Supplementary Material for: A Network Meta-Analysis of Pharmacological Treatments for Gastric Mucosal Protection in Artificial Ulcers Following Endoscopic Submucosal Dissection (ESD) of the Stomach

Background: Proton pump inhibitor (PPI) monotherapy is standard for artificial ulcer healing after gastric endoscopic submucosal dissection (ESD), but evidence on the efficacy of PPI combined with gastric mucosal protectants remains inconclusive.
Aim: To compare the efficacy of 10 mucosal protectants combined with PPIs through a network meta-analysis (NMA).
Methods: We systematically searched PubMed, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov until January 2025. Included were 20 randomized controlled trials (RCTs, n=2000) comparing PPI monotherapy versus PPI combined with protectants (e.g., rebamipide, ecabet, polaprezinc) or active controls. Primary outcomes included ulcer area reduction, healing rates (4/8 weeks), longest ulcer diameter, and bleeding risk. Frequentist random-effects models synthesized risk ratios and mean differences with 95% CIs. Consistency was evaluated using design-by-treatment interaction and node splitting. Risk of bias (RoB 2.0) was assessed at the outcome level. Certainty of evidence was graded with GRADE.
Results: Bismuth subcitrate-magnesium granules (BMG) + PPI most effectively reduced 4-week ulcer area (mean difference [MD]: -62.50 mm², 95% CI: -87.25 to -37.75 vs. PPI; SUCRA=94%). Ecabet sodium (EB) + PPI achieved the highest 8-week healing rate (risk ratio [RR]: 7.71, 95% CI: 5.52--9.91). Hydrotalcite (HT) + PPI best reduced ulcer diameter (MD: -1.87 mm), while teprenone (TN) + PPI optimally prevented bleeding (RR: -3.41, 95% CI: -5.43 to -1.38). Rebamipide + PPI showed efficacy heterogeneity, particularly in large ulcers (>40 mm).
Conclusions: PPI-based combinations likely accelerate healing versus PPI alone, but conclusions are hypothesis-generating given indirect evidence and regional concentration of trials. Combination therapy outperforms PPI monotherapy. BMG+PPI is optimal for early ulcer healing, EB+PPI for long-term healing, HT+PPI for diameter reduction, and TN+PPI for bleeding prevention. Stratified regimens by ulcer characteristics are recommended.