ORIGINAL ARTICLE. Abstract. Introduction. Yuan Wenzhen 1,2, Yang Kehu 1,MaBin 1,LiYumin 3, Guan Quanlin 1, Wang Donghai 4 and Yang Lijuan 5

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1 ORIGINAL ARTICLE Moxifloxacin-Based Triple Therapy Versus Clarithromycin-Based Triple Therapy for First-Line Treatment of Helicobacter pylori Infection: A Meta-Analysis of Randomized Controlled Trials Yuan Wenzhen 1,2, Yang Kehu 1,MaBin 1,LiYumin 3, Guan Quanlin 1, Wang Donghai 4 and Yang Lijuan 5 Abstract Background Moxifloxacin-based triple has been suggested as an alternative first line to clarithromycin-based triple for Helicobacter pylori infection. Aims To systematically review the efficacy and tolerance of moxifloxacin-based triple, and to conduct a meta-analysis of studies comparing this regimen with clarithromycin-based triple. Methods A search of The Cochrane Library, PUBMED, EMBASE, EBM Review databases, Science Citation Index Expanded, and CMB (Chinese Biomedical Literature Database) was performed. Randomized controlled trials comparing moxifloxacin-based triple to gold in the first-line treatment of Helicobacter pylori infection were selected for meta-analysis. Relative risk was used as a measure of the effect of the two above-mentioned regimens with a fixed-effects model using the methods of DerSimonian and Laird. Results Four randomized controlled trials totaling 772 patients were included. The meta-analysis showed that the mean eradication rate was 84.1 (318/378) in the moxifloxacin-based triple group and 73.6 (290/394) in the clarithromycin-based triple group; there was statistical significance between the two groups (RR, 1.13; 95% CI, 1.01, 1.27; P=0.04). There were no statistically significant difference in the overall side effects (RR, 0.61; 95% CI, 0., 1.48; P<0.28). Conclusions Moxifloxacin-based triple is more effective and does not increase the incidence of overall side effects compared to clarithromycin-based triple in the treatment of H. pylori infection. Key words: Helicobacter pylori, first-line treatment, moxifloxacin, clarithromycin, meta-analysis (Inter Med 48: , 2009) () Introduction Helicobacter pylori (H. pylori) is a highly prevalent chronic infection with a worldwide prevalence of nearly 50% and U.S. prevalence of -40% (1, 2). Helicobacter pylori is known to play a major contributory role in the pathogeneses of chronic gastritis, peptic ulcers, gastric mucosa-associated lymphoid tissue (MALT) lymphoma and distal gastric cancer (3-5). Although various antimicrobial regimens have been proposed and tested, the regimen combining a proton-pump inhibitor (PPI) with two antibiotics is currently considered the gold standard for achieving an eradication rate >80% (6-8). Evidence-Based Medicine Center of Lanzhou University, Lanzhou, China, The First Hospital of Lanzhou University, Lanzhou, China, The Second Hospital of Lanzhou University, Lanzhou, China, Montefiore Medical Center, Albert Einstein College of Medicine, NY, U.S.A and The School of Economics of Lanzhou University, Lanzhou, Gansu, China Received for publication April 7, 2009; Accepted for publication August 3, 2009 Correspondence to Dr. Li Yumin, liyumin168@yahoo.com.cn 2069

2 However, these schemes fail to eradicate H. pylori in up to 20% of patients (9). Resistance to antibiotics is the major reason for eradication failure (10). Metronidazole resistance was the first to be described (11, 12) and clarithromycin resistance was found to be the most important cause of eradication failure (13). The primary resistance to macrolides in Western countries varies from 2 to 12%. In the same areas, H. pylori resistance to nitroimidazoles ranges from 2 to 50% with a prevalence of 12-15% in Italy (14). The current background resistance rates of H. pylori in the United States are 37% for metronidazole and 10% for clarithromycin (15). The wide use of such antibiotics for community acquired upper and lower respiratory diseases and for otitis probably explains the increasing resistance of H. pylori in general population. Therefore, the ideal treatment for H. pylori infection is still far from being reached and more effective and better tolerated alternative regimens are needed (16). Conversely, resistance to fluoroquinolones remains a rare occurrence, varying from 3.3% in France (17), 4.7% in the Netherlands (18), 3.9% in five Eastern European countries (19), and a high resistance rate of 20.9% in Portugal (20). And the data on the primary resistance to moxifloxicin are limited. Only Bago et al reported a low resistance rate of 5.9% in Croatia, as far as we know (21). In recent years new treatment schemes based on fluoroquinolones have been under investigation (21-29); however, first-generation fluoroquinolones such as norfloxacin and pefloxacin did not show satisfactory eradication rates (, 31). Several studies have evaluated the efficacy of