Received: 2 June 2021 Accepted: 7 June 2021

DOI: 10.1111/1751-2980.13028

CONSENSUS

Chinese expert consensus on gastroesophageal reflux disease

in 2020

Ying Lian Xiao1 | Li Ya Zhou2 | Xiao Hua Hou3 | Yan Qing Li4 | Duo Wu Zou5 |
Min Hu Chen1 | on behalf of the Chinese Society of Gastroenterology
1
Department of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong Province, China
2
Department of Gastroenterology, Peking University Third Hospital, Beijing, China
3
Department of Gastroenterology, Union Hospital Affiliated to Tongji Medical College of Huazhong University of Science and Technology, Wuhan, Hubei Province,
China
4
Department of Gastroenterology, Qilu Hospital of Shandong University, Jinan, Shandong Province, China
5
Department of Gastroenterology, Ruijin Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China

Correspondence
Min Hu Chen, Department of Gastroenterology, First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan Road II, Guangzhou, Guangdong Province
510080, China.
Email: chenminhu@mail.sysu.edu.cn

I N T R O D U CT I O N The statements in the current consensus were first drafted with

Gastroesophageal reflux disease (GERD) is common in clinical practice
and its prevalence differs significantly in different countries and
regions. According to a global population-based study the prevalence
of GERD symptoms that occur at least once weekly is 13%. It is higher
in western countries1 and has been rising in the Asia-Pacific region.2
A population-based epidemiological survey in China has shown that
the prevalence of heartburn occurring at least once weekly is 1.9%-
3,4
7.0%. The risk factors for GERD include smoking, obesity, advanced
age, alcoholic consumption and psychological disorders, as well as
genetic factors.5
Various pathophysiological mechanisms are involved in GERD,
including anatomical or physiological defects in the esophagogastric
junction (EGJ), esophageal body dysfunction in clearance and injury to
the esophageal epithelial barrier function. Other factors in daily life,
including obesity and the intake of specific food, may also impair the
esophageal anti-reflux function. Esophageal hypersensitivity also plays
a role in the pathogenesis of GERD. Recently, immune-mediated
esophageal mucosal injury and esophageal dysfunction have been
reported to be associated with the pathogenesis of GERD.6,7 In recent
years, progress has been made in the diagnosis and treatment of
GERD. Therefore, it is necessary to update the consensus to better
instruct clinical practice in the management of the disease.
This expert consensus has been published in Chinese on the Chinese Journal of Digestion,
2020;40(10):649-663.
supporting evidence by a working group of five experts in the field of
GERD based on the 2014 Chinese consensus on GERD.8 The working
group conducted an extensive literature search for relevant Chinese
and English-language articles published up to 2020 in MEDLINE,
EMBASE and Cochrane Library databases as well as the Wanfang
Data Knowledge Service Platform, and formulated the initial draft
statements. Online discussions were carried out before these state-
ments were drafted. A voting group including experts in the field of
GERD from the Chinese Society of Gastroenterology were invited to
make three rounds of anonymous voting on the statements drafted
by the working group, the first two rounds of which were performed
online. The final round of voting was performed at a consensus meet-
ing in Hangzhou (Zhejiang Province, China) on 25 July 2020. During
this meeting, the working group presented the relevant data and
updated statements revised according to the previous online voting. A
final vote seeking to finalize these statements was performed after
detailed face-to-face discussions between the working group and the
voting group. The statements were graded on the quality of
the supporting evidence according to the Grading of Recommenda-
tions, Assessment, Development and Evaluation (GRADE) system:
(a) high quality: further research is very unlikely to change the confi-
dence in the estimate of effect; (b) moderate quality: further research
is likely to have an important impact on the confidence in the estimate
of effect and may change the estimate; (c) low quality: further
research is very likely to have an important impact on the confidence
in the estimate of effect and is likely to change the estimate; and

© 2021 Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of
Medicine and John Wiley & Sons Australia, Ltd.

376 wileyonlinelibrary.com/journal/cdd J Dig Dis. 2021;22:376–389.


XIAO ET AL.
(d) very low quality: any estimate of effect is very uncertain. The Del-
phi consensus process was applied and a six-point Likert scale was
used for voting: A+, strongly agree; A, agree with minor reservations;
A , agree with major reservations; D , disagree with major
reservations; D, disagree with minor reservations; and D+, strongly
disagree. The threshold of agreement was defined as an 80% agree-
ment by the group with a statement of A+ and A. The level of agree-
ment in the final vote for each statement was expressed as the
percentage of the vote at A+ and A. In this expert consensus, a total
of 32 statements were proposed and 28 attracted consensus.
Statement 1: Heartburn and regurgitation are typical symptoms
of GERD
Overall agreement: A+, 92.3%; A, 7.7%
Level of evidence: High
Heartburn is defined as a post-sternal burning sensation, while
regurgitation is the backward flow of gastric contents up into the phar-
ynx or the oral cavity. Both are the most common and typical symp-
toms of GERD. A cohort study of 2320 patients has shown that the
symptoms of GERD include, in order of descending prevalence, heart-
burn, chest pain or epigastric pain, regurgitation, dysphagia, nausea or
vomiting, laryngopharyngeal discomfort and cough.9 In a study of 1031
patients, heartburn and regurgitation were found to be the most com-
mon symptoms of GERD, accounting for 82.4% and 58.8% of all rele-
10
vant symptoms. In 2018 a review has demonstrated that both
heartburn and regurgitation are the typical symptoms of GERD.11
Statement 2: Chest pain, epigastric burning sensation, epigastric
pain, epigastric distension and belching are atypical symptoms
of GERD
Overall agreement: A+, 48.3%; A, 37.9%
Level of evidence: Moderate
Among the various clinical manifestations of GERD, some patients
only present with atypical or extraesophageal symptoms. Common
atypical symptoms include chest pain, epigastric burning sensation or
pain, epigastric distension and belching, etc. A randomized controlled
trial (RCT) including 1392 patients with GERD found reflux-related
symptoms such as heartburn, regurgitation, abdominal distension, early
12
satiety, abdominal pain, nausea and vomiting. As indicated in another
study, patients with GERD may also have other symptoms, including
abdominal distension, belching and dysphagia, besides typical heartburn
and regurgitation.10 In a cohort study including 186 patients with func-
tional dyspepsia in China, approximately one-third with no heartburn
and regurgitation had abnormal esophageal acid exposure, especially
those with an upper abdominal burning sensation, and these patients
respond to proton pump inhibitors (PPIs).13
Statement 3: Patients with chest pain should have GERD evalua-
tions only after cardiac factors are ruled out
Overall agreement: A+, 79.3%; A, 17.2%
Level of evidence: Moderate
Chest pain is an atypical symptom of reflux. The 2006 Montreal
classification states that gastroesophageal reflux may present
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
377
symptoms similar to ischemic chest pain without typical heartburn
and regurgitation symptoms.14 Therefore, cardiac factors should be
ruled out before the evaluation of gastroesophageal reflux, such as
esophageal reflux monitoring and empirical PPI therapy. In a popula-
tion survey in Hong Kong SAR, China the prevalence of chest pain
was 20.6%, and approximately 68% of cases presented as non-cardiac
chest pain.15 A meta-analysis of 24 849 participants indicated that the
prevalence of non-cardiac chest pain was approximately 13%.16 Popu-
lation surveys have shown that the prevalence of non-cardiac chest
pain is 19%-23%,17,18 with no statistically significant difference in sex.
For non-cardiac chest pain, 50%-60% of cases are caused by GERD,
while 15%-18% are caused by esophageal motility disorder.19
Statement 4: GERD may be initially diagnosed based on typical
symptoms of heartburn and regurgitation, and reflux questionnaires
may be used as supplementary tools to assist the diagnosis
Overall agreement: A+, 57.1%; A, 42.9%
Level of evidence: Moderate
Heartburn and regurgitation are two major symptoms of
GERD. Approximately half the patients with heartburn have
regurgitation, 20 and over 60% with positive esophageal reflux
monitoring have heartburn and regurgitation.21 A multivariate
regression analysis has shown that heartburn is the most relevant
symptom of reflux esophagitis (RE).22 Thus, GERD may be initally
diagnosed based on typical symptoms of heartburn and regurgita-
tion. However, studies on the diagnostic value of heartburn and
regurgitation in GERD suggest that heartburn predicts pathological
reflux with a sensitivity of 38% and a specificity of 89%.21 A retro-
spective study also showed that the phenotypes of patients with
heartburn were heterogeneous.23 Therefore, GERD can be initally
diagnosed based on typical symptoms.
As a simple and convenient method, GERD diagnostic question-
naires have been widely applied in the outpatient clinics. In one study
in which endoscopic esophagitis and pathological esophageal reflux,
as indicated by esophageal reflux monitoring, were used as positive
diagnostic criteria. It was observed that in 308 patients with upper
gastrointestinal symptoms the sensitivity and specificity of the reflux
disease questionnaire (RDQ) in diagnosing GERD were 62% and 67%,
respectively; while those of the gastroesophageal reflux disease ques-
tionnaire (GerdQ) were 65% and 71%, respectively.24,25 The diagnos-
tic value of both questionnaires is higher in patients with typical reflux
symptoms than in those with atypical symptoms. Therefore, reflux
questionnaires are as valuable as typical heartburn and regurgitation
symptoms for the diagnosis of GERD and may be used as supplemen-
tary diagnostic tools.
Statement 5: Empirical PPI therapy can be used as a preliminary
diagnostic test for patients with typical reflux symptoms
Agreement: A+, 75.0%; A, 21.4%
Level of evidence: High
For patients with suspected GERD, PPIs are often used as a diag-
nostic treatment for GERD; however, they cannot be used as a confir-
matory test for diagnosis of the disease. Previous studies in Western

