Consensus statement the Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults
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CONSENSUS STATEMENT The Toronto Consensus for the Treatment of Helicobacter pylori Infection in Adults Carlo A. Fallone, 1 Naoki Chiba, 2 , 3 Sander Veldhuyzen van Zanten, 4 Lori Fischbach, 5 Javier P. Gisbert, 6 Richard H. Hunt, 3 , 7 Nicola L. Jones, 8 Craig Render, 9 Grigorios I. Leontiadis, 3 ,
Paul Moayyedi, 3 , 7 and John K. Marshall 3 ,
1 Division of Gastroenterology, McGill University Health Centre, McGill University, Montreal, Quebec, Canada; 2 Guelph GI and Surgery Clinic, Guelph, Ontario, Canada; 3 Division of Gastroenterology, McMaster University, Hamilton, Ontario, Canada; 4 Division of Gastroenterology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada; 5 Department of Epidemiology, University of Arkansas for Medical Sciences, Little Rock, Arkansas; 6 Gastroenterology Service, Hospital Universitario de la Princesa, Instituto de Investigación Sanitaria Princesa (IIS-IP) and Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; 7 Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada; 8 Division of Gastroenterology, Hepatology, and Nutrition, The Hospital for Sick Children, Departments of Paediatrics and Physiology, University of Toronto, Toronto, Ontario, Canada; and 9 Kelowna General Hospital, Kelowna, British Columbia, Canada This article has an accompanying continuing medical education activity, also eligible for MOC credit, on page e25. Learning Objective: Upon completion of this examination, successful learners will be able to establish a treatment plan for patients with H pylori infection. BACKGROUND & AIMS: Helicobacter pylori infection is increasingly dif ficult to treat. The purpose of these consensus statements is to provide a review of the literature and speci fic,
updated recommendations for eradication therapy in adults. METHODS: A systematic literature search identi fied studies on H pylori treatment. The quality of evidence and strength of recommendations were rated according to the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach. Statements were developed through an online platform, finalized, and voted on by an international working group of specialists chosen by the Canadian Asso- ciation of Gastroenterology. RESULTS: Because of increasing failure of therapy, the consensus group strongly recommends that all H pylori eradication regimens now be given for 14 days. Recommended first-line strategies include concomitant nonbismuth quadruple therapy (proton pump inhibitor [PPI] þ amoxicillin þ metronidazole þ clarithromycin [PAMC]) and traditional bismuth quadruple therapy (PPI þ bismuth þ metronidazole þ tetracycline [PBMT]). PPI triple therapy (PPI þ clarithromycin þ either amoxicillin or metronidazole) is restricted to areas with known low clari- thromycin resistance or high eradication success with these regimens. Recommended rescue therapies include PBMT and levo floxacin-containing therapy (PPI þ amoxicillin þ levo- floxacin). Rifabutin regimens should be restricted to patients who have failed to respond to at least 3 prior options. CONCLUSIONS: Optimal treatment of H pylori infection re- quires careful attention to local antibiotic resistance and eradication patterns. The quadruple therapies PAMC or PBMT should play a more prominent role in eradication of H pylori infection, and all treatments should be given for 14 days.
