BMJ 2013;347:f4587 doi: 10.1136/bmj.f4587 (Published 7 August 2013)
Page 1 of 14
Research
RESEARCH Global eradication rates for Helicobacter pylori infection: systematic review and meta-analysis of sequential therapy OPEN ACCESS 12
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Luigi Gatta physician and gastroenterologist , Nimish Vakil clinical professor of medicine , Dino 4 Vaira professor of internal medicine , Carmelo Scarpignato professor of pharmacology and 2 therapeutics; associate professor of gastroenterology Gastroenterology and Endoscopy Unit, Versilia Hospital, Lido di Camaiore, Italy; 2Department of Clinical and Experimental Medicine, University of Parma, Parma, Italy; 3Department of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA; 4Department of Medical and Surgical Sciences, University of Bologna, Italy 1
Abstract Objective To do a systematic review and meta-analysis of studies comparing sequential therapy for eradication of Helicobacter pylori with pre-existing and new therapies, thus providing a glimpse of eradication success worldwide. Design Systematic review and meta-analysis. Data sources Medline, Embase, and Cochrane Central Register of Controlled Trials up to May 2013; abstract books of major European, American, and Asian gastroenterological meetings. Study selection Randomised controlled trials in previously untreated adults, in which sequential therapy was compared with a pre-existing or new therapy. Results 46 randomised controlled trials were reviewed and analysed. 5666 patients were randomised to sequential therapy and 7866 to other (established and new) treatments. The overall eradication rate of sequential therapy was 84.3% (95% confidence interval 82.1% to 86.4%). Sequential therapy was superior to seven day triple therapy (relative 2 risk 1.21, 95% confidence interval 1.17 to 1.25; I =29.3%; number needed to treat 6 , 95% confidence interval 5% to 7%), marginally superior to 2 10 day triple therapy (1.11, 1.04 to 1.19; I = 67.2%; NNT 10, 7 to 15), 2 but not superior to 14 day triple therapy (1.00, 0.94 to 1.06; I =54.3%), 2 bismuth based therapy (1.01, 0.95 to 1.06; I =21.1%), and non-bismuth 2 based therapy (0.99, 0.94 to 1.05; I =52.3%). Data on eradication according to pre-treatment antimicrobial susceptibility testing were available in eight studies, and sequential therapy was able to eradicate 72.8% (61.6% to 82.8%) of the strains resistant to clarithromycin.
Conclusions Eradication rates with pre-existing and new therapies for H pylori are suboptimal. Regional monitoring of resistance rates should help to guide treatment, and new agents for treatment need to be developed.
Introduction Helicobacter pylori infection causes peptic ulcers, gastric mucosa associated lymphoid tissue lymphoma, and gastric cancer.1 Standard treatments for H pylori infection that have been endorsed by US as well as European scientific societies and by regulatory authorities rely on clarithromycin, metronidazole, or amoxicillin in conjunction with gastric acid inhibitors.2 3 The prevalence of resistance to clarithromycin and metronidazole has increased substantially in recent years, and a corresponding decrease has occurred in the eradication rate for H pylori infection,4 which has declined to unacceptable levels in most Western countries.5 A new treatment regimen that would achieve the eradication rates of 90% or greater seen at the advent of H pylori treatment is urgently needed.5 Such a regimen would need to have high efficacy against clarithromycin resistant and metronidazole resistant strains of H pylori, as these strains are increasingly encountered in routine clinical practice. As the response to eradication therapy is significantly related to the prevalence of primary resistance in the population, the choice of a treatment regimen should be based on the knowledge of the underlying prevalence of resistant strains in the community, which needs to be monitored.
