Marys Medicine

Helicobacter pylori eradication with a capsule containing bismuth subcitrate potassium, metronidazole, and tetracycline given with omeprazole versus clarithromycin-based triple therapy: a randomised, open-label, non-inferiority, phase 3 trial

Helicobacter pylori eradication with a capsule containing
bismuth subcitrate potassium, metronidazole, and
tetracycline given with omeprazole versus
clarithromycin-based triple therapy: a randomised,
open-label, non-inferiority, phase 3 trial

Peter Malfertheiner, Franco Bazzoli, Jean-Charles Delchier, Krysztof Celiñski, Monique Giguère, Marc Rivière, Francis Mégraud, for the Pylera Study Group Summary
Background Helicobacter pylori
is associated with benign and malignant diseases of the upper gastrointestinal tract, Lancet 2011; 377: 905–13
and increasing antibiotic resistance has made alternative treatments necessary. Our aim was to assess the effi

cacy and Published Online
safety of a new, single-capsule treatment versus the gold standard for H pylori eradication.
Methods We did a randomised, open-label, non-inferiority, phase 3 trial in 39 sites in Europe, comparing the effi
cacy See Comment page 877
and safety of 10 days of quadruple therapy with omeprazole plus a single three-in-one capsule containing bismuth
subcitrate potassium, metronidazole, and tetracycline (quadruple therapy) versus 7 days of omeprazole, amoxicillin, Gastroenterologie, Hepatologie

und Infektiologie, Otto-von-
and clarithromycin (standard therapy) in adults with recorded H pylori infection. Patients were randomly assigned Guericke-Universtität,
treatment according to a predetermined list independently generated by Quintiles Canada (Ville St-Laurent, QC, Magdeburg, Germany

Canada). Our study was designed as a non-inferiority trial but was powered to detect superiority. Our primary outcome (Prof P Malfertheiner MD);
was H pylori
eradication, established by two negative ¹³C urea breath tests at a minimum of 28 and 56 days after the Department of Clinical
Medicine, University of
end of treatment. Our assessment for non-inferiority was in the per-protocol population, with subsequent assessment Bologna, Bologna, Italy
for superiority in the intention-to-treat population (ie, all participants randomly assigned treatment). This study is
(Prof F Bazzoli MD); AP-HP,
registered with ClinicalTrials.gov, number NCT00669955.

Groupe Hospitalier
Henri Mondor, Service
d'Hépatogastroentérologie et

Findings 12 participants were lost to follow-up and 101 were excluded from the per-protocol analysis. In the per- Centre d'Investigation
protocol population (n=339), the lower bound of the CI for treatment with quadruple therapy was greater than the Clinique 006, Créteil, France
pre-established non-inferiority margin of –10% (95% CI 15·1–32·3; p<0·0001). In the intention-to-treat population
(Prof J-C Delchier MD);
Department of
(n=440), eradication rates were 80% (174 of 218 participants) in the quadruple therapy group versus 55% (123 of 222) Gastroenterology, Medical
in the standard therapy group (p<0·0001). Safety profi les for both treatments were similar; main adverse events were University of Lublin, Lublin,
gastrointestinal and CNS disorders.

Poland (Prof K Celiñski MD);
Axcan Pharma Inc,
Mont-Saint-Hilaire, QC, Canada

Interpretation Quadruple therapy should be considered for fi rst-line treatment in view of the rising prevalence of (M Giguère PhD, M Rivière MD);
clarithromycin-resistant H pylori, especially since quadruple therapy provides superior eradication with similar safety and INSERM U853, Université
and tolerability to standard therapy.

Victor Segalen Bordeaux 2,
Bordeaux, France
(Prof F Mégraud MD)
Funding Axcan Pharma Inc.
Correspondence to:Prof Peter Malfertheiner, Conference,4 treatment with omeprazole—a proton Otto-von-Guericke-Universtität, Infection with Helicobacter pylori is a substantial public pump inhibitor (PPI)—and a combination of amoxicillin Magdeburg 39120, Germany
health problem1 that aff ects 20–50% of people in and clarithromycin (standard therapy) is recommended peter.malfertheiner@med.
