Quadruple therapy consisting of omeprazole plus a capsule combining bismuth subcitrate potassium, metronidazole, and tetracycline was superior at eradicating Helicobacter pylori infection, compared with the "gold standard" of three separate capsules containing omeprazole, amoxicillin, and clarithromycin, according to a report published online Feb. 21 in the Lancet.
The eradication rate in the intention-to-treat population was 80% with quadruple therapy and 55% with standard triple therapy (given for 10 days and 7 days, respectively), and the main reason for this difference was resistance to the clarithromycin in standard therapy. "Although rates of metronidazole resistance are also high, clarithromycin resistance reduces the efficacy of standard therapy, whereas metronidazole resistance has little effect on the efficacy of quadruple therapy," said Dr. Peter Malfertheiner of Otto-von-Guericke University in Magdeburg, Germany, and his associates in the Pylera Study Group.
This randomized, multicenter, phase III clinical trial is "the first large-scale comparative study of the efficacy and safety of standard and quadruple therapy for the eradication of H. pylori in nearly a decade." Antimicrobial resistance has increased during that time, and newer formulations of quadruple therapy needed to be assessed, the authors noted.
Although this study was designed as a noninferiority trial, it was powered to detect superiority.
The trial was conducted at 39 sites in France, Germany, Ireland, Italy, Poland, Spain, and the United Kingdom. The study was completed by a total of 204 patients who were assigned to receive quadruple therapy, and 195 who were assigned to receive standard triple therapy.
The primary efficacy outcome was eradication of H. pylori as established by two negative urea breath tests performed approximately 6 weeks and 10 weeks after treatment was concluded. This outcome was achieved in 93% of the quadruple therapy group in the per-protocol population, compared with 70% of the standard therapy group.
"Treatment with quadruple therapy fulfilled criteria for noninferiority to standard therapy in the per-protocol population. Accordingly, the intention-to-treat population was used for superiority testing, and quadruple therapy was significantly better than standard therapy in eradicating H. pylori," the investigators said (Lancet 2011 [doi:10.1016/S0140-6736(11)60020-2]).
Post hoc analysis confirmed the superiority of quadruple therapy in the study population as a whole. Further analyses of subgroups of patients showed that it remained superior regardless of whether patients had peptic ulcer disease or nonulcer dyspepsia.
The percentage of patients with treatment-emergent adverse events was similar between the two groups (approximately 50%), as was the percentage who discontinued therapy because of adverse effects (fewer than 2%). Severe adverse effects were more frequent with standard therapy.
Previous reports have raised concerns about toxic effects related to bismuth, with rare reports of heavy-metal poisoning and encephalopathy. "In our trial, with little bismuth exposure and use of a colloidal-bismuth subcitrate formulation, bismuth concentrations were below the toxic threshold," which should reassure clinicians on this point, Dr. Malfertheiner and his colleagues said.
The study findings suggest that "in regions with high levels of clarithromycin resistance, treatment with quadruple therapy should be considered as first-line therapy for H. pylori eradication."
This study was designed and funded by Axcan Pharma, maker of the bismuth-metronidazole-tetracycline capsule. Some of the authors received payment from Axcan for research and clinical trials. Two of the authors are Axcan employees.