Comparative Long-Term Effectiveness of Nintedanib and Pirfenidone in Idiopathic Pulmonary Fibrosis: A Systematic Literature Review

Abstract

Introduction: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive interstitial lung disease. Pirfenidone and nintedanib slow progression, but no head-to-head randomized trials have tested their long-term effectiveness, particularly in real-world and advanced disease.

Objective: To synthesize and appraise the long-term comparative effectiveness and safety of nintedanib versus pirfenidone in IPF.

Methods: We conducted a systematic review (PubMed, Embase, Cochrane CENTRAL; to March 2025) of studies ≥12 months in adults with IPF. Outcomes included forced vital capacity (FVC) decline, mortality, exacerbations, hospitalizations, adverse events, and quality of life. Risk of bias was assessed with Cochrane RoB 2.0, Newcastle–Ottawa Scale, and AMSTAR-2.

Results: Fourteen studies met criteria. Both agents reduced annual FVC decline by ~50% versus placebo. Long-term extensions showed sustained effects: pirfenidone ~141–150 mL/year and nintedanib ~125 mL/year. A post hoc analysis (CleanUP-IPF) favored nintedanib at 12 months for FVC (+106 mL; 95% CI, 34–178), a difference that diminished by 24 months. Mortality and exacerbation rates were broadly comparable. Safety profiles differed: pirfenidone more often produced gastrointestinal and cutaneous events; nintedanib was associated with diarrhea and transaminase elevations.

Conclusions: Evidence supports broadly comparable long-term efficacy of pirfenidone and nintedanib in IPF, with distinct tolerability profiles that may guide individualized selection. Real-world data corroborate benefits in advanced disease and comorbidity. The absence of direct randomized comparisons limits certainty; adequately powered head-to-head RCTs and biomarker-guided treatment strategies are needed.