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doi:10.1111/jgh.12769

O R I G I N A L A RT I C L E

Effect of supplementation with rebamipide for Helicobacter pylori eradication therapy: A systematic review and meta-analysis Toshihiro Nishizawa,*,† Yuko Nishizawa,‡ Naohisa Yahagi,* Takanori Kanai,† Masahiko Takahashi§ and Hidekazu Suzuki† *Division of Research and Development for Minimally Invasive Treatment, Cancer Center, †Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, ‡Pharmaceutical Department, National Center for Global Health and Medicine, and §Division of Gastroenterology, National Hospital Organization Tokyo Medical Center, Tokyo, Japan

Key words eradication, Helicobacter pylori, rebamipide. Correspondence Dr. Hidekazu Suzuki, Division of Gastroenterology and Hepatology, Department of Internal Medicine, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. Email: [email protected]

Abstract Background and Aim: Several studies have reported that the application of rebamipide during the eradication of Helicobacter pylori can improve the eradication rate. However, the efficacy and safety are controversial. The present study systematically evaluated whether rebamipide improves the eradication rate of H. pylori by conducting a metaanalysis based on randomized controlled trials (RCTs). Methods: Literature searches were conducted in the following database: PubMed, the Cochrane Library, and the Igaku-chuo-zasshi database in Japan. A meta-analysis of all RCTs comparing rebamipide supplementation with non-rebamipide-containing therapy was performed. Results: We identified six randomized trials (611 patients). Pooled H. pylori eradication rates by per-protocol analysis were 73.3% and 61.4% for patients with or without rebamipide, respectively. The odds ratio was 1.74 (95% confidence interval. 1.19–2.53). Conclusions: Supplementation with rebamipide might be effective in increasing the H. pylori eradication rates of proton-pump inhibitor–amoxicillin dual therapy.

Introduction

Methods

Eradication of Helicobacter pylori has been reported as an effective strategy in the treatment of peptic ulcer and gastric mucosaassociated lymphoid tissue lymphoma, and also preventing the recurrence of gastric cancer after endoscopic resection.1–3 With the increasing frequency of antibiotics-resistant H. pylori, there is rising concern about the potential decline in the eradication rate.4–9 Mucosal defensive agents are very safe and widely used as anti-ulcer drugs in East Asia. Rebamipide (2-(4chlorobenzoylamino)-3-[2-(1H)-quinolinon-4-yl] propionic acid) prevents gastric ulcer formation by inhibiting neutrophil activation. Rebamipide stimulates prostaglandin generation in the gastric mucosa, resulting in stimulation of mucus secretion. Rebamipide inhibits H. pylori adhesion to the gastric epithelial cells.10 Besides, rebamipide has been suggested to improve the efficacy of antibiotic therapy for eradication of H. pylori infection.11 However, the number of patients enrolled in some trials has been too few to achieve statistically conclusive results. The primary aim of the present systematic review and meta-analysis was to study whether rebamipide could improve success rates of anti-H. pylori treatment.

Before performing the meta-analysis, we developed a simplified protocol, including search strategies, criteria for study selection, how to exact related data, methods for assessing study quality, and statistical methodology.

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Search strategy. Electronic databases, PubMed (to July 2014), the Cochrane Controlled Trials Register (to July 2014), and the Igaku-chuo-zasshi database in Japan (to July 2014), were used for systematic literature searches. A search strategy was constructed by using a combination of the following words: (Helicobacter pylori OR H. pylori) AND (rebamipide). Articles published in any language were included. Inclusion and exclusion criteria. The selection criteria were as follows: 1 Only randomized controlled trials (RCTs) were included. 2 Confirmation of H. pylori eradication at least 4 weeks after therapy. 3 Studies including at least two branches of treatment consisting of (i) patients in a control group received proton-pump inhibitor

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(PPI) plus antibiotics with placebo or mucosal protective agents other than rebamipide and (ii) patients in experimental groups received PPI plus antibiotics with rebamipide. 4 Data of successful eradication or/and side-effects in H. pylori eradication were available.

