Sequential Therapy Is Superior to Standard Therapy for Treatment of Helicobacter pylori Infection: A Systematic Review and Meta-Analysis

Purpose: Authorities continue to recommend standard PPI-based triple or quadruple therapy for the treatment of H. pylori infection despite failure of eradication in around a quarter of patients. Sequential therapy (ST) (5 days of PPI + 1 antibiotic followed by 5 days of PPI + 2 other antibiotics) may be more efficacious. Methods: We performed a systematic search for randomized controlled trials (RCTs) comparing ST with standard therapy for H. pylori infection in Medline, EMBASE, and the Cochrane Central Register of Controlled Trials using Pubmed, Google Scholar and Ovid as search engines without language restriction. We also hand searched the references of original/review articles and evaluated symposia proceedings, poster presentations and abstracts from major gastrointestinal meetings. Relative risks (RR) were calculated for individual trials; data were pooled using a fixed effects model. Relative risk reduction (RRR), absolute risk reduction (ARR) and number needed to treat (NNT) were calculated and are reported with 95% confidence intervals (CI). Study quality was assessed with the Jadad scale. Results were subjected to sensitivity analysis. Results: 8 RCTs comprising 2202 patients (1071 men) met eligibility criteria. Mean age ranged from 9.9–70 years. 1095 patients were randomized to sequential therapy and 1107 to standard therapy. ST was superior with respect to eradication rates; RRR = 22% (95% CI: 18–27%), ARR = 17% (14–20%), NNT = 6 (5–7), and for ulcer healing; RRR = 17% (10–25%), ARR = 11% (7–16%), NNT = 9 (6–14). Compliance was similar in both arms (RR 0.99, 95% CI: 0.97–1.01). ST was superior in adults (RRR = 22% (18–27%), ARR = 17% (14–20%), NNT = 6 (5–7)), as well as in smokers (RRR = 25% (9–43%), ARR = 19% (9–29%), NNT = 5 (3–11)); and in patients with non-ulcer dyspepsia (NUD) (RRR = 25% (18–33%), ARR = 19% (14–23%), NNT = 5 (4–7)). When evaluating only RCTs of high quality (Jadad score ≥ 3) there was still a benefit to ST (RRR = 17% (11–24%), ARR = 14% (9–18%), NNT = 7 (5–11)). Lack of significant heterogeneity was noted among RCTs, except for ulcer healing. Side effect profile was similar in both arms. Conclusion: ST appears superior to standard therapy for eradication of H. pylori infection and ulcer healing. It also produced superior eradication rates in smokers and in patients with NUD. These outcomes were consistent by sensitivity analysis. However, all identified RCTs were from Italy, and results may not be replicable in the US. This approach should be tested in US-based RCTs.