Non‐Bismuth Quadruple Concomitant Treatment for Helicobacter pylori Eradication: A Systematic Review and Meta‐Analysis

BACKGROUND: Standard triple therapy fails to eradicate Helicobacter pylori (H. pylori) in at least 20% of the cases, largely due to antibiotic resistance. Non-bismuth concomitant quadruple therapy has emerged as a widely used alternative therapy. AIM: To conduct a meta-analysis evaluating the efficacy and safety of concomitant therapy-comprising a proton pump inhibitor, clarithromycin, amoxicillin, and a nitroimidazole-for H. pylori eradication. METHODS: A systematic search of PubMed, EMBASE, and relevant conference abstracts was conducted through November 2025. Meta-analyses included studies assessing concomitant therapy and comparisons with standard triple, sequential, hybrid, and bismuth-based quadruple therapies. RESULTS: A total of 144 studies (92 randomized clinical trials), involving 26,467 patients were included. Pooled eradication rates for concomitant therapy were 86% (intention-to-treat) and 91% (per-protocol). Analysis of randomized clinical trials showed that concomitant therapy demonstrated significantly higher efficacy than triple therapy (risk difference [RD] = 0.11; 95% CI = 0.08-0.13) and sequential therapy (RD = 0.03; 0.01-0.05), but similar efficacy to hybrid and bismuth quadruple regimens (containing nitroimidazole-tetracycline and clarithromycin-amoxicillin). Concomitant therapy achieved 87% and 95% eradication rates in clarithromycin- and metronidazole-resistant strains, respectively, but only 67% in dual-resistant strains. Adverse events were frequent (38%), although generally mild. CONCLUSIONS: Concomitant therapy is a highly effective first-line option for H. pylori eradication, particularly in single clarithromycin- or nitroimidazole-resistant strains. However, its efficacy is reduced in dual-resistant cases, in which alternative regimens may be preferred. Overall, its efficacy is comparable to that of hybrid and bismuth quadruple therapy. Its tolerability is generally acceptable.