Reports identified from literature search (n = 155)

Articles screened on basis of title and abstract Excluded (n = 144): Duplicate citations (n = 29) Unrelated topics (n = 46) Reviews (n = 34) Case reports (n = 4) Animal studies (n = 17) in vitro studies (n = 14)

Data extraction. Standardized data abstraction sheets were prepared. Data were extracted for study type and duration of rebamipide treatment, anti-H. pylori regimens, and the number, sex, and age of enrolled subjects, diagnostic methods of testing H. pylori infection before enrolment and after completing the study, and key outcome data, such as eradication rates, occurrence of diarrhea, nausea, taste disturbance, and epigastric pain, were abstracted from all included studies. All articles were examined independently for eligibility by two reviewers (T.N. and Y.N.). Disagreements were resolved by consulting a third reviewer (H.S.). Assessment of methodology quality. The methodological quality of each study was assessed using the risk-of-bias tool outlined in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0). Two reviewers (T.N. and Y.N.) reviewed all studies and assessed six different key aspects that influence the quality of an RCT, including sequence generation, allocation concealment, blinding of participants and outcome assessors, management of eventual incomplete outcome data, completeness of outcome reporting, and other potential threats to validity. Statistical analysis. Data were entered into the StatsDirect package. The outcome measure examined was the odds ratios (ORs) of improving H. pylori eradication rates and reducing sideeffects with rebamipide versus without rebamipide combining with the eradication regimens. Eradication rates and side-effects were analyzed by a fixed-effects model using the methods of Mantel–Haenszel both by a per-protocol and an intention-to-treat (ITT) analysis. Heterogeneity between the studies was assessed by Cochrane’s Q and I2 test. Because of the low power of the Q test, a cut-off value < 0.10 was used to reject homogeneity, indicating heterogeneity. An I2 score ≥ 50% indicates more than moderate heterogeneity. If significant heterogeneity exists, the random effect model was used for calculations. An analysis of sensitivity was performed in order to evaluate the stability of the results. Finally, we used funnel plot asymmetry to detect any publication bias in the meta-analysis, and Egger’s regression test to measure funnel plot asymmetry.

Results Literature search. Our database search yielded a total of 155 citations (Fig. 1). After adjusting for duplicates, 126 citations remained. Of these, 115 studies were discarded because after reviewing the abstracts, it appeared that these papers clearly did not meet the criteria (46 unrelated topics, 34 reviews, 4 case reports, 17 animal studies, and 14 in vitro studies). The full text of the remaining 11 citations was examined in more detail. We excluded some studies due to non-controlled studies (n = 1)12 and studies of rebamipide treatment after H. pylori

Manuscript review and application of inclusion criteria (n = 11) Excluded (n = 5): Non-controlled studies (n = 1) Rebamipide treatment after H. pylori eradication (n = 4)

RCTs included in this meta-analysis (n = 6)

Figure 1 Flow of randomized controlled trials (RCTs) included in the meta-analysis.

eradication (n = 4).13–16 Finally, six studies were included in the meta-analysis.17–22 Characteristics and quality of eligible studies. The characteristics of the six studies are summarized in Table 1. Four RCTs compared rebamipide-containing triple therapy with PPI and amoxicillin therapy. One RCT compared rebamipidecontaining triple therapy with teprenone-containing triple therapy. One RCT compared rebamipide-containing quadruple therapy with plaunotol-containing quadruple therapy. The risk of bias in the RCTs is shown in Table 2. In general, the included trials were at low risk of bias. Four RCTs did not describe the specific methods of allocation concealment. Information of blindness assessment was not described for five studies. Adequate assessment of incomplete outcome and selective outcome reporting avoided were not reported in one study. All six studies were free of other biases. Efficacy analysis. Pooled eradication rates were achieved in 200 of 273 patients (73.3%) with rebamipide supplementation and in 156 of 254 patients (61.4%) without rebamipide by per-protocol analysis (OR 1.737, 95% confidence interval [CI] 1.194–2.527, P = 0.0049) (Fig. 2). There was no significant heterogeneity among the trial results (χ2 = 6.76, P = 0.245, I2 = 25.2%). Overall, intention-to-treat eradication rates were 63.5% (200/315) and 52.7% (156/296) for rebamipide supplementation and without rebamipide, respectively. The OR was 1.586 (95% CI 1.136– 2.215, P = 0.0083) with no significant heterogeneity among trial results (χ2 = 7.14, P = 0.211, I2 = 29.9%). The sensitivity analysis performed using sequential excluding of one trial at a time did not alter the results. We excluded two studies comparing other mucosal protective agents for sensitivity analysis; however, eradication rates showed no significant change (OR 1.571; 95% CI 1.032–2.392).