industrialised nations and up to 80% in less-developed as fi rst-line therapy if clarithromycin resistance is 20% countries.2,3 H pylori is associated with many gastro- or less. Bismuth-containing therapy is proposed in duodenal disorders, including peptic ulcer disease, regions with high in-vitro resistance to clarithromycin gastric carcinoma, and gastric mucosa-associated or metro nidazole, because the addition of bismuth to lymphoid tissue lymphoma.2–4 In regions with high other antibiotic regimens has been shown to improve incidence of gastric carcinoma, eradication of H pylori is H pylori eradication.4,9advocated to prevent the development of this disease.5–7 A previous international study,10 which assessed the Further, patients benefi t from eradication after endoscopic cacy and safety of 10 days of omeprazole with a single resection of early gastric carcinoma because it reduces (three-in-one) capsule containing bismuth subcitrate the risk for metachronous gastric neoplasia.8 potassium, metronidazole, and tetracycline (quadruple In all international guidelines,5–7 including European therapy) for H pylori eradication in patients with peptic guidelines from the Third Maastricht Consensus ulcer disease or non-ulcer dyspepsia, reported overall www.thelancet.com Vol 377 March 12, 2011
eradication rates greater than 90%. This fi nding was boards or committees. Our study was done in accordance corroborated by a North American study,11 which with the principles of the Declaration of Helsinki and compared 10 days of this quadruple formulation with International Conference on Harmonisation of Technical 10 days of standard therapy in patients with peptic ulcer Requirements for Registration of Pharmaceuticals for disease; H pylori eradication rates were 88% for quadruple Human Use guidelines for Good Clinical Practice.
therapy and 83% for standard therapy. Quadruple therapy
eradicated 92% of in-vitro metronidazole-sensitive and Procedure
80% of metronidazole-resistant strains, whereas standard
We screened participants up to 1 month before they were therapy eradicated 92% of clarithromycin-sensitive randomly assigned treatment. Eligible patients who had H pylori but did not eradicate the organism in 78% of not been treated with contraindicated drugs underwent a patients infected with strains resistant to clarithromycin urea breath test during their fi rst visit; patients who had in vitro. Antimicrobial resistance rates have increased been treated with contraindicated drugs were allowed a since these trials,12,13 and treatments for H pylori need 2-week washout before the breath test. All patients with assessment. Accordingly, European health authorities positive breath tests underwent endoscopy of the upper have requested that quadruple therapy be compared with gastrointestinal tract and six biopsies (four from pyloric standard therapy (the gold standard) for 7 days in a antrum; two from the gastric body). Antral biopsy clinical trial for registration purposes. We aimed to assess specimens were submitted for rapid urease test, histology, cacy and safety of quadruple therapy for 10 days versus and centralised microbiology (ie, done in one laboratory), standard therapy given for 7 days for the eradication of including culture and testing for metronidazole and H pylori. Special attention has been directed to pre- clarithromycin resistance. Patients had to be positive for therapeutic H pylori resistance to clarithromycin and H pylori by both urea breath test and rapid urease test, metronidazole and the eff ect of resistance on the effi cacy and with one confi rmatory test (histology, culture, or of treatment.
PCR [amendment to protocol]) for participation. Sensitivity testing was by Etest (AB Biodisk, Solna, Sweden). Clarithromycin resistance was defi ned as a minimum inhibitory concentration (MIC) of 1·00 μg/mL Our trial was done at 39 sites in France, Germany, or greater, intermediate resistance was defi ned as Ireland, Italy, Poland, Spain, and the UK, between 0·25 μg/mL to less than 1·00 μg/mL, and sensitivity was June 11, 2008, and June 22, 2009; it was a randomised, defi ned as less than 0·25 μg/mL. Metronidazole open-label (technicians unaware of study drug allocation), resistance was defi ned as MIC greater than 8 μg/mL and non-inferiority, phase 3 trial. Eligible patients were aged sensitivity as 8 μg/mL or less.
18 years or older with confi rmed H pylori and upper Patients were randomly assigned (1:1) quadruple or gastrointestinal symptoms. Women were eligible if they standard therapy according to a predetermined list were not pregnant or nursing, and if they were of child- supplied to each site. The sponsor recruited sites and bearing potential they were required to use medically generated the randomisation schedule through a third acceptable contraception for the duration of the study party (Quintiles Canada, Ville St-Laurent, QC, Canada) and 30 days thereafter. Patients were excluded if they had without accessing or infl uencing the randomisation previously used antibiotics to eradicate adequately lists; this process also masked treatment allocation recorded infection with H pylori, contraindications to from the investigators.
study drugs, substantial organ impairment, severe or Study drugs were proprietary three-in-one capsules unstable cardiopulmonary or endocrine disease, containing 140 mg bismuth subcitrate potassium, undergone surgery of the upper gastrointestinal tract, 125 mg metronidazole, and 125 mg tetracycline evidence of bleeding or iron-defi ciency anaemia, Barrett's hydrochloride (Axcan Pharma, Mont-Saint-Hilaire, QC, oesophagus or high-grade dysplasia, dysphagia, or history Canada); 500 mg clarithromycin capsules (Abbott, of malignancy. Patients were excluded if they had history Abbott Park, IL, USA); 500 mg amoxicillin capsules of drug or alcohol misuse within 1 year of the trial, or (GlaxoSmithKline, Brentford, Middlesex, UK); and continuously used antiulcer drugs (including PPIs 20 mg omeprazole capsules (AstraZeneca, LP, during the 2 weeks before the ¹³C urea breath test), Wilmington, DE, USA). In the 10-day quadruple antibiotics or bismuth compounds (more than three regimen, three three-in-one capsules were taken four-times per week, 1 month before screening), systemic times daily (after meals and at bedtime), and swallowed glucocorticoids, non-steroidal anti-infl ammatory drugs, whole with 250 mL of water. An omeprazole capsule or anticoagulation or platelet aggregation inhibitors was taken with the three single three-in-one capsules (except acetylsalicylic acid ≤100 mg per day).