378
countries have shown that the response rate to PPI was approxi-
mately 57% for RE and 49% for non-erosive reflux disease (NERD).26
A study in China showed that for reflux patients with endoscopically
confirmed erosive esophagitis or with negative endoscopic findings
but positive esophageal reflux monitoring, the response rate to empir-
ical PPI test was approximately 70%.27 Studies in Western countries
showed that the sensitivity and specificity were 71% and 44%,
respectively, when using PPI test to diagnose GERD in patients with
the most troublesome reflux symptom.24 A meta-analysis revealed
that the sensitivity was 78% but the specificity was only 54% for PPI
28 29
test. Xu et al demonstrated that the sensitivity of PPI test was rel-
atively high (88.1%) but the specificity was low. Nevertheless, empiri-
cal PPI therapy is a convenient and valuable tool for the diagnosis of
GERD in clinical practice. It can be used as a supplementary diagnostic
tool for patients preliminarily diagnosed with GERD or with suspected
reflux-related extraesophageal symptoms, especially in those with
negative upper gastrointestinal endoscopic findings.
Studies on a novel antacid, potassium-competitive acid blocker
(P-CAB), for the treatment of RE have shown that the mucosal healing
rate was approximately 90% after 4 weeks of treatment,30 and symp-
toms are alleviated in approximately 60% of patients after 7-day ther-
apy.31 The evidence for P-CAB as a diagnostic therapy for GERD is
lacking, and further research is needed to investigate its diagnostic
value for GERD.
Statement 6: Endoscopy is recommended for treatment-naïve
patients with reflux symptoms to exclude malignancy and to detect
reflux-related disorders including RE, reflux stricture and Barrett's
esophagus
Overall agreement: A+, 70.0%; A, 30.0%
Level of evidence: High
The Chinese consensus on GERD (October 2006, Sanya)32 and
8
the Chinese consensus on GERD in 2014 have proposed that all
treatment-naïve patients with reflux symptoms should undergo
endoscopy due to a relatively high prevalence of upper gastrointesti-
nal tumor in China and a low medical cost of the gastroscopy. Early
gastroscopy assists in tumor screening and evaluation of the disease
status. A study performed in Guangzhou, China showed that the
detection rate of esophageal and gastric cancer was 0.8% in
33
treatment-naïve heartburn patients without warning signs. A meta-
analysis revealed that in Asia the detection rate of malignancy on
endoscopy was 1.3% in treatment-naïve patients with upper gastroin-
34
testinal symptoms.
The severity of erosive esophagitis can be evaluated and classi-
fied by endoscopy. The Los Angeles classification is the most com-
monly used system that is related to acid exposure and esophageal
motility disorder (low pressure of the lower esophageal sphincter
[LES] and decreased motility of the esophageal body), suggesting
that it can be used to determine the severity of GERD35,36 and to
predict treatment outcome and clinical prognosis. A Los Angeles
classification C or D indicates more nocturnal acid exposure, which
may be related to abnormal nocturnal acid clearance in these
37
patients. Some patients with NERD have minimal lesions on
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
XIAO ET AL.
endoscopy, which partially or completely disappear after antacid
treatment,38,39 suggesting that minimal lesions might be related to
NERD.38 Magnifying endoscopy combined with electronic staining
endoscopy helps visualize the fine structure of the EGJ in patients
with GERD and can be used to screen for early esophageal can-
cer.40,41 Moreover, some novel endoscopic enhancement technolo-
gies, such as flexible spectral imaging color enhancement, can
improve the detection rate of minimal lesions, although their sensi-
tivity and specificity are limited.
An esophageal barium examination is not recommended as a rou-
tine test for gastroesophageal reflux but it can be used to detect hiatal
hernia. For patients undergoing anti-reflux procedures, an esophageal
barium examination can be used to determine the size and location of
the hiatal hernia.42 For those with atypical reflux symptoms, such as
chest pain and dysphagia, an esophageal barium examination may be
performed to rule out EGJ outflow obstruction.43
Statement 7: Esophageal reflux monitoring provides objective
evidence of esophageal reflux for the confirmation of a diagnosis of
GERD. Esophageal pH monitoring alone can be used to detect acidic
reflux episodes while esophageal impedance-pH monitoring can
detect both acidic and non-acidic reflux episodes
Overall agreement: A+, 89.7%; A, 6.9%
Level of evidence: High
Esophageal reflux monitoring can detect the reflux of gastric con-
tents into the esophageal cavity and provide objective evidence for a
diagnosis of gastroesophageal reflux. Esophageal reflux monitoring is
indicated for patients with typical reflux symptoms but unremarkable
endoscopic findings, with atypical symptoms, showing no response to
medication or those scheduled to undergo anti-reflux procedures.44
The 2018 Lyon consensus for the diagnosis of GERD regards esopha-
geal reflux monitoring as one of the diagnostic methods for GERD.45
Esophageal reflux monitoring may be performed with a catheter or cap-
sule. Catheter monitoring usually lasts 24 hours, while wireless capsule
pH monitoring lasts up to 96 hours. Esophageal pH monitoring alone
can only detect acidic reflux, while esophageal impedance-pH monitor-
ing can detect both acidic and non-acidic reflux and identify the nature
of the reflux contents (liquid, gas or mixed reflux), thus improving the
diagnostic rate for GERD.46,47 The results can be used to develop treat-
ment strategies and improve treatment outcomes.48 The current rec-
ommendation is to perform esophageal pH monitoring alone in
patients who have not received PPIs to confirm a GERD diagnosis and
to guide treatment,49 and to perform esophageal impedance-pH moni-
toring in those receiving PPIs to identify the cause of uncontrolled
symptoms.48,50
The primary indicator of esophageal reflux monitoring is the
acid exposure time (AET), which is defined as the percentage of
time when esophageal pH remains below 4 in the distal esophagus
within 24 hours. A study has indicated that AET is an effective
predictive factor for PPI treatment in patients with GERD.51 Gen-
erally, AET >4.2% is considered the criterion for abnormal acid
reflux.52 In 2018, the Lyon consensus recommended increasing
the positive criterion for AET to over 6%45 to identify patients

XIAO ET AL.
with reflux. A Chinese study has demonstrated that, based on the
positive diagnostic criterion of AET >6% according to the Lyon
consensus, only 33% of patients with RE have pathological reflux,
indicating that the Lyon consensus is not entirely applicable to the
diagnosis of GERD in China. 53 During the process of esophageal
reflux monitoring, the reflux symptom index and symptom-related
probability can be used to assess the correlation between the
reflux episode and symptoms and to predict the efficacy of acid
suppressive therapy, so as to assist the diagnosis of GERD. 44,45
During esophageal impedance-pH monitoring, post-reflux
swallow-induced peristaltic wave index (PSPWI) can reflect the
patient's esophageal contractility reserve, assist a diagnosis of
GERD and effectively distinguish RE, NERD, functional heartburn
and healthy individuals.54 Mean nocturnal baseline impedance
(MNBI) reflects the condition of esophagitis, which can be used to
assist the diagnosis of GERD, distinguish among RE, NERD, func-
tional heartburn and healthy individuals, and predict the efficacy
of antacid therapy. 55 Currently, these new indicators have not
been adopted as the primary parameters for reflux detection, but
their values should be further studied in clinical practice.
Esophageal mucosal impedance is a novel, minimally invasive and
convenient technique recently developed for the diagnosis of GERD.
It reflects the esophageal mucosal barrier function by detecting
esophageal mucosal transient impedance values, thus can be used to
identify long-term chronic reflux. Studies have shown that esophageal
mucosal impedance value is significantly lower in patients with GERD
than in those without, and increases axially along the esophagus.
Moreover, esophageal mucosal impedance has a high specificity and
positive predictive value for the diagnosis of esophagitis.56 With fur-
ther development and improvement, a balloon catheter is now avail-
able with several impedance channels along each side of the balloon,
enabling a better fit to the esophagus to measure mucosal impedance
values and obtain mucosal impedance topography for a more intuitive
and accurate diagnosis of GERD.57
Statement 8: Esophageal high-resolution manometry detects the
status of esophageal motility in patients with GERD. A manometry
should be used as a routine preoperative evaluation, including both
endoscopic and surgical anti-reflux procedures
Overall agreement: A+, 62.1%; A, 34.5%
Level of evidence: Moderate
Esophageal high-resolution manometry can detect the status of
esophageal motility, including motility disorders of the esophageal
body and the morphology of the EGJ. Common motility disorders in
patients with GERD include ineffective esophageal motility and frag-
mental peristaltic breaks.58 The morphology of the EGJ shows the
relationship between the LES and diaphragm to facilitate the diagnosis
of hiatal hernia.59 Esophageal high-resolution manometry has limited
value for the diagnosis of GERD but it helps identify pathogenetic
mechanisms of GERD, including transient LES relaxation, low pressure
in the EGJ and decreased esophageal clearance.
Esophageal high-resolution manometry plays an important role in
the evaluation of GERD before endoscopic or surgical anti-reflux
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
379
procedures and can be used to identify contraindications for endo-
scopic treatment, including severe esophageal motility disorders such
as achalasia and Jackhammer esophagus.60 During esophageal
manometry, a provocation test, such as a multiple rapid drinking test,
is performed to assess the contraction reserve of the esophageal body
and to determine the risk of post-procedural complications, including
dysphagia.61 Moreover, esophageal manometry determines the loca-
tion of the LES to facilitate the placement of an esophageal reflux
monitoring catheter.
An endoluminal functional lumen imaging probe (EndoFLIP) is a
novel technique used to evaluate lumen distensibility. A balloon is
placed at the EGJ of patients with GERD and the distensibility of the
EGJ is then assessed using the ratio of pressure to the narrowest cross-
sectional area when the balloon is isometrically dilated at the plane of
intraluminal impedance measurement to help evaluate the anti-reflux
barrier function62 and guide anti-reflux procedures.63,64
Statement 9: Lifestyle adjustments including weight loss,
smoking cessation and elevating the bedhead are fundamental for
patients with GERD
Overall agreement: A+, 76.7%; A, 23.3%
Level of evidence: High
GERD is closely related to a poor lifestyle. A study on the rela-
tionship between body mass index (BMI) and GERD symptoms has
shown that BMI is positively correlated with the risk and severity
of GERD. The risk ratio of GERD symptoms at BMI ≥35 kg/m 2 is
2.93.65 Large population cohort surveys showed that weight loss
could significantly ameliorate GERD symptoms. A decrease in BMI
of >3.5 kg/m 2 is associated with significant amelioration in GERD
symptoms regardless of medication, suggesting that weight loss
improves the treatment success with anti-reflux medication and
that treatment outcomes are related to the decrease in BMI. 66
Smoking is also closely associated with GERD. 67,68 A systematic
review has shown that smoking cessation reduces reflux symp-
toms in patients with normal weight.69 Additionally, cohort studies
have shown that smoking cessation is beneficial to GERD treat-
ment, which significantly improves the symptoms and decreases
the daily episodes of reflux.70,71 Moreover, elevating the bedhead
during sleep has also been found to significantly reduce esopha-
geal AET and effectively control reflux symptoms. 72 A multicenter
study in China shows that the response rate is significantly higher
in patients receiving PPI treatment combined with diet and life-
style adjustment than in those receiving PPI treatment alone
(94.1% vs 85.9%).68
Statement 10: Both PPI and P-CAB are priority therapy for
GERD. A double-dose may be adopted if a single dose is ineffective
and acid suppressor may be converted from one to another when
necessary. The recommended treatment duration is 4-8 weeks
Overall agreement: A+, 58.6%; A, 27.6%
Level of evidence: Moderate
Numerous studies have indicated that PPI, as a preferred induc-
tion and maintenance therapy for GERD, is superior to histamine