different levofloxacin-based triple therapies and shown eradication rates up to 90% (22, 27). Saad et al concluded that a 10-day course of levofloxacin triple is more effective and better tolerated than 7-day bismuth-based quadruple in the treatment of persistent H. pylori infection after systematic review of all randomized controlled trials (RCTs) (32). Di Caro et al compared the efficacy of different 1-week moxifloxacin-based regimens and showed that moxifloxacin alone or in combination with lansoprazole had a poor eradication rate, but moxifloxacin associated with lansoprazole and clarithromycin achieved an eradication rate of 90% (24). Nista et al compared the efficacy of two 7-day moxifloxacin-based regimens with two standard treatments and found higher eradication rates of moxifloxacin-based regimens (90% or more) and a low occurrence of side effects (27). Cheon et al and Kang et al showed high eradication rates of moxifloxacin-based triple as an alternative second-line for eradication of H. pylori (23, 26). However, we could not find any systematic reviews or metaanalyses comparing the beneficial and harmful effects of moxifloxacin-based triple versus clarithromycinbased triple for H. pylori infection. We systematically reviewed all RCTs which compared the eradication rates and tolerability of moxifloxacin-based triple to clarithromycin-based triple in the treatment of H. pylori infection. By summarizing the data from RCTs, meta-analysis will provide greater statistical power and a more precise estimate of eradication rates with these regimens in patients with H. pylori infection. This analysis will also provide a more precise comparison of the frequency of side effects associated with each regimen. Study selection criteria Patients and Methods The titles and abstracts of all citations identified by the literature search were reviewed. Selection criteria were then applied to all potentially relevant studies. The selection criteria for inclusion in the meta-analysis were as follows: (i) Only RCTs that compared first-line therapies were included, (ii) They had to include at least two branches of treatment consisting of (a) moxifloxacin-based triple that included amoxicillin or nitroimidazoles and a PPI, and (b) clarithromycin-based triple ; (iii) Confirmation of infection eradication at least 4 weeks after the completion of treatment; and (iv) The confirmation of infection based on urea breath testing or gastric mucosal biopsy for histology or culture. Search strategy for identification of studies Trials were identified by searching the Cochrane Library (Issue ), PubMed (December 2008), EMBASE (December 2008), Science Citation Index Expanded, and CBM (Chinese Biomedical Literature Database). A search strategy was constructed by using a combination of the following words: (Helicobacter pylori OR H. pylori) AND (moxifloxacin OR Avelox). Articles published in any language were included. Reference lists from the trials selected by electronic searching were hand searched to identify further relevant trials. Abstracts of the articles selected in each of these multiple searches were reviewed and those meeting the inclusion criteria were recorded. In the case of duplicate reports, or studies obviously reporting results from the same study population, only the latest published results were used. Assessment of study quality The quality of the studies was assessed using the score proposed by Jadad et al (33) based on three items: (i) randomization; (ii) double blinding; and (iii) description of withdrawals and dropouts. The items were presented as questions to elicit yes or no answers. Points awarded for items one and two were dependent upon the quality of the description of the methods to generate the sequence of randomization and/or on the quality of the description of the method of double blinding. The third item, withdrawals and dropouts, was awarded as zero points for a negative answer and one point for a positive answer. For a positive answer, the number of withdrawals and dropouts and the reasons had to be stated in each of the comparison groups. Quality assessment of studies was performed independently by two reviewers. Discrepancies in the interpretation were resolved 2070

