Efficacy of Helicobacter pylori Eradication Therapy on Functional Dyspepsia A Meta-Analysis of Randomized Controlled Studies With 12-Month Follow-up

1. Efficacy of Helicobacter pylori Eradication Therapy
on Functional Dyspepsia
A Meta-Analysis of Randomized Controlled Studies
With 12-Month Follow-up
Bing Zhao, MD,* Jing Zhao, MD,w Wen-Fang Cheng, MD,w Wei-Jia Shi, MD,w
Wei Liu, MD,w Xiao-Lin Pan, MD,w and Guo-Xin Zhang, MD*w
Background: Whether patients with functional dyspepsia (FD)
should receive Helicobacter pylori eradication therapy remains
controversial.
Aims: This meta-analysis was to evaluate the long-term effects of
H. pylori eradication on dyspeptic symptoms of patients with FD, by
selecting the most recent well-designed randomized controlled trials.
Methods: English-language articles in the medical literature con-
taining information on the long-term (Z12mo) effects of H. pylori
eradication on dyspeptic symptoms in patients with FD were iden-
tified by searching the Medline, PubMed, and EMBASE databases.
The MeSH and/or keywords included Helicobacter pylori OR
H. pylori OR HP; functional dyspepsia OR non-ulcer dyspepsia;
eradication OR cure or treatment; and improvement OR resolution.
The Review Manager 4.2.2 was used for the meta-analysis.
Results: Fourteen randomized controlled studies were included
in the meta-analysis. Improvements of dyspepsia symptoms in
patients of eradication group were significantly better than in
patients of the control group [odds ratio (OR), 1.38; 95% con-
fidence interval (CI), 1.18-1.62] (Z = 4.00, P < 0.0001) at the end
of the follow-up period with low heterogeneity (I2
= 51.8%,
P = 0.01). In a subgroup analysis on geographical regions,
improvements of dyspepsia symptoms in patients of eradication
group were all significantly better than in patients of control group
in the European (OR, 1.49; 95% CI, 1.10-2.02), Asian (OR, 1.54;
95% CI, 1.07-2.21), and American populations (OR, 1.43; 95% CI,
1.12-1.83).
Conclusions: H. pylori eradication therapy is associated with
improvement of dyspeptic symptoms in patients with FD, which is
consistently demonstrated in the Asian, European, and American
populations.
Key Words: functional dyspepsia, Helicobacter pylori eradication,
meta-analysis
(J Clin Gastroenterol 2014;48:241–247)
Functional dyspepsia (FD), which refers to pain or dis-
comfort centered in the upper abdomen, described as
bloating, distension, fullness, or nausea but in the absence
of an identifiable organic disease for at least 3 months,1–2
affects up to 40% of the adult population in the western
world and is highly prevalent in the Asian countries.3–7
Although the pathogenesis of FD is still obscure, several
pathophysiological mechanisms such as abnormal visceral
sensory perception,8 H. pylori infection,9 and gastro-
duodenal motor dysfunction10–13 have been suggested to
contribute to the development. H. pylori infection has been
considered to be a class 1 carcinogen by the World Health
Organization, and many studies have revealed a strong
association between the organism infection and gastric
disorders.14 About 50% of patients with FD have coex-
istent H. pylori-associated gastritis.15–18 It has been specu-
lated that H. pylori infection causes inflammation of the
gastric mucosa, and is associated with specific disturbances
of gastric secretory or motor function, which, in turn, may
contribute to dyspeptic symptoms.19
There has been continuing investigation on FD as the
disease is very disturbing, and affects the quality of daily life
and work efficiency, but is hard to cure. Traditional therapies
include lifestyle modification, antacids, H2-receptor antago-
nists, prokinetic agents, and antiflatulents; however, the effi-
cacy is far from satisfaction. As H. pylori infection has been
found to be related with gastrointestinal diseases, many
investigators have tried to treat FD by means of eradication
of the infection. Different studies have reported various
estimates of association between H. pylori eradication and
improvement of dyspeptic symptoms,20–33 and whether
eradication of H. pylori infection improves dyspeptic symp-
toms in patients with FD remains controversial because of
the scarcity of large randomized controlled studies, and great
heterogeneity in study designs. A couple of meta-analyses
have suggested a possible association between H. pylori
eradication and improvement of dyspeptic symptoms.34,35
However, these meta-analyses either focused the short-term
(6mo) effect or limited to Chinese literature. Moreover, these
meta-analyses included some clinical trials that were not well
designed, which may, more or less, affect the overall con-
clusion. Therefore, we carried out the present meta-analysis
to further evaluate the long-term effects of H. pylori erad-
ication on the dyspeptic symptoms of patients with FD, by
selecting the most recent well-designed randomized con-
trolled trials (RCTs). In addition, we performed subgroup
analysis to determine if there is a difference in the effect
among studies from different geographic regions.