380
2 receptor antagonist (H2RA) in the alleviation of symptoms and
healing of erosive esophagitis. P-CAB suppresses acid secretion by
competitively blocking the activity of potassium in H-K-ATPase.
Several studies have shown that P-CAB is non-inferior to PPI in
terms of the mucosal healing rate in esophagitis and the alleviation
of reflux symptoms.30,73-77 A multicenter study in Asia, which was
led by China, showed that in patients with RE the response rate was
92.4% for vonoprazan (20 mg/d) and 91.3% for lansoprazole
(30 mg/d) after 8 weeks of treatment. Furthermore, a subgroup
analysis of severe esophagitis showed that vonoprazan was superior
to lansoprazole in terms of mucosal healing rate (84.0% vs 80.6%) in
patients with severe esophagitis (Los Angeles classifications C
and D).30
A double-dose PPI or P-CAB may be adopted if a single dose is
ineffective, and the acid suppressor used may be converted from one
to another when necessary. With a double-dose PPI, the time period
of gastric pH >4 can be maintained for 15.6–20.4 hours during a
24-hour period; higher doses produce similar effects.78 A double-dose
P-CAB is superior to a single dose for maintaining gastric pH >4.77 An
RCT in Japan revealed that in patients with RE who did not respond
to standard-dose PPI a higher dose could effectively alleviate reflux
symptoms and achieve endoscopic mucosal healing.79
The treatment duration of P-CAB or PPI is 4-8 weeks. A meta-
analysis of 15 316 patients studied the efficacy of different PPI for
the treatment of RE and indicated that the esophageal mucosal
healing rate (77.5%-94.1%) was higher after an 8-week treatment
than that (47.5%-81.7%) after 4 weeks of treatment, regardless of any
80
specific PPI used. Another RCT of PPI therapy in 408 patients with
mild esophagitis showed that at the follow-up visit of week 12, the
relapse rate was significantly lower in the 8-week treatment group
than in the 4-week treatment group (47.8% vs 62.5%, P = 0.009). 81
In
2015 an RCT including patients with RE receiving vonoprazan or
lansoprazole showed that the mucosal healing rate was 94.0% and
93.2%, respectively, after 4 weeks of treatment, which was signifi-
cantly higher than that after 2 weeks of treatment (91.9% and
82
88.6%).
Statement 11: Maintenance therapy of GERD includes on-
demand treatment and long-term treatment. Patients with NERD
and mild esophagitis (Los Angeles classification A and B) who
respond to the initial treatment can receive on-demand treatment
with PPI or P-CAB
Overall agreement: A+, 63.3%; A, 30.0%
Level of evidence: High
Maintenance therapy for GERD includes on-demand treatment
and long-term treatment. Considering the cost of long-term medi-
cation and potential adverse reactions, maintenance therapy
should be selected based on its overall efficacy, safety, medical
cost, medication preference and dosing frequency. To achieve
symptom relief and endoscopic mucosal healing, PPI and P-CAB
83,84
are the most economical and effective options, while on-
demand treatment can manage the symptoms of NERD and mild
esophagitis, especially the former. An RCT including 598 patients
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
XIAO ET AL.
with NERD showed that while considering patient compliance, on-
demand PPI treatment was non-inferior to daily treatment and
effectively improved heartburn and regurgitation in 82.1% of
patients at a much lower dose compared with daily treatment.85 In
a meta-analysis, 4574 patients with NERD and mild esophagitis
were divided into an on-demand treatment group, a daily PPI
group and a placebo group. On-demand treatment was superior to
daily PPI (odds ratio [OR] 0.50, 95% confidence interval
[CI] 0.35-0.72) and placebo (OR 0.21, 95% CI 0.15-0.29) in terms
of symptom control and patient compliance.86 In a prospective
study, 30 patients with NERD first received a regular standard-
dose PPI for 1 year or more and then received on-demand treat-
ment with vonoprazan (20 mg/d) for 8 weeks. This study found no
statistically significant difference in patients’ satisfaction or symp-
tom scores.87 Another study showed that on-demand treatment
with vonoprazan (20 mg) for 24 weeks achieved a remission rate
of 86.2% in patients with mild esophagitis. 88
Statement 12: Patients with severe esophagitis (Los Angeles
classification C and D) and those who relapse after PPI or P-CAB
withdrawal usually require long-term maintenance therapy
Overall agreement: A+, 80.0%; A, 13.3%
Level of evidence: Moderate
Studies have shown that patients with GERD who remain symp-
tomatic after discontinuation of antacid therapy and those with
severe esophagitis should receive long-term antacid maintenance
therapy.89 A prospective, randomized study including 539 patients
with different grades of esophagitis showed that those with severe
esophagitis were more likely to relapse after discontinuation. After
treated for 6 months, approximately 81% of patients in the daily
treatment group maintained esophageal mucosal healing, while the
proportion was only 58% in the on-demand treatment group,
suggesting that daily maintenance therapy is better than on-demand
treatment for maintaining esophageal mucosal healing in patients
with severe esophagitis.90 A study of long-term PPI maintenance
therapy in patients with RE showed that at month 6 of treatment,
the endoscopic response rate to daily PPI treatment was 84%-
85%.91 In a phase 3 study comparing vonoprazan with lansoprazole
as maintenance therapy in patients with RE in China, the relapse
rate was 13.3% in the vonoprazan group (10 mg/d) and 12.3% in the
vonoprazan group (20 mg/d) at week 24, which were lower than
that (25.5%) in the lansoprazole group (15 mg/d; data to be
published).
Statement 13: Patients undergoing long-term acid suppressive
therapy should be monitored for potential adverse reactions and
drug–drug interactions
Overall agreement: A+, 73.3%; A, 16.7%
Level of evidence: Moderate
Potential adverse reactions related to long-term PPI treatment
are primarily reported in retrospective studies instead of high-quality
RCTs. Long-term PPI use leads to high gastric pH, which subsequently
causes bacterial overgrowth, thereby increasing the risk of Clostridium

XIAO ET AL.
difficile (C. difficile) infection. In a retrospective cohort study of
754 cases of nosocomial infection with C. difficile, the multivariate
Cox proportional hazards model indicated that ongoing PPI treatment
increased the risk of infection (OR 1.5, 95% CI 1.1-2.0).92 A system-
atic review and meta-analysis of 56 studies showed that PPI use
increased the risk of C. difficile infection (OR 1.99, 95% CI
93
1.73-2.30). Whether the PPI–clopidogrel interaction increases car-
diovascular events is under investigation. A recent meta-analysis
including 66 studies showed that concurrent use of PPI and
clopidogrel did not increase the incidence of cardiovascular events.94
Based on high-quality studies and most medium-quality studies, the
2013 U.S. guidelines on the diagnosis and treatment of GERD and the
2015 Japanese evidence-based GERD clinical practice guidelines con-
clude that the concurrent use of PPI and clopidogrel does not increase
the incidence of cardiovascular events. Some studies suggest that
long-term use of PPI may increase the risk of community-acquired
pneumonia, gastric cancer and chronic kidney diseases; however, a
causal relationship cannot be established due to many confounding
factors in these studies. There are case reports of an increased risk of
bone fracture,95,96 malabsorption of nutrients97 and dementia with a
long-term use of PPI; however, a causal relationship cannot be
established from such observational studies with limited clinical
significance.
P-CAB has been launched to the market for a short time and
short-term studies have only indicated the possibility of antacid-related
hypergastrinaemia.98 So far, there have been no reports on potential
adverse reactions and safety related to a long-term administration of P-
CAB, which should be further evaluated in clinical practice.
Statement 14: Antacids rapidly alleviate reflux symptoms
Overall agreement: A+, 26.7%; A, 63.3%
Level of evidence: Moderate
Antacids are agents that rapidly neutralize gastric acid and allevi-
ate reflux symptoms. They are used on a short-term basis to treat
GERD symptoms but are not recommended for long-term administra-
tion. Commonly used antacids include aluminium hydroxide,
hydrotalcite and alginate. A short-term administration of antacids
improves regurgitation and heartburn.99-101 A randomized multicenter
study on the efficacy of antacid, H2RA and a placebo for managing
heartburn showed that antacids alleviated heartburn more quickly and
more effectively than H2RA or placebo.102
Statement 15: Prokinetics in combination with acid suppressors
may be effective for alleviating GERD symptoms
Overall agreement: A+, 26.7%; A, 53.3%
Level of evidence: Moderate
Prokinetics are more commonly used for treating GERD in Asian
countries than in the West. The Japanese and European guidelines
have recommended the use of prokinetics in combination with acid
suppressors for some patients with GERD to improve their symptoms;
100,101
however, prokinetics are not recommended to be used alone.
contrast, the U.S. guidelines clearly advise against the use of
prokinetics for GERD.103
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
381
Commonly used prokinetics include central and peripheral dopa-
mine D2 receptor antagonists (eg, metoclopramide and domperidone),
motilin agonists (eg, erythromycin and its analogues), selective
5-hydroxytryptamine4 (5-HT4) agonists (eg, mosapride), dopamine D2
receptor blockers/acetylcholinesterase inhibitors (eg, itopride) and 5-
HT4 agonists/dopamine receptor antagonists (eg, cinitapride). A meta-
analysis of 1437 patients from 14 RCTs in China showed that
prokinetics combined with PPI were more effective in alleviating
symptoms than PPI monotherapy; however, no significant intergroup
differences were observed in the mucosal healing rate.104
Statement 16: Endoscopic radiofrequency ablation (RFA) can
improve the GERD symptoms
Overall agreement: A+, 30.0%; A, 60.0%
Level of evidence: Moderate
Endoscopic treatments for GERD include endoscopic RFA, trans-
oral incisionless fundoplication (TIF) and anti-reflux mucosectomy
(ARMS). Comparatively more studies have been conducted to investi-
gate the efficacy of endoscopic RFA, with proven long-term efficacy
over the last two decades.100 Other endoscopic procedures have
shown short-term efficacy and good safety profile, but high-quality
reports are scarce.105
RCTs have demonstrated the short-term efficacy of radiofrequency
therapy to improve various clinical measures in patients with GERD,
including a significant decrease in esophageal AET and a significant
improvement in heartburn sensation.106-109 A meta-analysis of 2468
patients has shown that radiofrequency treatment facilitates the healing
of erosive esophagitis, reduces AET, increases LES basal pressure and
reduces heartburn scores. Moreover, 51% of patients discontinued PPI
after radiofrequency treatment and reported an improved quality of life
(QoL).110 Three prospective cohort studies with long-term follow-up
confirmed the long-term efficacy of radiofrequency treatment. After
being followed up for 8 years or more, 41%-76.9% of patients discon-
tinued PPI completely, 72% of them had a normal QoL score, and
patient satisfaction was improved by >60% in more than 55% of
patients.111-113 Two studies showed that ARMS reduced AET and the
gastroesophageal valve score, and increased LES pressure and complete
relaxation pressure;114 symptoms were partially or completely alleviated
in 93.6% of patients.114,115
One study followed up 37 patients with GERD for 1 year after
TIF.116 The results showed that the scores for QoL, heartburn and
regurgitation, and the reflux symptom index decreased; 65% of patients
discontinued PPI completely and 25% reduced their dose of PPI by
50%. A meta-analysis including five RCTs and 13 prospective observa-
tional studies in China revealed that at 6 months after TIF, the response
rate was 65.96%, with decreased esophageal AET and overall reflux epi-
sodes as well as an overall satisfaction rate of 69.15%.117
Statement 17: Fundoplication has proven efficacy for GERD
Overall agreement: A+, 58.6%; A, 27.6%
In Level of evidence: Moderate
Anti-reflux surgery is recommended for patients with GERD who
are unwilling to receive long-term PPI therapy in GERD guidelines

