title: Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis.
abstract: The prevalence of idiopathic pulmonary fibrosis (IPF) is increasing every year. Pirfenidone and nintedanib were approved for treatment of IPF in 2014, but they received only a conditional recommendation for use and, thus, to date no drugs are strongly recommended for IPF. The aim of this study was to assess the effectiveness and safety of the currently approved drugs for IPF and N-acetylcysteine (NAC), the most debated drug in the last update of guidelines for IPF treatment.
  
  
  
  RCTs in IPF were identified searching from databases of published and unpublished studies. The influence of pirfenidone, nintedanib and NAC on clinical outcomes, safety, and mortality was assessed via pair-wise meta-analysis.
  
  
  
  Ten papers (3847 IPF patients; 2254 treated; 1593 placebo) were included in this study. Our results showed that both pirfenidone and nintedanib, but not NAC, were significantly effective in reducing FVC decline and the risk of FVC ≥10% decline in percent predicted over 12 months. Nintenadib significantly protected against the risk of acute exacerbation and mortality. Pirfenidone and nintedanib showed a similar and good safety profile, whereas NAC provided a signal for increased adverse events.
  
  
  
  The rank of effectiveness emerging from this meta-analysis represents an indirect indicator of potential differences between currently approved doses of pirfenidone and nintedanib. Direct comparisons are necessary to assess this matter, and well designed bench-to-bedside studies would permit to understand the potential of combined, sequential, or adjunctive treatment regimens in which perhaps NAC may have a role for specific clusters of IPF patients.
authors.affiliation: University of Rome Tor Vergata, Department of Systems Medicine, Unit of Respiratory Clinical Pharmacology, Rome, Italy; University of Rome Tor Vergata, Department of Systems Medicine, Chair of Respiratory Medicine, Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Rogliani
authors.affiliation: University of Rome Tor Vergata, Department of Systems Medicine, Unit of Respiratory Clinical Pharmacology, Rome, Italy. Electronic address: luigino.calzetta@uniroma2.it.
authors.forename: Luigino
authors.initials: L
authors.lastname: Calzetta
authors.affiliation: University of Rome Tor Vergata, Department of Systems Medicine, Chair of Respiratory Medicine, Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Cavalli
authors.affiliation: Second University of Naples, Department of Experimental Medicine, Unit of Pharmacology, Naples, Italy.
authors.forename: Maria Gabriella
authors.initials: MG
authors.lastname: Matera
authors.affiliation: University of Rome Tor Vergata, Department of Systems Medicine, Unit of Respiratory Clinical Pharmacology, Rome, Italy; University of Rome Tor Vergata, Department of Systems Medicine, Chair of Respiratory Medicine, Rome, Italy.
authors.forename: Mario
authors.initials: M
authors.lastname: Cazzola
mesh_terms: D000111:Acetylcysteine / Q000009:adverse effects / Q000627:therapeutic use*; D000893:Anti-Inflammatory Agents / Q000009:adverse effects / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000627:therapeutic use; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis / Q000188:drug therapy* / Q000503:physiopathology; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D017410:Practice Guidelines as Topic; D011728:Pyridones / Q000009:adverse effects / Q000627:therapeutic use*; D016032:Randomized Controlled Trials as Topic; D016896:Treatment Outcome
chemical_list: D000893:Anti-Inflammatory Agents; D004791:Enzyme Inhibitors; D007211:Indoles; D011728:Pyridones; C093844:pirfenidone; C530716:nintedanib; D000111:Acetylcysteine
keywords: IPF; Meta-analysis; Therapy