Correspondence

Absence of Benefit of Eradicating Helicobacter pylori in Patients with Nonulcer Dyspepsia

N Engl J Med 2000; 342:589-590February 24, 2000

Article

To the Editor:

Talley et al. (Oct. 7 issue)1 report the absence of a symptomatic benefit of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. The study was conducted in the United States. Previous double-blind, randomized studies performed elsewhere in the world have shown a significant benefit2-4 or a trend in that direction.5,6 What is the explanation for the different findings?

The patients in the study by Talley et al. were unusu-al in that they had little benefit from the eradication of H. pylori infection as a means of preventing the subsequent development of ulcer disease. The proportion of patients in whom ulcers developed within 12 months was 4 percent in the group randomly assigned to receive anti–H. pylori treatment, as compared with 6 percent in the group randomly assigned to receive placebo. In other studies of nonulcer dyspepsia, the eradication of H. pylori had a much more dramatic effect in reducing the subsequent development of ulcers. For example, in the study by Blum et al.,5 ulcers developed in 6 percent of the patients randomly assigned to receive placebo but in only 1 percent of those randomly assigned to receive anti–H. pylori treatment. Previous studies of ulcer disease have shown that H. pylori infection has a less important causative role in the United States than in other parts of the world. More widespread use of nonsteroidal antiinflammatory drugs in the United States may be a partial explanation.

The symptomatic benefit of eradicating H. pylori in patients with nonulcer dyspepsia may be related to the background prevalence of H. pylori–related ulcer disease in the population being studied. Northern Ireland, southern Ireland, and Scotland have high prevalences of H. pylori–related ulcer disease. Studies in each of these countries have shown a symptomatic benefit of eradicating H. pylori in patients with normal endoscopic findings.2-4 Because of geographic and national differences in the causes of both ulcer disease and nonulcer dyspepsia, treatment that is beneficial in one country may be ineffective in another.

Kenneth E.L. McColl, M.D.
University of Glasgow, Glasgow G11 6NT, United Kingdom

6 References

1
Talley NJ, Vakil N, Ballard ED II, Fennerty MB. Absence of benefit of eradicating Helicobacter pylori in patients with nonulcer dyspepsia. N Engl J Med 1999;341:1106-1111
Full Text | Web of Science | Medline

2
Gilvarry J, Buckley MJM, Beattie S, Hamilton H, O'Morain CA. Eradication of Helicobacter pylori affects symptoms in non-ulcer dyspepsia. Scand J Gastroenterol 1997;32:535-540
CrossRef | Web of Science | Medline

3
McColl K, Murray L, El-Omar E, et al. Symptomatic benefit from eradicating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med 1998;339:1869-1874
Full Text | Web of Science | Medline

4
Heaney A, Collins JSA, Watson RGP, McFarland RJ, Bamford KB, Tham TCK. A prospective randomised trial of a “test and treat“ policy versus endoscopy based management in young Helicobacter pylori positive patients with ulcer-like dyspepsia, referred to a hospital clinic. Gut 1999;45:186-190
CrossRef | Web of Science | Medline

5
Blum AL, Talley NJ, O'Morain C, et al. Lack of effect of treating Helicobacter pylori infection in patients with nonulcer dyspepsia. N Engl J Med 1998;339:1875-1881
Full Text | Web of Science | Medline

6
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: the Optimal Regimen Cures Helicobacter Induced Dyspepsia (ORCHID) Study Group. BMJ 1999;318:833-837
CrossRef | Web of Science | Medline

To the Editor:

The conclusion that there is no benefit of eradicating H. pylori infection in patients with nonulcer dyspepsia is misleading, since at least a histologic improvement in gastritis is apparent from the data reported by Talley et al. It is uncertain whether such improvement leads to the relief of dyspeptic symptoms. In a previous study, Talley et al. found a positive association between an improvement in gastritis and relief of symptoms.1 Moreover, in the current study, there was a twofold (although not significant) increase in the rate of duodenal ulceration at 12 months. This suggests that eradication of H. pylori may be beneficial in a subgroup of patients with nonulcer dyspepsia.

Talley et al. state, “For patients whose symptoms were not assessed at 12 months but whose symptoms had been assessed at the 4-to-6-week visit or afterward, the most recent results were used for the 12-month values.” The authors report conclusive data on H. pylori status at the 12-month visit for only 217 patients; 19 patients (all in the active-treatment group) had indeterminate results. Consequently, 57 of the 274 patients evaluated at the 4-to-6-week visit were lost to follow-up or their H. pylori status at the 12-month visit was unclear. Nevertheless, these patients were included in the final analysis. The rate of successful treatment was determined by extrapolating symptom scores at 12 months from the scores recorded at the 4-to-6-week visit or afterward. These data may be inaccurate, since symptoms may have changed substantially after the last visit.

The dropout rate in the group of patients who were still considered positive for H. pylori at 12 months was 11 percent (17 of 150 patients), as compared with 32 percent (40 of 124 patients) in the group that was considered negative for H. pylori infection (P<0.001). It may be that the patients in whom the infection cleared had a substantial improvement in symptoms and were less likely to complete the follow-up portion of the study than were the patients with persistent infection. What was the rate of successful treatment for the 217 patients whose H. pylori status and symptom scores were actually assessed at 12 months?