382
both in China and abroad. Currently, fundoplication is considered the
best anti-reflux procedure and a laparoscopic fundoplication performs
better than an open fundoplication.32,100,101,103,118
Meta-analyses of different periods have confirmed the efficacy and
safety of fundoplication for GERD.32,119,120 A meta-analysis of 1892
patients from 29 RCTs showed that fundoplication was superior to PPI
119 120
for managing heartburn and regurgitation. Another meta-analysis
was conducted on the efficacy of laparoscopic fundoplication, TIF and
PPI. The results showed that a laparoscopic fundoplication was superior
to TIF and PPI for reducing the proportion of patients with pH <4,
increasing LES pressure and improving patients’ QoL. RCTs have con-
firmed the 5-to-10-year efficacy of fundoplication, by reducing acid
reflux, increasing LES pressure, alleviating symptoms, and reducing the
PPI dose in some patients.121
Magnetic sphincter augmentation (MSA) is a procedure in which
magnetic beads are laparoscopically placed at the EGJ to enhance the
anti-reflux barrier. An RCT including 152 patients compared the 1-
year efficacy of MSA and PPI for GERD. The results showed that
MSA was superior to PPI in reducing reflux symptoms and had fewer
122
complications. A meta-analysis of 19 studies in which MSA was
used to treat GERD has revealed that MSA and fundoplication are
both effective, and there are no significant differences between them
with respect to the reduction of PPI use and improvement of patients’
QoL, and only 13.2% of patients require PPI after MSA.123 At present,
RCTs and long-term follow-up studies of MSA are scarce; therefore,
more clinical evidence is required.
Statement 18: GERD is a potential cause of asthma, chronic
cough, and laryngitis. Non-reflux causes should be ruled out before
the diagnosis of reflux-related symptoms. Patients with unexplained
asthma, chronic cough or laryngitis may receive experimental acid
suppressor if they have typical reflux symptoms
Overall agreement: A+, 56.7%; A, 33.3%
Level of evidence: Moderate
Studies have shown that patients with asthma may present typi-
cal symptoms of GERD, such as heartburn and regurgitation, and that
124
the incidence of GERD in these patients is 32%-82%. Monitoring the
esophageal pH of patients with asthma for 24 hours has shown that
125
53% of them have pathological acid reflux. Some patients with
chronic laryngitis or sleep apnoea syndrome also have pathological acid
reflux.126,127 These data suggest that GERD may play an important role
in asthma, chronic cough and laryngitis. However, a meta-analysis of
chronic cough and asthma did not provide sufficient evidence to sup-
port PPI treatment among these patients.128 Studies have shown that
for patients with typical GERD symptoms such as heartburn, regurgita-
tion and extraesophageal symptoms, 10%-40% have persistent non-
acidic reflux after standard PPI treatment.129 Some Chinese researchers
found that proximal acidic reflux and distal reflux-reflex are related to
reflux-induced cough in patients with GERD.130 Although the use of
diagnostic acid suppressive therapy remains a matter of debate for
patients with extraesophageal symptoms, it is particularly indicated for
patients with esophagitis who have typical esophageal and
extraesophageal symptoms, as it is simple and non-invasive.
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
XIAO ET AL.
Statement 19: Patients with extraesophageal symptoms who do
not respond to acid suppressive therapy should be further evaluated
to identify the causes
Overall agreement: A+, 65.5%; A, 27.6%
Level of evidence: Moderate
Chronic laryngitis is a persistent inflammation of the larynx. The
common causes of chronic laryngitis include exogenous (such as
smoking and alcohol consumption) and endogenous stimuli (such
as asthma and GERD). Studies have shown that 50%-60% of the cases
of chronic laryngitis and refractory sore throat are related to GERD.
However, GERD-related laryngopharyngeal symptoms, such as
hoarseness, dysphonia and laryngospasm, are non-specific, as these
symptoms can also be induced by post-nasal drip (leakage) and envi-
ronmental irritation, such as exposure to certain allergens or other irri-
tants. The effect of acid suppressive treatment for GERD-related
extraesophageal symptoms remains a matter of debate.128,131-133
Thus, patients who do not respond to acid suppressive treatment
should be further evaluated by specialists for other diseases, such as
laryngopharyngeal or lung diseases.2,134-136
Statement 20: Patients with RE, in particular those with severe
esophagitis (Los Angeles classification C and D), should be regularly
followed up after treatment
Overall agreement: A+, 90.0%; A, 10.0%
Level of evidence: High
RE accounts for 30%-40% of all GERD cases. The severity of RE
is an important predictor of patient prognosis. Studies have shown
that mucosal healing usually occurs after 4 weeks of treatment in
patients with mild esophagitis (Los Angeles classifications A and B),
while it takes 8 weeks or longer in patients with severe esophagitis
(Los Angeles classifications C and D).137 The response rate to PPI
treatment decreases with the increased severity of esophagitis,138-141
and severe esophagitis affects the detection of Barrett's esopha-
gus.142,143 A study including 172 patients with esophagitis showed
that 12% of them had previously undetected Barrett's esophagus
after an average of 11-week treatment with PPI.143 Thus, for patients
with severe esophagitis (Los Angeles classification C and D), post-
treatment endoscopy aims to assess the healing of esophagitis and to
rule out Barrett's esophagus.144,145
Statement 21: As a complication of GERD, Barrett's esophagus
is diagnosed based on endoscopic and pathologic examinations
Overall agreement: A+, 57.1%; A, 38.1%
Level of evidence: High
Barrett's esophagus is a notable complication of GERD, and is
defined as the upward shifting of the borderline of the esophageal squa-
mous epithelium and columnar epithelium relative to the EGJ on endos-
copy, and the histologically confirmed replacement of normal stratified
squamous epithelium with metaplastic columnar epithelium. The histolog-
ical types of Barrett's esophagus include gastric fundic mucosa metaplasia,
cardiac metaplasia and intestinal metaplasia, among which Barrett's
esophagus with intestinal metaplasia is at the highest risk of developing
esophageal adenocarcinoma. Barrett's esophagus should be confirmed

XIAO ET AL.
through both endoscopic and pathological examinations. Further informa-
tion including the histological type and the presence of dysplasia is essen-
tial for treatment and follow-up strategies.2,146,147
Statement 22: Patients with dysplastic Barrett's esophagus
should be followed up intensively and undergo appropriate endo-
scopic or surgical treatment
Overall agreement: A+, 60.7%; A, 39.3%
Level of evidence: Moderate
Available evidence suggests that Barrett's esophagus may progress
to esophageal adenocarcinoma and that follow-up facilitates an early
detection of dysplasia and early cancer. A single-center study showed
that 53% of patients with a confirmed diagnosis of advanced intra-
epithelial neoplasia or esophageal cancer had undergone at least two
consecutive endoscopies and biopsies but the results indicated non-
neoplastic lesions.148 A meta-analysis showed that the annual incidence
of progression to esophageal adenocarcinoma was 0.33%, 0.54% and
6.58% for Barrett's esophagus without dysplasia, with low-grade dys-
149-151
plasia and with high-grade dysplasia, respectively. Endoscopy
with biopsy is the only evidence-based follow-up method available for
Barrett's esophagus.2,146 For Barrett's esophagus without dysplasia,
guidelines from the United States, United Kingdom, and Asia-Pacific
region recommend a follow-up duration of 3 to 5 years; however,
guidelines from the Asia-Pacific region have also stated that the bene-
fits of an endoscopic follow-up remain unknown.2 Patients with
Barrett's esophagus with low-grade dysplasia should be followed up
regularly or undergo endoscopic resection or ablation. Those with
Barrett's esophagus and high-grade dysplasia or early esophageal ade-
nocarcinoma may consider endoscopic resection after a comprehensive
evaluation of the invasive depth of the lesion and the risk of lymph
node metastasis. Additionally, surgical treatment can be indicated when
endoscopic procedures are contraindicated.2,146,152,153
Statement 23: Patients with esophageal stenosis require mainte-
nance acid suppressive therapy after dilatation to ameliorate dys-
phagia and reduce the need for re-dilatation
Overall agreement: A+, 58.1%; A, 35.5%
Level of evidence: Moderate
Esophageal stenosis is one of the complications of RE, for which the
primary therapeutic methods include balloon dilatation or bouginage, but
there is a considerable postoperative recurrence rate.154 One study155
enrolled patients with esophageal stenosis. Those with confirmed GERD
(based on esophageal manometry and pH monitoring) were prescribed
long-term oral omeprazole, while the remaining patients were randomized
to receive either oral omeprazole or placebo. It was found that none of the
patients with confirmed GERD experienced recurrence after the oral
administration of PPI, while the remaining patients prescribed oral omepra-
zole had a significantly lower recurrence rate than those with placebo, indi-
cating that oral PPI may reduce the recurrence rate after dilatation for
esophageal stenosis. Other studies have also demonstrated that P-CAB
may effectively treat RE, thus providing a new option for acid suppressive
maintenance therapy after esophageal dilatation in patients with
GERD.29,30
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
383
Statement 24: Refractory GERD is a condition in which the
reflux symptoms (including regurgitation and heartburn) do not
improve after at least 8 weeks of treatment with double-dose PPI
Overall agreement: A+, 51.7%; A, 41.4%
Level of evidence: Moderate
The definition of refractory GERD is controversial due to a lack of
uniform standards for the dose and duration of PPI treatment. Some
researchers believe that PPI treatment fails only when patients do not
respond to a double dose of oral PPI, while others state that it should be
considered when patients do not respond to a standard-dose PPI.156 The
Asia-Pacific consensus defines refractory GERD as a lack of response to a
standard-dose PPI.2 Moreover, some experts define refractory GERD as
no improvements in heartburn or regurgitation symptoms after at least a
12-week double-dose treatment with PPI,157 while others propose that
refractory GERD shall be diagnosed when there is no significant improve-
ment of symptoms after at least 8 weeks of double-dose PPI treat-
ment.158 In the current consensus, after discussions and voting, our
expert group defines refractory GERD as a condition when the symptoms
(such as regurgitation and heartburn) do not significantly improve after
8 weeks of double-dose acid suppressive therapy.
Statement 25: There are various causes of refractory GERD, in
which patient compliance should be initially checked to optimize the
administration of PPI or replace PPI with P-CAB
Overall agreement: A+, 56.7%; A, 36.7%
Level of evidence: Moderate
Refractory GERD may result from various causes including a persis-
tently poor lifestyle, non-compliance with medication, inadequate acid
suppression, esophageal hypersensitivity and psychiatric factors. Esopha-
geal impedance-pH monitoring may be performed to identify the causes
of unresponsiveness to PPI treatment and to adjust treatment strategies.
However, PPI may be changed or converted to P-CAB when esophageal
impedance-pH monitoring is not available. In a prospective study,
24 patients with endoscopically confirmed PPI-resistant RE underwent
endoscopic examination and GerdQ evaluation after 4 weeks of
vonoprazan treatment (20 mg), showing that the symptom scores signifi-
cantly improved since the first day of vonoprazan administration and even
disappeared after 6 days. Moreover, some patients remained symptom-
free for 4 weeks.159 An open-label, single-center observational study
showed that both initial and maintenance vonoprazan therapies signifi-
cantly improved heartburn in patients with PPI-resistant GERD.160
Statement 26: Patients with refractory GERD should be further
evaluated by endoscopy, high-resolution manometry and esophageal
impedance-pH monitoring
Overall agreement: A+, 69.0%; A, 31.0%
Level of evidence: Moderate level
Further investigations, including endoscopy, high-resolution manom-
etry and esophageal impedance-pH monitoring, are required for patients
with refractory GERD. Endoscopy and biopsy help rule out other
esophagogastric conditions, such as eosinophilic esophagitis and other
causes of esophagitis. High-resolution manometry can identify esopha-
geal motility disorders, including achalasia and diffuse spasm of the