Received for publication January 31, 2013; accepted June 4, 2013.
From the *Department of Gastroenterology, Shengze Hospital of
Nanjing Medical University, Wujiang, Jiangsu; and wDepartment
of Gastroenterology, the First Affiliated Hospital of Nanjing
Medical University, Nanjing, China.
B.Z. and J.Z. contributed equally to this work.
Supported by the National Natural Science Funds of China (No.
81270476 and 81072032).
The authors declare that they have nothing to disclose.
Reprints: Guo-Xin Zhang, MD, Department of Gastroenterology,
Shengze Hospital of Nanjing Medical University, Wujiang 215200,
Jiangsu, China (e-mail: guoxinz@njmu.edu.cn).
Copyright r 2013 by Lippincott Williams & Wilkins
ORIGINAL ARTICLE
J Clin Gastroenterol Volume 48, Number 3, March 2014 www.jcge.com | 241

2. METHODS
Literature Search
We followed PRISMA guidelines for conducting
meta-analysis.36 The Medline, PubMed, and EMBASE
digital dissertation databases were searched for clinical
trials, covering all published papers in English up to August
2012. The search was limited to humans. The search
methodology used combinations of the following keywords:
Helicobacter pylori OR H. pylori OR HP; functional dys-
pepsia OR non-ulcer dyspepsia; eradication OR cure OR
treatment; and improvement OR resolution. When further
information was required, the corresponding authors of
relevant papers were contacted.
Inclusion and Exclusion Criteria
Studies to be included in the meta-analysis must meet
the following criteria: (1) RCTs evaluating the effects of
H. pylori eradication therapy on dyspeptic symptoms of
patients with FD; (2) dyspeptic symptoms of FD defined as
an outcome measurement of the study as determined by the
global overall symptom scale for dyspepsia; (3) follow-up of
patients for at least 12 months; (4) H. pylori infection
confirmed by rapid urease test, 13
C-urea breath test, and/or
histologic examination; (5) the quality of the study equal to
or more than Jadad score 3 as assessed using the score
proposed by Jadad et al37; and (6) studies published in
English language only. Case report, observational studies,
reviews, articles published only in abstract form, and RCTs,
of which the required data for meta-analysis were not
available, were excluded from the analysis. In case that
there were duplicate publications from the same study, the
latest publication was included.
Global Overall Symptom Scale for Dyspepsia
The 5-point global overall symptom scale for dyspep-
sia was used in the studies to be included in the meta-
analysis.38 This scale evaluates the severity of dyspeptic
symptoms as 0 (no discomfort), 1 (mild pain or discomfort,
which can be forgotten), 2 (moderate pain or discomfort,
which cannot be forgotten but without influencing daily
activities), 3 (severe pain or discomfort, which influences
concentration or daily activities), and 4 (very severe pain or
discomfort, which stops daily activities and needs rest).
Data Extraction
Data from each paper meeting the inclusion criteria
were reviewed and separately extracted by 2 investigators,
who recorded details on authors, year of publication, study
design, methods for the detection of H. pylori infection,
number of patients in the treated and control group, time of
follow-up, treatment regimen for H. pylori infection, and
methodology for symptom improvement scoring, and the
number of subjects with or without improvement in dys-
peptic symptoms for those receiving H. pylori eradication
therapy and those who did not. Any differences that could
not be resolved through discussion were decided by a third
investigator, and consensus was obtained in all the cases.
Statistical Analysis
We used Review Manager 4.2.2 to perform the meta-
analysis. The outcome considered in this meta-analysis was
the summary odds ratio (OR) of improvement of dyspeptic
symptoms in FD patients with and those without H. pylori
eradication, and a 95% confidence interval (CI) was exe-
cuted. We examined heterogeneity using w2
tests. We used a
random-effects model if the tests were significant
(P 0.10); otherwise we used a fixed-effects model. To
enhance the confidence of the results of the statistics when
the number of combined studies was lacking, we used the I2
metrics, which describes the proportion of variability across
studies that is because of score heterogeneity. I2
50% was
considered to be indicative of heterogeneity. Larger values
indicate greater heterogeneity. Publication bias was also
assessed by a funnel plot.
