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We read with interest the recent paper comparing 1 and 2 weeks of triple therapy for Helicobacter pylori infection in patients with duodenal ulcer disease. (Gut 2007;56:475–9) H pylori is an infectious disease and the goal of treatment is to cure the infection. In 2007, one would hope to be able to reliably cure ⩾95% of the treated patients (discussed by Graham et al).1 In 1989, a successful treatment has been defined as one that cures >80% of the patients.2 By 1995, it seemed that 90% was achievable.3 The Maastricht consensus conferences defined a useful therapy as the one with an intention to treat (ITT) cure rate of >80%, which is a relatively low hurdle (ie, those with cure rates of ⩽80% would be unacceptable).5 Although the authors concluded that 7 and 14 days therapy provided essentially equivalent results, the focus should have been on the fact that the cure rates obtained were unacceptably low with either duration (eg, ITT of 79.7 for 7 days and 81.7 for 14 days), especially among patients with duodenal ulcer disease where the cure rates are typically higher than among patients without ulcers.5–8
Their results are not unexpected as large studies of this legacy triple therapy (proton-pump inhibitor (PPI), amoxicillin and clarithromycin) have recently yielded unacceptably low eradication rates in Europe and the US, and have only infrequently achieved the minimum 80% success rate (table 1).10–17 Overall, these results suggest that traditional triple therapy should no longer be used in Western populations unless pretreatment susceptibility is confirmed and then it should be used for 14 days.18,19
H pylori is a serious, chronic, transmissible infectious disease that causes damage to gastric structure and function, and is a major cause of morbidity and mortality worldwide. All the patients in this study had H pylori-related ulcer disease, and untreated 10–25% would be expected to develop complications such as haemorrhage. We are concerned about the inclusion of the dual therapy arm of omeprazole and amoxicillin in the trial. The dual therapy at these doses typically yields a cure rate of ⩽50% and is listed under the category of “not recommended”. The manuscript states that the protocol was approved by institutional review boards, and all patients gave informed consent. What was the nature of the informed consent? How was a known ineffective therapy justified to the patients with duodenal ulcer disease and to the review boards? We believe that the information given to patients and the justifications must be described in detail in the publication including what the patients were told, and that they entered the trial knowing that they would have a high chance of treatment failure. Finally, what was done to ensure that the large number of patients with failed treatment subsequently receive appropriate therapy for H pylori-related duodenal ulcer disease? It may also be good time to rethink current approaches to H pylori treatment.
This material is based upon work supported in part by the Office of Research and Development Medical Research Service Department of Veterans Affairs and by Public Health Service grant DK56338, which funds the Texas Gulf Coast Digestive Diseases Center.
We thank Dr Graham and Dr Yamaoka for their interest in our recent publication comparing the efficacy of 1 and 2 weeks of triple therapy for the eradication of Helicobacter pylori. They ask about the information given to the patients concerning the dual therapy arm (omeprazole and amoxicillin) with a known low efficacy. As explained in our paper, this arm was included both as a measure of the internal validity of the study and as part of a second long-term follow-up study. Each patient was provided, both verbally and via a written information form, with complete details of the treatments, objectives, possible risks and benefits of the study, and informed consent was obtained from all participants. The full versions of the information form and the informed consent form completed by all participants were approved by the ethical committee of each participating centre. The patients with treatment failure received triple therapy at any time during the study if they asked for it, or at the end of the study if they did not wish to be enrolled in the follow-up study. Those who were enrolled in the second study received triple therapy at the end of follow-up or if the ulcer recurred. Furthermore, during the trial, we used a dual therapy with amoxicillin and not with clarithromycin so that in the case of treatment failure, clarithromycin-based triple therapy could be subsequently used without the risk of acquired resistance to clarithromycin and consequent reduced efficacy.1
Dr Graham and Dr Yamaoka also suggest that rather than focusing on the similar efficacy of 1 and 2 weeks of triple therapy, we should have highlighted that the efficacy of this therapy is “unacceptably low”, regardless of its duration. As we discuss in our paper, the eradication rates obtained in our study (1 week of triple therapy intent to treat 79.7%, per protocol 83.6%; 2 weeks of triple therapy intent to treat 81.7%, per protocol 84.9%) add to the body of evidence showing that the efficacy of triple therapy has undoubtedly decreased in recent years. However, these are not substantially below the threshold of 80% defined by the Maastricht III Consensus Report as clinically unacceptable for the treatment of H pylori infection.2 Moreover, triple therapy, referred to by Dr Graham and Dr Yamaoka as a “legacy” treatment, is the treatment recommended by the Maastricht III Consensus Report. Dr Graham is himself one of the authors of this report. We must agree with this recent recommendation, at least until the higher efficacy demonstrated for new treatments3 has been confirmed by other investigators and in large studies in different regions worldwide.
We argue that the importance of our study lies rather in its large sample size and demonstration that extending the duration of triple therapy from 1 to 2 weeks does not significantly increase the rate of H pylori eradication (the difference in eradication rate between 1 and 2 weeks of triple therapy was 2%; 95% CI −4% to 8%). Our trial involved a large number of centres (n = 81) in the south, centre and north of Italy, and so patients were recruited from a broad population, providing a good basis for the generalisation of results. Before our study, two meta-analyses reported that compared with 1 week of treatment, 2 weeks of triple therapy increases the eradication rate by 9–12%.4,5 However, although the results of meta-analyses are relevant, they cannot substitute for large clinical trials. Indeed, in their meta-analysis, Calvet et al4 specifically mentioned that their results suggest that larger studies comparing 1 and 2 weeks of therapy are needed. We think that our study has addressed this need.
Competing interests: DYG has received small amounts of grant support and/or free drugs or urea breath tests from Meretek, Jannsen/Eisai, TAP, and BioHit for investigator initiated and completely investigator controlled research in the area of H pylori infections. In addition, DYG is a paid consultant for Otsuka Pharmaceuticals and a member of the Board of Directors of Meretek, Diagnostics, the manufacturer of the 13C-urea breath test. He is also a consultant to Novartis with regards to H pylori vaccine development and also receives royalties on the Baylor College of Medicine patent covering the serologic test, HM-CAP. YY has no potential conflicts of interest to declare.
Competing interests: RMZ has received reimbursement from Janssen-Cilag and Abbot for attending symposia, and fees for speaking from AstraZeneca, Takeda and Abbott. FB has received fees for speaking from AstraZeneca and Takeda, reimbursement for organising education from Altana and has carried out consultancy work for AstraZeneca.
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