Histamine H2 antagonists for functional dyspepsia

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Introduction
Functional dyspepsia (FD) is a common but unexplained medical condition thought to originate from the gastroduodenal region. According to the Rome IV criteria, FD is divided into 2 subtypes: postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). [1] PDS is characterized by meal-induced dyspeptic symptoms such as postprandial fullness and early satiety. EPS refers to bothersome epigastric pain or burning. FD affects 8% to 23% of the population in Asia, [2] and accounts for 10% to 15% of the general population. [3] The high prevalence of FD substantially reduces the quality of life and has significant socioeconomic consequences. [4] Unfortunately, there is no definitive treatment for all individuals. [5] Current management of FD focuses on symptom relief. Acid-suppressive agents such as histamine H 2 antagonists (H 2 RAs) or proton pump inhibitors (PPIs) are commonly prescribed to patients with the condition. [6,7] H 2 RAs are a group of drugs that can reduce gastric acid secretion by competitive inhibition of histamine H2 receptors located on the parietal cells. [8] They have played an important role in the treatment of acid-related disorders such as gastroesophageal reflux disease and peptic ulcers. [9] As for FD, The effects of H 2 RAs have been reported in several randomized clinical trials (RCTs). These trials, however, with inconsistent methodologies or outcomes may lack sufficient evidence to reach definitive conclusions. [10] From 2000 to 2009, 2 meta-analyses of RCTs were published which suggested that H 2 RAs were superior to placebo in improving FD symptoms. [6,11] While the results were limited due to severe methodological flaws such as the inclusion of cross-over trials, short treatment duration, and no subgroup analysis by dose of H 2 RA or H 2 RA subtype. Since then, a previous Cochrane Review has been withdrawn from publication [12] and new RCTs have been developed. However, no more updated systematic reviews have been conducted. We will, therefore, perform this systematic review and meta-analysis Trial registration number: PROSPERO CRD42019127924.
It is not necessary for ethical approval because individuals cannot be identified. The results of this study will be disseminated in a peer-reviewed journal.
This study is supported by National Natural Science Foundation of China (No.81673853).
The funders had no role in the design, execution, or writing of the study. to determine the efficacy of H 2 RAs compared with placebo in the improvement of global symptoms of dyspepsia and quality of life in FD, and to assess potential side effects as well.

Study registration
This systematic review protocol will adhere to the preferred reporting items for systematic reviews and meta-analysis Protocols (PRISMA-P) 2015 statement. [13] Besides, The protocol is registered on the International Prospective Register of Systematic Reviews (PROSPERO registration number: CRD42019127924).

2.2.
Criteria for considering studies for this review 2.2.1. Types of studies. Any parallel-group RCTs of H 2 RA for the treatment of FD will be included. The first period of crossover studies will be also included. Cluster-randomized trials, Quasi-RCTs will be excluded.

Types of participants.
Participants aged 18 years or over, diagnosed with FD based on either the Rome Criteria (I to IV) or a physician's opinion with a negative upper gastrointestinal endoscopy, will be included regardless of gender or race. While participants with predominant heartburn or reflux symptoms will be excluded.

Types of interventions.
Only trials comparing oral administration of any dose of H 2 RAs with placebo will be eligible for inclusion. H 2 RAs will include cimetidine, ranitidine, famotidine, nizatidine, as well as any other H 2 RAs. The minimum duration of treatment2 weeks will be included. H 2 RAs combined with any other treatment in the intervention group will be included if the combined treatment is also present in the control group. ). There is no language or publication status restriction. We will perform searching by using a combination of subject headings and text words. The search strategy for the MEDLINE will be shown in the Supplemental File 1, http://links. lww.com/MD/D405, and modified by using other databases.

2.3.2.
Searching other resources. We will manually search conference proceedings and ClinicalTrials.gov for eligible trials. We will also check the reference lists of all studies retrieved. Besides, We will contact the authors of identified trials, manufacturers, and experts within the field to obtain further relevant studies.
2.4. Data collection and analysis 2.4.1. Selection of studies. Studies retrieved by the search strategies will be imported and managed in the reference management software EndnoteX9. Two independent reviewers (LJJ and ZEJ) will remove duplicates and exclude irrelevant trials by screening the titles and abstracts. Then, they will review the full texts of the selected studies to determine the final included trials. Both authors will also independently collect the final data in a Microsoft Excel sheet and compare the results. Any disagreement will be resolved through discussion or by a third author (LL). The study selection process is recorded and presented in preferred reporting items for systematic reviews and meta-analysis (PRISMA) flow diagram (Fig. 1).