384
esophagus.161 Esophageal impedance-pH monitoring detects various
types of reflux events, thereby differentiating between functional heart-
burn and esophageal hypersensitivity.156,158 With esophageal impedance-
pH monitoring, two novel parameters, PSPWI and MNBI were developed
to help diagnose GERD according to the Lyon consensus.45 Reflux symp-
toms of persistent GERD after oral PPI treatment may be related to weak
acidic or non-acidic reflux, the fundamental mechanism of which is yet to
be clarified. One possible underlying explanation is esophageal dilatation
due to increased reflux, hypersensitivity to weak acidic reflux and a com-
promised esophageal mucosa after repeated exposure to weak acidic
157,162
reflux. Moreover, studies have shown that for patients who do not
respond to PPIs, the severity of proximal weak acidic reflux detected by
esophageal impedance-pH monitoring is the most important determinant
of symptomatic reflux events.163 For refractory GERD, esophageal
impedance-pH monitoring during double-dose PPI use is recommended
to determine the adequacy of acid suppression, as well as the relationship
between refractory symptoms and reflux events.161
Statement 27: For patients with refractory GERD who have
failed medication and have evident reflux, endoscopic or surgical
treatment may be performed after weighing the advantages and dis-
advantages. Other causes should be comprehensively and carefully
ruled out before the procedure
Overall agreement: A+, 35.5%; A, 51.6%
Level of evidence: Moderate
Patients with uncontrolled symptoms after active acid suppres-
sion and have confirmed reflux-related symptoms may undergo anti-
reflux procedures. Those who respond to acid suppressors but are
unwilling to receive long-term medication may also undergo anti-
reflux procedures. Anti-reflux procedures are not recommended for
those who have failed acid suppression and have not undergone fur-
ther evaluation. Anti-reflux procedures may be endoscopic or surgi-
cal. Endoscopic procedures include radiofrequency treatment and
TIF, and the primary surgical procedure mainly includes laparoscopic
fundoplication. Patients scheduled for anti-reflux procedures must
first undergo endoscopic examination. Patients with suspected hia-
tus hernia should receive esophageal barium examination. Moreover,
manometry should be performed to rule out esophageal motility dis-
orders. Patients with negative endoscopic findings should have pH
monitoring (with or without impedance) to identify their candidacy
for anti-reflux procedures.164 In a recent randomized study,
366 patients with refractory heartburn were screened with endos-
copy, esophageal biopsy, manometry and impedance-pH monitoring.
Of those studied, 23 had other esophageal conditions and 99 had
functional heartburn. Finally, 78 patients were enrolled and random-
ized to a laparoscopic Nissen fundoplication group, a drug treatment
group (PPI, baclofen and placebo) and a control group (PPI, baclofen
placebo and desipramine placebo). The response rate of the three
groups was 67% (18/27), 28% (7/25) and 12% (3/26), respectively.
These results show that for carefully selected patients with PPI-
resistant heartburn, surgical procedures are more effective than
medication.165
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
XIAO ET AL.
Statement 28: For patients with GERD and hiatal hernia, the
dose of PPI may be doubled if they do not respond to standard-
dose PPI
Overall agreement: A+, 41.9%; A, 58.1%
Level of evidence: Moderate
In a Chinese study, 76 patients with GERD who were positive for
a reflux examination were enrolled, including 13 with hiatal hernia. All
patients took esomeprazole (40 mg once daily) and underwent pH
monitoring after 4 weeks of treatment. The results showed that
46.8% of patients with hiatal hernia were still positive for acid expo-
sure, which was alleviated after the dose of PPI was doubled.166 The
2008 American Gastroenterological Association Medical Position
Statement on the management of GERD has also stated that the dose
of PPI may be increased from once daily to twice daily for patients
with hiatus hernia and uncontrolled GERD symptoms.167
SUMMARY
This consensus was established on the basis of the Chinese expert
consensus of GERD in 2014, in which clinical characteristics and con-
ventional diagnostic methods remained and novel diagnostic methods
elaborated. The emergence of P-CAB has provided new options for
the treatment of GERD, so updated evidence from clinical trial of P-
CAB has been added in this consensus. In recent years, anti-reflux
endoscopic procedure and surgery have gradually increasingly per-
formed in China, thus their efficacy and indications have been specifi-
cally elaborated in this consensus. Treating patients with refractory
GERD and extraesophageal symptoms remains challenging in clinical
practice, and the present evidence indicates that these patients need
further specific evaluation as well as tailored strategies for treatment.
EXPERTS PARTICIPATING IN THE DRAFTING
A ND V O T I N G O F T H I S CO N S E N S U S B Y
A L P H A B E T I C A L O R D E R OF F A M I L Y N A M E
Min Hu Chen (Department of Gastroenterology, First Affiliated Hospi-
tal, Sun Yat-sen University), Fei Dai (Department of Gastroenterology,
Second Affiliated Hospital of Xi'an Jiaotong University), Ning Dai
(Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhe-
jiang University School of Medicine), Zhi Jun Duan (Department of
Gastroenterology, First Affiliated Hospital of Dalian Medical Univer-
sity), Xiu Cai Fang (Department of Gastroenterology, Peking Union
Medical College Hospital), Jian Yu Hao (Department of Gastroenterol-
ogy, Beijing Chao-Yang Hospital, Capital Medical University), Xiao
Hua Hou (Department of Gastroenterology, Union Hospital Affiliated
to Tongji Medical College of Huazhong University of Science and
Technology), Yu Lan (Department of Gastroenterology, Beijing
Jishuitan Hospital), Shi Liu (Department of Gastroenterology, Union
Hospital Affiliated to Tongji Medical College of Huazhong University
of Science and Technology), Yan Qing Li (Department of

XIAO ET AL.
Gastroenterology, Qilu Hospital of Shandong University), Lin Lin
(Department of Gastroenterology, Jiangsu Province Hospital), Bin Lyu
(Department of Gastroenterology, First Affiliated Hospital of Zhejiang
Chinese Medical University), Fan Dong Meng (Department of Gastro-
enterology, Beijing Friendship Hospital, Capital Medical University), Li
Hua Peng (Department of Gastroenterology, Chinese PLA General
Hospital), Zhan Min Shang (Department of Gastroenterology, Beijing
Chao-Yang Hospital, Capital Medical University), Jun Song
(Department of Gastroenterology, Union Hospital Affiliated to Tongji
Medical College of Huazhong University of Science and Technology),
An Jiang Wang (Department of Gastroenterology, First Affiliated Hos-
pital of Nanchang University), Bang Mao Wang (Department of Gas-
troenterology, Tianjin Medical University General Hospital), Hua Hong
Wang (Department of Gastroenterology, Peking University First Hos-
pital), Xue Hong Wang (Department of Gastroenterology, Qinghai
University Affiliated Hospital), Ji Min Wu (Department of Gastro-
esophageal Reflux Disease, PLA Rocket Force Characteristic Medical
Center), Xue Lian Xiang (Department of Gastroenterology, Union Hos-
pital Affiliated to Tongji Medical College of Huazhong University of
Science and Technology), Ying Lian Xiao (Department of Gastroenter-
ology, First Affiliated Hospital, Sun Yat-sen University), Chen Xi Xie
(Department of Gastroenterology, Zhongshan Hospital Xiamen Uni-
versity), Hong Wei Xu (Department of Gastroenterology, Shandong
Provincial Hospital), Min Yang (Department of Gastroenterology,
Daping Hospital, Army Medical University), Zhao Xia Yang (Department
of Gastroenterology, Second Affiliated Hospital of Chongqing Medical
University), Ling Zhang (Department of Gastroenterology, Ruijin Hospi-
tal, School of Medicine, Shanghai Jiao Tong University), Ni Na Zhang
(Department of Gastroenterology, Nanjing Drum Tower Hospital, Affili-
ated Hospital of Nanjing University Medical School), Li Ya Zhou
(Department of Gastroenterology, Peking University Third Hospital),
Duo Wu Zou (Department of Gastroenterology, Ruijin Hospital, School
of Medicine, Shanghai Jiao Tong University), Xiu Li Zuo (Department of
Gastroenterology, Qilu Hospital of Shandong University).
CONF LICT OF IN TE RE ST
All experts declare that they had no conflict of interest.
RE FE R ENC E S
1. Eusebi LH, Ratnakumaran R, Yuan Y, Solaymani-Dodaran M,
Bazzoli F, Ford AC. Global prevalence of, and risk factors for, gastro-
oesophageal reflux symptoms: a meta-analysis. Gut. 2018;67(3):
430-440.
2. Fock KM, Talley N, Goh KL, et al. Asia-Pacific consensus on the man-
agement of gastro-oesophageal reflux disease: an update focusing
on refractory reflux disease and Barrett's oesophagus. Gut. 2016;65
(9):1402-1415.
3. Pan GZ, Xu GM, Guo HP, et al. An epidemiologic study on symptom-
atic GER in Beijing and Shanghai [in Chinese]. Chin J Dig. 1999;19(4):
223-226.
4. Xiong LS, Chen MH, Chen HX, Xu AG, He LJ, Hu PJ. A
population-based epidemiologic study on gastroesophageal
reflux disease in Guangdong Province [in Chinese]. Chin J Dig.
2006;26(4):239-242.
5. Zhang L, Zou DW. Epidemiology and risk factors of gastroesopha-
geal reflux disease [in Chinese]. Clin Focus. 2017;32(1):1-4.
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
385
6. Woodland P, Shen Ooi JL, Grassi F, et al. Superficial esophageal muco-
sal afferent nerves may contribute to reflux hypersensitivity in non-
erosive reflux disease. Gastroenterology. 2017;153(5):1230-1239.
7. Dunbar KB, Agoston AT, Odze RD, et al. Association of acute gastro-
esophageal reflux disease with esophageal histologic changes. JAMA.
2016;315(19):2104-2112.
8. Chinese Society of Gastroenterology. Chinese consensus on gastro-
esophageal reflux disease 2014 [in Chinese]. Chin J Dig. 2014;34(10):
649-661.
9. Hongo M, Kinoshita Y, Miwa H, Ashida K. The demographic charac-
teristics and health-related quality of life in a large cohort of reflux
esophagitis patients in Japan with reference to the effect of
lansoprazole: the REQUEST study. J Gastroenterol. 2008;43(12):
920-927.
10. Broderick R, Fuchs KH, Breithaupt W, et al. Clinical presentation of
gastroesophageal reflux disease: a prospective study on symptom
diversity and modification of questionnaire application. Dig Dis.
2020;38(3):188-195.
11. Richter JE, Rubenstein JH. Presentation and epidemiology of gastro-
esophageal reflux disease. Gastroenterology. 2018;154(2):267-276.
12. Eggleston A, Katelaris PH, Nandurkar S, Thorpe P, Holtmann G;
Treat Study Group. Clinical trial: the treatment of gastro-
oesophageal reflux disease in primary care - prospective randomized
comparison of rabeprazole 20 mg with esomeprazole 20 and 40 mg.
Aliment Pharmacol Ther. 2009;29(9):967-978.
13. Xiao YL, Peng S, Tao J, et al. Prevalence and symptom pattern of
pathologic esophageal acid reflux in patients with functional dyspep-
sia based on the Rome III criteria. Am J Gastroenterol. 2010;105(12):
2626-2631.
14. Vakil N, van Zanten SV, Kahrilas P, Dent J, Jones R; Global Consen-
sus Group. The Montreal definition and classification of gastro-
esophageal reflux disease: a global evidence-based consensus.
Am J Gastroenterol. 2006;101(8):1900-1920.
15. Wong WM, Lam KF, Cheng C, et al. Population based study of
noncardiac chest pain in southern Chinese: prevalence, psychosocial
factors and health care utilization. World J Gastroenterol. 2004;10(5):
707-712.
16. Ford AC, Suares NC, Talley NJ. Meta-analysis: the epidemiology of
noncardiac chest pain in the community. Aliment Pharmacol Ther.
2011;34(2):172-180.
17. Eslick GD, Jones MP, Talley NJ. Non-cardiac chest pain: prevalence,
risk factors, impact and consulting - a population-based study. Ali-
ment Pharmacol Ther. 2003;179(9):1115-1124.
18. Locke GR 3rd, Talley NJ, Fett SL, Zinsmeister AR, Melton LJ 3rd.
Prevalence and clinical spectrum of gastroesophageal reflux: a
population-based study in Olmsted County, Minnesota. Gastroenter-
ology. 1997;112(5):1448-1456.
19. Fass R, Dickman R. Non-cardiac chest pain: an update.
Neurogastroenterol Motil. 2006;18(6):408-417.
20. Moayyedi P, Axon AT. The usefulness of the likelihood ratio in the
diagnosis of dyspepsia and gastroesophageal reflux disease.
Am J Gastroenterol. 1999;94(11):3122-3125.
21. Klauser AG, Schindlbeck NE, Müller-Lissner SA. Symptoms in gastro-
oesophageal reflux disease. Lancet. 1990;335(8683):205-208.
22. Okamoto K, Iwakiri R, Mori M, et al. Clinical symptoms in endo-
scopic reflux esophagitis: evaluation in 8031 adult subjects. Dig Dis
Sci. 2003;48(12):2237-2241.
23. Zhang M, Chen M, Peng S, Xiao Y. The Rome IV versus Rome III
criteria for heartburn diagnosis: a comparative study. United
European Gastroenterol J. 2018;6(3):358-366.
24. Dent J, Vakil N, Jones R, et al. Accuracy of the diagnosis of GORD
by questionnaire, physicians and a trial of proton pump inhibitor
treatment: the Diamond Study. Gut. 2010;59(6):714-721.
25. Norder Grusell E, Mjörnheim AC, Finizia C, Ruth M, Bergquist H.
The diagnostic value of GerdQ in subjects with atypical symptoms