after morning and evening meals. In the 7-day standard Written informed consent was obtained from all regimen, omeprazole, amoxicillin, and clarithromycin patients before enrolment. Our protocol and one capsules were taken twice daily (before morning and amendment were approved by investigators' research evening meals). Patients were asked to refrain from ethics, investigational review, or independent ethics consuming alcohol during the entire treatment period www.thelancet.com Vol 377 March 12, 2011
724 individuals assessed for eligibility 236 did not meet inclusion criteria 18 refused to participate30 excluded for other reasons 440 randomly assigned to treatment groups 218 assigned quadruple therapy (2 did not 222 assigned standard therapy receive treatment) 14 did not complete the study 27 did not complete the study 5 lost to follow-up 7 lost to follow-up 1 serious adverse event 2 withdrew consent 1 serious adverse event 1 violation of exclusion criteria 3 withdrew consent 1 protocol violation 1 violation of inclusion criteria 3 violations of exclusion criteria3 protocol violations1 investigator/sponsor judgment3 other 218 in the intention-to-treat population 222 in the intention-to-treat population 40 excluded from the per-protocol analysis 61 excluded from the per-protocol analysis 9 violations of inclusion or exclusion criteria 6 compliance not 80–120% 8 violations of inclusion or exclusion criteria 4 prohibited drugs 10 compliance not 80–120% 21 missing UBTs at weeks 6 or 10 8 prohibited drugs 33 missing UBTs at weeks 6 or 10 178 in the per-protocol population 161 in the per-protocol population Figure: Trial profi le
Quadruple therapy is omeprazole, bismuth, metronidazole, and tetracycline. Standard therapy is omeprazole, amoxicillin, and clarithromycin.
UBT=¹³C urea breath test.
and for 48 h after the last dose, and not to take the study patients in the quadruple therapy group) within 1 week of drugs with milk, other dairy products, or antacids. Two the end of trial. Patients were instructed to return all combination tablets (200 mg aluminium hydroxide, drug containers at the end of trial visit to assess 200 mg magnesium hydroxide, and 25 mg simeticone; compliance. Patients returned for the fi rst follow-up visit Sanofi -Aventis, Paris, France) could be taken as rescue about 6 weeks after the start of treatment, but not before medication up to four-times daily.
28 days after the end of trial. Participants were re- cacy outcome was H pylori eradication, examined and reassessed with a second urea breath test established by two negative urea breath tests at least 28 and routine laboratory studies. Breath tests were also and 56 days after the end of treatment (week 6 and done on all patients who did not complete their full week 10 visits). Secondary objectives were to compare course of therapy. Patients with a positive breath test at eradication as a function of antibiotic resistance and the fi rst follow-up underwent repeat endoscopy with disease or disorder (non-ulcer dyspepsia, peptic ulcer biopsies for reassessment of antibiotic resistance. If the disease); monitor safety through adverse events, results of the breath test were negative, the patient was laboratory abnormalities, and plasma bismuth scheduled for the end of study visit about 10 weeks after concentrations at baseline, end of treatment, and end of treatment onset, when a third set of breath test, routine study; and assess compliance through pill count.
examination, and clinical laboratory procedures Patients returned for repeat examination and laboratory (including serum pregnancy testing for women of studies (including measurement of plasma bismuth in childbearing potential) was done.
www.thelancet.com Vol 377 March 12, 2011
assessed with the Cochran-Mantel-Haenszel test adjusted OBMT (N=216)
OAC (N=222)
for pooled sites (sites [within each country] or countries with <12 intention-to-treat patients were incorporated into pooled sites). Eradication was confi rmed with negative urea breath tests at both the week 6 and week 10 Median (minimum, maximum) visits. A positive breath test at week 6 suggested that treatment had failed; these patients were classifi ed as non-eradicated. Per-protocol patients did not need imputation of missing test results; both week 6 and week 10 assessments needed to be available for patients whose week 6 breath test was negative. In the event of Body-mass index (kg/m2) missing intention-to-treat assessments, non-eradicated was imputed for missing (or done outside the allocated Median (minimum, maximum) timeframe) breath test values. All other results were Present or past history of peptic ulcers assessed on an observed-case basis.