RESULTS
Selection and Description of Studies and
Characteristics of Patients Included in the
Analysis
Both investigators agreed on the result of data extrac-
tion. The flowchart of the selection for the studies is shown
in Figure 1. After a thorough literature search, a total of 548
articles were identified, 91 of which were excluded by lan-
guage screening, 43 were rejected as reviews, and 336 were
excluded for the abstract suggesting that the articles were
irrelevant. In the remaining 78 articles, 64 were excluded
because they were either non-RCTs, or RCTs with a period
of follow-up of 12 months, or without the complete
required data. We ultimately included 14 RCTs published
between 1998 and 2011 with a total of 2993 patients in the
meta-analysis; 1490 in the treatment group and 1503 in the
control group. All of the 14 included studies were approved
by the Ethics Committee of their respective institute and
informed consents were obtained from all patients before
their enrolling in the studies. No publications for the assess-
ment of social or ethical issues could be found.
Table 1 shows the main characteristics of the studies
that met the inclusion criteria. Of the 14 included studies, 5
were from Europe, 4 from East-Asia (2 from Singapore),
Database search
(n=548)
Potentially relevant
studies identified (n=78)
Studies with usable information
included in the analysis (n=14)
Potentially relevant studies
identified (n=414)
Potentially relevant studies
identified (n=457)
Excluded (n=91)
Non-English articles
Excluded (n=64)
Not meeting the inclusion
Excluded (n=336)
Irrelevant studies
Excluded (n=43)
Review
FIGURE 1. Summary of article selection process.
Zhao et al J Clin Gastroenterol Volume 48, Number 3, March 2014
242 | www.jcge.com r 2013 Lippincott Williams Wilkins

3. 1 from Oceania (Australia), 2 from North America (Can-
ada), and 2 from South America (Brazil). We made sub-
group analysis on different geographical regions, which
included Europe, Asia, and America. Rapid urease test,
13
C-urea breath test, and/or histology were used in the
studies as the methods to confirm H. pylori infection. Triple
therapies containing a proton pump inhibitor (PPI) such as
omeprazole or lansoprazole and 2 antimicrobial agents
such as clarithromycin and amoxicillin were as the main
eradication regimens for H. pylori infection. Ranitidine,
metronidazole, and tinidazole were also used in the regi-
mens for eradicating H. pylori infection. In the control
groups, placebo alone, a PPI or H2-receptor inhibitor
alone, a PPI with placebo, and prokinetic alone were used
as control therapies, which were shown to have little effect
on H. pylori infection. The baseline characteristics of the
patients with and those without H. pylori eradication
therapy are shown in Table 2. In each study, there was no
significant difference with regard to age, sex, smoking habit,
and alcohol consumption.
Outcomes of the Meta-Analysis
Four of 14 studies included in the meta-analysis
showed significant improvement of dyspeptic symptoms in
the treatment group (605/1490) compared with the control
group (511/1503). Number needed to treat is 15. The
summary OR and OR for each of the 14 eradication trials
are shown in Figure 2. The pooled OR was 1.38 (95% CI,
1.18-1.62, P 0.0001), indicating that patients who
received H. pylori eradication therapy had a higher prob-
ability of symptom relief compared with patients without
H. pylori eradication. There was no significant hetero-
geneity (I2
= 51.8%). Figure 3 shows the funnel plot of
publication bias with the OR value as the horizontal axis
and the SE of the OR as the vertical axis. This graphical
funnel plot of the 14 studies appears symmetric, which
indicates no publication bias.
