Efficacy of Potassium-Competitive Acid Blockers Versus Proton Pump Inhibitors in Eradication Regimens for Clarithromycin-Resistant Helicobacter pylori: A Systematic Review and Meta-Analysis

Background: Clarithromycin resistance represents the primary obstacle to the success of conventional proton pump inhibitor (PPI)-based triple therapy for Helicobacter pylori (H. pylori) eradication. Potassium-competitive acid blockers (P-CABs) offer faster and more potent acid suppression, which may enhance the efficacy of eradication regimens in this resistant population. The present study aimed to systematically evaluate the comparative efficacy of P-CAB-based versus PPI-based eradication regimens specifically in adult patients with documented clarithromycin-resistant H. pylori infection. Methods: This systematic review and meta-analysis was conducted in accordance with the PRISMA 2020 guidelines. The protocol was prospectively registered in PROSPERO (CRD420261407870). A systematic literature search was performed in Embase; MEDLINE/PubMed; CENTRAL; and Web of Science for articles published from 1 February 2015 to 31 March 2026. The included evidence comprised randomized and non-randomized comparative studies, as well as non-comparative studies. The primary outcome was the H. pylori eradication rate. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a random-effects model (DerSimonian–Laird method). Risk of bias was assessed using RoB 2 for randomized comparative studies, ROBINS-I for non-randomized comparative studies, and the JBI Critical Appraisal Checklist for Case Series for non-comparative studies. Results: A total of 20 unique publications were included; 12 contributed data to the comparative analysis and 9 contributed data to the non-comparative single-arm analysis, with one publication contributing to both analyses. Across the 12 comparative studies, successful eradication was achieved in 464 of 621 patients (74.7%) receiving P-CAB-based regimens and in 301 of 571 patients (52.7%) receiving PPI-based comparators. P-CAB-based regimens were associated with a significantly higher probability of successful eradication compared with PPIs (RR, 1.42; 95% CI, 1.14–1.76; p < 0.00001). Subgroup analysis according to the P-CAB agent demonstrated that vonoprazan-based regimens exhibited the strongest comparative effect (RR, 1.78; 95% CI, 1.55–2.04), while tegoprazan-based regimens also remained superior (RR, 1.26; 95% CI, 1.04–1.54). The benefit of P-CABs was most pronounced in the clarithromycin-containing triple therapy subgroup (RR, 1.79; 95% CI, 1.55–2.07). Conclusions: P-CAB-based eradication regimens are significantly more effective than PPI-based comparators in patients with clarithromycin-resistant H. pylori infection. Further well-designed studies are warranted to determine the optimal antibiotic combinations, treatment durations, and regional applicability of these regimens.