Comparative Efficacy and Pharmacological Heterogeneity of Individual Potassium-Competitive Acid Blockers: A Systematic Review and Network Meta-Analysis

Background & Aims: Vonoprazan consistently demonstrates superior H. pylori eradication (HPE) rates compared to other P-CABs, yet the pharmacological basis for this heterogeneity remains unclear. We hypothesized that acid dissociation constant (pKa)—which determines acid stability and parietal cell accumulation—may explain differential efficacy among individual P-CABs. This study aims to examine whether pKa values predict clinical efficacy of P-CABs for HPE and erosive esophagitis (EE) healing. Methods: SR and network meta-analysis was conducted. RCTs comparing P-CABs with PPIs were identified from core databases (~January 2026). Risk of bias was assessed using RoB 2.0 and certainty of evidence using GRADE. Results: Thirty RCTs (7639 patients) were included for HPE. High-pKa P-CABs (vonoprazan 9.06, keverprazan 9.12) achieved 82–84% eradication in clarithromycin-resistant infections versus 32-40% with PPIs, while low-pKa P-CAB achieved only 47.8% (NS vs PPI). For EE (10 RCTs; 4,196 patients), high-pKa zastaprazan (9.95) achieved 100% LA Grade C/D healing versus 83.3% with esomeprazole, whereas low-pKa P-CABs showed inferior outcomes. Spearman correlation analysis revealed a positive association between pKa and efficacy (ρ=0.80). However, fexuprazan (pKa 9.04) showed PPI-equivalent outcomes despite high pKa, highlighting pKa as necessary but not sufficient for clinical efficacy. Network ranking confirmed high-pKa P-CABs as top-ranked agents. No publication bias was detected. Conclusion: P-CAB efficacy may not be uniform across the class. High-pKa P-CABs (≥9.0) were associated with higher eradication rates in clarithromycin-resistant infections and superior healing in severe esophagitis, whereas low-pKa P-CABs showed limited advantages over PPIs. pKa may serve as a hypothesis-generating pharmacological parameter, though all P-CAB comparisons were indirect and prospective validation is needed.