386
of gastro-esophageal reflux disease. Scand J Gastroenterol. 2018;53
(10-11):1165-1170.
26. Bytzer P, Jones R, Vakil N, et al. Limited ability of the proton-pump
inhibitor test to identify patients with gastroesophageal reflux dis-
ease. Clin Gastroenterol Hepatol. 2012;10(12):1360-1366.
27. Xiao YL, Li YQ, Tang CW, et al. The value of esomeprazole test in
diagnosing gastroesophageal reflux disease: a randomized multi-
center controlled trial [in Chinese]. Chin J Dig. 2008;28(4):233-236.
28. Numans ME, Lau J, de Wit NJ, Bonis PA. Short-term treatment with
proton-pump inhibitors as a test for gastroesophageal reflux disease:
a meta-analysis of diagnostic test characteristics. Ann Intern Med.
2004;140(7):518-527.
29. Xu GM, Fang YQ, Cheng NN, et al. Diagnostic value of omeprazole
test in gastro-esophageal reflux disease [in Chinese]. Chin J Dig.
2002;22(1):7-10.
30. Xiao Y, Zhang S, Dai N, et al. Phase III, randomised, double-blind,
multicentre study to evaluate the efficacy and safety of vonoprazan
compared with lansoprazole in Asian patients with erosive
oesophagitis. Gut. 2020;69(2):224-230.
31. Oshima T, Arai E, Taki M, et al. Randomised clinical trial: vonoprazan
versus lansoprazole for the initial relief of heartburn in patients with
erosive oesophagitis. Aliment Pharmacol Ther. 2019;49(2):140-146.
32. Expert Group of the Chinese Consensus on Gastroesophageal
Reflux Disease. Chinese consensus on gastroesophageal reflux dis-
ease (October 2006, Sanya) [in Chinese]. Chin J Int Med. 2007;46(2):
170-173.
33. Peng S, Xiong LS, Xiao YL, et al. Prompt upper endoscopy is an appro-
priate initial management in uninvestigated Chinese patients with typ-
ical reflux symptoms. Am J Gastroenterol. 2010;105(9):1947-1952.
34. Chen SL, Gwee KA, Lee JS, et al. Systematic review with meta-analysis:
prompt endoscopy as the initial management strategy for
uninvestigated dyspepsia in Asia. Aliment Pharmacol Ther. 2015;
41(3):239-252.
35. Lundell LR, Dent J, Bennett JR, et al. Endoscopic assessment of
oesophagitis: clinical and functional correlates and further validation
of the Los Angeles classification. Gut. 1999;45(2):172-180.
36. Liu L, Li S, Zhu K, et al. Relationship between esophageal motility
and severity of gastroesophageal reflux disease according to the Los
Angeles classification. Medicine (Baltimore). 2019;98(19):e15543.
https://doi.org/10.1097/MD.0000000000015543.
37. Adachi K, Fujishiro H, Katsube T, et al. Predominant nocturnal acid
reflux in patients with Los Angeles grade C and D reflux esophagitis.
J Gastroenterol Hepatol. 2001;16(11):1191-1196.
38. Lynch CR, Wani S, Rastogi A, et al. Effect of acid-suppressive ther-
apy on narrow band imaging findings in gastroesophageal reflux dis-
ease: a pilot study. Dis Esophagus. 2013;26(2):124-129.
39. Edebo A, Tam W, Bruno M, et al. Magnification endoscopy for diag-
nosis of nonerosive reflux disease: a proposal of diagnostic criteria
and critical analysis of observer variability. Endoscopy. 2007;39(3):
195-201.
40. Parikh ND, Viana AV, Shah S, Laine L. Image-enhanced endoscopy is
specific for the diagnosis of non-erosive gastroesophageal reflux dis-
ease. Scand J Gastroenterol. 2018;53(3):260-264.
41. Fock KM, Teo EK, Ang TL, Tan JYL, Law NM. The utility of narrow
band imaging in improving the endoscopic diagnosis of gastroesoph-
ageal reflux disease. Clin Gastroenterol Hepatol. 2009;7(1):54-59.
42. Weitzendorfer M, Köhler G, Antoniou SA, et al. Preoperative diagno-
sis of hiatal hernia: barium swallow X-ray, high-resolution manome-
try, or endoscopy? Eur Surg. 2017;49(5):210-217.
43. Richter JE, Castell DO. Gastroesophageal reflux. Pathogenesis, diag-
nosis, and therapy. Ann Intern Med. 1982;97(1):93-103.
44. Roman S, Gyawali CP, Savarino E, et al; GERD Consensus Group.
Ambulatory reflux monitoring for diagnosis of gastro-esophageal
reflux disease: update of the Porto consensus and recommendations
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
XIAO ET AL.
from an international consensus group. Neurogastroenterol Motil.
2017;29(10):1-15.
45. Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of
GERD: the Lyon consensus. Gut. 2018;67(7):1351-1362.
46. Frazzoni M, Conigliaro R, Mirante VG, Melotti G. The added value of
quantitative analysis of on-therapy impedance-pH parameters in dis-
tinguishing refractory non-erosive reflux disease from functional
heartburn. Neurogastroenterol Motil. 2012;24(2):141-e87.
47. Zhou LY, Wang Y, Lu JJ, et al. Accuracy of diagnosing gastroesopha-
geal reflux disease by GerdQ, esophageal impedance monitoring and
histology. J Dig Dis. 2014;15(5):230-238.
48. Becker V, Bajbouj M, Waller K, Schmid RM, Meining A. Clinical trial:
persistent gastro-oesophageal reflux symptoms despite standard
therapy with proton pump inhibitors - a follow-up study of
intraluminal-impedance guided therapy. Aliment Pharmacol Ther.
2007;26(10):1355-1360.
49. Hemmink GJ, Bredenoord AJ, Weusten BLAM, Monkelbaan JF,
Timmer R, Smout AJPM. Esophageal pH-impedance monitoring in
patients with therapy-resistant reflux symptoms: 'on' or 'off' proton
pump inhibitor? Am J Gastroenterol. 2008;103(10):2446-2453.
50. Sharma N, Agrawal A, Freeman J, Vela MF, Castell D. An analysis of
persistent symptoms in acid-suppressed patients undergoing
impedance-pH monitoring. Clin Gastroenterol Hepatol. 2008;6(5):
521-524.
51. Patel A, Sayuk GS, Gyawali CP. Parameters on esophageal pH-
impedance monitoring that predict outcomes of patients with gas-
troesophageal reflux disease. Clin Gastroenterol Hepatol. 2015;13(5):
884-891.
52. Kahrilas PJ, Quigley EM. Clinical esophageal pH recording: a techni-
cal review for practice guideline development. Gastroenterology.
1996;110(6):1982-1996.
53. Zhang M, Tan N, Li Y, Chen M, Xiao Y. Esophageal physiologic pro-
files within erosive esophagitis in China: predominantly low-grade
esophagitis with low reflux burden. Neurogastroenterol Motil. 2019;
31(12):e13702. https://doi.org/10.1111/nmo.13702.
54. Frazzoni M, Savarino E, de Bortoli N, et al. Analyses of the post-
reflux swallow-induced peristaltic wave index and nocturnal baseline
impedance parameters increase the diagnostic yield of impedance-
pH monitoring of patients with reflux disease. Clin Gastroenterol
Hepatol. 2016;14(1):40-46.
55. Xie C, Sifrim D, Li Y, Chen M, Xiao Y. Esophageal baseline imped-
ance reflects mucosal integrity and predicts symptomatic outcome
with proton pump inhibitor treatment. J Neurogastroenterol Motil.
2018;24(1):43-50.
56. Ates F, Yuksel ES, Higginbotham T, et al. Mucosal impedance dis-
criminates GERD from non-GERD conditions. Gastroenterology.
2015;148(2):334-343.
57. Patel DA, Higginbotham T, Slaughter JC, et al. Development and
validation of a mucosal impedance contour analysis system to
distinguish esophageal disorders. Gastroenterology. 2019;156(6):
1617-1626.e1.
58. Xiao Y, Kahrilas PJ, Kwasny MJ, et al. High-resolution manometry
correlates of ineffective esophageal motility. Am J Gastroenterol.
2012;107(11):1647-1654.
59. Weijenborg PW, van Hoeij FB, Smout AJ, Bredenoord AJ. Accuracy
of hiatal hernia detection with esophageal high-resolution manome-
try. Neurogastroenterol Motil. 2015;27(2):293-299.
60. Chan WW, Haroian LR, Gyawali CP. Value of preoperative esopha-
geal function studies before laparoscopic antireflux surgery. Surg
Endosc. 2011;25(9):2943-2949.
61. Shaker A, Stoikes N, Drapekin J, Kushnir V, Brunt LM, Gyawali CP.
Multiple rapid swallow responses during esophageal high-resolution
manometry reflect esophageal body peristaltic reserve.
Am J Gastroenterol. 2013;108(11):1706-1712.