3 48 potentially relevant literatures identified from search strategy 23 articles were excluded owing to publication types 14 comparative studies nine reviews papers from Initial Screening 11 non-clinical trials Seven unrelated articles Seven potentially relevant papers retrieved for more detailed assessment Three papers were excluded Two moxifloxacin-based used as second-line treatment One without as contrast group Four satisfied inclusion criteria Figure1. Theflowchartofstudyselection. by consensus. Data extraction Two investigators (Yuan Wenzhen and Ma Bin) extracted the data from the studies meeting the selection criteria. Data were extracted according to the following: (a) study design; (b) number of patients enrolled in the study; (c) number of patients in each treatment arm; (d) testing used to confirm persistent infection prior to study enrollment; (e) drug regimen, including specific doses and treatment duration; (f) testing used to confirm eradication, including timing of such testing after completion of treatment; (g) number of patients in which H. pylori infection was successfully eradicated (either directly provided or calculated given the intention-totreat and per-protocol analyses); and (h) number of patients with side effects. The following variables were also extracted: year of publication, format (abstract or journal article), type of disease (see Tables 1, 3). There was greater than 98% agreement in data extraction between the two investigators. Statistical analysis The primary study outcomes for the meta-analysis were (a) the eradication rate of moxifloxacin-based triple compared to clarithromycin-based triple ; (b) incidence of adverse events in the moxifloxacin-based versus clarithromycin-based triple. Following data extraction, eradication rates from intention-to-treat analyses were entered into Review Manager 5.0 software programs (Cochrane Collaboration) for the performance of metaanalysis. In summarizing the data from these comparative trials, risk ratio (RR) was used as the measure of association, and summary relative RRs along with its 95% confidence interval (CI) were calculated based on a fixed-effects model using the methods of DerSimonian and Laird (34). A test of heterogeneity was also performed using the I 2 statistic to establish whether or not any clinical, methodological, or statistical variability existed among the studies used in metaanalysis. Statistical significance for the test of heterogeneity was set at The same method of meta-analysis was applied to the incidence of adverse events and discontinuation of due to adverse events for the RCTs. Results The flowchart of reviews shows the detailed process of selection (Fig. 1). Of seven potential eligible articles, we excluded two more articles as the moxifloxacin-based was used as second-line treatment for Helicobacter pylori infection (23, 26) and one paper without as contrast group (24). Finally, four RCTs (n=772 patients) were included which compared moxifloxacin-based triple to clarithromycin-based triple (21, 27, 29, 35). The quality of the included studies is shown in Table 1. The included patients did not differ in baseline characteristics (disease and sex) (see Table 2). The results of the four studies are summarized in Table 3 (21, 27, 29, 35). A meta-analysis of the eradication rates with intention-to-treat analyses demonstrated the superiority of the moxifloxacin-based triple to clarithromycin-based triple (RR, 1.13; 95% CI, 1.01, 1.27; P=0.04) (see Fig. 2). Three trials compared the incidence of side effects of moxifloxacin-based triple versus clarithromycin-based triple (21, 27, 35). The incidence of adverse events is summarized in Table 3. Metaanalysis of the incidence of overall side effects revealed no significant difference between moxifloxacin-based triple and clarithromycin-based triple (RR, 0.61; 95% CI, 0., 1.48; P=0.28) (see Fig. 3). The sensitivity analysis showed that both the eradication rate and the inci- 2071

4 Table1. CharacteristicsofIncludedStudies(21,27,29,35) Study Nista (27) 2005 Bago (21) 2007 Patients positive non-ulcer dyspepsia adults positive non-ulcer dyspepsia adults Patient Enrollment/Male Study Design Test Confirming Infection 320/172 RCT Histology 13C-UBT (Both of them positive) 277/143 RCT Histology Culture RUT (2/3 of above positive) Treatment Regimen moxifloxacin triple MTE MAE CET ACE moxifloxacin triple MLMe MAL CLMe ACL Treatment Duration Test Confirming Eradication Duration assed the eradication 1W UBT 6 W 1W Histology Culture RUT 4-6W Liu (29) 2007 Kilic (35) 2008 positive adults positive non-ulcer dyspepsia adults 55/27 RCT Gastroscope 14C-UBT (Both of them positive) 120/63 RCT RUT Or Histology moxifloxacin triple MAO ACO moxifloxacin triple MAB MAE ABC ACE 1W UBT 4-6W 2W UBT 8W A, amoxicillin; B, ranitidine bismuth citrate; C, clarithromycin; E, esomeprazole; L, lansoprazole; M, moxifloxacin; Me, metronidazole; O, omeprazole; RUT rapid urease test; T, tinidazole; UBT, urea breath test; W, week Table2. QualityAsesmentofIncludedStudies(21,27,29,35) Study Randomization Allocated Concealment Blinding Follow-up itime (W) Dropout N Jadad scores Nista et al (27) Adequate Adequate Not used 6w 13 3 Bago et al (21) Adequate Adequate Adequate 4-6w 12 5 (double-blind) Liu et al (29) Unclear Unclear Not described 4-6w 0 2 Kilic et al (35) Unclear Unclear Not used 8w 0 2 W, week; N, number dence of side effects were statistically significantly different between moxifloxacin-based triple and clarithromycin-based