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Table 1

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Study characteristics

Author, year

Country

Rebamipide-containing regimen

Non-rebamipidecontaining regimen

H. pylori infection initial diagnosis/re-check

Saita, 199617

Japan

LPZ 30 mg bid, 2w AMX 500 mg bid, 2w

Histology, serology, culture and RUT (at least two positive)/Histology, culture and RUT

Hahn, 199818

Korea

LPZ 30 mg/day, 2w AMX 1500 mg/day, 2w

Histology and RUT/Histology, RUT and UBT

Kato, 199819

Japan

Japan

LPZ 30 mg o.d, 2w AMX 500 mg tid, 2w Teprenone 50 mg tid, 8w OPZ 20 mg bid, 2w AMX 500 mg tid, 2w

RUT and UBT/UBT

Nebiki, 199820

Kimura, 199921

Japan

Fujioka, 200322

Japan

LPZ 30 mg bid, 2w AMX 500 mg bid, 2w Rebamipide 100g tid, 8w LPZ 30 mg/day, 2w AMX 1500 mg/day, 2w Rebamipide 300 mg/day, 2w LPZ 30 mg o.d, 2w AMX 500 mg tid, 2w Rebamipide 100g bid, 8w OPZ 20 mg bid, 2w AMX 500 mg tid, 2w Rebamipide 100 mg tid, 2w LPZ 30 mg/day, 8w AMX 1500 mg/day, 1w MNZ 500 mg/day, 1w Rebamipide 300 mg/day, 12w LPZ 30 mg bid, 2w AMX 500 mg bid, 2w Rebamipide 100 mg tid, 8w

LPZ 30 mg/day, 8w AMX 1500 mg/day, 1w MNZ 500 mg/day, 1w Plaunotol 240 mg/day, 12w LPZ 30 mg bid, 2w AMX 500 mg bid, 2w

Both RUT and histology, or culture/RUT, histology and culture RUT, histology and culture/RUT, histology and culture

Both RUT and histology, or culture or UBT/ histology, culture and UBT

AMX, amoxicillin; LPZ, lansoprazole; MNZ, metronidazole; OPZ, omeprazole; RUT, rapid urease test; UBT, urea breath test; w, weeks.

Table 2

Evaluation of bias of randomized controlled trials (RCTs) included in the meta-analysis

Author

Random sequence generation

Allocation concealment

Blinding of participants and personnel

Blinding of outcome assessment

Adequate assessment of incomplete outcome

Selective reporting avoided

No other bias

Saita17 Hahn18 Kato19 Nebiki20 Kimura21 Fujioka22

Yes Yes Yes Yes Yes Yes

Unclear Unclear Unclear Yes Unclear Yes

No No No No No Yes

No No No No No Yes

Yes Unclear Yes Yes Yes Yes

Yes Unclear Yes Yes Yes Yes

Yes Yes Yes Yes Yes Yes

No, high risk of bias; Unclear, unclear risk of bias; Yes, low risk of bias.

Description

Regimen with

Regimen without

Odds ratio meta-analysis plot

Odds ratio

rebamipide

rebamipide

(fixed effects, 95% CI)

(95% CI)

n/N

n/N

Saita 1996

25/33

15/27

Hahn 1998

27/36

12/21

Kato 1998

26/38

21/45

Nebiki 1998

44/58

31/56

Kimura 1999

25/26

24/27

Fujioka 2003

53/82

53/78

200/273

156/254

Total

Heterogeneity: χ2=6.69 (df=5), P =0.245 I2=25.2%

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Figure 2 Forest plot displaying the odds ratio and 95% confidence intervals (CIs) of each study for Helicobacter pylori eradication rates by per-protocol analysis.

Journal of Gastroenterology and Hepatology 2014; 29 (Suppl. 4): 20–24 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

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ratio 0.86).22 Further studies with large number of patients are warranted to clarify the efficacy of rebamipide-containing quadruple therapy. In conclusion, our analysis demonstrates that supplementation with rebamipide might be effective in increasing H. pylori eradication rates of PPI–amoxicillin dual therapy.