Keywords: Helicobacter pylori; Eradication; Resistance; Proton Pump Inhibitor; Amoxicillin; Bismuth; Clarithromycin; Metro- nidazole; Tetracycline; Levo floxacin; Rifabutin. A lthough the prevalence of H pylori is decreasing in some parts of the world, the infection remains pre- sent in 28% to 84% of subjects depending on the population tested. 1
the lowest general prevalence, 1 –4 report high proportions of infected individuals in certain communities (eg, 38% –75% of Alaskan or Canadian aboriginal populations). 2,3,5 –8 H pylori is implicated in the development of and its eradication is recommended in the treatment of duodenal or gastric ulcers, early gastric cancer, and gastric mucosa- associated lymphoid tissue lymphomas (in
4,9
–14 Treatment has been suggested for prevention of gastric cancer in high-risk individuals, 11 –13,15 as well as in patients with uninvestigated 16 and functional dyspepsia, 17 given
evidence that eradication of the infection leads to sustained improvements in symptoms in a proportion of patients. 10,16,17
The increasing prevalence of antibiotic-resistant strains of H pylori has led to reduced success with traditional H Abbreviations used in this paper: BPAL, bismuth compounds D proton pump inhibitor D amoxicillin D levofloxacin; CAG, Canadian Association of Gastroenterology; CI, con fidence interval; GRADE, Grading of Recom- mendation Assessment, Development and Evaluation; ITT, intention-to- treat; NNT, number needed to treat; PA, proton pump inhibitor D amoxi-
cillin; PAC, proton pump inhibitor D amoxicillin D clarithromycin; PAL, proton pump inhibitor D amoxicillin D levofloxacin; PAM, proton pump inhibitor D amoxicillin D metronidazole; PAMC, proton pump inhibitor D amoxicillin D metronidazole D clarithromycin; PAR, PPI D amoxicillin D rifabutin; PBMT, proton pump inhibitor D bismuth compounds D metronidazole D tetracycline; PICO, Population, Intervention, Compar- ator, Outcomes; PMC, proton pump inhibitor D metronidazole D clari- thromycin; PPI, proton pump inhibitor; RCT, randomized controlled trial; RD, risk difference. Most current article © 2016 by the AGA Institute 0016-5085/$36.00 http://dx.doi.org/10.1053/j.gastro.2016.04.006 Gastroenterology 2016;151:51 –69
pylori treatments. 18 –24 Proton pump inhibitor (PPI) triple therapies (a PPI plus two of the following antibiotics: clar- ithromycin, amoxicillin, or metronidazole) for 7 to 10 days were once standard and recommended as first-line therapy
11 –13,25
but have become increasingly ineffective, with some studies reporting eradication in less than 50% of cases. 21,22,26
–28 Suboptimal patient compliance may be another cause of treatment failure. 4,29
–31 It has been suggested that the goal of H pylori therapy should now be eradication in !90% of treated patients. 32 This arbitrary threshold is not easily achieved, especially in real-world settings. However, the most ef ficacious ther- apies available should be used first to avoid the cost, inconvenience, and risks associated with treatment failure. Some of the more common regimens for H pylori eradi- cation include bismuth quadruple therapy (PPI þ bismuth compounds þ metronidazole þ tetracycline [PBMT]), non- bismuth quadruple therapy (concomitant [PPI þ
þ metronidazole þ clarithromycin {PAMC}] or sequential [PPI þ amoxicillin {PA} followed by PPI þ metronidazole þ clarithromycin {PMC}]), PPI triple therapy (PPI
þ amoxicillin þ clarithromycin [PAC], PMC, or PPI þ amoxicillin þ metronidazole [PAM]), and quinolone- containing regimens (PPI þ amoxicillin þ levofloxacin [PAL]). De finitions of these and other regimens discussed in this consensus paper are shown in Table 1 , with suggested doses listed in Table 2
. The increasing prevalence of antibiotic-resistant strains and evidence of more frequent failures of triple therapies suggest the need for more effective therapies given for a longer duration (14 days instead of 10 or 7 days) than were recommended in prior consensus statements. 11,12 For this
reason, as well as the existence of new therapies, the Canadian Association of Gastroenterology (CAG) and the Canadian Helicobacter Study Group determined that an update was needed. The purpose of this consensus process was to systematically review the literature relating to the management of H pylori infection and to provide speci fic, updated recommendations for eradication therapy in adults. This consensus was limited to adults, because updated pediatric recommendations are currently in prog- ress from the European Society for Paediatric Gastroenter- ology, Hepatology and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology and Nutrition. Methods Scope and Purpose The consensus development process was initiated in the summer of 2013 with the first meeting of the steering com- mittee and lasted approximately 2 years, with the meeting of the full consensus group taking place in June 2015. Sources and Searches The Editorial Of fice of the Cochrane Upper Gastrointestinal and Pancreatic Diseases Group at McMaster University Table 1.Recommendations for Regimens Used for the Eradication of H pylori Recommendation Regimen
