Meta-Analysis
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 28, 2016; 22(12): 3486-3495
Published online Mar 28, 2016. doi: 10.3748/wjg.v22.i12.3486
Helicobacter pylori eradication therapy for functional dyspepsia: Systematic review and meta-analysis
Li-Jun Du, Bin-Rui Chen, John J Kim, Sarah Kim, Jin-Hua Shen, Ning Dai
Li-Jun Du, Bin-Rui Chen, John J Kim, Sarah Kim, Jin-Hua Shen, Ning Dai, Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, Hangzhou 310020, Zhejiang Province, China
John J Kim, Division of Gastroenterology, Loma Linda University, Loma Linda, CA 92354, United States
Author contributions: Du LJ and Dai N designed the research; Du LJ and Chen BR performed the research; Du LJ and Shen JH analyzed the data; Du LJ and Kim JJ wrote the paper; Kim JJ, Kim S and Dai N provided critical feedback and revised the manuscript.
Conflict-of-interest statement: The authors have no conflict-of-interest to declare.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ning Dai, MD, Professor, Department of Gastroenterology, Sir Run Run Shaw Hospital, Zhejiang University, No. 3 East Qingchun Road, Hangzhou 310020, Zhejiang Province, China. ndaicn@yahoo.com
Telephone: +86-571-86006144 Fax: +86-571-86044817
Received: November 30, 2015
Peer-review started: December 1, 2015
First decision: December 21, 2015
Revised: January 19, 2016
Accepted: January 30, 2016
Article in press: January 30, 2016
Published online: March 28, 2016

Abstract

AIM: To evaluate whether Helicobacter pylori (H. pylori) eradication therapy benefits patients with functional dyspepsia (FD).

METHODS: Randomized controlled trials (RCTs) investigating the efficacy and safety of H. pylori eradication therapy for patients with functional dyspepsia published in English (up to May 2015) were identified by searching PubMed, EMBASE, and The Cochrane Library. Pooled estimates were measured using the fixed or random effect model. Overall effect was expressed as a pooled risk ratio (RR) or a standard mean difference (SMD). All data were analyzed with Review Manager 5.3 and Stata 12.0.

RESULTS: This systematic review included 25 RCTs with a total of 5555 patients with FD. Twenty-three of these studies were used to evaluate the benefits of H. pylori eradication therapy for symptom improvement; the pooled RR was 1.23 (95%CI: 1.12-1.36, P < 0.0001). H. pylori eradication therapy demonstrated symptom improvement during long-term follow-up at ≥ 1 year (RR = 1.24; 95%CI: 1.12-1.37, P < 0.0001) but not during short-term follow-up at < 1 year (RR = 1.26; 95%CI: 0.83-1.92, P = 0.27). Seven studies showed no benefit of H. pylori eradication therapy on quality of life with an SMD of -0.01 (95%CI: -0.11 to 0.08, P = 0.80). Six studies demonstrated that H. pylori eradication therapy reduced the development of peptic ulcer disease compared to no eradication therapy (RR = 0.35; 95%CI: 0.18-0.68, P = 0.002). Eight studies showed that H. pylori eradication therapy increased the likelihood of treatment-related side effects compared to no eradication therapy (RR = 2.02; 95%CI: 1.12-3.65, P = 0.02). Ten studies demonstrated that patients who received H. pylori eradication therapy were more likely to obtain histologic resolution of chronic gastritis compared to those who did not receive eradication therapy (RR = 7.13; 95%CI: 3.68-13.81, P < 0.00001).

CONCLUSION: The decision to eradicate H. pylori in patients with functional dyspepsia requires individual assessment.

Key Words: Functional dyspepsia, Helicobacter pylori eradication, Symptom improvement, Quality of life, Peptic ulceration, Meta-analysis

Core tip: The decision to eradicate Helicobacter pylori (H. pylori) in patients with functional dyspepsia requires individual assessment. This meta-analysis suggests that H. pylori eradication therapy is beneficial for symptom relief, reduces the development of peptic ulceration, and leads to histologic resolution of chronic gastritis but does not improve the quality of life and may even result in adverse events. Otherwise, other validated treatment such as acid suppression, prokinetics, and psychiatric treatment should also be considered.


