| BackgroundHelicobacter pylori(H pylori) is a spiral, microaerophilic Gram negative bacterium. Dyspepsia, gastritis, peptic ulcer disease, gastric mucosa associated lymphoid tissue lymphoma(MALT), and gastric cancer have been proved to associated with H pylori. Besides, H pylori is a potentially curable cause of a diverse spectrum of diseases, including haematological disorders, cardiovascular diseases, as well as neurological disorders. On a global scale, H pylori is one of the most infectious human pathogens. H pylori had been classified as group I carcinogen by the International Agency for Research on Cancer in 1994.In order to effectively cure H pylori, different countries and regions have developed many treatment regimens. European guidelines on the management of H pylori infection in the early 2000’s recommended a “standard triple therapy” composed of a proton pump inhibitor(PPI) plus clarithromycin, together with amoxicillin or metronidazole. “Ranitidine bismuth citrate-based triple therapy” including ranitidine bismuth citrate together with any two of amoxicillin, clarithromycin and metronidazole has proved to have similar efficacy as the standard triple therapy, and was also studied by some studies. However, in less than a decade, the effectiveness of the most commonly recommended therapies declined to unacceptably low levels of less than 70% according to some studies, mainly due to the development of resistance to antibiotics, the occurrence of adverse events(AEs) and the decline of the compliance.Treatment regimens have been evolving to find the most effective therapeuticapproaches, which including sequential therapy(5-day of a PPI plus amoxicillin followed by 5 additional days of a PPI plus clarithromycin and a 5-nitroimidazole or amoxicillin), bismuth-based quadruple therapy(bismuth, PPI and two antibiotics), non-bismuth-containing quadruple therapy with a PPI and three different antibiotics, levofloxacin-based triple therapy(PPI, levofloxacin and one antibiotic), probiotic-supplemented triple therapy and a novel hybrid therapy(a dual therapy with a PPI and amoxicillin for 7 days, followed by a concomitant quadruple therapy with a PPI, amoxicillin, clarithromycin and 5-nitroimidazole for another 7 days).Durations of the treatment regimens are also various. The standard triple therapy, ranitidine bismuth citrate-based triple therapy, bismuth-based quadruple therapy, concomitant therapy, levofloxacin-based triple therapy and probiotic-supplemented triple therapy can be used for 7 days, and can be extended to 10 days or 14 days. The sequential therapy is generally used for 10 days and can be extended to 14 days. The hybrid therapy is commonly used for 14 days. According to previous studies, durations of therapies may affect their efficacy.Many therapeutic approaches have been developed. However, it is unknown which eradication treatments are more effective and also tolerable. In the conventional meta-analysis approach, only direct comparisons between regimens are possible where these have been reported in studies. This limits any conclusion about the relative efficacy and tolerance of treatments that have not been directly compared in existing studies. Network meta-analyses contain both direct and indirect comparisons in terms of efficacy across treatments, providing that a common comparator exists. With this method, we can also calculate the absolute rates and relative ranks of different eradication treatments, maximize clinical efficacy, and reduce treatment costs and AEs. In this study, we aim to use network meta-analysis method to compare the efficacy and tolerance among different eradication therapies for the treatment of H pylori infection, and provide evidences with high quality for clinical practice and decision.Objectives(1) To compare the efficacy of different eradication treatments, according to ITT analysis;(2) To compare the tolerance of different eradication treatments, including the occurrence of total AEs and each kind of AE.MethodsCochrane Library, Pub Med, and Embase were searched. Comparisons were made among the following eradication regimens: 7-day standard triple therapy, 10/14-day standard triple therapy, 7-day ranitidine bismuth citrate-based triple therapy, 10/14-day ranitidine bismuth citrate-based triple therapy, 7-day bismuth-based quadruple therapy, 10/14-day bismuth-based quadruple therapy, 7-day levofloxacin-based triple therapy, 10/14-day levofloxacin-based triple therapy, 7-day probiotic-supplemented triple therapy, 10/14-day probiotic-supplemented triple therapy, 7-day concomitant therapy, 10/14-day concomitant therapy, 10/14-day sequential therapy and 14-day hybrid therapy. Only full text reports of randomised controlled trials(RCTs) were included.The mean/median age of H pylori patients was over 18 years. Patients had not received previous treatment for eradication of H pylori. Patients should not have comorbidities like renal failure, cancer etc.The primary outcome of this study was the efficacy of each eradication therapy, according to ITT analysis. The secondary outcome was the tolerance analysis, including the occurrence of AEs in each eradication therapy. Quality of evidence was assessed using both Jadad scale and the Cochrane Collaboration’s tool for evaluating study bias. Cochrane Collaboration review manager software 5.3 and Meta Analyst 3.13 were used for traditional meta-analyses. Summary effect sizes in using traditional meta-analyses were calculated as relative risks(RRs) with 95% confidence intervals(CIs). A random-effects model, that accounted for both within- and between-study variability and provided more conservative estimated effects, was applied. Heterogeneity among studies was evaluated using the Cochran’s Q test and the I2 index statistic. Win BUGS1.4.3 and Stata 11.0 were used for network meta-analyses. Summary effect sizes in using network meta-analyses were calculated as RRs with 95% credible intervals(Cr Is). Using network meta-analyses, the absolute rates and the ranks of different eradication therapies were also calculated in order to summarize the efficacy and tolerance of all therapies. A random-effects model, that provides more conservative estimated effects, was applied in the network meta-analysis. For the primary outcome, country-specific subgroup network meta-analyses were performed based on different countries if five or more studies were available for a country. Meta-regression analyses were used for the primary outcome by adding