Efficacy of Helicobacter pylori Eradication Therapy on Functional Dyspepsia

  • 239 views
Uploaded on

Efficacy of Helicobacter pylori Eradication Therapy on Functional Dyspepsia …

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

  • Full Name Full Name Comment goes here.
    Are you sure you want to
    Your message goes here
    Be the first to comment
    Be the first to like this
No Downloads

Views

Total Views
239
On Slideshare
0
From Embeds
0
Number of Embeds
0

Actions

Shares
Downloads
3
Comments
0
Likes
0

Embeds 0

No embeds

Report content

Flagged as inappropriate Flag as inappropriate
Flag as inappropriate

Select your reason for flagging this presentation as inappropriate.

Cancel
    No notes for slide

Transcript

  • 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