Citation: Du LJ, Chen BR, Kim JJ, Kim S, Shen JH, Dai N. Helicobacter pylori eradication therapy for functional dyspepsia: Systematic review and meta-analysis. World J Gastroenterol 2016; 22(12): 3486-3495
INTRODUCTION

Functional dyspepsia (FD) is a common gastrointestinal disorder and affects as many as 21%[1] of the population worldwide and 2%-24%[2,3] of the Chinese population. Characterized by epigastric pain, postprandial fullness, and early satiation without organic causes, FD adversely impacts the patient’s quality of life. FD is diagnosed by Rome III criteria, which are symptom-based criteria[4]. Although the pathophysiology is not well established, gastro-duodenal motility dysfunction[5,6], visceral hypersensitivity[7,8], and psychological disturbance[9] may play a role in the pathogenesis of FD. Helicobacter pylori (H. pylori) infection is more common in patients with dyspepsia (OR = 2.3; 95%CI: 1.9-2.7) in comparison to healthy controls[10]. However, the effects of H. pylori eradication therapy in FD are inconsistent in previously published randomized trials and meta-analyses.

Previous meta-analyses mainly focused on symptom improvement after H. pylori eradication therapy; their findings (whether or not to eradicate) were not consistent because of variable study designs and follow-up durations[11-13]. One meta-analysis conducted by Moayyedi et al[14] provided an economic evaluation and suggested that H. pylori eradication therapy is the most cost-effective treatment method. We carried out this meta-analysis not only to evaluate benefits of H. pylori eradication therapy for symptom relief, but also to discuss the effects on the quality of life, adverse events, and the risk of subsequent peptic ulcer disease. We performed a more comprehensive meta-analysis than previous studies in order to assess the overall clinical impact of H. pylori eradication therapy in this population.

MATERIALS AND METHODS
Search strategy

A standard protocol, based on current PRISMA guidelines, was implemented for study inclusion, data extraction, and data analysis. PubMed, EMBASE, and The Cochrane Library were searched for published randomized controlled trials (RCTs) in English from 1988 to 2015. The main search strategies were as follows: “Helicobacter pylori OR Campylobacter OR Campylobacter pylori OR C. pylori OR Helicobacter infection” AND “treat OR eradication OR eradicating OR therapy OR anti-“ AND “dyspepsia OR functional gastrointestinal disorder OR non-ulcer dyspepsia OR functional dyspepsia.”

Inclusion and exclusion criteria

Studies were considered eligible if they met the following criteria: (1) RCTs; (2) study population of patients with dyspepsia (symptom-based criteria including ROME I, II, or III) and H. pylori infection (13C breath test, histology, or rapid urease teat); (3) H. pylori eradication regimens (dual, triple, quadruple, and sequential therapies) as intervention for treatment group and placebo or other drugs known not to eradicate H. pylori (no antibiotics or bismuth) as intervention for control groups; and (4) age above 17 years old. Studies were excluded if they were available only as abstracts, review studies, case reports, or if predefined outcome data required for analyses were lacking.

Data extraction and quality evaluation

Two investigators (Du LJ, Chen BR) reviewed all the titles and abstracts independently. Data was extracted from eligible full-text studies. The data included study population, demographical characteristics, year of publication, country, age, gender, H. pylori eradication regimens, duration of follow-up, H. pylori eradication rate, and study outcomes. The individual study quality was assessed according to the Cochrane collaboration’s tool for risk of bias, which contains random sequence generation, allocation concealment, blindness, incomplete outcome data, selective outcome reporting, and other biases. Any disagreement was resolved by a third investigator (Dai N).

Study endpoints

The primary outcome for this study was the pooled risk ratio (RR) of successful treatment (presence of no more than mild pain or discomfort after treatment) with a 95%CI. The secondary outcomes were the pooled RR of improvement of dyspepsia at short-term (< 1 year) and long-term (≥ 1 year) follow-up, standard mean difference (SMD) of improvement in quality of life (SF-36), pooled RR of incidence of peptic ulceration during follow-up, pooled RR of development of treatment-related adverse events, and pooled RR of histologic resolution of chronic gastritis. If the studies were homogeneous (I2 < 50%), the fixed-effects model was used; otherwise (I2 > 50%), the random-effects model was chosen. Intervention was considered statistically significant when a P-value was < 0.05. If the studies were heterogeneous, a sensitivity analysis was performed. Publication bias was assessed by the funnel plot. All data were analyzed with RevMan 5.3 and Stata 12.0. The statistical methods of this study were reviewed by professor Yun-Xian Yu from Department of Epidemiology and Health Statistics of Zhejiang University.