De finition (see dose table) First line Recommended option Bismuth quadruple (PBMT) PPI þ bismuth þ metronidazole a þ tetracycline Recommended option
Concomitant nonbismuth quadruple (PAMC) PPI
þ amoxicillin þ metronidazole a þ clarithromycin Restricted option b PPI triple (PAC, PMC, or PAM) PPI þ amoxicillin þ clarithromycin PPI þ metronidazole a þ clarithromycin PPI þ amoxicillin þ metronidazole a Not recommended Levo floxacin triple (PAL) PPI þ amoxicillin þ levofloxacin Not recommended Sequential nonbismuth quadruple (PA followed by PMC) PPI
þ amoxicillin followed by PPI þ metronidazole a þ clarithromycin Prior treatment failure Recommended option Bismuth quadruple (PBMT) PPI þ bismuth þ metronidazole a þ tetracycline Recommended option
Levo floxacin-containing therapy (usually PAL) PPI
þ amoxicillin þ levofloxacin c Restricted option d Rifabutin-containing therapy (usually PAR) PPI þ amoxicillin þ rifabutin Not recommended Sequential nonbismuth quadruple therapy (PA followed by PMC) PPI
þ amoxicillin followed by PPI þ metronidazole a þ clarithromycin Undetermined Concomitant nonbismuth quadruple therapy (PAMC) PPI
þ amoxicillin þ metronidazole a þ clarithromycin a Tinidazole may be substituted for metronidazole. b Restricted to areas with known low clarithromycin resistance ( <15%) or proven high local eradication rates (>85%) (see statement 5). c There is some evidence that adding bismuth to this combination may improve outcomes. d Restricted to cases in which at least 3 recommended options have failed (see statement 13). 52 Fallone et al Gastroenterology Vol. 151, No. 1 performed a systematic literature search of the Cochrane Reg- ister, MEDLINE, EMBASE, and CENTRAL for trials published from January 2008 to December 2013. The main focus of all literature searches was to identify data on cure rates of H pylori infection. We did not systematically search the literature before 2008 because we did not want older data, where higher erad- ication success rates were likely a result of lower antibiotic resistance, to confound newer data. Key search terms were Helicobacter pylori, eradication, bismuth, clarithromycin, metronidazole, amoxicillin, levo floxacin, tetracycline, and rifa- butin, among others, to address each of the statements. Search strategies were limited to the English language and human studies, and further details are provided in Supplementary Appendix 1 . A formal systematic review was performed for every statement. This included a literature search and, as described in more detail in the following text, a review of the citations to identify potentially relevant articles, review of selected full-text articles to identify articles that satis fied the predefined PICO components (Population, Intervention, Comparator, Outcomes), a risk-of-bias assessment, and at least a qualitative synthesis of evidence presented formally to the panel members verbally and/or with slide presentations at the face-to-face meeting. The panel also had access to the entire text of all the selected ar- ticles should they choose to refer to it. The literature search produced 2943 citations; after removal of duplicates, 2373 citations remained. These citations were sorted into three separate lists: (1) results enriched with randomized controlled trials (RCTs), systematic reviews/meta- analyses, and practice guidelines (1509 citations); (2) results enriched with Canadian studies (an additional 13 citations); and (3) the remaining 851 citations. Additional focused, updated searches up to June 2015 were conducted for pre- sentation at the consensus meeting. In the absence of updated systematic reviews or meta-analyses on a speci fic treatment, a meta-analysis was performed for this consensus when suf fi- cient data were available. When a recent well-done meta- analysis was found, a literature review was also performed to see if more current data altered the results and conclusions. Review and Assessment of Evidence Two nonvoting methodologists (GIL and PM) assessed the quality (certainty) of evidence using the Grading of Recom- mendation Assessment, Development and Evaluation (GRADE) method. 33
dividual studies and overall across studies), indirectness, inconsistency, imprecision, and other considerations (including publication bias) to determine the overall quality of evidence for each statement. GRADE assessments were then reviewed and agreed on by voting members of the consensus group at the meeting.
