NPC Archive Item: Sequential therapy may improve eradication rates for H pylori

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Jafri NS, Hornung CA, Howden CW. Meta-analysis: Sequential therapy appears superior to standard therapy for Helicobacter pylori infection in patients naïve to treatment. Ann Intern Med 2008; 148 published early on-line 20 May 2008

May 22nd 2008

This meta-analysis of RCTs largely conducted in Italy found that sequential therapy, involving 3 different antibiotics may be superior to standard triple therapy for H pylori treatment-naïve patients. However, this MA and its constituent RCTs have several methodological limitations, and the H pylori eradication rate with standard regimens in this MA (77%) was lower than that in the MA conducted by NICE (80 to 85%).  In addition a sequential regimen is more complicated for patients, and if a sequential regimen was widely adopted patients with failed eradication would have limited options for further treatment, as they would already have received 3 different antibiotics. Clinicians should continue to prescribe standard 7-day triple therapy regimens recommended by NICE pending further analyses.

What was the study and what did it find?
This meta-analysis evaluated data from 10 randomised controlled trials (RCTs) (n=2747) comparing sequential and standard triple therapies in treatment-naïve patients with documented H pylori infection. 10-day sequential therapy (5 days of proton pump inhibitor [PPI] + usually amoxicillin, followed by 5 days of PPI + usually clarithromycin & imidazole) was superior to 7 or 10-day standard triple therapy in increasing the crude rate of H pylori eradication (93.4% vs. 76.9%).

What’s the background to this?
For patients who test positive for H pylori infection, the NICE clinical guideline on the management of dyspepsia (CG17) recommends a 7-day, twice-daily course of treatment consisting of a full-dose PPI, with either metronidazole 400mg and clarithromycin 250mg, or amoxicillin 1g and clarithromycin 500mg. Eradication is effective in 80–85% of patients, which is higher than the eradication rate for standard triple therapy found in this study (76.9%, 95%CI 71.0% to 82.8%).

What action should you take?
Clinicians should not change their practice as a result of this study, and continue to follow NICE guidance. Sequential therapy for 10 days is a complicated regimen for patients, involving 4 different drugs, and the study has several important limitations (see later) which affects its generalisability to UK clinical practice.

Study details
This was a meta-analysis of data from 10 randomised trials (n=2747) that compared sequential and standard triple therapies in treatment-naïve patients with documented H pylori infection. The crude rates of H pylori infection were 93.4% (95%CI 91.3% to 95.5%) for sequential therapy and 76.9% (95%CI 71.0% to 82.8%) for standard triple therapy; relative risk reduction, 71% (95%CI 64% to 77%); absolute risk reduction, 16% (95%CI 14% to 19%). See the full paper for more details.

What are the limitations of the study?
All 10 studies included in the meta-analysis were conducted in Italy, which may not reflect antimicrobial resistance patterns in the UK. Six studies were open-label and only one was double-blinded. There were variations in the study design (for example, inclusion criteria, duration and dosing of antibiotic therapy).

Most studies compared 7 days of a standard regimen with a 10 day sequential regimen. It is unclear whether a difference of 3 days duration of treatment affects eradication rates, but the NICE MA found that the eradication rate increases by 9% (95%CI 5 to 14%) when moving from 7 days to 14 days of eradication treatment. However, NICE estimated that the two week regimen costs an additional £16.30 for 0.03 months free from dyspepsia over one year. NICE stated this was “prohibitively expensive” when subjected to cost effectiveness modelling. We are unaware of any cost effectiveness analysis of sequential regimens versus standard regimens of any duration.

The investigators found strong evidence for publication bias, small numbers of patients in some RCTs, and some relatively low quality RCTs (only 5 were considered high quality). Median adherence rates were 97.4% for sequential therapy and 96.8% for standard triple therapy and it is unlikely these rates would be achieved in routine clinical practice, particularly as sequential therapy is a complicated 10 day regimen.

Finally, patients with failed eradication would have limited options for further treatment, as they would already have received three different antibiotics. For patients requiring a second course of eradication, NICE recommends a regimen that does not include the antibiotics given previously.

There was no external funding source.

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