The per-protocol population was used to assess primary cacy. The primary analysis (comparing non-inferiority ¹³C urea breath test of the two drug combinations) was assessed through Helicobacter pylori positive hypothesis testing and derivation of a two-sided 95% CI with an asymptotic normal approximation procedure H pylori negative with continuity correction. If the lower bound of this CI Rapid urease test exceeded –10%, non-inferiority of quadruple versus H pylori positive standard therapy could be concluded. If the lower bound H pylori negative was –10% or lower non-inferiority was not supported. If the non-inferiority of quadruple over standard therapy H pylori positive was concluded with the per-protocol population, the H pylori negative same CI was derived with the intention-to-treat population. If the lower bound of this CI was greater H pylori positive than zero, superiority of quadruple over standard therapy H pylori negative could be concluded. If the urea breath tests were missing Data are n (%) unless otherwise indicated. OBMT is omeprazole, bismuth, for week 6, week 10, or both, non-eradication was metronidazole, and tetracycline. OAC is omeprazole, amoxicillin, and assumed for this component of the analysis. Sensitivity clarithromycin. *Percentages based on number of patients with available data.
analyses were done with the intention-to-treat population Table 1: Baseline characteristics in the treated population
without imputed data.
Two post-hoc analyses were done: the fi rst used a diff erent defi nition of eradication (one or more negative Our hypotheses for sample size calculations were based urea breath tests at the week 6 or week 10 visit, provided on previously documented H pylori antibiotic-resistance that it was done ≥28 days after the end of trial), and the rates,11,14 85% quadruple therapy eradication rates and second imputed patients with missing breath tests as 80% standard therapy eradication rates, Δ (defi ning treatment successes. No inferential analyses were done equivalence range or non-inferiority margin) of –10%, on safety data and no missing values were imputed. The expected diff erence of 5%, power of 90%, and α of 0·025 number and percentage of patients with bismuth (one-sided). Our trial was designed as a non-inferiority concentrations greater than 50 mg/L at all assessments trial but was powered to detect superiority. 135 patients were reported with descriptive statistics. Bismuth per group (completers) were needed to show non- concentrations measured at screening, end of trial, and inferiority of the experimental drug versus active control end of study were compared with paired t tests (quadruple on the basis of the primary effi cacy variable. An estimated therapy group). This study is registered with ClinicalTrials.
30% of patients would not be included in the per-protocol gov, number NCT00669955.
analysis because of one or more major protocol deviations;
therefore, 193 patients randomly assigned treatment per Role of the funding source
group were planned to protect the trial's power. If non-
The trial was conceived and designed by the sponsor inferiority was concluded with the per-protocol and the principal investigator (PM). The principal population, testing for superiority with the intention-to- investigator substantially contributed to designing the treat population was permitted (we defi ned the intention- trial, wrote the fi rst and fi nal drafts of the report and to-treat population as all participants randomly assigned decided, in consultation with the other authors, to treatment). SAS software (version 9.1.3 or higher) submit for publication. All authors had full access to produced statistical outputs. Categorical variables were the data.
www.thelancet.com Vol 377 March 12, 2011
95% CI for diff erence
between quadruple and
standard therapy

166/178 (93%); 88·5–96·5 112/161 (70%); 61·8–76·6 ITT population with data imputation* 174/218 (80%); 73·9–84·9 123/222 (55%); 48·6–62·1 ITT population without imputed data: observed case† 174/188 (93%); 87·8–95·9 123/182 (68%); 60·3–74·3 Diff erent defi nition in the PP population‡ 168/178 (94%); 89·9–97·3 114/161 (71%); 63·1–77·7 Diff erent defi nition in the ITT population‡ 200/218 (92%); 87·3–95·0 152/222 (69%); 61·9–74·5 Data are n/N (%); 95% CI. Quadruple therapy=omeprazole, bismuth, metronidazole, and tetracycline. Standard therapy=omeprazole, amoxicillin, and clarithromycin. PP=per protocol. ITT=intention to treat. UBT=13C urea breath test. *Since the non-inferiority of OBMT vs OAC was shown in the PP population, the same CI was derived with the ITT population. For this analysis, if the week 6 or week 10 UBTs were not available, the patient was classifi ed as non-eradicated. †Analysis of the ITT population without data imputation provided similar results as those obtained with other populations. ‡We also did a post-hoc analysis with the PP and the ITT populations, whereas eradication was defi ned as ≥1 negative UBT at week 6 or 10 (study days ≥39), instead of negative UBTs at both timepoints.
Table 2: Eradication rates in the PP and ITT populations
Eradication rate by baseline metronidazole resistance*
Baseline metronidazole resistance 38/42 (91%); 77·4–97·3 98/103 (95%); 89·0–98·4 28/41 (68%); 51·9–81·9 64/90 (71%); 89·0–98·4 Eradication rate by baseline clarithromycin resistance*
Baseline clarithromycin resistance 30/33 (91%); 75·7–98·1 106/112 (95%); 88·8–98·0 2/25 (8%); 1·0–26·0 90/106 (85%); 76·6–91·1 Eradication rate by baseline combined metronidazole and clarithromycin resistance*
Baseline combined metronidazole and clarithromycin resistance 11/12 (92%); 61·5–99·8 125/133 (94%); 88·5–97·4 2/10 (20%); 2·5–55·6 90/121 (74%); 65·6–81·9 Data ate n/N (%); 95% CI unless otherwise indicated. Quadruple therapy is omeprazole, bismuth, metronidazole, and tetracycline. Standard therapy is omeprazole, amoxicillin, and clarithromycin. PP=per protocol. *Percentages are based on the number of patients with both baseline and post-baseline resistance data in the PP population; not all cultures provided resistance or sensitivity data.