pre-specified covariates(age, Jadad scores, sex ratio, and the observation intervals) to the network meta-analysis model. For the primary outcome, differences between direct and indirect estimates were calculated using a loop specific method. Sensitivity analyses were adopted for the primary outcome according to the following pre-specified variables: publication year, quality of included studies and sample size. Publication bias was also tested using funnel plots.Results(1) Study characteristics and quality assessment: 143 studies were included. In total, 32056 patients contributed to the efficacy analysis. The average age of H pylori patients was 47 years and approximately 53% of participants were male. Only 58% of the included studies present the details about the generation of randomization sequence. There are only 42% of the included studies present the details about the allocation concealment, and only 9.8% of the included studies mentioned using double blind methods. Some studies did not mention the number of people who were loss to follow-up and their reasons.(2) Treatment efficacy:(1) Traditional pairwise meta-analysis results: for the efficacy outcome, the pairwise meta-analysis estimations indicated that 7-day concomitant therapy, 10/14-day sequential therapy, 10/14-day standard triple therapy, 10/14-day bismuth-based quadruple therapy, 7-day probiotic-supplemented triple therapy and 7-day ranitidine bismuth citrate-based triple therapy were more effective than 7-day standard triple therapy; 10/14-day concomitant therapy, 10/14-day levofloxacin-based triple therapy, 10/14-day sequential therapy and 10/14-day probiotic-supplemented triple therapy were more effective than 10/14-day standard triple therapy; 10/14-day bismuth-based quadruple therapy were more effective than 7-day bismuth-based quadruple therapy; 10/14-day probiotic-supplemented triple therapy were more effective than 10/14-day bismuth-based quadruple therapy; 10/14-day levofloxacin-based triple therapy were more effective than 10/14-day probiotic-supplemented triple therapy.(2) Network meta-analysis results: the network meta-analysis estimations indicated most therapies were better than the previously recommended 7-day standard triple therapy, the two exceptions being the 7-day levofloxacin-based triple therapy and 7-day bismuth-based quadruple therapy, which were comparable to 7-day standard triple therapy. In the comparisons between 7-day therapies and 10/14-day therapies, longer treatments in most cases were better. For the concomitant treatments and ranitidine bismuth citrate based triple treatments, the efficacy of the shorter treatments was comparable to that of the longer treatments. Absolute effects results of the eradication rates indicated that of 7-day concomitant therapy(eradication rate: 94%, 95%Cr I: 89%-98%) was the best, followed by 10/14-day concomitant therapy(eradication rate: 91%, 95%Cr I: 87%-94%), 10/14-day probiotic-supplemented triple therapy(eradication rate: 90%, 95%Cr I: 85%-94%), 10/14-day levofloxacin-based triple therapy(eradication rate: 90%, 95%Cr I: 84%-94%), 14-day hybrid therapy(eradication rate: 89%, 95%Cr I: 81%-94%), 10/14-day sequential therapy(eradication rate: 87%, 95%Cr I: 85%-90%), 10/14-day ranitidine bismuth citrate-based triple therapy(eradication rate: 86%, 95%Cr I: 78%-91%) and 10/14-day bismuth-based quadruple therapy(eradication rate: 85%, 95%Cr I: 82%-89%). According to ITT analysis, the eradication rate of 7-day standard triple therapy(eradication rate: 73%, 95%Cr I: 71%-75%) was the lowest. The relative ranks’ results were the same with the ranks of absolute effects results.(3) Tolerance of therapies: according to the results of the network meta-analysis, all therapies were considered tolerable. Generally, the shorter the therapy time was, the lower the likelihood was for AEs. In our network meta-analysis comparisons, 7-day probiotic-supplemented triple therapy(total AE occurrence: 14%, 95%Cr I: 9%-20%) and 7-day levofloxacin-based triple therapy(total AE occurrence: 15%, 95%Cr I: 10%-21%) were significantly better than 7-day standard triple therapy. These two kinds of therapies ranked the best in terms of tolerance. Common AEs are epigastric or abdominal pain, taste alteration, headaches with or without vomiting and diarrhea. Most comparisons did not reach statistical significance considering these AEs.(4) Network assumptions, sensitivity analysis, and publication bias: the meta-regression with efficacy outcomes indicated that age, sex ratio, Jadad score, and the observation interval between the end of eradication therapy and the time of confirming H pylori eradication did not lead to significant changes in the results. Sensitivity analyses of the publication year and the risks of bias of the included studies did not show any major change in the primary outcome. In the subgroup network meta-analysis, the efficacies of regimens differ by geographic locations. By visual inspection of funnel plots for the primary outcomes, we did not find distinct asymmetry.ConclusionsThis study used network meta-analysis method to study the efficacy and tolerance of different H pylori eradication therapies for the first time. In addition, it established a relative rank of the regimens according to their efficacy and tolerance. This comprehensive network meta-analysis showed that the previously widely used 7-day standard triple therapy, though effective, was out-performed in effectiveness by most other treatments. Therapies such as the concomitant therapy, the 10/14-day probiotic-supplemented triple therapy, 10/14-day levofloxacin-based triple therapy, 14-day hybrid therapy and the 10/14-day sequential therapy might be optimal alternatives. Prolonging the duration of therapies above 7 days appears to significantly enhance eradication rates and may increase AEs. However, different regions are likely to have different features of H pylori resistance to antibiotics and findings from the smaller number of studies that have examined these apparently more effective treatments may not apply to different locations. H pylori eradication was more frequently studied in regions such as China, South Korea, Southern Europe and the Middle-East, with relatively few in other areas. Therefore, more well-designed RCTs in different countries, with large sample sizes and that include antibiotic resistance tests are crucial to enable assessment of these varying treatments. |
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