The quality of evidence for each statement was graded as high, moderate, low, or very low, as described in GRADE 33,34 and prior CAG consensus documents. 35,36 Approved product labeling from government regulatory agencies varies from country to country; although not ignored, recommendations are based on evidence from the literature and consensus discussion and may not fully re flect the product labeling for a given country. Consensus Process The consensus group was composed of 8 voting members (5 participants and 3 steering committee members), including gastroenterologists, clinical epidemiologists (one of whom was not a gastroenterologist), and microbiologists from Canada, the United States, and Europe with expertise in managing H pylori infection. There was representation from a pediatric and com- munity, nonacademic gastroenterologist (not an H pylori expert), and there was a nonvoting moderator for the meeting (Dr John K. Marshall). Although there was no primary care representative, the impact of the recommendations on primary care physicians, as well as community resources and local availability, was discussed before voting for each statement. Before the 2-day consensus meeting was held in Toronto, Ontario, Canada, in June 2015, CAG facilitated the majority of the consensus process through the use of a web-based consensus Table 2.Recommendations for Dose of Agents Used in H pylori Eradication Therapies Doses for agents in bismuth quadruple therapy Bismuth X mg
a QID
b Metronidazole 500 mg TID to QID c PPI
Y mg d BID Tetracycline 500 mg
QID Doses for agents in all regimens other than bismuth quadruple therapy (includes PPI triple, concomitant and sequential nonbismuth quadruple, levo floxacin, and rifabutin therapies) Amoxicillin 1000 mg BID
Clarithromycin 500 mg
BID Levo
floxacin 500 mg
QD e Metronidazole 500 mg BID
PPI Y mg
d BID
Rifabutin 150 mg
BID NOTE. These are the doses in North America; they may vary in different parts of the world (eg, 400 mg of metronidazole or 200 mg of clarithromycin may be the preferred doses in parts of Europe and Asia, respectively). QID, 4 times a day; TID, 3 times daily; BID, twice daily; QD, once daily. a The dose depends on the formulation used. In clinical trials, the most common doses were as follows: bismuth subsa- licylate (262 mg), 2 tablets QID; colloidal bismuth subcitrate (120 mg), 2 tablets BID or 1 tablet QID; bismuth biskalcitrate (140 mg), 3 tablets QID; Pylera (Aptalis Pharma US, Inc) (the combination pill; bismuth subcitrate potassium; 140 mg), 3 tablets QID. b Studies (from China) have suggested that giving double the dose of bismuth twice daily is also effective. 62 c Good evidence for QID dosing of metronidazole is lacking; however, some members of the consensus group suggested that a QID regimen may help simplify dosing for patients (400 mg QID dosing for metronidazole would also be acceptable in countries where a 400-mg dose is available). d The dose depends on the PPI used. Standard doses are esomeprazole 20 mg, lansoprazole 30 mg, omeprazole 20 mg, pantoprazole 40 mg, and rabeprazole 20 mg (see statement 8 for discussion of high-dose PPI use). In fact, in many countries, double doses (eg, esomeprazole 40 mg BID) are more commonly used (vs standard doses). Although ev- idence is lacking, the presumed dose for dexlansoprazole is either 30 mg or 60 mg. e In clinical trials, eradication appears to be similar in studies that use levo floxacin 250 mg BID or 500 mg QD dosing. 138 July 2016 Toronto Consensus for H pylori Treatment 53
platform (ECD Solutions, Atlanta, GA). The steering committee (CAF, NC, SVvZ) developed the initial statements using PICO components of the underlying research question for each state- ment (eg, for statement 3, the PICO components were as follows: population, patients with H pylori infection who have not un- dergone previous eradication attempts; intervention, traditional bismuth quadruple therapy for 14 days; comparator, any other individual eradication therapy [standard triple, sequential, concomitant, levo floxacin-based triple, and so on] or compared with a standard threshold for ef ficacy [eg, >80% intention-to- treat {ITT} eradication rate] and safety; outcomes, ITT eradica- tion rate and safety). They then reviewed the literature search results for every statement (each article reviewed by at least 2 people) through the web-based platform and “tagged” (selected and linked) all relevant references to a speci fic statement. Only one member was required to tag a reference for it to remain linked to the statement. Subsequently, the tagged references were again assessed by the steering committee; when a meta-analysis (of suf ficient quality) was tagged to a statement, any tagged study that was already included in the meta-analysis was removed from that particular statement. Any studies performed after the meta- analysis remained tagged and were used to determine if the more current data altered the results or conclusions of the meta- analysis. At the end of this process, 116 papers were selected and uploaded onto the online platform. All members of the consensus group had access to complete copies of the “tagged”
references. The entire consensus group then voted anonymously on their level of agreement with the speci fic statements using a modi
fied Delphi process. 37,38
Two subsequent iterations of the statements that incorporated suggested changes from the group followed, after which the statements were finalized at the live meeting. At the 2-day face-to-face meeting, the methodologists, epi- demiologists, and other members of the panel who had con- ducted systematic reviews or meta-analyses for the conference presented, for each statement, a summary of data from existing meta-analyses from the literature as well as the systematic reviews or meta-analyses conducted for that statement. The Yüklə 0,75 Mb. Dostları ilə paylaş:
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