Table 3: Eradication rates and antibiotic resistance in the PP population
positive breath tests) confi rmed the superiority of The fi gure shows the trial profi le. 204 patients assigned quadruple therapy. There was an imbalance in the number to receive quadruple therapy and 195 assigned to receive of patients excluded from the per-protocol analysis due to standard therapy completed the study, with lack of missing breath tests (fi gure); post-hoc analysis imputing effi cacy in 11 and 56 respectively. Two patients in the patients with missing breath tests as treatment successes quadruple therapy group did not receive the study showed the same degree of diff erence between groups.
drugs; safety analyses were done on the remaining Baseline H pylori in-vitro metronidazole sensitivity was 438 patients. Table 1 shows the baseline characteristics similar between the quadruple (71% [103 of of the two groups.
145 participants]) and standard therapy groups (69% Treatment with quadruple therapy fulfi lled criteria for [90 of 131]; p=0·695); metronidazole sensitivity did not non-inferiority to standard therapy in the per-protocol signifi cantly aff ect the effi cacy of quadruple therapy in population. Accordingly, the intention-to-treat population the per-protocol population (p=0·283; table 3). Baseline was used for superiority testing, and quadruple therapy clarithromycin sensitivity was also similar between the was signifi cantly better than standard therapy in eradicating quadruple (77% [112 of 145]) and standard therapy groups H pylori (all p<0·0001; table 2). In the per-protocol (81% [106 of 131]; p=0·464); however, this sensitivity population, eradication rates were greater for quadruple seemed to signifi cantly aff ect the effi cacy of standard than for standard therapy; in the intention-to-treat therapy (p<0·0001; table 3). Simultaneous metronidazole population with missing urea breath test data imputed as and clarithromycin resistance reduced effi positive (ie, persistent infection), eradication rates were patients treated with standard therapy (no eradication in lower for both groups (table 2). Post-hoc analysis eight [80%] of ten patients with resistant bacteria vs 31 (eradication defi ned as one or more negative breath tests at [26%] of 121 with non-resistant bacteria; p=0·001). fi rst follow-up [week 6] or end of study [week 10] and no Although few patients with peptic ulcer disease were www.thelancet.com Vol 377 March 12, 2011
(7% [16 of 222 participants]) than the quadruple therapy Quadruple therapy
Standard therapy
group (5% [11 of 216]). Incidence of serious TEAEs and discontinuations due to a TEAE were similar between groups (<2·0%). Four patients in the quadruple therapy Patients with a TEAE group reported a total of seven serious adverse events (eczema, psychotic episode, Escherichia coli or Proteus mirabilis urinary tract infection, renal artery stenosis, acute renal failure, and small bowel Abdominal pain, upper neuroendocrine carcinoma); two patients in the quadruple therapy group withdrew because of treatment-limiting adverse events (epigastric pain, dyspepsia, nausea, and Faeces discoloured abdominal pain). Three patients in the standard therapy group reported a total of nine serious adverse events (arrhythmia, emesis, pyrexia, dehydration, under- nourishment, vascular dementia, acute appen exacerbation of chronic pancreatitis, and aggravation of the general condition); three patients in the standard therapy group withdrew because of treatment-limiting adverse events (epigastric pain, tachycardia, hyperhidrosis, and cardiovascular complications). The sole death during Infections and infestations the trial was suicide of a patient in the standard therapy group 2 months after study entry—we did not deem this Upper respiratory tract infection related to the study drug. No clinically signifi cant changes were reported in physical examination, vital signs, or General disorders and administration-site conditions laboratory indices. Bismuth plasma concentrations increased slightly with quadruple therapy (45 [22%] of 209 patients in this group developed plasma bismuth Respiratory, thoracic, and mediastinal disorders concentrations of 4–20 μg/L after having undetectable baseline values of <4 μg/L). All bismuth concentrations Musculoskeletal and connective tissue disorders were below the toxic threshold (50 μg/L).15 Five (3%) of 200 patients treated with quadruple therapy had detectable plasma bismuth concentrations at the end of study visit Psychiatric disorders versus three (1%) of 210 who had detectable plasma bismuth concentrations at baseline.
Quadruple therapy is omeprazole, bismuth, metronidazole, and tetracycline. Standard therapy is omeprazole, amoxicillin, and clarithromycin. TEAE=treatment-emergent adverse event.
