Oral Antifibrotic Agents for the Treatment of Progressive Pulmonary Fibrosis: A Systematic Review and Network Meta-Analysis of Randomized Controlled Trials

Introduction: Progressive pulmonary fibrosis (PPF) is a form of interstitial lung disease characterized by irreversible fibrotic progression and deteriorating lung function. Although antifibrotic agents approved for idiopathic pulmonary fibrosis (IPF) are used in PPF, their comparative efficacy and safety remain unclear. Methods: A Bayesian network meta-analysis (NMA) was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) NMA guidelines. Randomized controlled trials (RCTs) assessing oral antifibrotic agents, including Nintedanib, Pirfenidone, and Nerandomilast, in PPF were identified from major databases up to May 2025. The outcomes assessed included alterations in forced vital capacity (FVC), all-cause mortality, and serious adverse events (SAEs). Treatments were ranked using surface under the cumulative ranking curve (SUCRA) values. Results: Four RCTs (n = 1,209) were incorporated into the analysis. The combination of Nintedanib with both low-dose and high-dose Nerandomilast (NRD_LN and NRD_HN) demonstrated the greatest efficacy in reducing FVC decline compared to placebo, with mean differences (MDs) of 200 mL (95% confidence interval [CI]: 133 to 268) and 185 mL (95% CI: 117 to 253), respectively. Nintedanib monotherapy followed, with an MD of 107 mL (95% CI: 65 to 149). Combination therapies that included Nerandomilast were more effective than either Nerandomilast or Nintedanib monotherapy but did not surpass the efficacy of Pirfenidone. None of the treatments significantly reduced all-cause mortality or increased SAEs, and no regimen demonstrated a clear safety advantage. Pirfenidone demonstrated the lowest odds ratios for mortality (OR = 0.29; 95% CI, 0.03–2.30) and serious adverse events (OR = 0.69; 95% CI, 0.35–1.40), although these differences were not statistically significant. Conclusion: Antifibrotic therapies demonstrated efficacy in slowing FVC decline among patients with PPF, with Nintedanib, either used alone or in combination with Nerandomilast, showing the highest efficacy. These findings support the use of antifibrotics in PPF and emphasize the need for future head-to-head trials and long-term outcome assessments.