triple after we excluded one trial (35) which confirmed H. pylori infection by histology in some subjects, it combined moxifloxacin and clarithromycin in one branch, and H. pylori treatment was given for two weeks rather than one week (see Figs. 4, 5). Discussion In general, the most important predictors of H. pylori treatment failure include pretreatment resistance to antimicrobial agents (12) and patient noncompliance with the medical regimen (10). Compliance with any medical is influenced by the complexity of the dosing regimen (number of pills and frequency) and the frequency and severity of associated side effects. Disadvantages of clarithromycin-based triple include the large daily pill count (potentially exceeding 12 pills) and frequent side effects (occurring in.9%-64.7% of patients in some studies) (36-38). Related to these drawbacks, more effective, simpler, and better tolerated regimens 2072

5 Moxifloxacin-basedtriple Clarithromycin-basedtriple Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI Bago P % 1.21 [1.08, 1.35] Kiliç % 0.86 [0.66, 1.12] Liu % 1.10 [0.84, 1.44] Nista EC % 1.20 [1.08, 1.34] Total (95% CI) % 1.13 [1.01, 1.27] Total events Heterogeneity: Tau² = 0.01; Chi² = 6.35, df = 3 (P = 0.10); I² = 53% Test for overall effect: Z = 2.04 (P = 0.04) Favours control Favours experimental Figure2. EficacyonHelicobacterpylorieradication. Table3. EficacyandSideEfects(21,27,29,35) Study Treatment Arm Patients Enrolled Patients Completed The study Patients with successfully eradicated Eradication Rate (ITT) Eradication Rate (PP) Overal side effects Incidence (N) Nista (27) moxifloxacin triple MTE MAE % 87.5% 92.3% 88.6% Standard triple CET ACE % 72.5% 78.9% Bago (21) moxifloxacin triple MLMe MAL % 86.4% 96.7% 90.5% 5 3 CLMe ACL % 78.2% 75.8% 80.3% 13 7 Liu (29) moxifloxacin triple MAO 83.3% 83.3% Unknown ACO 19 76% 76% Unknown Kilic (35) moxifloxacin triple MAB MAE % 53.3% 66.7% 53.3% ABC ACE % 63.3% 76.7% 63.3% A, amoxicillin; B, ranitidine bismuth citrate; C, clarithromycin; E, esomeprazole; ITT, intention-to-treat; L, lansoprazole; M, moxifloxacin; Me, metronidazole; N number; O, omeprazole; PP, per-protocol; T, tinidazole for H. pylori infection are needed. The antibacterial effect of moxifloxacin, an 8-metoxyfluoroquinolone with a broad spectrum of activity, an improved coverage of Gram-positive and anaerobic bacte- 2073

6 Moxifloxacin-based triple Clarithromycin-based triple Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Random, 95% CI M-H, Random, 95% CI Bago P % 0.47 [0.21, 1.02] Kiliç % 1.21 [0.86, 1.72] Nista EC % 0.38 [0.24, 0.] Total (95% CI) % 0.61 [0., 1.48] Total events Heterogeneity: Tau² = 0.53; Chi² = 18.92, df = 2 (P < ); I² = 89% Test for overall effect: Z = 1.09 (P = 0.28) Favours experimental Favours control Figure3. Theincidenceofsideefects. Moxifloxacin-based triple Clarithromycin-based triple Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Bago P % 1.21 [1.08, 1.35] Liu % 1.10 [0.84, 1.44] Nista EC % 1.20 [1.08, 1.34] Total (95% CI) % 1.20 [1.11, 1.29] Total events Heterogeneity: Chi² = 0.43, df = 2 (P = 0.81); I² = 0% Test for overall effect: Z = 4.71 (P < ) Favours control Favours experimental Figure4. Sensitivityanalysis:eficacyonHelicobacterpylorieradication. ria (39-41), is based on the inhibition of bacterial topoisomerase II, the enzyme responsible for DNA superspiralized rolling and unrolling. Moxifloxacin is characterized by rapid absorption after oral administration with an absolute bioavailability of 89% and a wide penetration into tissues and fluids. Excretion is predominantly renal with a mean elimination half-life of 9-16 hours that allows a single daily dose. Dosage adjustment is not required for elderly patients or those with renal or mild hepatic impairment. In contrast to other fluoroquinolones, this antibacterial agent has low interactions with other drugs and a low incidence of adverse events. The most common side effects are gastrointestinal disturbances such as nausea and diarrhea (31). Moxifloxacin-based triple offers a number of advantages over clarithromycin-based triple. First and foremost, moxifloxacin-based triple appears to be more effective at eradicating H. pylori infection than clarithromycin-based triple. The present results have also shown better overall tolerance of the moxifloxacinbased triple compared to clarithromycin-based triple. In combination with the very low rate of moxifloxacin resistance among H. pylori strains, we speculate that the improved tolerability of this regimen leads to improved compliance and ultimately, greater eradication rates compared to clarithromycin-based triple. Several methodological weaknesses may limit the validity and generalizability of this meta-analysis. Initially, of the four included studies, only Bago et al (21) mentioned double blinding whereas none of the other studies mentioned