. Consequently, the estimated sample size required for the study was N = 264, with an equal 1:1 ratio of 132 patients in both the treatment and control groups.

Randomization and blinding

To ensure that the key influencing factors were balanced between the groups, this study considered two primary factors: gender and disease type. We used these factors for stratified randomization, pairing them based on the treatment center. Furthermore, a statistician affiliated with Shanghai University of Traditional Chinese Medicine, who was not part of the clinical trial team, oversaw the blinded randomization of drug allocation. Random sequences for the allocation of participants into the treatment and control groups were generated using SPSS 21.0 statistical software. The number of blinded cases was 264, divided into treatment and control groups of 132 cases each. Each subject's drug box received a unique number, and an emergency letter was prepared for each case. The envelope holding the emergency letter was clearly marked with the patient's center number, patient number, drug code, and randomization number. It also showed the patient's assigned group and the exact medication type and dosage for that group in case of emergency unblinding. These emergency letters were given to each study center with the study medication and were kept by the principal investigator at each center. In the event of severe adverse events or complications occurring during the clinical trials, the blinding of the study should be promptly unsealed, and instances of unblinding should be considered as cases of participant dropout. Before the trial was over, the amount of blind leakage or emergency letter opening could not exceed 20%.

Allocation

The process of randomization was handled by a person responsible for issuing the appropriate drugs according to the subject's number and randomization number, without altering the order of drug numbers. The implementation of randomization was managed as part of the quality control of the clinical study.

Baseline scoring

The baseline levels of the treatment and control groups were assessed by measuring the following indicators: demographic characteristics (gender, age, BMI index), medical history data (type of PPI administration before enrollment, duration of PPI administration, concomitant medication for GERD, allergic history, concomitant diseases, and treatment of concomitant diseases), vital signs (temperature, breathing, heart rate, systolic pressure, and diastolic pressure), and physical examination (digestive system, circulatory system, respiratory system, nervous system, endocrine system, skeletal system, urogenital system).

Clinical symptom scoring

In this study, the GERD-Q scores mainly included clinical symptom scoring and SF-36 scoring. The scoring method was employed to assess each efficacy indicators. The clinical symptom score was developed following the diagnostic criteria outlined in the 2006 China Consensus on Gastroesophageal Reflux Disease and adheres to the "Guiding Principles for Clinical Research of New Traditional Chinese Medicine". (Supplementary Table 1). In addition, electronic endoscopic scoring was employed to assess the improvement of esophageal mucosa before and after treatment using the LA Classification [17]. The definitions for each category within the LA Classification: (1). recovery (esophageal mucosa appeared normal under endoscopy); significant effect (2 points); effective (1 points); invalid (score of 0 or negative).

Criteria for determining symptomatic efficacy

The clinical efficacy was evaluated as follows: recovery: regurgitation symptoms have completely disappeared, and the symptom score has been reduced by ≥ 95%; marked efficacy: reflux symptoms have essentially disappeared, with occasional symptoms that quickly vanish, and the symptom score has been reduced by ≥ 70%; effective: reflux symptoms have not disappeared but have decreased, and the symptom score has been reduced by ≥ 30%; ineffective: reflux symptoms have not disappeared, and the symptom score has been reduced by < 30%.

Quality of life scoring

The SF-36 scale mainly reflects patients' quality of life from eight dimensions, specifically including physical functioning (PF); role limitations due to physical health (RP); role limitations due to emotional problems (RE); vitality (VT); mental health (MH); social functioning (SF); body Pain (BP); general health (GH). Two comprehensive scores were calculated by integrating eight dimensions, namely the physical component summary (PCS) and the mental component summary (MCS). Among them, PCS included PF, RP, BP, and GH, representing the overall physiological health score. MCS included VT, SF, RE, and MH, representing the overall mental health score. Ultimately, the accumulated points were transformed into a conclusive score ranging from 0 to 100, standard score = (actual score − lowest possible score/general average possible score) × 100. A higher score signified an enhanced quality of life, while a lower score implied a diminished quality of life.

Safety indicator detection

Following 8 weeks of treatment, patients underwent comprehensive testing, including blood, urine, and fecal routine tests, evaluation of liver function (ALT and AST), assessment of renal function (Cr and BUN), as well as electrocardiogram examinations.

