Meta-analysis: Sequential Therapy Appears Superior to Standard Therapy for Helicobacter pylori Infection in Patients Naïve to Treatment

Abstract & Commentary

By Malcolm Robinson MD, FACP, FACG, Emeritus Clinical Professor of Medicine, University of Oklahoma College of Medicine, Oklahoma City. Dr. Robinson reports no financial relationship to this field of study.

Synopsis: With minor reservations, 10 days of sequential therapy seems superior to standard triple therapy for the eradication of H. pylori infection.

Source: Nadim F Jafri, et al. Ann Intern Med. 148:12:923-931.

Standard eradication therapy for H. pylori in the U.S. has involved use of a proton pump inhibitor (PPI) plus clarithromycin and either amoxicillin or an imidazole (metronidazole). Ranitidine bismuth citrate is often substituted for a PPI in this regimen outside of the U.S. In North America, most triple therapy regimens involve treatment durations of 7-10 days. In Europe, 7 day therapy is more commonly utilized. Unfortunately, probably due to antibiotic resistance, H. pylori eradication rates have been declining. This results in therapeutic failure in 25% (or even higher percentages) of patients treated traditionally for H. pylori. Some reports have suggested that sequential therapy may have better results than conventional triple therapy. The authors of this study have performed a very careful meta-analysis of randomized controlled trials comparing traditional triple therapy lasting either 7 or 10 days with sequential H. pylori eradication therapy. The latter approach usually begins with 5 days of a PPI plus an antibiotic (usually amoxicillin) and continues with another 5 days of a PPI plus 2 antibiotics (usually clarithromycin and an imidazole). None of these patients in the meta-analysis had undergone any previous H. pylori eradication regimen. Various tests were utilized to diagnose H. pylori infection: fecal antigen, biopsy urease, histology, or urea breath testing. Study populations included were evaluated for heterogeneity in terms of diagnosis (eg, duodenal ulcer vs gastric ulcer vs nonulcer dyspepsia), patient age, study quality, and documentation of resistance to clarithromycin and/or imidazoles. Results indicated that sequential therapy was superior to traditional triple therapy in all subgroup analyses. Studies were almost exclusively performed in Italy, and the possibility of publication bias was raised (funnel plot testing and other statistical maneuvers). There were differences in methodology among the studies selected for this meta-analysis. However, these authors' results mirrored two previous reviews. Outside the U.S., rates of eradication therapy failure have been as high as 40 to 50%. Most U.S. studies now report 25% failure rates. Jafri et al comments that there are no comparisons of sequential therapy in significant numbers of U.S. patients nor has this approach been compared to quadruple therapy (PPI, bismuth salt, tetracycline, imidazole) or with 14 days of traditional triple therapy.

Commentary

In an accompanying editorial, Australian Nobel Laureate Barry Marshall (Ann Intern Med. 148:12:962-963) states that sequential therapy is both rational and practical. He asserts that the cost of sequential therapy should be comparable to traditional triple therapy, adherence should be good, and the effects of the sequential regimen on H. pylori's microenvironment should favor improved eradication by major inhibition (8-10 log reduction) of most H. pylori during the first 5 days of therapy and elimination of the far fewer remaining deep-seated organisms during the final 5 day period. This reviewer (MR) agrees that H. pylori infection remains a source of major morbidity and mortality in many parts of the world. Fortunately for us, the situation in most of North America is far different. H. pylori infection is declining here, and its virulence also appears to be decreasing. Nevertheless patients with peptic ulcer disease or MALT lymphoma found to have H. pylori infection clearly continue to require eradication of this organism. The situation is far less clear for other indications such as nonulcer dyspepsia or the incidental discovery of the organism. If therapy is to be undertaken, there appears to be some fairly compelling initial evidence that sequential therapy may be the best available option. Further studies are awaited, preferably focused on North American populations and comparing sequential therapy to 14-day triple therapy and/or quadruple therapy.