this, without which it is possible to produce high performance bias and measuring bias. Of the four included studies, two of them did not mentioned allocation concealment (29, 35). This problem with allocation concealment might bring selective bias in these trials, because it was possible for those responsible for recruiting the participants to alter their assignment if allocation was concealed. The findings of the meta-analysis demonstrated a superiority of moxifloxacin-based triple over clarithromycin-based triple. However, this analysis also demonstrated statistically significant heterogeneity calling into question the validity of combining these results into a meta-analysis. The study of Kiliç et al was excluded (35) when we did sensi- 2074

7 Moxifloxacin-based triple Clarithromycin-based triple Risk Ratio Risk Ratio Study or Subgroup Events Total Events Total Weight M-H, Fixed, 95% CI M-H, Fixed, 95% CI Bago P % 0.47 [0.21, 1.02] Nista EC % 0.38 [0.24, 0.] Total (95% CI) % 0.40 [0.27, 0.] Total events Heterogeneity: Chi² = 0.18, df = 1 (P = 0.67); I² = 0% Test for overall effect: Z = 4.54 (P < ) Favours experimental Favours control Figure5. Sensitivityanalysis:theincidenceofsideefects. tivity analysis, due to the confirmation of H. pylori infection by histology alone in some subjects, combined moxifloxacin and clarithromycin in one branch, H. pylori treatment for two weeks rather than one week, and the relative lower quality. The sensitivity analysis corrected the heterogeneity and still demonstrated superiority of moxifloxacin-based. There is also the theoretical concern of publication bias in favor of new drugs. We considered the creation of a funnel plot to determine if we could identify evidence of publication bias. However, given the small number of studies included in this review, there were not enough data points to perform a funnel plot with any interpretative value. Lastly, there are no studies involving patients from North America. The studies included were conducted in Italy, Croatia, Turkey and China. It is well established that antibiotic resistance profiles of H. pylori vary among different geographical regions for which a pharmacogenomic difference could exist (11). Such resistance profiles are likely to significantly impact the efficacy of both moxifloxacin-based triple and clarithromycin-based triple (42), and thus, may limit the generalizability of these results to Africa or American populations. Therefore, we still need more high-quality, multicenter, randomized, controlled trials from other countries and regions. Conclusion In conclusion, our analysis demonstrates that moxifloxacin-based triple was more effective and did not increase the incidence of overall side effects compared to clarithromycin-based triple in the treatment of H. pylori infection. We recommend that a more highquality, multicenter, randomized, controlled trial comparing moxifloxacin-based triple and clarithromycin-based triple be performed in Americans and Africans with H. pylori infection to confirm the results of our meta-analysis, in view of the pharmacogenomic difference that might exist in different populations. However, on the basis of these results, we propose that moxifloxacin-based triple provides an effective alternative regimen to clarithromycin-based triple. Acknowledgement This study was not funded by any Pharmaceutical Company. Potential Conflict of Interest None known. References 1. Peterson WL, Fendrick AM, Cave DR, et al. Helicobacter pylorirelated disease: guidelines for testing and treatment. Arch Intern Med : , Proceedings of the American Digestive Health Foundation International Update Conference on Helicobacter pylori. McLean, Virginia, USA, February 13-16, Gastroenterology 113 (6 Suppl ): S1- S169, Parsonnet J, Hansen S, Rodriguez L, et al. Helicobacter pylori infection and gastric lymphoma. N Engl J Med 3: , Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med 347: , Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345: , Bazzoli F. Italian omeprazole triple --a 1-week regimen. Scand J Gastroenterol Suppl 215: 118, Lam SK, Talley NJ. Report of the 1997 Asia Pacific Consensus Conference on the management of Helicobacter pylori infection. J Gastroenterol Hepatol 13: 1-12, Malfertheiner P, Megraud F, O Morain C, et al. Current concepts in the management of Helicobacter pylori infection--the Maastricht Consensus Report. Aliment Pharmacol Ther 16: , Houben MH, van Beek D, Hensen EF, et al. A systematic review of Helicobacter pylori eradication --the impact of antimicrobial resistance on eradication rates. Aliment Pharmacol Ther 13: , Graham DY. Antibiotic resistance in Helicobacter pylori: implications for. Gastroenterology 115 (5): , Megraud F. H. pylori antibiotic resistance: prevalence, importance, and advances in testing. Gut 53 (9): ,

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