Endpoints

The primary endpoint was clinical symptoms total efficacy, and secondary endpoints included clinical symptom score, SF-36 score, safety indicator, and adverse events.

Follow-up

The treatment duration was 8 weeks, followed by a 2-week follow-up period. Detailed information is shown in Supplementary Table 2.

Analytical planning

The full analysis set (FAS) primarily comprised eligible cases and dropout cases while excluding excluded cases. This analysis set consisted of cases who have taken the investigational drug at least once and have at least one baseline efficacy data. The per-protocol set (PPS) was a subset of the FAS, comprising cases that meet inclusion criteria, did not meet exclusion criteria, and completed the treatment plan. Safety set (SS) referred to actual data from at least one treatment with documented safety indicators. Statistical analysis was conducted on the clinical efficacy, endoscopic mucosal improvement, and quality of life of this study based on the FAS and PPS datasets.

Statistical analysis

Hypothesis tests were conducted using a two-tailed test, with statistical significance set at P ≤ 0.05. Data analysis was performed using SPSS 21.0. The confidence interval was set at 95%. In descriptive statistical analysis, normally distributed data were described using mean ± standard deviation (mean ± SD), and the range with minimum and maximum values (min, max). Non-normally distributed data were described using the median (M), lower quartiles (P25), upper quartiles (P75), and the range with minimum and maximum values (min, max). Statistical comparisons between the two groups for categorical variables was conducted using the Chi-squared test, Fisher’s exact probability method, and the Wilcoxon rank-sum (WRS) test. The t-test was used to compare continuous variables that conformed to a normal distribution. The Wilcoxon rank-sum test was employed for comparing those that conformed to a non-normal distribution. Multiple parametric groups were compared using a one‐way analysis of variance (ANOVA) test. For comparing continuous observation indicators at multiple time points between groups, a generalized estimation equation (GZZ) was used.

Results

Demographic factors and baseline characteristics

The present study was conducted between April 2014 and March 2016, involving a total of 264 cases from three different hospitals: Yueyang Hospital of Integrative Medicine affiliated with Shanghai University of Traditional Chinese Medicine (150 patients); Shanghai Hospital of Traditional Chinese Medicine (72 patients); and Shuguang Hospital affiliated to Shanghai University of Traditional Chinese Medicine (42 patients). These patients were suffering from rGERD. Patients from each of the three hospitals were randomly divided into treatment and control groups in a 1:1 ratio. Ultimately, the treatment group consisted of 132 patients, and the control group also included 132 patients. During the study period, a total of 22 patients were shed and the dislodgement rate was 8.33%, which included 11 lost to follow-up, 8 cases refused treatment, 2 patients left due to adverse events, and 1 case were pregnant (Tables 1and 2). There were no statistically significant differences in demographic characteristics (gender, age, BMI index), medical history data (type of PPI administration before enrollment, duration of PPI administration, concomitant medication for rGERD, allergic history, concomitant diseases, and treatment of concomitant diseases), as well as vital signs and physical examination results (Tables 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14).

Table 1 Distribution of case shedding and excluding in three centers

Table 2 Case-specific causes of shedding and excluding

Table 3 Comparison of gender composition between two groups

Table 4 Comparison of the age of patients in the two groups

Table 5 Comparison of obesity levels between the two groups

Table 6 Comparison of disease duration (months) between the two groups

Table 7 Comparison of the composition of the types of PPIs taken before enrollment between the two groups

Table 8 Comparison of the course of PPI administration before enrollment

Table 9 Comparison of comorbid medications prior to enrollment

Table 10 Comparison of allergy history between the two groups

Table 11 Comparison of concomitant diseases in the two groups

Table 12 Comparison of treatment of concomitant diseases in the two groups

Table 13 Comparison of vital signs between the two groups (FAS)

Table 14 Comparison of the 7 major systems of physical examination between the two groups of patients (FAS)

SHF combined with rabeprazole treatment improved clinical symptoms total efficacy of rGERD patients