XIAO ET AL.
62. Kwiatek MA, Pandolfino JE, Hirano I, Kahrilas PJ. Esophagogastric
junction distensibility assessed with an endoscopic functional lumi-
nal imaging probe (EndoFLIP). Gastrointest Endosc. 2010;72(2):
272-278.
63. Su B, Novak S, Callahan ZM, Kuchta K, Carbray J, Ujiki MB. Using
impedance planimetry (EndoFLIP™) in the operating room to assess
gastroesophageal junction distensibility and predict patient out-
comes following fundoplication. Surg Endosc. 2020;34(4):1761-
1768.
64. Su B, Dunst C, Gould J, et al. Experience-based expert consensus on
the intra-operative usage of the Endoflip impedance planimetry sys-
tem. Surg Endosc. 2021;35(6):2731-2742.
65. Jacobson BC, Somers SC, Fuchs CS, Kelly CP, Camargo CA Jr. Body-
mass index and symptoms of gastroesophageal reflux in women. N
Engl J Med. 2006;354(22):2340-2348.
66. Ness-Jensen E, Lindam A, Lagergren J, Hveem K. Weight loss and
reduction in gastroesophageal reflux. A prospective population-
based cohort study: the HUNT study. Am J Gastroenterol. 2013;108
(3):376-382.
67. Hallan A, Bomme M, Hveem K, Møller-Hansen J, Ness-Jensen E.
Risk factors on the development of new-onset gastroesophageal
reflux symptoms. A population-based prospective cohort study: the
HUNT study. Am J Gastroenterol. 2015;110(3):393-400.
68. Yuan LZ, Yi P, Wang GS, et al. Lifestyle intervention for gastro-
esophageal reflux disease: a national multicenter survey of lifestyle
factor effects on gastroesophageal reflux disease in China. Therap
Adv Gastroenterol. 2019;12:1756284819877788. https://doi.org/
10.1177/1756284819877788.
69. Kaltenbach T, Crockett S, Gerson LB. Are lifestyle measures effec-
tive in patients with gastroesophageal reflux disease? An evidence-
based approach. Arch Intern Med. 2006;166(9):965-971.
70. Ness-Jensen E, Lindam A, Lagergren J, Hveem K. Tobacco smoking
cessation and improved gastroesophageal reflux: a prospective
population-based cohort study: the HUNT study. Am J Gastroenterol.
2014;109(2):171-177.
71. Waring JP, Eastwood TF, Austin JM, Sanowski RA. The immediate
effects of cessation of cigarette smoking on gastroesophageal reflux.
Am J Gastroenterol. 1989;84(9):1076-1078.
72. Ness-Jensen E, Hveem K, El-Serag H, Lagergren J. Lifestyle interven-
tion in gastroesophageal reflux disease. Clin Gastroenterol Hepatol.
2016;14(2):175-182.e3.
73. Cremonini F, Ziogas DC, Chang HY, et al. Meta-analysis: the effects
of placebo treatment on gastro-oesophageal reflux disease. Aliment
Pharmacol Ther. 2010;32(1):29-42.
74. Sigterman KE, van Pinxteren B, Bonis PA, Lau J, Numans ME. Short-
term treatment with proton pump inhibitors, H2-receptor antago-
nists and prokinetics for gastro-oesophageal reflux disease-like
symptoms and endoscopy negative reflux disease. Cochrane Data-
base Syst Rev. 2013;2013(5):CD002095. https://doi.org/10.1002/
14651858.CD002095.pub5.
75. Lee KJ, Son BK, Kim GH, et al. Randomised phase 3 trial: tegoprazan,
a novel potassium-competitive acid blocker, vs. esomeprazole in
patients with erosive oesophagitis. Aliment Pharmacol Ther. 2019;49
(7):864-872.
76. Kirchheiner J, Glatt S, Fuhr U, et al. Relative potency of proton-
pump inhibitors—comparison of effects on intragastric pH. Eur J Clin
Pharmacol. 2009;65(1):19-31.
77. Shibli F, Kitayama Y, Fass R. Novel therapies for gastroesophageal
reflux disease: beyond proton pump inhibitors. Curr Gastroenterol
Rep. 2020;22(4):16. https://doi.org/10.1007/s11894-020-0753-y.
78. Graham DY, Tansel A. Interchangeable use of proton pump inhibi-
tors based on relative potency. Clin Gastroenterol Hepatol. 2018;16
(6):800-808.e7.
79. Kinoshita Y, Hongo M; Japan TWICE Study Group. Efficacy of
twice-daily rabeprazole for reflux esophagitis patients refractory to
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
387
standard once-daily administration of PPI: the Japan-based TWICE
study. Am J Gastroenterol. 2012;107(4):522-530.
80. Gralnek IM, Dulai GS, Fennerty MB, Spiegel BMR. Esomeprazole
versus other proton pump inhibitors in erosive esophagitis: a meta-
analysis of randomized clinical trials. Clin Gastroenterol Hepatol.
2006;4(12):1452-1458.
81. Hsu PI, Lu CL, Wu DC, et al. Eight weeks of esomeprazole therapy
reduces symptom relapse, compared with 4 weeks, in patients with
Los Angeles grade A or B erosive esophagitis. Clin Gastroenterol
Hepatol. 2015;13(5):859-866.e1.
82. Ashida K, Sakurai Y, Nishimura A, et al. Randomised clinical trial: a
dose-ranging study of vonoprazan, a novel potassium-competitive
acid blocker, vs. lansoprazole for the treatment of erosive
oesophagitis. Aliment Pharmacol Ther. 2015;42(6):685-695.
83. Fujimoto K, Hongo M; Maintenance Study Group. Risk factors for
relapse of erosive GERD during long-term maintenance treatment
with proton pump inhibitor: a prospective multicenter study in
Japan. J Gastroenterol. 2010;45(12):1193-1200.
84. Yokoya Y, Igarashi A, Uda A, Deguchi H, Takeuchi T, Higuchi K.
Cost-utility analysis of a 'vonoprazan-first' strategy versus
'esomeprazole- or rabeprazole-first' strategy in GERD.
J Gastroenterol. 2019;54(12):1083-1095.
85. Bayerdörffer E, Bigard MA, Weiss W, et al. Randomized, multicenter
study: on-demand versus continuous maintenance treatment with
esomeprazole in patients with non-erosive gastroesophageal reflux
disease. BMC Gastroenterol. 2016;16:48. https://doi.org/10.1186/
s12876-016-0448-x.
86. Khan Z, Alastal Y, Khan MA, et al. On-demand therapy with proton
pump inhibitors for maintenance treatment of nonerosive reflux disease
or mild erosive esophagitis: a systematic review and meta-analysis.
Gastroenterol Res Pract. 2018;2018:6417526. https://doi.org/10.1155/
2018/6417526.
87. Hoshikawa Y, Kawami N, Hoshino S, et al. Efficacy of on-demand
therapy using 20-mg vonoprazan for non-erosive reflux disease.
Esophagus. 2019;16(2):201-206.
88. Umezawa M, Kawami N, Hoshino S, et al. Efficacy of on-demand
therapy using 20-mg vonoprazan for mild reflux esophagitis. Diges-
tion. 2018;97(4):309-315.
89. Carlsson R, Galmiche JP, Dent J, Lundell L, Frison L. Prognostic fac-
tors influencing relapse of oesophagitis during maintenance therapy
with antisecretory drugs: a meta-analysis of long-term omeprazole
trials. Aliment Pharmacol Ther. 1997;11(3):473-482.
90. Sjöstedt S, Befrits R, Sylvan A, et al. Daily treatment with esomeprazole
is superior to that taken on-demand for maintenance of healed erosive
oesophagitis. Aliment Pharmacol Ther. 2005;22(3):183-191.
91. Goh KL, Benamouzig R, Sander P, Schwan T; EMANCIPATE. Efficacy
of pantoprazole 20mg daily compared with esomeprazole 20mg
daily in the maintenance of healed gastroesophageal reflux disease:
a randomized, double-blind comparative trial - the EMANCIPATE
study. Eur J Gastroenterol Hepatol. 2007;19(3):205-211.
92. McDonald EG, Milligan J, Frenette C, Lee TC. Continuous proton
pump inhibitor therapy and the associated risk of recurrent Clostrid-
ium difficile infection. JAMA Intern Med. 2015;175(5):784-791.
93. Trifan A, Stanciu C, Girleanu I, et al. Proton pump inhibitors therapy
and risk of Clostridium difficile infection: systematic review and
meta-analysis. World J Gastroenterol. 2017;23(35):6500-6515.
94. Farhat N, Fortin Y, Haddad N, et al. Systematic review and meta-
analysis of adverse cardiovascular events associated with proton
pump inhibitors used alone or in combination with antiplatelet
agents. Crit Rev Toxicol. 2019;49(3):215-261.
95. Targownik LE, Leslie WD, Davison KS, et al; CaMos Research Group.
The relationship between proton pump inhibitor use and longitudi-
nal change in bone mineral density: a population-based study from
the Canadian multicentre osteoporosis study (CaMos).
Am J Gastroenterol. 2012;107(9):1361-1369.

388
96. Targownik LE, Goertzen AL, Luo Y, Leslie WD. Long-term proton
pump inhibitor use is not associated with changes in bone strength
and structure. Am J Gastroenterol. 2017;112(1):95-101.
97. Ito T, Jensen RT. Association of long-term proton pump inhibitor ther-
apy with bone fractures and effects on absorption of calcium, vitamin
B12, iron, and magnesium. Curr Gastroenterol Rep. 2010;12(6):448-457.
98. Ashida K, Sakurai Y, Hori T, et al. Randomised clinical trial:
vonoprazan, a novel potassium-competitive acid blocker,
vs. lansoprazole for the healing of erosive oesophagitis. Aliment
Pharmacol Ther. 2016;43(2):240-251.
99. Hunt R, Armstrong D, Katelaris P, et al. World Gastroenterology
Organisation global guidelines: GERD global perspective on gastro-
esophageal reflux disease. J Clin Gastroenterol. 2017;51(6):467-478.
100. Iwakiri K, Kinoshita Y, Habu Y, et al. Evidence-based clinical practice
guidelines for gastroesophageal reflux disease 2015. J Gastroenterol.
2016;51(8):751-767.
101. Fuchs KH, Babic B, Breithaupt W, et al; European Association of
Endoscopic Surgery (EAES). EAES recommendations for the man-
agement of gastroesophageal reflux disease. Surg Endosc. 2014;28
(6):1753-1773.
102. Holtmeier W, Holtmann G, Caspary WF, Weingärtner U. On-
demand treatment of acute heartburn with the antacid hydrotalcite
compared with famotidine and placebo: randomized double-blind
cross-over study. J Clin Gastroenterol. 2007;41(6):564-570.
103. Katz PO, Gerson LB, Vela MF. Guidelines for the diagnosis and man-
agement of gastroesophageal reflux disease. Am J Gastroenterol.
2013;108(3):308-328.
104. Xi L, Zhu J, Zhang H, Muktiali M, Li Y, Wu A. The treatment efficacy
of adding prokinetics to PPIs for gastroesophageal reflux disease: a
meta-analysis. Esophagus. 2020;18(1):144-151.
105. Rouphael C, Padival R, Sanaka MR, Thota PN. Endoscopic treat-
ments of GERD. Curr Treat Options Gastroenterol. 2018;16(1):58-71.
106. Corley DA, Katz P, Wo JM, et al. Improvement of gastroesophageal
reflux symptoms after radiofrequency energy: a randomized, sham-
controlled trial. Gastroenterology. 2003;125(3):668-676.
107. Triadafilopoulos G, DiBaise JK, Nostrant TT, et al. The Stretta proce-
dure for the treatment of GERD: 6 and 12 month follow-up of the
U.S. open label trial. Gastrointest Endosc. 2002;55(2):149-156.
108. Triadafilopoulos G. Changes in GERD symptom scores correlate
with improvement in esophageal acid exposure after the Stretta pro-
cedure. Surg Endosc. 2004;18(7):1038-1044.
109. Ma L, Li T, Liu G, Wang J, Yin Z, Kang J. Stretta radiofrequency
treatment vs Toupet fundoplication for gastroesophageal reflux dis-
ease: a comparative study. BMC Gastroenterol. 2020;20(1):162.
https://doi.org/10.1186/s12876-020-01310-2.
110. Fass R, Cahn F, Scotti DJ, Gregory DA. Systematic review and meta-
analysis of controlled and prospective cohort efficacy studies of
endoscopic radiofrequency for treatment of gastroesophageal reflux
disease. Surg Endosc. 2017;31(12):4865-4682.
111. Noar M, Squires P, Noar E, Lee M. Long-term maintenance effect of
radiofrequency energy delivery for refractory GERD: a decade later.
Surg Endosc. 2014;28(8):2323-2333.
112. Noar M, Squires P, Khan S. Radiofrequency energy delivery to the
lower esophageal sphincter improves gastroesophageal reflux
patient-reported outcomes in failed laparoscopic Nissen
fundoplication cohort. Surg Endosc. 2017;31(7):2854-2862.
113. Dughera L, Rotondano G, De Cento M, Cassolino P, Cisarò F. Dura-
bility of Stretta radiofrequency treatment for GERD: results of an
8-year follow-up. Gastroenterol Res Pract. 2014;2014:531907.
https://doi.org/10.1155/2014/531907.
114. Inoue H, Ito H, Ikeda H, et al. Anti-reflux mucosectomy for gastro-
esophageal reflux disease in the absence of hiatus hernia: a pilot
study. Ann Gastroenterol. 2014;27(4):346-351.
115. Yoo IK, Ko WJ, Kim HS, et al. Anti-reflux mucosectomy using a cap-
assisted endoscopic mucosal resection method for refractory
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
XIAO ET AL.
gastroesophageal disease: a prospective feasibility study. Surg
Endosc. 2020;34(3):1124-1131.
116. Testoni PA, Testoni S, Mazzoleni G, et al. Transoral incisionless
fundoplication with an ultrasonic surgical endostapler for the treat-
ment of gastroesophageal reflux disease: 12-month outcomes.
Endoscopy. 2020;52(6):469-473.
117. Huang X, Chen S, Zhao H, et al. Efficacy of transoral incisionless
fundoplication (TIF) for the treatment of GERD: a systematic review
with meta-analysis. Surg Endosc. 2017;31(3):1032-1044.
118. Seo HS, Choi M, Son SY, Kim MG, Han DS, Lee HH. Evidence-based
practice guideline for surgical treatment of gastroesophageal reflux
disease 2018. J Gastric Cancer. 2018;18(4):313-327.
119. Andreou A, Watson DI, Mavridis D, Francis NK, Antoniou SA.
Assessing the efficacy and safety of laparoscopic antireflux proce-
dures for the management of gastroesophageal reflux disease: a sys-
tematic review with network meta-analysis. Surg Endosc. 2020;34
(2):510-520.
120. Richter JE, Kumar A, Lipka S, Miladinovic B, Velanovich V. Efficacy
of laparoscopic Nissen fundoplication vs transoral incisionless
fundoplication or proton pump inhibitors in patients with gastro-
esophageal reflux disease: a systematic review and network meta-
analysis. Gastroenterology. 2018;154(5):1298-1308.e7.
121. Anvari M, Allen C. Five-year comprehensive outcomes evaluation in
181 patients after laparoscopic Nissen fundoplication. J Am Coll
Surg. 2003;196(1):51-57.
122. Bell R, Lipham J, Louie BE, et al. Magnetic sphincter augmentation
superior to proton pump inhibitors for regurgitation in a 1-year ran-
domized trial. Clin Gastroenterol Hepatol. 2020;18(8):1736-1743.e2.
123. Guidozzi N, Wiggins T, Ahmed AR, Hanna GB, Markar SR. Laparoscopic
magnetic sphincter augmentation versus fundoplication for gastro-
esophageal reflux disease: systematic review and pooled analysis. Dis
Esophagus. 2019;32(9):doz031. https://doi.org/10.1093/dote/doz031.
124. Naik RD, Vaezi MF. Extra-esophageal gastroesophageal reflux dis-
ease and asthma: understanding this interplay. Expert Rev
Gastroenterol Hepatol. 2015;9(7):969-982.
125. Kiljander TO, Salomaa ER, Hietanen EK, Terho EO. Gastroesopha-
geal reflux in asthmatics: a double-blind, placebo-controlled cross-
over study with omeprazole. Chest. 1999;116(5):1257-1264.
126. Wang AJ, Liang MJ, Jiang AY, et al. Gastroesophageal and
laryngopharyngeal reflux detected by 24-hour combined impedance
and pH monitoring in healthy Chinese volunteers. J Dig Dis. 2011;12
(3):173-180.
127. Xiao YL, Liu FQ, Li J, et al. Gastroesophageal and laryngopharyngeal reflux
profiles in patients with obstructive sleep apnea/hypopnea syndrome as
determined by combined multichannel intraluminal impedance-pH moni-
toring. Neurogastroenterol Motil. 2012;24(6):e258-e265.
128. Chang AB, Lasserson TJ, Gaffney J, Connor FL, Garske LA. Gastro-
oesophageal reflux treatment for prolonged non-specific cough in
children and adults. Cochrane Database Syst Rev. 2011;2011(1):
CD004823. https://doi.org/10.1002/14651858.CD004823.pub4.
129. Abou-Ismail A, Vaezi MF. Evaluation of patients with suspected
laryngopharyngeal reflux: a practical approach. Curr Gastroenterol
Rep. 2011;13(3):213-218.
130. Li X, Lin S, Wang Z, et al. Gastroesophageal reflux disease and
chronic cough: a possible mechanism elucidated by ambulatory pH-
impedance-pressure monitoring. Neurogastroenterol Motil. 2019;31
(12):e13707. https://doi.org/10.1111/nmo.13707.
131. Wang AJ, Liang MJ, Jiang AY, et al. Predictors of acid suppression
success in patients with chronic laryngitis. Neurogastroenterol Motil.
2012;24(5):432-437.
132. Shaheen NJ, Crockett SD, Bright SD, et al. Randomised clinical trial:
high-dose acid suppression for chronic cough - a double-blind,
placebo-controlled study. Aliment Pharmacol Ther. 2011;33(2):225-234.
133. Qadeer MA, Phillips CO, Lopez AR, et al. Proton pump inhibitor
therapy for suspected GERD-related chronic laryngitis: a meta-

