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Editor—Several weaknesses in Talley et al’s study may explain its failure to detect symptomatic benefit from eradicating infection with Helicobacter pylori in functional dyspepsia.1 The first is inadequate follow up. Of the three quarters of patients said to have completed the study, some did not reach their one year assessment. The outcome measurement even in those reaching the one year end point seems to have been inadequate as symptom diary cards in which only three fifths were completed were considered acceptable. The proportion of randomised patients reaching the one year end point with complete outcome documentation needs to be reported.
In our study, funded by the Medical Research Council, 318 patients were randomised and 97% were fully reassessed one year after treatment.2 This reassessment showed a significant benefit of active compared with placebo treatment of 14% (95% confidence interval 7% to 22%; P<0.001). Even before the problems with follow up are taken into account, Talley et al’s study only had the power to detect a benefit of 20%, and its negative result in no way refutes the findings of our study.
Another problem in the authors’ study is that, despite functional dyspepsia being common, half of the 40 centres recruited fewer than six patients. How representative were these patients of patients with the disorder? The symptom characteristics indicate that patients with the motility type of functional dyspepsia—the group least likely to benefit from eradication treatment—were overrepresented, making up most of those randomised. In our study every patient fulfilling the entry criteria was randomised apart from nine (3%) who did not consent.
Despite the above shortcomings, there are several pointers in Talley et al’s study towards symptomatic benefit from eradicating H pylori. Resolution of symptoms was 8% greater in those who became negative for H pylori than in those who remained positive for it, and the use of antacids was 18% less. Furthermore, symptoms resolved in 15% more of those with little or no persisting H pylori gastritis, and this was highly significant (P=0.008) even on secondary analysis.
The magnitude of benefit of 14% over placebo treatment detected by our study, but missed by studies of inadequate power, is clinically important. The treatments currently used, such as anti-secretory agents and anti-nociceptive agents, produce a benefit of only 10% over placebo.3,4 Consequently, the benefit of treatment to eradicate H pylori is at least as great as that of any other currently available treatment. Moreover, the benefit is achieved by a single week’s course of treatment rather than by long term, expensive maintenance treatment.
Footnotes
Competing interests: Professor McColl has received lecture fees and funds for research and for a member of staff from several companies that produce proton pump inhibitors.
References
1.Talley N J, Janssens J, Lauritsen K, Racz I, Bolling-Sternevald E. Eradication of Helicobacter pylori in functional dyspepsia: randomised double blind placebo controlled trial with 12 months’ follow up. BMJ 1999;318:833-7. (27 March.) [DOI] [PMC free article] [PubMed]
2.McColl KEL, Murray L, El-Omar E, Dickson A, El-Nujumi A, Wriz A, et al. Symptomatic benefit from eradicating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med. 1998;339:1869–1874. doi: 10.1056/NEJM199812243392601. [DOI] [PubMed] [Google Scholar]
3.Talley NJ, Meineche-Schmidt M, Pare P, Duckworth M, Raisanen P, Pap A, et al. Efficacy of omeprazole in functional dyspepsia: double-blind, randomised, placebo-controlled trials (the Bond and Opera studies) Aliment Pharmacol Ther. 1998;12:1055–1065. doi: 10.1046/j.1365-2036.1998.00410.x. [DOI] [PubMed] [Google Scholar]
4.Read NW, Abitbol JL, Bardhan KD, Whorwell PJ, Fraitag B. Efficacy and safety of the peripheral kappa agonist fedotozine versus placebo in the treatment of functional dyspepsia. Gut. 1997;41:664–668. doi: 10.1136/gut.41.5.664. [DOI] [PMC free article] [PubMed] [Google Scholar]
Editor—McColl et al have several misconceptions about our paper. Recently, three high quality randomised controlled trials have addressed the question of eradication of Helicobacter pylori in functional dyspepsia and relief of symptoms: ours (the ORCHID trial),1-1 the OCAY trial,1-2 and the Medical Research Council trial.1-3 Only the MRC trial reached significance despite a similar sample size in all three trials. The ORCHID trial was the only one to include a placebo arm (rather than omeprazole). As the ORCHID and OCAY trials were otherwise closely similar in design, reference to all three is relevant here.
Follow up was adequate in all the trials; 87% of patients who completed the ORCHID trial and 97% of those who completed the OCAY trial had valid diary data. The outcome in the ORCHID and OCAY trials was similar. When the results of these two trials are combined (n=603) the therapeutic gain in terms of complete symptom relief over placebo was 5%, which was not significant (95% confidence interval −2% to 11%). The power of the ORCHID and OCAY trials combined to detect a true difference of 10% (assuming a 15% response to placebo and 25% for active treatment, with an α level of 0.05) was 84%; for a difference of 15% the power was over 99%. Therefore, the assertion that the negative trials were underpowered is rejected.
There were no important centre effects in the ORCHID trial. When the analysis was restricted to only centres that recruited more than six patients, symptom relief was 21% in both the active and placebo arms.
Was the MRC trial flawed? The issue of the low placebo response (7%) merits special attention. In the MRC trial few patients had endoscopic follow up, although it was known that the region where patients were recruited has a high background prevalence of ulcer disease in people infected with H pylori.1-4 Conceivably, therefore, after placebo treatment many unrecognised cases of ulcer relapsed over 12 months, resulting in an exceptionally low placebo response. Did the MRC trial therefore reach the wrong conclusion because of the patient population included?
When the results from the three trials are pooled the therapeutic gain over placebo was 8% (3% to 13%, P=0.003), but there was also significant inhomogeneity when the MRC trial was included (P= 0.04, Breslow Day test). The overall results support the view that the patient populations were different.
Our trial (the ORCHID trial) produced a robust result. Treatment to eradicate H pylori in functional dyspepsia is disappointing compared with placebo in terms of symptom relief 12 months after treatment. The results do not preclude a symptom response to eradication treatment in some cases, but the number who will truly benefit must be small.
Footnotes
Competing interests: NJT has been a consultant for Astra Hässle (Sweden) and Abbott Laboratories (USA). EB-S is an employee of Astra Hässle (Molndal, Sweden).
References
1-1.Talley NJ, Janssens J, Lauritsen K, Racz I, Bolling-Sternevald E. Eradication of Helicobacter pylori in functional dyspepsia: randomised double blind placebo controlled trial with 12 months’ follow up. BMJ. 1999;318:833–837. doi: 10.1136/bmj.318.7187.833. . (27 March.) [DOI] [PMC free article] [PubMed] [Google Scholar]
1-2.Blum AL, Talley NJ, O’Morain C, van Zanten SV, Labenz J, Stolte M, et al. Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. Omeprazole plus Clarithromycin and Amoxicillin Effect On Year after Treatment (OCAY) Study Group. N Engl J Med. 1998;339:1875–1881. doi: 10.1056/NEJM199812243392602. [DOI] [PubMed] [Google Scholar]
1-3.McColl K, Murray L, El-Omar E, Dickson A, El-Nujumi A, Wirz A, et al. Symptomatic benefit from eradicating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med. 1998;339:1869–1874. doi: 10.1056/NEJM199812243392601. [DOI] [PubMed] [Google Scholar]
1-4.McColl KE, El-Nujumi A, Murray L, El-Omar E, Gillen D, Dickson A, et al. The Helicobacter pylori breath test: a surrogate marker for peptic ulcer disease in dyspeptic patients. Gut. 1997;40:302–306. doi: 10.1136/gut.40.3.302. [DOI] [PMC free article] [PubMed] [Google Scholar]