Table 4: TEAEs in the treated population
Our results show that 10 days of treatment with quadruple therapy yields H pylori eradication rates superior to 7 days included in this trial (table 1), effi cacy was still assessed of treatment with standard therapy. Standard therapy is in this group. Quadruple (93% [147 of 158]) and standard at present the standard fi rst-line treatment in Europe and therapy (67% [95 of 141]; p<0·0001) effi cacy in patients elsewhere,4–7 but failure rates in about 40% of patients with non-ulcer dyspepsia was similar to the overall study have been reported and continue to increase.14,16 population. Patients with peptic ulcer disease responded Antibiotic resistance is the main factor that contributes better to quadruple (95% [18 of 19]) than to standard to the failure of PPI-based triple therapy to adequately therapy (83% [15 of 18]; p=0·340); however, this result eradicate H pylori. Resistance-inducing muta tions happen should be interpreted with caution in view of the small spontaneously during bacterial replication, and previous number of patients in this subgroup. Compliance antibiotic treatment for other infections favour the exceeded 95% in both treatment groups.
selection of drug-resistant H pylori;17 resistance can rapidly The proportion of patients with treatment-emergent emerge during the fi rst course of treatment18 and parallels adverse events (TEAEs) were similar between the national antibiotic consumption.19 Clarithromycin is a key treatment groups (table 4). Gastrointestinal symptoms, component of many fi rst-line PPI-based triple therapies, including dyspepsia and diarrhoea, were the most and resistance to it is constantly rising (paralleled by commonly reported TEAEs and were more common in increasing standard therapy failure).20 Conversely, the the standard than the quadruple therapy group. effi cacy of metronidazole-containing combination therapy Severe TEAEs (dyspepsia, upper-abdominal pain, (with bismuth and tetracycline) is maintained in patients nausea, eructation, headache, dysgeusia, and general- harbouring metronidazole-resistant H pylori.9,21 The ised infection) were more common in the standard discrepancy is explained partly by metronidazole resistance www.thelancet.com Vol 377 March 12, 2011
as assessed in vitro, but does not adequately relate to negative test was obtained in 437 of 438 patients. The in-vivo states, partly because of metronidazole–bismuth extremely conservative approach of imputing all patients synergism that overcomes resistance.22 Further, with one breath test outside the allocated timeframe as metronidazole resistance is complex and associated with non-eradicated explains the underestimation of eradication the presence of redox-related bacterial-gene mutations in the intention-to-treat population.
(rdxA, frxA, ferric uptake regulator protein).23 Criticisms of our study might include the varying Bismuth has an established history in the treatment treatment duration in each group and choice of of H pylori.24 Colloidal bismuth subcitrate has potent metronidazole-resistance test. The eff anti-H pylori activity (MIC 4–32 μg/mL), and in-vitro standard therapy durations has been assessed in a recent resistance has not been induced. Further, bismuth meta-analysis of 21 studies, with data showing that the increases eradication when included in double, triple, extension of standard therapy beyond 7 days provided a and quadruple regimens.22,25 In our trial, eradication slight increase (about 5%) in eradication when the longest rates with quadruple therapy were similar duration (14 days) was assessed.31 However, when the four (about 88–93%) to those of previous studies that used highest-quality trials (as assessed by the Jadad scale)33 from the same three-in-one capsule with 20 mg omeprazole this analysis were considered, prolonging treatment with twice daily.10,11 Such high eradication rates contrast with standard therapy beyond 7 days (with extension up to those reported from a meta-analysis by Luther and 10 days) was not associated with additional benefi t.31 A colleagues26 that com cacy of bismuth- randomised trial of patients infected with H pylori34 showed based quadruple therapy (about 78% eradication) with that extending treatment with standard therapy for up to standard therapy (about 77%). Although standard therapy dosing regimens were consistent across trials, Panel: Research in context
they were highly variable for bismuth-based quadruple therapy; further, choice of bismuth salt also varied.10,11,26 Although we could postulate that inclusion in the three- We searched published work with PubMed, Ovid Medline, in-one capsule is ideal, head-to-head trials are needed Abridged Index Medicus, and various gastrointestinal to establish the bismuth dosing regimen that provides congresses (including the American Gastroenterological Association, Digestive Disease Week, and the United European Concerns have been raised about toxic eff ects related Gastroenterology Week). Publications were limited to 1980 or to bismuth. There have been rare reports of heavy-metal later. Search terms included "Helicobacter pylori", "peptic ulcer poisoning and encephalopathy at plasma bismuth disease", "eradication", "guideline", "therapy", and concentrations greater than 50 μg/L in patients treated "treatments". Authors independently extracted and validated with bismuth subgallate and greater than 20 g per day references. Data from systematic reviews of randomised bismuth subnitrate for 6 months to 20 years.27–29 In our controlled trials, individual randomised controlled trials, trial, with little bismuth exposure and use of a colloidal systematic reviews of cohort studies, cohort studies, bismuth subcitrate formulation, bismuth concentrations systematic reviews of case-control studies, case-control were below the toxic threshold. Data from a recent studies, case series, and opinions without explicit critical systematic review and meta-analysis of 35 randomised appraisal were prioritised for inclusion in descending order. controlled trials showed that stool discolouration Our search was limited to studies in English.