RESULTS
Literature search and description of included studies

According to the search strategy, 2355 citations were identified from three databases. After removing the duplicates (n = 1076), two reviewers screened the titles and abstracts of potentially relevant studies (n = 1279) independently. Out of 97 full-text studies that were reviewed, 66 did not meet the inclusion criteria. Twenty-five RCTs with a total of 5555 people Which met the inclusion criteria were included in this systematic review (Figure 1)[15-39]. The assessment on the quality of the individual study is shown in Figure 2. The demographic data, eradication regimens, and eradication rates are listed in Table 1.

Table 1 Characteristics of studies included in the meta-analysis.
StudySample (M/F)Age, meanCountryLast visit (mo)InterventionHelicobacter pylori eradication
Ang, 2006130 (47/83)38.0Singapore12LAC73.2%
Blum, 1998328 (136/192)47.0Global12OAC79%
Chiba, 2002394 (148/246)49.5Canada12OMC75%
Dhali, 199962 (44/18)32.5India12BMTe87.5%
Froehlich, 2001144 (64/80)44.6Switzerland12LAC75%
Gisbert, 200450 (15/35)41.5Spain12OAC76%
Greenberg, 1999100 (31/69)46.5United States12OC70.5%
Gwee, 200982 (38/44)40.4Singapore12OCT68.3%
Hsu, 2001161 (78/83)50.9China12LMTe78%
Koelz, 2003181 (74/107)47.5Switzerland6AO51.7%
Koskenpato, 2001151 (52/99)51.7Finland12AMO82%
Lan, 2011195 (89/106)47.4China3RAC85.7%
Malfertheiner, 2003800 (380/420)46.2Germany12LAC63.9%
Mazzoleni, 200689 (20/69)41.3Brazil12LAC91.3%
Mazzoleni, 2011404 (86/318)46.0Brazil12OAC88.6%
McColl, 1998318 (155/163)42.1United Kingdom12AMO88%
Miwa, 200085 (40/45)51.5Japan3OAC85.4%
Naeeni, 2002157 (47/110)32.5Iran9ABM52.6%
Sodhi, 2013519 (169/350)44.5India12OAC69.9%
Talley, 1999293 (133/160)46.4United States12LCA80%
Talley, 1999 (ORCHID)275 (98/177)50.0Australia12OAC85%
Varannes, 2001253 (112/141)51.0France12RaAC69%
Varasa, 200848 (21/27)37.0Spain12RA81.4%
Xu, 2013396 (135/261)40.0China12ACE76.36%
Zanten, 2003157 (72/81)48.0Canada12LCA82%
Figure 1
Figure 1 Study flow diagram.
Figure 2
Figure 2 Risk of bias graph. The Cochrane collaboration’s tool was used to evaluate risk of bias.
Benefits of H. pylori eradication therapy on symptom improvement

Twenty-three of 25 studies reported information on treatment success. Eradication therapy groups were treated with antibiotics, proton pump inhibitors, and bismuth, while control groups were treated with placebo, prokinetics, and/or proton pump inhibitors. Primary analysis demonstrated that 1183 (40%) of 2939 patients in the eradication therapy group and 795 (32%) of 2468 in the control groups had no or mild symptoms during the last follow-up visit (pooled RR = 1.23; 95%CI: 1.12-1.36, P < 0.0001). Although there was no significant heterogeneity (I2 = 42%) among the selected studies, the asymmetry in the funnel plot (Figure 3) indicated existing publication bias. H. pylori eradication therapy demonstrated symptom improvement at long-term (≥ 1 year) (RR = 1.24; 95%CI: 1.12-1.37, P < 0.0001) but not at short-term (< 1 year) (RR = 1.26; 95%CI: 0.83-1.92, P = 0.27) follow-up. The studies that reported short-term outcomes demonstrated significant heterogeneity (I2 = 64%). The forest plot and sensitivity analysis are shown in Figures 4 and 5, respectively.

Figure 3
Figure 3 Funnel plot of included studies for potential publication bias. The funnel plot was not absolutely symmetrical.
Figure 4
Figure 4 Forest plot of the effects comparing Helicobacter pylori eradication therapy vs control on symptom relief. Twenty-three studies were included. The random effect model (Mantel-Haenszel method) was applied.
Figure 5
Figure 5 Sensitivity analysis of the effects comparing Helicobacter pylori eradication therapy vs control on symptom relief.
Benefits of H. pylori eradication therapy on quality of life

Seven studies reported data on quality of life both at baseline and at the last visit required for the meta-analysis. Five trials used the SF-36, one used the general well-being index, and one used QoL-PEI. A fixed effect model (I2 = 0%) was performed on all seven studies. Overall, H. pylori eradication therapy had no significant benefit on quality of life, with an SMD of -0.01 (95%CI: -0.11 to 0.08, P = 0.80). Detailed information is shown in Figure 6.