As the trends in the results of the FAS and PPS data analyses were essentially identical, the subsequent data analysis primarily relied on the FAS data analysis. WRS test showed that after 2 weeks of treatment, there was no significant difference in clinical efficacy between the treatment and control groups (Z = 0.248, P = 0.804). After 4 weeks, 6 weeks, and 8 weeks of treatment, there were statistically significant differences in clinical efficacy between the two groups (Z = 1.964, P = 0.050 at 4 weeks; Z = 2.054, P = 0.040 at 6 weeks; and Z = 9.422 at 8 weeks; P < 0.05; Table 15). Additionally, the results of the GEE analysis revealed a statistically significant difference between the treatment group and the control group (Wald χ² = 25.657, P < 0.001). The clinical efficacy of the treatment group was significantly better than that of the control group. The repeated measurement ANOVA (rmANOVA) also revealed significant differences in clinical efficacy between the two groups at various time points, including 2 weeks, 4 weeks, 6 weeks, 8 weeks treatments (Wald χ² = 272.697, P < 0.001). Notably, the clinical efficacy became increasingly pronounced as the treatment duration extended in two groups (Table 16).

Table 15 Comparison of efficacy between the two groups at different times (FAS)

Table 16 Generalized estimating equation to estimate the total efficacy of clinical symptoms (FAS)

SHF combined with rabeprazole treatment reduced total symptom scores

There were no differences in total symptom scores between the treatment and control groups before interventions (F = 0.549, P = 0.459), suggesting the same baseline between the two groups. WRS test showed that there was a statistically significant difference between pre-treatment and 8 weeks of treatment in both the treatment group (F = 435.172, P < 0.001) and the control group (F = 322.442, P < 0.001). At 6 weeks of treatment (F = 5.579, P = 0.019) and 8 weeks of treatment (F = 74.490, P < 0.001), a statistically significant difference emerged between the two groups, with the treatment group demonstrating superiority over the control group (Table 17). Results from the rmANOVA analysis indicated a statistically significant divergence between the total clinical symptom scores of all patients before and after treatment (F = 752.547, P < 0.001). Furthermore, there was an interaction between time and group (F = 13.565, P < 0.001; Table 18). Based on the graph, both the treatment group and the control group showed a similar decreasing trend in total clinical symptom scores before, after 2 weeks, and after 4 weeks treatment. However, the treatment group exhibited a faster reduction in total clinical symptom scores at 6 weeks and 8 weeks of treatment (Fig. 1).

Table 17 Comparison of total symptom scores between the two groups at different treatment times (FAS)

Table 18 Repeated measures ANOVA results of total clinical symptom scores in the two groups (FAS)

Fig. 1

Trends in total clinical scores at different times in two groups (FAS)

SHF combined with rabeprazole treatment reduced major symptom scores

Subsequently, we investigated the impact of SHF on primary symptoms of rGERD, which encompassed heartburn, retrosternal pain, regurgitation and belching, and acid regurgitation. Before the interventions, there were no differences in these main symptoms between the treatment and control groups (P > 0.05), which indicated that baseline was same for both groups. WRS test showed that after 2 weeks, 4 weeks, and after 6 weeks of treatment, there was no statistically significant difference in these main symptoms between the two groups (P > 0.05). After 8 weeks of treatment, a statistically significant difference was observed in these main symptoms between the two groups of patients (P < 0.05). Based on the mean rank, it could be concluded that the treatment group exhibited superior efficacy in managing these main symptoms compared to the control group. The results of the GEE analysis showed that there was no statistically significant difference between the treatment and control groups in the main symptom scores of heartburn, retrosternal pain, regurgitation and belching, and acid regurgitation after 8 weeks of treatment (P > 0.05). Furthermore, compared with pre-treatment, the results of the rmANOVA revealed statistically significant differences in these symptom scores both in the two groups after 2 weeks, 4 weeks, 6 weeks, and 8 weeks of treatment (P < 0.05). Moreover, as the treatment duration increased, both groups showed improved treatment effects (Tables 19, 20, 21, 22, 23, 24, 25and26).