(clinically irrelevant) was the only adverse eff ect signifi cantly associated with bismuth ingestion.24 Our trial compared the effi cacy and safety of omeprazole, Inclusion of antisecretory therapy (PPIs) in H pylori- amoxicillin, and clarithromycin (standard therapy; fi rst-line eradication regimens is crucial to optimise the local treatment in international guidelines) and omeprazole, activity of antibiotics via synergism,30 and our trial bismuth subcitrate potassium, metronidazole, and clarifi es the timing of PPI in relation to meals. By contrast tetracycline (quadruple therapy) and, as shown by the with giving a PPI with amoxicillin and clarithromycin results of our systematic review, is the fi rst large-scale (whose stability and activity are highly dependent on comparative study of these treatments for the eradication high pH), there is no such need with tetracycline of H pylori in nearly a decade. Data from our study and metronidazole.
corroborate the safety and tolerability of bismuth in Europe In our trial, two negative urea breath tests in the allocated and highlight the eff ect of antibiotic resistance on timeframe were needed for a patient to be deemed cacy between combination treatments. successfully treated. In view of the high accuracy of the Clarithromycin-resistant H pylori continues to increase in breath test, treatment guidelines and most studies and prevalence, and although rates of metronidazole resistance meta-analyses judge eradication to be confi rmed after one are also high, the results from our study showed that breath test 4–6 weeks after completion of treatment.4,26,31,32 clarithromycin resistance reduces the effi cacy of standard In our study, seven patients had a negative breath test at therapy, whereas resistance to metronidazole has a slight week 6 and a positive test at week 10 (two on quadruple eff ect on the effi cacy of quadruple therapy.
therapy, fi ve on standard therapy); confi rmation of a www.thelancet.com Vol 377 March 12, 2011
14 days did not provide any benefi t over 7 days of treatment. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med Regarding quadruple therapy, 10 days of treatment is 2002; 347: 1175–86.
advocated by international guide lines5–7 and is the approved Malfertheiner P, Chan FK, McColl KE. Peptic ulcer disease. Lancet
2009; 374: 1449–61.
duration of treatment in some countries. 7 days of 4 Malfertheiner P, Megraud F, O'Morain C. Current concepts in quadruple therapy has not been rigorously assessed.
the management of Helicobacter pylori infection: the Maastricht III There is no recommendation for metronidazole testing. Consensus Report. Gut 2007; 56: 772–81.
Asaka M, Kato M, Takahashi S, et al, for the Japanese Society Etest is convenient to use and its results relate well with for Helicobacter Research. Guidelines for the management agar dilution;35 although Etest can overestimate resistance, of Helicobacter pylori infection in Japan: 2009 revised edition. our results are consistent with previous data.36 Helicobacter 2010; 15: 1–20.
Chey WD, Wong BCY. American College of Gastroenterology Our trial is the fi rst large-scale comparative study of the guideline on the management of Helicobacter pylori infection. cacy and safety of standard and quadruple therapy for Am J Gastroenterol 2007; 102: 1808–25.
the eradication of H pylori in nearly a decade (panel). In 7 Fock KM, Katelaris P, Sugano K, et al, for the Second Asia-Pacifi c view of the variable availability of bismuth across Europe, Conference. Second Asia-Pacifi c Consensus Guidelines for Helicobacter pylori infection. J Gastroenterol Hepatol 2009; the fi ndings of our trial provide assurance to clinicians on the safety and tolerability of bismuth. Furthermore, 8 Fukase K, Kato M, Kikuchi S, et al, for the Japan Gast Study Group. we highlight the eff ect of antibiotic resistance on Eff ect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early cacy between combination therapies. gastric cancer: an open-label, randomised controlled trial. Lancet Although several other new eradication strategies have 2008; 372: 392–97.
been proposed, their effi cacy and use in practice need to 9 Graham DY, Opekun AR, Belson G, El-Zimaity HM, Carlson MR. Novel bismuth-metronidazole-tetracycline triple-layer tablet for treatment of Helicobacter pylori. Aliment Pharmacol Ther 2005; 10 days of treatment with quadruple therapy was superior to 7 days of standard therapy for H pylori 10 O'Morain CA, Borody T, Farley A, et al, for the International Multicentre Study. Effi cacy and safety of single triple capsule of eradication in patients with or without the presence or bismuth biskalcitrate, metronidazole, and tetracycline given with history of peptic ulcer disease. Clarithromycin-resistant omeprazole for eradication of Helicobacter pylori: an international H pylori isolates continue to increase in prevalence multicenter study. Aliment Pharmacol Ther 2003; 17: 415–20.