Figure 6
Figure 6 Forest plot of the effects comparing Helicobacter pylori eradication therapy vs control on quality of life. Seven studies were included. The fixed effect model (Inverse Variance method) was applied.
Benefits of H. pylori eradication therapy on long-term peptic ulceration

Six studies reported endoscopic data at the last visit to evaluate for the development of peptic ulcer disease. H. pylori eradication therapy compared to no eradication therapy reduced the development of peptic ulcer disease (RR = 0.35; 95%CI: 0.18-0.68, P = 0.002). There was no significant study heterogeneity (I2 = 0%). Detailed information is shown in Figure 7.

Figure 7
Figure 7 Forest plot of the effects comparing Helicobacter pylori eradication therapy vs control on long-term peptic ulceration. Six studies were included. The fixed effect (Inverse Variance method) model was applied.
H. pylori eradication therapy on the development of adverse events

Eight studies provided data on development of common side effects associated with the intervention. Patients who received H. pylori eradication therapy were more likely to have side effects compared to controls (RR = 2.02; 95%CI: 1.12-3.65, P = 0.02). The random effect model was used because significant study heterogeneity (I2 = 94%) was detected. The forest plot and sensitivity analysis are shown in Figures 8 and 9.

Figure 8
Figure 8 Forest plot of the effects comparing Helicobacter pylori eradication therapy vs control on adverse events. Eight studies were included. The random effect model (Mantel-Haenszel method) was applied.
Figure 9
Figure 9 Sensitivity analysis of the effects comparing Helicobacter pylori eradication therapy vs control on adverse events.
Other outcomes comparing H. pylori eradication therapy and control groups

One study provided outcome data on the cost of interventions such as medication, diagnostic tests, and physician consultation and did not demonstrate a difference between eradication therapy and the control[38]. However, the cost of intervention from this study was derived from utilization of healthcare services rather than the actual cost. Ten studies reported histological outcomes following intervention (Figure 10). Patients who received H. pylori eradication therapy were more likely to obtain histologic resolution of chronic gastritis compared to control (RR = 7.13; 95%CI: 3.68-13.81, P < 0.00001).

Figure 10
Figure 10 Forest plot of the effects comparing Helicobacter pylori eradication therapy vs control on histologic resolution of chronic gastritis. Six studies were included. The random effect model (Mantel-Haenszel method) was applied.
DISCUSSION

Our meta-analysis based on well-designed RCTs demonstrated that the effect size of symptom relief from H. pylori eradication therapy in patients with FD was small (RR = 1.23; 95%CI: 1.12-1.36, P < 0.0001) with an undetectable short-term benefit. Eradication therapy was nearly three times more likely to reduce the development of peptic ulcer disease compared with no eradication therapy. Furthermore, histologic findings of chronic gastritis were more likely to resolve after H. pylori eradication therapy compared to controls. However, H. pylori eradication therapy did not improve the quality of life for patients with FD compared to anti-acids, prokinetics, or placebo therapy. Eradication therapy was also more likely to be associated with side effects (RR = 2.02; 95%CI: 1.12-3.65, P = 0.02) compared to control.

H. pylori infection is more prevalent in Asia than in Western countries with high prevalence observed in China and South Korea[40]. Eradication therapy appears to be more effective in Asian populations as shown by the meta-analysis conducted by Jin and Li[13] on the Chinese population. Their study showed that H. pylori eradication therapy compared to controls increased the likelihood of improvement in dyspeptic symptoms by 3.6-fold. Another meta-analysis performed by Zhao et al[12] found that H. pylori eradication therapy compared to no eradication therapy was beneficial for improvement of dyspepsia in European (OR = 1.49; 95 CI% 1.10-2.02) and American populations (OR = 1.43; 95%CI: 1.12-1.83).