Subgroup Analysis on Geographical Regions
We also analyzed the effects of eradicating H. pylori
infection in patients with FD in different geographical
TABLE 1. The Main Characteristics of the Studies That Met the Inclusion Criteria
References Country Study Design
Treatment
Regimen
Follow-up
(mo)
Case
(n/N)
Control
(n/N) P
McColl et al20 UK Randomized controlled OAM 12 33/154 11/154 0.01
Talley et al21 Australia Randomized controlled OAC 12 69/150 71/142 NS
Koskenpato et al22 Finland Randomized controlled OMA 12 16/71 11/65 0.01
Hsu et al23 China Randomized controlled LMT 12 47/81 44/80 NS
Bruley et al24 France Randomized controlled RAC 12 55/129 38/124 NS
Veldhuyzen et al25 Canada Randomized controlled OAC 12 77/297 65/306 NS
Koelz et al26 Switzerland Randomized controlled OMA 12 55/89 61/92 NS
Veldhuyzen et al27 Canada Randomized controlled LAC 12 44/75 46/82 NS
Gisbert et al28 Spain Randomized controlled OAC 12 8/16 21/34 Not
mentioned
Mazzoleni et al29 Brazil Randomized controlled LAC 12 16/46 9/43 NS
Tiing et al30 Singapore Randomized controlled LAC 12 45/71 40/59 NS
Kok et al31 Singapore Randomized controlled OTC 12 10/35 3/36 0.01
Lan et al32 China Randomized controlled RAC 12 36/84 19/89 0.05
Mazzolani et al33 Brazil Randomized controlled OAC 12 94/192 72/197 0.01
A indicates amoxicillin; C, clarithromycin; Case (n/N), number of patients with improvement of dyspeptic symptoms after treatment/overall number in
treatment group, Control (n/N), number of patients with improvement of dyspeptic symptoms after treatment/overall number in control group; L, lanso-
prazole; M, metronidazole; n/N, number of patients with improvement of dyspeptic symptoms after treatment/overall number. NS, nonsignificant;
O, omeprazole; R, ranitidine; T, tinidazole.
TABLE 2. The Baseline Characteristics of the Helicobacter pylori Eradication Groups and Control Groups
Mean Age (y) Sex (% Male) Smoking (%) Drinking (%)
References Case Control Case Control Case Control Case Control
McColl et al20 42 ± 12 42.2 ± 13 51 47 34 33 32.8 31.4
Talley et al21 46.3 46.5 43 48 27 26 41 41
Koskenpato et al22 51.5 ± 9.5 51.8 ± 11.8 30 39 54 59
Hsu et al23 50.3 ± 15.1 51.6 ± 16.4 49.4 47.6 15.7 14.6 7.2 4.9
Bruley et al24 50 ± 16 52 ± 14 43 46 26 27 28 30
Veldhuyzen et al25 49 ± 13 50 ± 15 39 41 30.6 28.9 19.4 23.3
Koelz et al26 46 ± 15 49 ± 16 42 40 21 21 44 51
Veldhuyzen et al27 47 ± 13 49 ± 13 41.3 50 33.4 29.7 20.6 23.2
Gisbert et al28 42 41 30 28 33 36
Mazzoleni et al29 43.2 ± 11.9 39.2 ± 13.8 19.6 25.6 17.4 11.6 13 16.3
Tiing et al30 38.6 38.4 35.2 37.3 34.7 26.8 17.3 29.3
Kok et al31 44.7 ± 11.4 36.1 ± 12.1 43.9 46.3 30.7 26.7 17.9 27.8
Lan et al32 49.2 ± 14.1 45.5 ± 14.9 48 43.3 39.1 36.4 16.7 24.6
Mazzolani et al33 46.1 ± 12.4 46.0 ± 12.2 23.4 19.2 45.3 39.4 15.4 14.3
J Clin Gastroenterol Volume 48, Number 3, March 2014 Helicobacter pylori Eradication Therapy and Functional Dyspepsia
r 2013 Lippincott Williams Wilkins www.jcge.com | 243

4. regions. Whereas dyspeptic symptoms was significantly
improved in the eradication group than in patients of
control group in the European (OR,1.49; 95% CI, 1.10-
2.02), Asian (OR, 1.54; 95% CI, 1.07-2.21), and American
populations (OR, 1.43; 95% CI, 1.12-1.83), which were
showed in Figures 4A to C.
DISCUSSION
A large number of studies including RCTs have been
conducted to investigate the effects of H. pylori eradication
on resolution of dyspeptic symptoms, but with conflicting
results. Whereas several studies have observed that erad-
ication of H. pylori infection resolves dyspeptic symptoms in
FD patients, others have failed to confirm the observation.
In the present meta-analysis, we selected 14 well-designed
RCTs among 548 relevant articles and demonstrated that
patients with FD who received H. pylori eradication therapy
were almost 1.38 times more likely to show a symptom
improvement than those who received placebo or other
traditional therapy. In the subgroup analysis, improvements
of dyspeptic symptoms were achieved in significantly more
patients who received eradication therapy than in those who
did not in the European, Asian, and American populations.