Table 19 Comparison of the degree of heartburn in the two groups at different times (FAS)

Table 20 Generalized estimating equations results of heartburn score (FAS)

Table 21 Comparison of the degree of retrosternal pain in the two groups at different times (FAS)

Table 22 Results of generalized estimation equation for estimating retrosternal pain (FAS)

Table 23 Comparison of the degree of regurgitation and belching between two groups of patients at different times (FAS)

Table 24 Results of generalized estimation equation for estimating regurgitation and belching (FAS)

Table 25 Comparison of the degree of acid regurgitation in the two groups at different times (FAS)

Table 26 Results of generalized estimation equation for estimating acid regurgitation (FAS)

SHF combined with rabeprazole treatment improved reflux esophagitis

WRS test showed that there were no differences in the incidence of reflux esophagitis between the treatment and control groups prior to the interventions (F = 0.129, P = 0.897), indicating that all groups had the same baseline. After 8 weeks treatment, there was no statistically significant difference in the severity of reflux esophagitis between the two groups (F = 1.410, P = 0.159; Table 27). After 8 weeks of treatment, compared with pre-treatment, there was a statistically significant difference in the both the treatment (Z = 8.169, P < 0.001) and control groups (Z = 9.800, P < 0.001; Table 28). Analysis based on the FAS indicated that in the treatment group, patients with esophagitis grade A decreased from 40.34% to 17.23%, and those with grade B decreased from 11.76% to 3.78%. In the control group, patients with esophagitis grade A decreased from 40.25% to 15.35%, and those with grade B decreased from 11.20 to 2.49% (Fig. 2). This suggested that both groups exhibited similar efficacy in improving the degree of esophageal inflammation.

Table 27 Comparison of severity of reflux esophagitis between the two groups at different times

Table 28 Comparison of reflux esophagitis in the treatment and control groups before treatment and at 8 weeks of treatment

Fig. 2

Distribution of esophagitis types (FAS) before and after treatment in both groups

SF-36 scale reliability analysis

SF-36 was used to assess quality of life for patients with rGERD. The assessment of the SF-36 scale's reliability revealed that the Cronbach's α for the pre-treatment scale exceeded 0.8, indicating a high level of reliability in the researcher's evaluation of the patients' health status. In the case of the post-treatment scale, Cronbach's α exceeded 0.8 across all groups, with the exceptions of 0.796 in the control group at the Shanghai Hospital of Traditional Chinese Medicine and 0.761 in the treatment group at Shuguang Hospital. This suggested that the researcher's second assessment of the patients' health status following treatment remained highly reliable. The combined Cronbach's α for the pre-treatment assessments was 0.900, while for the post-treatment assessments, it was 0.877 (Table 29).

Table 29 Reliability analysis of the SF-36 scale for patients (FAS)

SHF combined with rabeprazole treatment improved the quality of life of patients with rGERD

Before interventions, there were no differences in the scores of each indicator between the treatment group and the control group (P > 0.05). In terms of all eight evaluation dimensions, both groups exhibited a significant improvement in patients' quality of life after 8 weeks of treatment compared to before treatment (P < 0.05; Table 30). Furthermore, rmANOVA showed that after 8 weeks of treatment, the treatment group demonstrated a significantly greater improvement in quality of life compared to the control group (P < 0.05). Additionally, there was a significant interaction between time and group for PF, RP, VT, BP, and RE (P < 0.05), suggesting that the scores in these five dimensions increased more rapidly with prolonged treatment. Statistically, the treatment group outperformed the control group in terms of RP, VT, and GH (P < 0.05; Table 31), indicating that scores in the treatment group improved more significantly over time compared to the control group.

Table 30 Comparison of the dimensions of the SF-36 scale between the two groups (FAS)

Table 31 Results of repeated measurement ANOVA for SF-36 dimension (FAS)

SHF combined with rabeprazole treatment increased total somato-physical health and psychiatric mental health scores

WRS test showed that there was no statistical difference between the two groups at the pre-treatment in terms of total scores for somatic-physical health (F = 0.954, P = 0.330) and psychiatric mental health (F = 0.817, P = 0.367), allowing for follow-up comparisons. Both groups significantly improved their scores on somato-physical health and psychiatric mental health scores after 8 weeks of treatment compared to pre-treatment (P < 0.05; Figs. 3and4). Additionally, following 8 weeks of treatment, there were also statistically significant differences in scores between the two groups (P < 0.05). Based on the mean values, the treatment group was superior to the control group. The rmANOVA showed that all patients had significantly higher somato-physical health and psychiatric mental health scores after 8 weeks of treatment compared to pre-treatment (P < 0.05). There was an interaction between time and group (F = 17.909, P < 0.001), suggesting that the total somato-physical health and psychiatric mental health scores gradually increased with the prolongation of treatment. After 8 weeks of treatment, the treatment group was significantly faster than the control group in rising scores (Tables 32, 33, 34and35).