H. pylori is strongly associated with many diseases, including functional dyspepsia, gastric or duodenal ulcer, gastric cancer, and gastric mucosa-associated lymphoid tissue lymphoma[41,42]. However, H. pylori-induced gastritis is the most important risk factor for development of peptic ulcer disease[43]. Most patients with H. pylori infection have asymptomatic gastritis, and experience variable clinical symptoms depending on bacteria, host, and environmental factors. Whether H. pylori infection delays gastric emptying is unclear[44,45], but H. pylori appears to alter gastric acid production by changing gastrin and somatostatin secretion[46]. Abnormal gastric acid secretion causes mainly dysmotility-like, dyspeptic symptoms[47]. Duodenal acid exposure indirectly induces fullness, bloating, and epigastric pain by suppressing antral contractions, which may contribute to delayed gastric emptying[48,49].

According to the results of this meta-analysis, decision to eradicate H. pylori may be influenced by several key points. First, eradication therapy may be preferable among patients with risk factors for peptic ulcer disease or gastric cancer. Our study showed long-term benefits such as reduction in incidence of future peptic ulcer disease and resolution of gastritis, which are associated with gastric cancer[50,51]. Second, because of apparent adverse effects associated with eradication therapy, alternative validated therapy for FD such as acid suppression, prokinetics, or lifestyle changes for mild dyspeptic symptoms should also be considered. A large study of 1425 patients showed that H. pylori infection was a significant risk factor for dyspepsia. However, other factors such as NSAIDs use, unemployment, and heavy smoking demonstrated larger magnitude of association compared to H pylori infection[52]. Furthermore, rising prevalence of antibiotics resistance[53] and H. pylori reinfection[54] cannot be ignored. Third, it has been well established that the presence of psychiatric disorders, such as anxiety disorder, is more common in patients with functional gastrointestinal disorders than in the general population[55,56]. Psychiatric treatment with antidepressants is helpful in the reduction of dyspeptic symptoms[57]. Anxiety and depression are considered to be the best predictors of quality of life[58]. Cognitive-behavioral therapy (CBT), psychotherapy, anxiolytics, and antidepressants can also relieve dyspeptic symptoms[59,60].

The strength of this meta-analysis includes a comprehensive analysis of high-quality studies with evaluation of various FD outcomes other than symptom improvement alone. There are some limitations to this meta-analysis. First, some well-designed studies were excluded because they were published in non-English language. Second, the random effect model was chosen to evaluate the short-term symptom improvement and development of adverse events in the presence of significant study heterogeneity resulting from different study designs and methods. Third, there is a possibility of publication bias as we excluded some RCTs that did not have sufficient data for meta-analysis or were not published in manuscript form at the time of submission.

In conclusion, H. pylori eradication therapy compared to no eradication therapy has a statistically significant but small magnitude of benefit for symptom relief and can also reduce the development of peptic ulcer disease. However, H. pylori eradication therapy was associated with higher incidence of adverse events during the treatment and failed to demonstrate any effect in improving the quality of life. In addition to H. pylori eradication therapy, alternative therapies such as acid-suppression, prokinetics, psychotherapy, and anxiolytics should also be considered after an individualized assessment.

ACKNOWLEDGMENTS

We would like to thank professor Yun-Xian Yu for reviewing the statistical methods of this study.

COMMENTS
Background

Functional dyspepsia (FD) is a common gastrointestinal disorder and affects as many as 21% of the population worldwide. Helicobacter pylori (H. pylori) infection is one of the most important factors for development of dyspeptic symptoms.

Research frontiers

Benefits of H. pylori eradication therapy in patients with FD are not consistent. Relying on antibiotics may lead to an increased rate of drug resistance, which may consequently lead to an increased rate of eradication failure.

Innovations and breakthroughs

Compared to previous studies, the current meta-analysis included additional clinical outcomes on the benefits of H. pylori eradication therapy other than symptom relief such as quality of life, adverse events, and development of peptic ulceration.

Applications

According to the current meta-analysis, H. pylori eradication therapy should be considered after individual assessment. The authors have highlighted that H. pylori eradication therapy was significantly beneficial for symptom relief and reduced the risk of development of peptic ulceration in patients with functional dyspepsia. However, H. pylori eradication therapy failed to improve the quality of life and was associated with higher likelihood of treatment-related adverse effects. Otherwise, alternative validated therapies such as acid suppression, prokinetics, and psychiatric treatment should also be considered.

Peer-review

The conclusions are warranted by the results, and it is a useful meta-analysis.

Footnotes

P- Reviewer: Ananthakrishnan N, Kurtoglu E, Lember M, Otegbayo JA S- Editor: Yu J L- Editor: Wang TQ E- Editor: Zhang DN

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