2.4.2.
Data extraction and management. We will use a specially developed form for data collection. Two review authors (XL and ZZD) will independently extract data and import it into RevMan v.5.3 software. Discrepancies will be resolved by consensus. The extracted data will include the following: the first author; publication date; study design; study setting; country of origin; sample size; diagnostic criteria used for FD; age and gender of Participants; name, dose and schedule of H 2 RA administered; duration of therapy; primary and secondary outcomes specified and collected; time points reported; withdrawals/drop-outs. Data will be extracted according to an intention-to-treat analysis.

Assessment of risk of bias in included studies.
The risk of bias in included studies will be assessed independently by 2 review authors (LJJ and ZEJ) using the Cochrane's risk of bias tool. [14] There are 7 domains as follows: random sequence generation (selection bias), allocation concealment (selection bias), blinding of participants and personnel (performance bias), blinding of outcome assessment (detection bias), incomplete outcome data (attrition bias), selective reporting (reporting bias), and other bias. Each domain will be graded as high, low or unclear.

2.4.4.
Measures of treatment effect. The continuous outcomes will be presented as mean difference (MD) or standardized MD (SMD) with 95% confidence interval (95% CI). The binary outcomes will be presented as a risk ratio (RR) with 95% CI. Besides, we will also report the number needed to treat (NNT) and the number needed to harm (NNH), with 95% CI, according to the formula: NNT or NNH = 1/(control event rate Â (1 À RR)).

2.4.5.
Dealing with missing data. As for the missing data, we will attempt to contact the study authors to obtain it whenever possible. If it is not available, we will perform analysis based on available data, and state how the missing data may have potential impacts on the findings in the text.
2.4.6. Assessment of heterogeneity. Both the I 2 statistic and the Chi 2 test will be calculated to assess statistical heterogeneity. I 2 greater than 50% or P value less than .1 will be considered as significant heterogeneity. [15] If there is significant heterogeneity, we will perform subgroup analysis and sensitivity analysis for exploring possible sources.

Assessment of reporting bias.
A funnel plot will be constructed to identify publication bias when there are 10 or more trials. Asymmetric funnel plots suggest publication bias or small-study effects, and the results should be taken into caution. Additionally, we will also use Egger test for further quantitative analysis. [16] 2.4.8. Data synthesis. Data synthesis will be performed by using RevMan v.5.3 from Cochrane Collaboration. We will conduct a forest plot of the meta-analysis for quantitative synthesis. If there is significant heterogeneity (P < .1, I 2 > 50%), the random-effects model will be used for meta-analysis. Otherwise, we will consider the fixed-effects model.

Subgroup analysis and investigation of heterogeneity.
We will perform the following subgroup analysis to explore the sources of heterogeneity: 2.4.10. Sensitivity analysis. Sensitivity analysis will be conducted to explore whether the results of our meta-analysis are robust. Pre-specified factors in sensitivity analysis are as follows: studies with a high risk of bias, small sample size studies, abstract inclusion, studies with the missing data.

2.4.11
. Grading the quality of evidence. The quality of evidence will be assessed by using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system, [17] which involves the 5 items: study limitations, consistency of effect, imprecision, indirectness, and publication bias. We will grade the quality of evidence as high, moderate, low, or very low.

Discussion
FD is a chronic and recurrent gastrointestinal disorder characterized by bothersome postprandial fullness, early satiety, epigastric pain, or burning. [18] Treating FD can be challenging as a considerable overlap of symptoms and multiple mechanisms exist such as disturbed gastroduodenal motility, gastric acid secretion, and visceral hypersensitivity. [19] Some evidence has suggested that a subset of FD patients respond well to acid suppression with H 2 RA or PPI therapy, even if these patients have normal gastric acid secretion. [20] Unlike PPIs, H 2 RAs including cimetidine, ranitidine, famotidine, and nizatidine are not recommended as the first-line treatments for FD. Nevertheless, these drugs are widely used in clinical practice. [21] Some patients even find them helpful if PPIs fail. However, the efficacy of H 2 RAs in FD remains controversial. We will perform this systematic review of H 2 RAs for the treatment of FD to inform patients, clinicians, and policymakers of the efficacy and safety of this medication. However, there may be potential limitations to this research. First, inter-study variability in the diagnosis of FD, country of origin, sample size, and definition of symptom improvement may contribute to heterogeneity risks. Second, the quality of trials likely affects the reliability of the final results.