11 Laine L, Hunt R, El-Zimaity H, Nguyen B, Osato M, Spénard J. throughout the world, and although rates of metronidazole Bismuth-based quadruple therapy using a single capsule of resistance are also high, clarithromycin resistance bismuth biskalcitrate, metronidazole, and tetracycline given with cacy of standard therapy whereas omeprazole versus omeprazole, amoxicillin, and clarithromycin for eradication of Helicobacter pylori in duodenal ulcer patients: metronidazole resistance has little eff ect on the effi a prospective, randomized, multicenter, North American trial. of quadruple therapy. In regions with high levels of Am J Gastroenterol 2003; 98: 562–67.
clarithromycin resistance, treatment with quadruple 12 De Francesco V, Zullo A, Ierardi E, et al. Phenotypic and genotypic Helicobacter pylori clarithromycin resistance and therapeutic therapy should be considered as fi rst-line therapy for outcome: benefi ts and limits. J Antimicrob Chemother 2010; H pylori eradication.
13 Graham DY, Fischbach L. Helicobacter pylori treatment in the era of increasing antibiotic resistance. Gut 2010; 59: 1143–53.
PM, MG, and MR contributed to the study concept and design. H pylori antibiotic resistance: prevalence, importance, PM, FB, J-CD, and KC enrolled and treated patients and collected and advances in testing. Gut 2004; 53: 1374–84.
data. FM provided central microbiological review. All authors 15 Hillemand P, Pallière M, Laquais B, Bouvet P. Bismuth treatment contributed to analyses and interpretations of results and the writing and blood bismuth levels. Sem Hop 1977; 53: 1663–69 (in French).
or review of the paper.
16 De Francesco V, Margiotta M, Zullo A, et al. Prevalence of primary Pylera Study Group investigators
clarithromycin resistance in Helicobacter pylori strains over a 15 year France (30 patients) A Aisene, M Bougnol, J Cassigneul, P Coulom, period in Italy. J Antimicrob Chemother 2007; 59: 783–85.
P Houcke, D Lamarque, D Lamouliatte, J-F Roques, A Thevenin, 17 Blaser MJ. The genetic gymnastics of our indigenous microbes. J-C Delchier, S Ecuer, G Bagnouls, T Helbert. Germany (182) H Andree, N Engl J Med 2002; 346: 2083–85.
H Bouzo, W Brandt, H-J Cordes, A Dettmer, H Juergens, 18 Koletzko S, Richy F, Bontems P, et al. Prospective multicentre study P Malfertheiner, I Rehmann, A Ryschka, T Schaefer. Ireland (3) on antibiotic resistance of Helicobacter pylori strains obtained from
children living in Europe. Gut 2006; 55: 1711–16.
C O'Morain. Italy (18) F Bazzoli, G Gasbarrini, L Cipolletta, V Stanghellini. Netherlands (0) E Kuipers, W A de Boer. Poland (184) 19 Boyanova L. Prevalence of multidrug-resistant Helicobacter pylori in Bulgaria. J Med Microbiol 2009; 58: 930–35.
K Celiñski, W Gachowski, J Huk, Z Jamrozik-Kruk, W Karnafel, D Kleczkowski, K Kujawski, K Linke, R Petryka, D Serwin, B Wozniak, 20 Mégraud F, Lehours P. Helicobacter pylori detection and antimicrobial susceptibility testing. Clin Microbiol Rev 2007; A Wysokinski. Spain (7) M Castro, J L Calleja, X Calvet, J Gisbert, E Domínguez Muñoz. UK (7) C Bundy, I Orpen, D St John Mohr, 21 Graham DY, Osato MS, Hoff man J, et al. Metronidazole containing I Parker, T Cahill.
quadruple therapy for infection with metronidazole resistant Confl icts of interest
Helicobacter pylori: a prospective study. Aliment Pharmacol Ther 2000; PM, FB, J-CD, KC, and FM have received payment from Axcan Pharma for research and clinical trials. MG and MR are employees of Axcan Pharma.
22 Goodwin CS, Marshall BJ, Blincow ED, Wilson DH, Blackbourn S, Phillips M. Prevention of nitroimidazole resistance in Campylobacter pylori by coadministration of colloidal bismuth The authors thank Jonathan M Wert for editorial assistance in the subcitrate: clinical and in vitro studies. J Clin Pathol 1988; preparation of this report, which was supported by Axcan Pharma.
23 Tsugawa H, Suzuki H, Satoh K, et al. Two amino acids mutation Moayyedi P, Hunt RH. Helicobacter pylori public health of ferric uptake regulator determines Helicobacter pylori resistance implications. Helicobacter 2004; 9 (suppl 1): 67–72.
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24 Ford AC, Malfertheiner P, Giguere M, Santana J, Khan M, 33 Jadad AR, Moore RA, Carroll D, et al. Assessing the quality Moayyedi P. Adverse events with bismuth salts for Helicobacter of reports of randomized clinical trials: is blinding necessary? pylori eradication: systematic review and meta-analysis. Control Clin Trials 1996; 17: 1–12.
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