Fig. 3

Time and group interaction plot for somato-physical health scores (FAS)

Fig. 4

Time and group interaction plot for psychiatric mental health scores (FAS)

Table 32 Comparison of total somato-physical health scores

Table 33 Repeated measurement ANOVA of somato-physical health scores

Table 34 Comparison of total psychiatric mental health scores

Table 35 Repeated measurement ANOVA of psychiatric mental health scores

Characteristics of the first symptoms of rGERD in Chinese medicine

Two hundred and sixty-four patients diagnosed with rGERD based on Chinese medicine evidence were subjected to systematic cluster analysis using Ward's method and Euclidean distance. The analysis revealed five distinct categories based on the degree of symptom similarity (Fig. 5). Further analysis by gender yielded consistent results, suggesting that patients with rGERD could be classified into five categories (Fig. 6).

Fig. 5

Cluster diagram of Ward method sample system for all rGERD patients

Fig. 6

Cluster diagram of Ward method sample system for rGERD patients of different genders

Cluster analysis of indicator system

Using systematic cluster analysis with Ward's method and Euclidean distance, we categorized the primary and secondary symptoms of 264 patients with rGERD based on their initial visit to a Chinese medicine doctor. The analysis identified two categories of symptoms. The first category included symptoms such as heartburn (SX), acid reflux (FS), retrosternal pain (XGHTT), regurgitation belching (FWAQ), dry mouth and bitter mouth (KGKK), and the sensation of pharyngeal obstruction (YBGZG). The second category comprised symptoms like dysphagia (TYKN), dyspareunia (NC), constipation (BM), loose bowel movements (BT), fatigue (SPFL), coldness and limb discomfort (WHZL), cough (KS), dry and sore throat (YGYT), epigastric pain (SFT), abdominal distension (FZ), and heartburn-induced insomnia (XFSM; Fig. 7).

Fig. 7

Systematic clustering of Ward's method indicators for all rGERD patients

Gender-based cluster analysis revealed distinct patterns in symptom grouping. Among male patients, symptoms such as heartburn (SX), acid reflux (FS), retrosternal pain (XGHTT), regurgitation, belching (FWAQ), pharyngeal obstruction sensation (YBGZG), and abdominal distension (FZ) were clustered together. In contrast, female patients exhibited a different pattern, with heartburn (SX), pantothenic acid (FS), pharyngeal obstruction sensation (YBGZG), dry pharynx, sore throat (YGYT), fatigue (SPFL), and distraction-induced insomnia (XFSM) forming a distinct symptom cluster. These findings indicated some variation in symptom grouping between the two genders (Fig. 8).

Fig. 8

Clustering diagram of the Ward method indicator system for patients of different genders

The grading of symptom severity during the patient's initial visit

The primary symptoms observed during the initial visit of patients with rGERD, ranked in descending order based on the severity composition ratio (Table 36), were as follows: regurgitation and belching (25.4%), retrosternal pain (20.8%), acid reflux (14.4%), and heartburn (13.6%). When considering the composition ratio of moderate and severe cases, the order of prevalence was as follows: regurgitation and belching (59.9%), acid reflux (46.2%), heartburn (44.3%), and retrosternal pain (40.5%).

Table 36 Grading of the severity of Chinese medicine symptoms in the first consultation of patients in the three centers

Among the other symptoms in patients with rGERD, the top five in terms of severity included dry mouth and bitterness (26.9%), pharyngeal obstruction (25.0%), insomnia and heartburn (16.7%), abdominal distension (15.9%), and fatigue (14.4%). When considering the component ratios of moderate and severe cases, the top five included dry mouth (53.0%), pharyngeal obstruction (48.9%), bloating (41.7%), insomnia (38.7%), and fatigue (35.5%).