Bias assessment plot Standard error 0.3

0.6

References 0.9

1.2 –2

–1

0

1

2

3 Log(Odds ratio)

Figure 3 Funnel plot of the included studies for Helicobacter pylori eradication rates by per-protocol analysis.

Data for the occurrence of overall side-effects could be obtained for five RCTs. Meta-analysis of the incidence of overall sideeffects revealed no significant difference between rebamipide supplementation and without rebamipide (OR 0.699; 95% CI 0.376–1.300; P = 0.329). We found the funnel plot had almost symmetrical distribution (Fig. 3) and Egger’s regression test suggested no significant asymmetry of the funnel plot (P = 0.22), indicating no evidence of substantial publication bias.

Discussion The present meta-analysis suggested that rebamipide containing therapy was more effective than non-rebamipide-containing therapy for H. pylori eradication treatment. However, the positive effect in rebamipide-containing quadruple therapy has not been validated. Rebamipide was not found to have direct effects (antibacterial effects or urease inhibition) on H. pylori in in vitro study.23 Rebamipide inhibits adherence of H. pylori to gastric cells.10 This effect may aid antibiotics in curing H. pylori infection. In addition, rebamipide scavenges free radicals, inhibits inflammatory cell responses, and reduces interleukin-8 production in response to H. pylori.24–26 These effects might alter H. pylori status. The present systematic review and meta-analysis has several limitations that need to be taken into account in interpreting the results. The most of these studies were performed in Japan, and similar publications examining other ethnic populations are limited. In addition, although most studies in the present analysis evaluated the supplementary effect of rebamipide on the PPI+amoxicillin dual therapy, it is rather outdated because the main stream of the recent H. pylori eradication regimens are based on the triple therapy. Due to the limited number of eligible studies, subgroup analysis was not performed. The highest quality study by Fujioka et al. showed no significant effect of rebamipide (odds

1 Fukase K, Kato M, Kikuchi S et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 2008; 372: 392–7. 2 Nishizawa T, Suzuki H, Nakagawa I et al. Early Helicobacter pylori eradication restores sonic hedgehog expression in the gastric mucosa of Mongolian gerbils. Digestion 2009; 79: 99–108. 3 Suzuki H, Nishizawa T, Hibi T. Helicobacter pylori eradication therapy. Future Microbiol. 2010; 5: 639–48. 4 Nishizawa T, Suzuki H, Tsugawa H et al. Enhancement of amoxicillin resistance after unsuccessful Helicobacter pylori eradication. Antimicrob. Agents Chemother. 2011; 55: 3012–4. 5 Nishizawa T, Suzuki H, Suzuki M, Takahashi M, Hibi T. Proton pump inhibitor-amoxicillin-clarithromycin versus proton pump inhibitor-amoxicillin-metronidazole as first-line Helicobacter pylori eradication therapy. J. Clin. Biochem. Nutr. 2012; 51: 114–6. 6 Nishizawa T, Suzuki H, Kurabayashi K et al. Gatifloxacin resistance and mutations in gyra after unsuccessful Helicobacter pylori eradication in Japan. Antimicrob. Agents Chemother. 2006; 50: 1538–40. 7 Nishizawa T, Suzuki H, Nakagawa I, Iwasaki E, Masaoka T, Hibi T. Gatifloxacin-based triple therapy as a third-line regimen for Helicobacter pylori eradication. J. Gastroenterol. Hepatol. 2008; 23 (Suppl. 2): S167–70. 8 Nishizawa T, Suzuki H, Takahashi M, Suzuki M, Hibi T. Delay of second-line eradication therapy for H. pylori can increase eradication failure. J. Gastroenterol. Hepatol. 2013; 28: 1608–10. 9 Nishizawa T, Maekawa T, Watanabe N et al. Clarithromycin versus metronidazole as first-line helicobacter pylori eradication: a multicenter, prospective, randomized controlled study in Japan. J. Clin. Gastroenterol. 2014; June 11. 10 Hayashi S, Sugiyama T, Amano K et al. Effect of rebamipide, a novel antiulcer agent, on Helicobacter pylori adhesion to gastric epithelial cells. Antimicrob. Agents Chemother. 1998; 42: 1895–9. 11 Hojo M, Miwa H, Kikuchi S, Sato N. Do mucosal defensive agents improve the cure rate when used with dual or triple therapy regimens for eradicating Helicobacter pylori infection? Aliment. Pharmacol. Ther. 2000; 14: 193–201. 12 Nomura H, Miyake K, Kashiwagi S, Sugiyama T, Asaka M. A short-term eradication therapy for Helicobacter pylori acute gastritis. J. Gastroenterol. Hepatol. 2000; 15: 1377–81. 13 Terano A, Arakawa T, Sugiyama T et al. A pilot study to evaluate a new combination therapy for gastric ulcer: helicobacter pylori eradication therapy followed by gastroprotective treatment with rebamipide. J. Gastroenterol. Hepatol. 2006; 21 (1 Pt 1): 103–9. 14 Song KH, Lee YC, Fan DM et al. Healing effects of rebamipide and omeprazole in Helicobacter pylori-positive gastric ulcer patients after eradication therapy: a randomized double-blind, multinational, multi-institutional comparative study. Digestion 2011; 84: 221–9. 15 Terano A, Arakawa T, Sugiyama T et al. Rebamipide, a gastro-protective and anti-inflammatory drug, promotes gastric ulcer healing following eradication therapy for Helicobacter pylori in a