H. pylori is one of the most genetically diverse of
bacterial species.39,40 Large population studies have shown
that it exists more frequently in dyspeptic patients than in
the healthy controls.4 Loffeld et al41 found that FD patients
with cagA-positive H. pylori strains have more dyspeptic
symptoms and higher symptom scores than patients with
cagA-negative strains as well as H. pylori-negative FD
patients, suggesting an important role of H. pylori espe-
cially cagA-positive H. pylori strains, in the pathogenesis of
FD. Several studies have suggested that H. pylori infection
produces several alterations in gastric functions, such as
hypergastrinemia, hyperpepsinogenemia, and acid hyper-
secretion, which are known to contribute to the develop-
ment of peptic ulcer disease.42 These functional alterations
may also play a role in the pathogenesis of FD; however,
large-scale cross-sectional studies should be taken to further
confirm this hypothesis.
Currently, acid suppression therapy combined with a
prokinetic agent is the most common way to treat dyspeptic
symptoms in clinical practice, because of the current
knowledge on the possible pathogenesis of FD involving
gastric acid secretion and gastrointestinal motility disorder.
Hsu et al23 found that eradicating H. pylori infection pre-
vented the subsequent development of peptic ulcers in the
patients with “ulcer-like” FD, indicating that, in addition to
the relief of the dyspeptic symptoms, H. pylori eradication
can also benefit to patients with FD in other respects.
Suzuki et al reported that successful H. pylori eradication
improved the quality of life in patients with ulcer-like or
dysmotility-like FD.43 Harvey et al44 found that eradication
of H. pylori infection in the community gives cumulative
long-term benefit, with a continued reduction in the
development of dyspepsia severe enough to require a con-
sultation with a general practitioner up to at least 7 years,
which suggested that gastric physiology may require long
FIGURE 2. Forest plot for the effects of Helicobacter pylori eradication on the symptom relief in patients with functional dyspepsia.
CI indicates confidence interval; OR, odds ratio.
FIGURE 3. Funnel plot for publication bias in the odds ratio (OR)
analysis. Each dot represents the OR for the percentage of
symptom relief between functional dyspepsia patients with and
those without Helicobacter pylori eradication. The dashed line
represents the 95% confidence interval line.
Zhao et al J Clin Gastroenterol Volume 48, Number 3, March 2014
244 | www.jcge.com r 2013 Lippincott Williams Wilkins

5. time to return in basal conditions following H. pylori
eradication. However, the economic impact of H. pylori
eradication in patients with FD has to be considered. As a
chronic disease, FD is difficult to cure. In our opinion,
compared with traditional medications, H. pylori erad-
ication may be a better long-term treatment for the symp-
toms of FD and relieve the pain of FD patients. However,
with the widespread use of antimicrobial agents and sub-
sequent rising prevalence of antimicrobial resistance, the
clinical efficacy (ie, eradication rates of H. pylori infection)
with currently used standard regimens has been compro-
mised, and decreased to unacceptable levels (ie, r80%) in
most countries.45 Consequently, rescue or even sequential
therapies have been recommended.46,47 Thus, there are
substantial costs for eradication of H. pylori infection in
FD patients, because of the high prevalence of H. pylori-
positive FD and the increased difficulties in H. pylori
eradication. Further cost-utility studies should be taken in
the future to assess the benefits and risks of H. pylori
eradication in FD. Nevertheless, our study did provide
strong support for the eradication of H. pylori in patients
with FD in terms of long-term symptomatic improvement
and may trigger physicians’ awareness of the cost.
A previous review article by Laheij et al48 in 1996
reported that symptom improvement after treatment was
found in 73% of the patients who became H. pylori-neg-
ative and 45% of the patients who remained H. pylori-
positive. This is the earliest review article about symptom
improvement in FD patients after H. pylori eradication,
although the articles included were very limited, it had
certain credibility. Then, Gisbert et al34 performed the first
meta-analysis to compare the efficacy of H. pylori erad-
ication treatment in patients with FD in 2002. In contrast
with our results and the early meta-analysis, they found
FIGURE 4. Forest plot for the effects of Helicobacter pylori eradication on the symptom relief in patients with functional dyspepsia in the
European (A), Asian (B), and American (C) populations. CI indicates confidence interval.