XIAO ET AL.
analysis of randomized controlled trials. Am J Gastroenterol. 2006;
101(11):2646-2654.
134. Vaezi MF, Katzka D, Zerbib F. Extraesophageal symptoms and dis-
eases attributed to GERD: where is the pendulum swinging now?
Clin Gastroenterol Hepatol. 2018;16(7):1018-1029.
135. Hom C, Vaezi MF. Extra-esophageal manifestations of gastroesoph-
ageal reflux disease: diagnosis and treatment. Drugs. 2013;73(12):
1281-1295.
136. Naik RD, Vaezi MF. Extra-esophageal manifestations of GERD: who
responds to GERD therapy? Curr Gastroenterol Rep. 2013;15(4):318.
https://doi.org/10.1007/s11894-013-0318-4.
137. Labenz J, Malfertheiner P. Treatment of uncomplicated reflux dis-
ease. World J Gastroenterol. 2005;11(28):4291-4299.
138. Kahrilas PJ, Falk GW, Johnson DA, et al; The Esomeprazole Study
Investigators. Esomeprazole improves healing and symptom resolu-
tion as compared with omeprazole in reflux oesophagitis patients: a
randomized controlled trial. Aliment Pharmacol Ther. 2000;14(10):
1249-1258.
139. Richter JE, Kahrilas PJ, Johanson J, et al; Esomeprazole Study Inves-
tigators. Efficacy and safety of esomeprazole compared with omep-
razole in GERD patients with erosive esophagitis: a randomized
controlled trial. Am J Gastroenterol. 2001;96(3):656-665.
140. Castell DO, Kahrilas PJ, Richter JE, et al. Esomeprazole (40 mg) com-
pared with lansoprazole (30 mg) in the treatment of erosive esopha-
gitis. Am J Gastroenterol. 2002;97(3):575-583.
141. Labenz J, Armstrong D, Lauritsen K, et al; Expo Study Investigators.
A randomized comparative study of esomeprazole 40 mg versus
pantoprazole 40 mg for healing erosive oesophagitis: the EXPO
study. Aliment Pharmacol Ther. 2005;21(6):739-746.
142. Modiano N, Gerson LB. Risk factors for the detection of Barrett's
esophagus in patients with erosive esophagitis. Gastrointest Endosc.
2009;69(6):1014-1020.
143. Hanna S, Rastogi A, Weston AP, et al. Detection of Barrett's esophagus
after endoscopic healing of erosive esophagitis. Am J Gastroenterol.
2006;101(7):1416-1420.
144. Malfertheiner P, Lind T, Willich S, et al. Prognostic influence of
Barrett's oesophagus and Helicobacter pylori infection on healing
of erosive gastro-oesophageal reflux disease (GORD) and symptom
resolution in non-erosive GORD: report from the ProGORD study.
Gut. 2005;54(6):746-751.
145. Lichtenstein DR, Cash BD, Davila R, et al; Standards of Practice
Committee. Role of endoscopy in the management of GERD. Gas-
trointest Endosc. 2007;66(2):219-224.
146. National Clinical Research Center for Digestive Diseases, Chinese
Digestive Endoscopy Society, Chinese Digestive Doctor Association.
Chinese consensus: screening, diagnosis and management of
Barrett's esophagus and adenocarcinoma (2017, Wanning)
[in Chinese]. Chin J Dig Endosc. 2017;34(9):609-620.
147. Clermont M, Falk GW. Clinical guidelines update on the diagnosis
and management of Barrett's esophagus. Dig Dis Sci. 2018;63(8):
2122-2128.
148. Sharma P, Falk GW, Weston AP, Reker D, Johnston M,
Sampliner RE. Dysplasia and cancer in a large multicenter cohort of
patients with Barrett's esophagus. Clin Gastroenterol Hepatol. 2006;4
(5):566-572.
149. Desai TK, Krishnan K, Samala N, et al. The incidence of oesophageal
adenocarcinoma in non-dysplastic Barrett's oesophagus: a meta-
analysis. Gut. 2012;61(7):970-976.
150. Singh S, Manickam P, Amin AV, et al. Incidence of esophageal ade-
nocarcinoma in Barrett's esophagus with low-grade dysplasia: a sys-
tematic review and meta-analysis. Gastrointest Endosc. 2014;79(6):
897-909.e4.
151. Rastogi A, Puli S, El-Serag HB, Bansal A, Wani S, Sharma P. Inci-
dence of esophageal adenocarcinoma in patients with Barrett's
17512980, 2021, 7, Downloaded from https://onlinelibrary.wiley.com/doi/10.1111/1751-2980.13028 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [28/08/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
389
esophagus and high-grade dysplasia: a meta-analysis. Gastrointest
Endosc. 2008;67(3):394-398.
152. Shaheen NJ, Falk GW, Iyer PG, Gerson LB; American College of Gas-
troenterology. ACG clinical guideline: diagnosis and management of
Barrett's esophagus. Am J Gastroenterol. 2016;111(1):30-50.
153. Weusten B, Bisschops R, Coron E, et al. Endoscopic management of
Barrett's esophagus: European Society of Gastrointestinal Endos-
copy (ESGE) Position Statement. Endoscopy. 2017;49(2):191-198.
154. Bansal A, Kahrilas PJ. Treatment of GERD complications (Barrett's,
peptic stricture) and extra-oesophageal syndromes. Best Pract Res
Clin Gastroenterol. 2010;24(6):961-968.
155. Sgouros SN, Vlachogiannakos J, Karamanolis G, et al. Long-term acid
suppressive therapy may prevent the relapse of lower esophageal
(Schatzki's) rings: a prospective, randomized, placebo-controlled
study. Am J Gastroenterol. 2005;100(9):1929-1934.
156. Hershcovici T, Fass R. Step-by-step management of refractory gas-
tresophageal reflux disease. Dis Esophagus. 2013;26(1):27-36.
157. Sifrim D, Zerbib F. Diagnosis and management of patients with
reflux symptoms refractory to proton pump inhibitors. Gut. 2012;61
(9):1340-1354.
158. Yadlapati R, DeLay K. Proton pump inhibitor-refractory gastro-
esophageal reflux disease. Med Clin North Am. 2019;103(1):15-27.
159. Hoshino S, Kawami N, Takenouchi N, et al. Efficacy of vonoprazan
for proton pump inhibitor-resistant reflux esophagitis. Digestion.
2017;95(2):156-161.
160. Gotoh Y, Ishibashi E, Honda S, et al. Efficacy of vonoprazan for initial
and maintenance therapy in reflux esophagitis, nonerosive esophagi-
tis, and proton pump inhibitor-resistant gastroesophageal reflux dis-
ease. Medicine (Baltimore). 2020;99(11):e19520. https://doi.org/10.
1097/MD.0000000000019520.
161. Spechler SJ. Refractory gastroesophageal reflux disease and func-
tional heartburn. Gastrointest Endosc Clin N Am. 2020;30(2):
343-359.
162. Tutuian R, Vela MF, Hill EG, Mainie I, Agrawal A, Castell DO. Char-
acteristics of symptomatic reflux episodes on acid suppressive ther-
apy. Am J Gastroenterol. 2008;103(5):1090-1096.
163. Zerbib F, Duriez A, Roman S, Capdepont M, Mion F. Determinants
of gastro-oesophageal reflux perception in patients with persistent
symptoms despite proton pump inhibitors. Gut. 2008;57(2):
156-160.
164. Pauwels A, Boecxstaens V, Andrews CN, et al. How to select
patients for antireflux surgery? The ICARUS guidelines (international
consensus regarding preoperative examinations and clinical charac-
teristics assessment to select adult patients for antireflux surgery).
Gut. 2019;68(11):1928-1941.
165. Spechler SJ, Hunter JG, Jones KM, et al. Randomized trial of medical
versus surgical treatment for refractory heartburn. N Engl J Med.
2019;381(16):1513-1523.
166. Peng S, Xiao YL, Cui Y, et al. High-dose esomeprazole is required for
intraesophageal acid control in gastroesophageal reflux disease patients
with hiatus hernia. J Gastroenterol Hepatol. 2012;27(5):893-898.
167. Kahrilas PJ, Shaheen NJ, Vaezi MF, et al; American Gastroenterolog-
ical Association. American Gastroenterological Association Medical
Position Statement on the management of gastroesophageal reflux
disease. Gastroenterology. 2008;135(4):1383-1391.e5.
How to cite this article: Xiao YL, Zhou LY, Hou XH, et al.
Chinese expert consensus on gastroesophageal reflux disease
in 2020. J Dig Dis. 2021;22(7):376–389. https://doi.org/10.
1111/1751-2980.13028