Safety assessment

Research has demonstrated that certain Chinese herbal medicines may have adverse effects on liver and kidney function. In this study, we assessed the incidence of abnormalities in ALT, AST, BUN, Cr, WBC, urinalysis, fecal routine, electrocardiogram in both groups. The results indicated that there was no statistically significant difference in the incidence of abnormalities in these parameters before treatment and after 8 weeks of treatment within each group (P > 0.05). Furthermore, when comparing the treatment group to the control group, there was no statistically significant difference in the incidence of abnormalities before treatment and after 8 weeks of treatment (P > 0.05).

Adverse events

Among the 264 subjects, adverse events were reported in 9 cases at Yueyang Hospital, with 3 cases in the treatment group and 5 cases in the control group. At Shuguang Hospital, there was 1 case in the treatment group. Out of these 9 patients, 1 patient was removed from the clinical trial due to a suspected drug-related adverse reaction, while the other 2 were removed from the trial due to other medical conditions necessitating treatment.

Discussion

GERD is a condition that is characterized by symptoms and complications resulting from the backward flow of stomach contents into the esophagus, mouth (including the larynx), or even the lungs [18]. Its clinical presentation varies, mostly characterized by heartburn, acid reflux, and retrosternal burning pain, along with the presence of a variety of symptoms related to extraesophageal reflux [19]. PPIs are the preferred medication for treating GERD. However, many patients do not respond effectively to PPIs [20]. This subset of patients is referred to as having rGERD. Hence, it was imperative to investigate adjunctive approaches to PPI therapy for rGERD. In recent years, more researchers have recognized the distinct advantages of TCM in treating GERD [21]. In this study, we demonstrated that the combination of SHF and rabeprazole was superior to rabeprazole monotherapy in the treatment of rGERD. This superiority was evident in various aspects, including symptom scores, clinical main symptom scores (heartburn, retrosternal pain, regurgitation and belching, acid regurgitation, reflux esophagitis), and SF-36 scale. Then, a systematic clustering analysis using Ward's method and Euclidean distance was conducted on a sample of 264 patients with rGERD, based on their first Chinese medicine evidence. This analysis clustered the patients according to the degree of symptom similarity, resulting in the categorization of patients into five distinct groups. Subsequently, an index systematic clustering analysis was carried out.

The rGERD is characterized by an incomplete or lack of response to PPI therapy, often accompanied by severe and recurrent reflux symptoms [22]. Currently, research has identified multiple factors contributing to rGERD. The weakening of the physiological antireflux barrier, whether caused by a weak resting lower esophageal sphincter or the displacement of the lower esophageal sphincter and crural diaphragm (hiatal hernia), can lead to heightened reflux and an increased exposure to stomach acid [20, 23]. Reduced esophageal clearance can have an impact on esophageal peristalsis, salivary secretion, and the basal rates of esophageal clearance, thereby worsening reflux symptoms [24,25,26]. Moreover, delayed gastric emptying potentially play a role in PPI-refractory GERD by causing increased gastric distension and triggering reflux events through transient lower esophageal sphincter relaxations [27]. In addition, esophageal hypersensitivity, hypervigilance, and lower baseline mucosal impedance lead to rGERD [28,29,30]. Therefore, it is best to personalize the care of PPI-refractory GERD to the mechanism, patient profile, and patient desire.

Current research has identified a variety of modified regimens of PPIs for the treatment of rGERD. The modified PPI formulation, dexlansoprazole extended-release (MR), is a recently introduced medication for managing individuals with erosive esophagitis or nighttime symptoms of GERD. However, it is costly and may be effective in individuals who do not truly have GERD [31]. Splitting PPI-dose can also improve the therapeutic effect of PPIs on rGERD [32]. Intravenous PPI formulations act more quickly to suppress gastric acid secretion compared to oral PPI preparations. This leads to a rapid elevation in intragastric pH, effectively alleviating the patient's symptoms associated with reflux [33]. In addition, combining specific anxiolytic medications with PPI treatments and gastric stimulant drugs has shown promise in ameliorating both the physiological and psychological aspects of rGERD in patients [34]. However, these improvement methods are still limited in improving the efficacy of PPIs in the treatment of rGERD.