J Clin Gastroenterol Volume 48, Number 3, March 2014 Helicobacter pylori Eradication Therapy and Functional Dyspepsia
r 2013 Lippincott Williams Wilkins www.jcge.com | 245

6. that H. pylori eradication treatment was not associated with
a significant improvement of symptoms in patients with
FD. This may be because of the small sample size (9 studies
with 953 cases and 958 controls) and shorter follow-up
period (studies with follow-up of 6 mo were included) in
their meta-analysis. Jin and Li35 conducted a meta-analysis
on the association between H. pylori eradication and
improvement of FD in 2007, which included RCTs and
observational studies, however only limited studies were
published in Chinese. On the basis of the Chinese articles,
they reported a beneficial effect of H. pylori eradication in
patients with FD in studies published in Chinese, which was
consistent with the findings of the present meta-analysis
based on worldwide English articles. In addition, we per-
formed subanalysis of studies from different geographical
regions, and confirmed that in Asian, European, and
American populations, dyspeptic symptoms were sig-
nificantly improved in patients of eradication group than in
patients of control group, which further confirmed the
benefit of eradicating H. pylori infection in patients with
FD in different geographical regions.
Several limitations of this meta-analysis should be
mentioned. First, the number of subjects included in our
study affected the quality of the meta-analysis. Although we
used Medical Subject Heading terms and keywords to search
as many publications as possible in English, we acknowledge
that there might be a few well-designed, well-conducted
studies that were published in other languages and thus were
not included in the present meta-analysis. Second, because
not all articles reported H. pylori eradication rate in the
study, we were not able to assess the association between
successful H. pylori eradication and the improvement of
dyspeptic symptoms. Obviously, different eradication regi-
mens with different eradication rates of H. pylori infection
were used, which would influence the outcome. Finally, all
patients in the trials were recruited from hospitals, and thus,
the findings may not be generalizable to primary care patients
who have less severe disease and symptoms.
In conclusion, H. pylori eradication therapy is asso-
ciated with improvement of dyspeptic symptoms in patients
with FD, which is consistently demonstrated in the Asian,
European, and American populations. However, cost-util-
ity studies should be performed before H. pylori eradication
therapy can be recommended for H. pylori-positive FD,
because of the increasing antimicrobial resistance in H.
pylori, with the decreased eradication rate of currently used
regimens for H. pylori eradication.
ACKNOWLEDGMENT
The authors thank Medjaden Bioscience Limited for
assisting in the preparation of the manuscript.
REFERENCES
1. Tack J, Talley NJ, Camilleri M, et al. Functional gastro-
duodenal disorders. Gastroenterology. 2006;130:1466–1479.
2. Heatley RV, Rathborne BJ. Dyspepsia: a dilemma for doctors?
Lancet. 1987;332:779–781.
3. Jones RH, Lydeard SE, Hobbs FD, et al. Dyspepsia in
England and Scotland. Gut. 1990;31:401–405.
4. Shah SS, Bhatia SJ, Mistry FP. Epidemiology of dyspepsia in
the general population in Mumbai. Indian J Gastroenterol.
2001;20:103–106.
5. Hirakawa K, Adachi K, Amano K, et al. Prevalence of non-
ulcer dyspepsia in the Japanese population. J Gastroenterol
Hepatol. 1999;14:1083–1087.
6. Kawamura A, Adachi K, Takashima T, et al. Prevalence of
functional dyspepsia and its relationship with Helicobacter
pylori infection in a Japanese population. J Gastroenterol
Hepatol. 2001;16:384–388.
7. Jeong JJ, Choi MG, Cho YS, et al. Chronic gastrointestinal
symptoms and quality of life in the Korean population. World
J Gastroenterol. 2008;14:6388–6394.
8. Mertz H, Fullerton S, Naliboff B, et al. Symptoms and visceral
perception in severe functional and organic dyspepsia. Gut.
1998;42:814–822.
9. Rosenstock S, Kay L, Rosenstock C, et al. Relation between
Helicobacter pylori infection and gastrointestinal symptoms
and syndromes. Gut. 1997;41:169–176.
10. Quartero AO, de Wit NJ, Lodder AC, et al. Disturbed solid-
phase gastric emptying in functional dyspepsia: a meta-
analysis. Dig Dis Sci. 1998;43:2028–2033.
11. Tack J, Piessevaux H, Coulie B, et al. Role of impaired gastric
accommodation to a meal in functional dyspepsia. Gastro-
enterology. 1998;115:1346–1352.