Francesco Perri, M.D., Ph.D.
Angelo Andriulli, M.D.
Casa Sollievo della Sofferenza Hospital, 71013 San Giovanni Rotondo, Italy

1 References

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: the Optimal Regimen Cures Helicobacter Induced Dyspepsia (ORCHID) Study Group. BMJ 1999;318:833-837
CrossRef | Web of Science | Medline

Author/Editor Response

The authors reply:

To the Editor: We agree with McColl that the symptomatic benefit reported in some European trials of H. pylori eradication in patients with nonulcer dyspepsia is probably explained, at least in part, by the inclusion of patients with either unrecognized peptic ulcer disease or an ulcer diathesis.1 This effect is likely to be observed in countries where the background prevalence of ulcer disease due to H. pylori is remarkably high (e.g., Scotland or Ireland), and the study design must take this potential bias into account.1 Since the benefit of H. pylori eradication in patients with ulcer disease is not disputed, we did not wish to contaminate the findings in our trial of nonulcer dyspepsia by including patients with ulcers. The selection criteria for our cohort of patients were similar to those used in studies of nonulcer dyspepsia that have been conducted in various countries.1,2 Our results are also consistent with those of another recent U.S. trial.3

Perri and Andriulli claim that our results are misleading in part because of histologic improvement in gastritis after eradication therapy. However, the healing of gastritis was expected with successful eradication of H. pylori, and this criticism misses the point that at 12 months, the rate of symptom resolution in the active-treatment group was not significantly greater than that in the placebo group, despite histologic improvement in the active-treatment group. It is true that in our previous study there was a significant association between the complete healing of gastritis and an improvement in symptoms in patients with nonulcer dyspepsia, but this was a secondary analysis,4 and the finding could not be confirmed in the current trial, in which we tested the hypothesis.

Perri and Andriulli also express concern that in our analysis, we used the most recent data in the case of patients for whom data were not available at 12 months. This is a well-accepted technique for dealing with the problem of missing data. The success rate (defined as mild dyspepsia or none) in the 210 patients for whom complete data were available on H. pylori status and symptoms at 12 months was 46 percent (44 of 95 patients) in the active-treatment group and 52 percent (60 of 115) in the placebo group (P=0.41). These results are highly consistent with the results of the original intention-to-treat analysis. The dropout rate due to the lack of availability of diary-card data on symptoms was similar in the active-treatment group (32 of 150 patients) and the placebo group (25 of 143). It is therefore unlikely that dropouts were due to the resolution of symptoms with active treatment, and we stand by our original conclusions.

Nicholas J. Talley, M.D., Ph.D.
University of Sydney, Penrith, NSW 2751, Australia

Nimish Vakil, M.D.
University of Wisconsin Medical School, Milwaukee, WI 53233

M. Brian Fennerty, M.D.
Oregon Health Sciences University, Portland, OR 97201

4 References

1
Xia HH, Talley NJ. Helicobacter pylori eradication in patients with non-ulcer dyspepsia. Drugs 1999;58:785-792
CrossRef | Web of Science | Medline

2
Talley NJ, Meineche-Schmidt V, Pare P, et al. Efficacy of omeprazole in functional dyspepsia: double-blind, randomized, placebo-controlled trials (the Bond and Opera studies). Aliment Pharmacol Ther 1998;12:1055-1065
CrossRef | Web of Science | Medline

3
Greenberg PD, Cello JP. Lack of effect of treatment for Helicobacter pylori on symptoms of nonulcer dyspepsia. Arch Intern Med 1999;159:2283-2288
CrossRef | Web of Science | Medline

4
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: the Optimal Regimens Cures Helicobacter Induced Dyspepsia (ORCHID) Study Group. BMJ 1999;318:833-837
CrossRef | Web of Science | Medline

Citing Articles (5)

Citing Articles

1
McColl, Kenneth E.L., . (2010) Helicobacter pylori Infection. New England Journal of Medicine 362:17, 1597-1604
Full Text
2
Luiz E. Mazzoleni, Guilherme B. Sander, Eduardo A. Ott, Sérgio G. S. Barros, Carlos F. Francesconi, Carisi A. Polanczyk, André C. Wortmann, Alexandro L. Theil, Leandro G. Fritscher, Luis F Rivero, André Cartell, Maria I. A. Edelweiss, Diego M. Uchôa, João C. Prolla. (2006) Clinical Outcomes of Eradication of Helicobacter pylori in Nonulcer Dyspepsia in a Population with a High Prevalence of Infection: Results of a 12-Month Randomized, Double Blind, Placebo-Controlled Study. Digestive Diseases and Sciences 51:1, 89-98
CrossRef
3
A Andriulli, E Grossi, M Buscema, V Festa, N.M Intraligi, P Dominici, R Cerutti, F Perri. (2003) Contribution of artificial neural networks to the classification and treatment of patients with uninvestigated dyspepsia. Digestive and Liver Disease 35:4, 222-231
CrossRef
4
F. Perri, V. Festa, E. Grossi, N. Garbagna, G. Leandro, A. Andriulli. (2003) Dyspepsia and Helicobacter pylori infection: a prospective multicentre observational study. Digestive and Liver Disease 35:3, 157-164
CrossRef
5
N. J. Talley, C. Quan. (2002) Helicobacter pylori and nonulcer dyspepsia. Alimentary Pharmacology and Therapeutics 16:s1, 58-65
CrossRef