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16

17

18

19

20

21

24

T Nishizawa et al.

Japanese population: a randomized, double-blind, placebo-controlled trial. J. Gastroenterol. 2007; 42: 690–3. Kamata T, Sato M, Tokutomi T et al. Effects of rebamipide after H. pylori eradication treatment: multicenter trial. J. Jpn. Soc. Gastroenterol. 2013; 110: A893. Saita H, Takahashi Y, Sou Y et al. Combination therapy with lansoprazole, amoxicillin, and rabeprazole for cure of Helicobacter pylori infection and histlogical gastritis in gastric ulcer patients. Jpn. Arch. Intern. Med. 1996; 43: 15–25. Hahm KB, Lee KJ, Kim YS et al. Augmented eradication rates of Helicobacter pylori by new combination therapy with lansoprazole, amoxicillin, and rebamipide. Dig. Dis. Sci. 1998; 43: 235–40. Kato M, Asaka M, Sugiyama T et al. Effects of rebamipide in combination with lansoprazole and amoxicillin on Helicobacter pylori-infected gastric ulcer patients. Dig. Dis. Sci. 1998; 43 (9 Suppl.): 198S–202S. Nebiki H, Higuchi K, Arakawa T et al. Effect of rebamipide on Helicobacter pylori infection in patients with peptic ulcer. Dig. Dis. Sci. 1998; 43 (9 Suppl.): 203S–6S. Kimura M, Urakami Y, Seki H. Effects of mucosalprotective agents in combinaiton with eradication therapy on Helicobacter

22

23

24

25

26

pylori-infected gastric ulcer. Frontiers in Gastroenterology 1999; 4: 202–8. Fujioka T, Arakawa T, Shimoyama T et al. Effects of rebamipide, a gastro-protective drug on the Helicobacter pylori status and inflammation in the gastric mucosa of patients with gastric ulcer: a randomized double-blind placebo-controlled multicentre trial. Aliment. Pharmacol. Ther. 2003; 18 (Suppl. 1): 146–52. Naito Y, Yoshikawa T. Rebamipide: a gastrointestinal protective drug with pleiotropic activities. Expert Rev. Gastroenterol. Hepatol. 2010; 4: 261–70. Suzuki M, Miura S, Mori M et al. Rebamipide, a novel antiulcer agent, attenuates Helicobacter pylori induced gastric mucosal cell injury associated with neutrophil derived oxidants. Gut 1994; 35: 1375–8. Suzuki H, Mori M, Kai A et al. Effect of rebamipide on H. pylori-associated gastric mucosal injury in Mongolian gerbils. Dig. Dis. Sci. 1998; 43 (9 Suppl.): 181S–7S. Nishizawa T, Suzuki H, Nakagawa I et al. Rebamipide-promoted restoration of gastric mucosal sonic hedgehog expression after early Helicobacter pylori eradication. Digestion 2009; 79: 259–62.

Journal of Gastroenterology and Hepatology 2014; 29 (Suppl. 4): 20–24 © 2014 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd

Effect of supplementation with rebamipide for Helicobacter pylori eradication therapy: a systematic review and meta-analysis.

Several studies have reported that the application of rebamipide during the eradication of Helicobacter pylori can improve the eradication rate. Howev...
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