Correspondence to: L Gatta, Clinical Pharmacology and Digestive Pathophysiology Unit, Department of Clinical and Experimental Medicine, University of Parma, 43125 Parma, Italy
[email protected] Extra material supplied by the authors (see http://www.bmj.com/content/347/bmj.f4587?tab=related#webextra) Supplementary tables Supplementary figures No commercial reuse: See rights and reprints http://www.bmj.com/permissions
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BMJ 2013;347:f4587 doi: 10.1136/bmj.f4587 (Published 7 August 2013)
Page 2 of 14
RESEARCH
Sequential therapy, a new regimen administering antimicrobials in a given sequence rather than all simultaneously, has generated worldwide interest. This kind of treatment is not actually new, as it uses established drugs, all approved for eradication of H pylori. However, the administration strategy is innovative. The sequential regimen is a simple dual therapy including a proton pump inhibitor plus amoxicillin 1 g (both twice daily) given for the first five days, followed by a triple therapy including a proton pump inhibitor, clarithromycin 500 mg, and a nitroimidazole antimicrobial (all twice daily) for the remaining five days. Initial studies of sequential therapy suggested that its superiority over standard triple therapy might be due to improved eradication of clarithromycin resistant strains.6 7 Recently, several randomised controlled trials have compared sequential therapy with other established and new therapies. These provide a glimpse into eradication rates for H pylori in the countries where those studies were conducted. The aim of this study was to assess the efficacy of sequential therapy compared with other eradication regimens, by doing a systematic review and meta-analysis of randomised controlled trials.
Methods
Search strategy and study selection This meta-analysis was developed according to the PRISMA (preferred reporting items for systematic reviews and meta-analyses) statement guidelines.8 We searched the medical literature by using Medline (1950 to May 2013), Embase (1980 to May 2013), and the Cochrane Central Register of Controlled Trials (May 2013). Randomised controlled trials examining the eradication rate of sequential therapy compared with other treatments were eligible for inclusion (box). We identified eligible studies with the terms “Helicobacter pylori”, “H. pylori”, “H pylori”, “Campylobacter pylori”, “C. pylori”, “C pylori”, “infection”, “dyspepsia”, “sequential”, “triple”, “concomitant”, “quadruple”, “treatment”, “therapy”, “omeprazole”, “lansoprazole”, “rabeprazole”, “pantoprazole”, “esomeprazole”, “bismuth”, “clarithromycin”, “metronidazole”, “tinidazole”, “amoxicillin”. We imposed no language restrictions. Two investigators (LG and NV) evaluated abstracts of the papers identified by the initial search for appropriateness, independently and in a blinded manner. Foreign language papers were translated where necessary. We also searched the abstract books from the British Society of Gastroenterology (2001-12), American Gastroenterological Association (2000-13), American College of Gastroenterology (2004-12), United European Gastroenterology Week (2000-12), European Helicobacter pylori Study Group (2000-12), and Asian Pacific Digestive Week (2003-12). We used bibliographies of all relevant studies identified to do a recursive search. In addition, we contacted authors to obtain unpublished data from their studies, whenever we deemed it necessary.
Outcome assessment The primary outcome was the efficacy of sequential therapy compared with established and new therapies in eradicating H pylori infection. Secondary outcomes included safety and efficacy according to the antimicrobial resistance pattern, where reported.
Data extraction Two investigators (LG and NV) assessed articles independently, using pre-designed data extraction forms. Disagreement between investigators was resolved by discussion with the other two No commercial reuse: See rights and reprints http://www.bmj.com/permissions
investigators (DV and CS). Data on eradication were based on intention to treat analysis. In addition, the following clinical data were extracted for each trial: country of origin, type of publication (article, abstract), proton pump inhibitor used, use of tinidazole (versus other nitroimidazole derivatives), duration of comparative eradication treatment, and adverse event rate.
Evaluation of risk of bias We assessed risk of bias as described in the Cochrane handbook,9 by evaluating the random sequence generation, concealment of allocation, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other sources of bias. We considered randomised controlled trials as being at low risk of bias if all the domains except blinding of participants or personnel were properly assured. As the outcome (that is, eradication) was almost always assessed by objective means, we did not consider blinding to be crucial.
Statistical analysis We assessed data for the primary outcome by using a random effects model,10 to give a conservative estimate of the 95% confidence intervals. Results were expressed as relative risk for success of H pylori eradication and as difference in eradication rates among patients assigned to sequential therapy versus other eradication regimens. We also used a random effects model to pool data for safety,10 and expressed them as relative risk for adverse events. We required at least three comparable study groups for every comparison for randomised controlled trials to be included in the meta-analysis. We also calculated prediction intervals at 95% confidence intervals for the primary outcome, as they might be considered a more appropriate future treatment summary.11 12
We assessed heterogeneity between trials with the χ2 test for heterogeneity at a significance level of P