In China, TCM formulas have a well-established history of providing benefits for GERD [35], and clinical studies have consistently demonstrated the efficacy and safety of these TCM formulas in the treatment of GERD [36, 37]. TCM focuses on clearing the liver and stomach, resolving phlegm and resolving depression in the treatment of rGERD. Research has suggested that Wendan decoction associated with Ligan Hewei therapy may address issues related to phlegm and restore gastrointestinal homeostasis by affecting both acid and bile secretion [38]. Furthermore, acupuncture aimed at regulating qi based on the compatibility of the five meridians (affiliated with Ligan Hewei therapy) may also play a significant role in treating GERD with liver and stomach disharmony syndrome. Its mechanisms could be related to the regulation of the neuro-endocrine-immune system, which may help alleviate transient lower esophageal sphincter relaxations, enhance gastrointestinal motility, reduce acid secretion, and protect the gastric mucosa [39]. In recent years, a promising approach has emerged in the treatment of GERD, involving the combination of TCM formula and Western medicine. This combined therapy has demonstrated notable advantages, including substantial improvements in treatment effectiveness, reduced recurrence rates, minimized side effects associated with western medicine, and the potential to decrease the required dosage and treatment duration of western medications [40].

Most PPI drugs (e.g., omeprazole, cimetidine, etc.) are metabolized by P450 enzymes, 12% of which are dependent on CYP2C19, and Asians are a high-frequency population in which CYP2C19 occurs [41]. Rabeprazole, as a new generation of PPI preparation, does not rely on P450 enzyme system for metabolism, thus avoiding individual differences in acid inhibition caused by polymorphisms in the CYP2C19 gene, and has a strong inhibitory effect on gastric acid secretion [42]. A growing number of investigations suggest that multiple TCM formulas combined with Rabeprazole may be a promising new strategy for rGERD treatment. A prospective, randomized, multicenter trial in Japan revealed a significant reduction in Frequency Scale for the Symptoms of GERD (FSSG) score after 4 weeks of treatment with rikkunshito combined with rabeprazole, which is similar to the effect of double-dose rabeprazole in rGERD [43]. Another study has shown that there is no significant difference in FSSG scores between Hangeshashinto combined with rabeprazole therapy and double-dose rabeprazole therapy, and that Hangeshashinto combined with Rabeprazole therapy showed superiority in the treatment of non-obese and non-elderly rGERD patients with dyspeptic symptoms [44]. Moreover, the combined Yukgunja-tang and Rabeprazole has demonstrated both effectiveness and safety in the treatment of rGERD [45]. In this study, based on detoxification of the liver, harmonization of the stomach and reduction of rebelliousness, and regulation of qi throughout the body, we constructed SHF formula with 12 herbs and combined it with rabeprazole for the treatment of rGERD. The results showed that compared with rabeprazole alone, SHF combined with rabeprazole treatments significantly improved clinical outcomes, reduced total clinical symptom score, major symptom score, as well as improved quality of life in patients with rGERD. Based on the composition ratio of symptom severity during the first Chinese medicine consultation, regurgitation and belching were the most prevalent main symptoms. Dry mouth and bitter mouth, along with the sensation of pharyngeal obstruction, were the top two among other symptoms. In conclusion, the combination of SHF formula with rabeprazole demonstrates significant efficacy and safety in treating rGERD, suggesting its potential as a combined Chinese and Western medicine approach for rGERD treatment.

When SHF was used with rabeprazole, it greatly improved the overall effectiveness of treatment for symptoms and lowered total symptom scores more than rabeprazole alone. Combined LHF and rabeprazole treatment was also more effective at lowering rGERD major symptom scores, such as heartburn, retrosternal pain, regurgitation and coughing, acid reflux, and reflux esophagitis. Also, SHF treatment along with rabeprazole was better at improving quality of life than rabeprazole treatment alone. In this study, we found that SHF treatment with rabeprazole treatment significantly improved the therapeutic efficacy of rGERD, providing new treatment options and insights for TCM combined with Western medicine in the treatment of rGERD.