12. Leahy A, Besherdas K, Clayman C, et al. Abnormalities of the
electrogastrogram in functional gastrointestinal disorders. Am
J Gastroenterol. 1999;94:1023–1028.
13. Koch KL, Hong SP, Xu L. Reproducibility of gastric
myoelectrical activity and the water load test in patients with
dysmotility-like dyspepsia symptoms and in control subjects.
J Clin Gastroenterol. 2000;31:125–129.
14. WHO IARC. Schistosomes, liver flukes and Helicobacter
pylori. IARC Working Group on the evaluation of carcino-
genic risks to humans. Lyon, June 7-14, 1994. IARC Monogr
Eval Carcinog Risks Hum. 1994;61:1–241.
15. Armstrong D. Helicobacter pylori infection and dyspepsia.
Scand J Gastroenterol. 1996;31:38–47.
16. Strauss RM, Wang TC, Kelsey PB, et al. Association of
Helicobacter pylori infection with dyspeptic symptoms in patients
undergoing gastroduodenoscopy. Am J Med. 1990;89:464–469.
17. Schubert TT, Schubert AB, Ma CK. Symptoms, gastritis, and
Helicobacter pylori in patients referred for endoscopy. Gastro-
intest Endosc. 1992;38:357–360.
18. Nandurkar S, Talley NJ, Xia H, et al. Dyspepsia in the
community is linked to smoking and aspirin use but not to Helico-
bacter pylori infection. Arch Intern Med. 1998;158:1427–1433.
19. Parente F, Imbesi V, Maconi G, et al. Effects of Helicobacter
pylori eradication on gastric function indices in functional
dyspepsia. Scand J Gastroenterol. 1998;33:461–467.
20. McColl K, Murray L, EL-Omar E, et al. Symptomatic benefit
from eradicating Helicobacter pylori infection in patients with
nonulcer dyspepsia. N Engl J Med. 1998;339:1869–1874.
21. Talley NJ, Vakil N, Ballard ED II, et al. Absence of benefit of
eradicating Helicobacter pylori in patients with nonulcer
dyspepsia. N Engl J Med. 1999;341:1106–1111.
22. Koskenpato J, Farkkila M, Sipponen P. Helicobacter pylori
eradication and standardized 3-month omeprazole therapy in
functional dyspepsia. Am J Gastroenterol. 2001;96:2866–2872.
23. PI Hsu, Lai KH, Tseng HH, et al. Eradication of Helicobacter
pylori prevents ulcer development in patients with ulcer-like
functional dyspepsia. Aliment Pharmacol Ther. 2001;15:195–201.
24. Bruley DV, Fle´ jou JF, Colin R, et al. There are some benefits
for eradicating Helicobacter pylori in patients with non-ulcer
dyspepsia. Aliment Pharmacol Ther. 2001;15:1177–1185.
25. Veldhuyzen SJO, Talley NJ, Blum AL, et al. Combined
analysis of the ORCHID and OCAY studies: does eradication
of Helicobacter pylori lead to sustained improvement in
functional dyspepsia symptoms? Gut. 2002;50:26–30.
26. Koelz HR, Arnold R, Stolte M, et al. Treatment of
Helicobacter pylori in functional dyspepsia resistant to conven-
tional management: a double blind randomized trial with a six
month follow up. Gut. 2003;52:40–46.
27. Veldhuyzen S, Fedorak RN, Lambert J, et al. Absence of
symptomatic benefit of lansoprazole, clarithromycin, and
amoxicillin triple therapy in eradication of Helicobacter pylori
positive, functional (nonulcer) dyspepsia. Am J Gastroenterol.
2003;98:1963–1969.
Zhao et al J Clin Gastroenterol Volume 48, Number 3, March 2014
246 | www.jcge.com r 2013 Lippincott Williams Wilkins

7. 28. Gisbert JP, Cruzado AI, Garcia-Gravalos R, et al. Lack of
benefit of treating Helicobacter pylori infection in patients with
functional dyspepsia. Randomized one year follow-up study.
Hepotogastroenterology. 2004;51:303–308.
29. Mazzoleni LE, Sander GB, Ott EA, et al. Clinical outcomes of
eradication of Helicobacter pylori in nonulcer dyspepsia in a
population with a high prevalence of infection: results of a
12-month randomized, double blind, placebo-controlled study.
Dig Dis Sci. 2006;51:89–98.
30. Tiing LA, Kwong MF, Eng KT, et al. Helicobacter pylori
eradication versus prokinetics in the treatment of functional
dyspepsia: a randomized, double blind study. J Gastroenterol.
2006;41:647–653.
31. Kok AG, Leyan T, Reuben KM, et al. The response of Asian
patients with functional dyspepsia to eradication of Helicobacter
pylori infection. Eur J Gastroenterol Hepatol. 2009;21:417–424.
32. Lan L, Yu J, Chen YL, et al. Symptom-based tendencies of
Helicobacter pylori eradication in patients with functional
dyspepsia. World J Gastroenterol. 2011;17:3242–3247.
33. Mazzoleni LE, Sander GB, Francesconi CF, et al. Helicobacter
pylori eradication in functional dyspepsia: HEROES trail. Arch
Intern Med. 2011;171:1929–1936.
34. Gisbert JP, Calvet X, Gabriel R, et al. Helicobacter pylori
infection and functional dyspepsia. Meta-analysis of efficacy of
eradication therapy. Med Clin (Barc). 2002;118:405–409.
35. Jin X, Li YM. Systematic review and meta-analysis from
Chinese literature: the association between Helicobacter pylori
eradication and improvement of functional dyspepsia. Heli-
cobacter. 2007;12:54–56.
36. David M, Alessandro L, Jennifer T, et al. Preferred reporting
items for systematic reviews and meta-analyses: the PRISMA
statement. Open Med. 2009;3:123–130.
37. Jadad AR, Moore RA, Carroll D, et al. Assessing the quality
of reports of randomized clinical trials: is blinding necessary?
Control Clin Trials. 1996;17:1–12.
38. Veldhuyzen SJO, KMAJ Tytgat, Pollak PT, et al. Can severity
of symptoms be used as an outcome measure in trials of
non-ulcer dyspepsia and Helicobacter pylori associated gas-
tritis? J Clin Epidemiol. 1993;46:273–279.
39. Marcelo LR, Anita PO, Benvengo YH, et al. Clinical relevance
of the cag A, vacA and iceA genotypes of Helicobacter pylori in
Brazilian clinical isolates. FEMS Immunol Med Microbiol.
2003;36:181–185.
40. Daniela B, Carlo FZ, Darren PL, et al. Clinical relevance of
Helicobacter pylori cagA and vacA gene polymorphisms.
Gastroenterology. 2008;135:91–99.
41. Loffeld RJ, Werdmuller BF, Kusters JG, et al. Functional
dyspepsia is associated with cagA-positive Helicobacter pylori
strains. Scand J Gastroenterol. 2001;36:351–355.
42. McColl KE. Helicobacter pylori and acid secretion: where are
we now? Eur J Gastroenterol Hepatol. 1997;9:333–335.
43. Suzuki H, Masaoka T, Sakai G, et al. Improvement of
gastrointestinal quality of life scores in cases of Helicobacter
pylori-positive functional dyspepsia after successful eradication
therapy. J Gastroenterol Hepatol. 2005;20:1652–1660.
44. Harvey RF, Lane JA, Nair P, et al. Clinical trial: prolonged
beneficial effect of Helicobacter pylori eradication on dyspepsia
consultations—the Bristol Helicobacter Project. Aliment Phar-
macol Ther. 2010;32:394–400.
45. Georgopoulos SD, Papastergiou V, Karatapanis S. Helico-
bacter pylori eradication therapies in the era of increasing
antibiotic resistance: a paradigm shift to improved efficacy.
Gastroenterol Res Pract. 2012;10:1155–1164.
46. Sang PY, Han GS, Chang SO, et al. Rifaximin plus
levofloxacin-based rescue regimen for the eradication of
Helicobacter pylori. Gut Liver. 2012;6:452–456.
47. Jyh ML, Chieh CC, Mei JC, et al. Sequential versus triple
therapy for the first-line treatment of Helicobacter pylori:
a multicentre, open-label, randomized trial. Lancet. 2012;
381:205–213.
48. Laheij RJ, Jansen JB, Van de Lisdonk EH, et al. Review
article: symptom improvement through eradication of Heli-
cobacter pylori in patients with non-ulcer dyspepsia. Aliment
Pharmacol Ther. 1996;10:843–850.
J Clin Gastroenterol Volume 48, Number 3, March 2014 Helicobacter pylori Eradication Therapy and Functional Dyspepsia
r 2013 Lippincott Williams Wilkins www.jcge.com | 247