Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis

Abstract

Background

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.

Methods

RCTs in IPF were identified searching from databases of published and unpublished studies.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.

Results

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.

Conclusions

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.

Introduction

Idiopathic pulmonary fibrosis (IPF) has been defined as a distinctive type of chronic, progressive fibrosing interstitial pneumonia of unknown cause, occurring primarily in older adults, limited to the lungs, and characterized by a histological pattern of usual interstitial pneumonia (UIP) [1]. The prevalence estimate ranges from 2 to 43 cases per 100,000 in the general population, depending by the definition used to identify the cases of IPF, differences in study designs and populations [1], [2]. On the other hand, a recent study on data from the years 2000–11 showed that the annual cumulative prevalence increased from 202 to 495 cases per 100,000 people aged 65 years and older [3].

Although the prevalence of IPF is increasing annually, in 2011 the ATS/ERS/JRS/ALAT Committee on IPF did not find sufficient evidence to support the use of any specific pharmacologic therapy for patients suffering from IPF [1]. Nevertheless, paradoxically the Committee recommended some therapeutic agents accordingly with their evidence-based effectiveness.

Recently, the prior guideline in 2011 have been re-analyzed and, consequently, the treatment recommendation have been updated, when necessary, in agreement with results of recent randomized clinical trials (RCTs) [4].

Surprisingly, even in this update no drug was strongly recommended for use in IPF, although pirfenidone and nintedanib, which are the only currently approved drugs for pharmacological therapy of IPF by 2014, received a conditional recommendation for use, with moderate confidence in effect estimates [4]. Nevertheless, the Authors of this document did not provide suggestions for or against combination regimens or sequential therapies, excluded the recommendation against using prednisone in combination with azathioprine and N-acetylcysteine (NAC) [4].

Contrary to the statement concerning other drugs, the recommendation not to use NAC as monotherapy in patients with IPF generated a wide debate in the Committee, especially since it is not yet clear if a subgroup of patients with IPF characterized by significant oxidative impairment could benefit from NAC. Furthermore, the safety profile of NAC administered as inhaled or oral monotherapy did not suggest for treatment discontinuation [4].

Thus, the current scenario of clinical practice guideline for the treatment of IPF [4] shows considerable differences compared with the previous recommendations [1]. In particular, nintedanib has been added as recommended drug, whereas the recommendation on pirfenidone has been switched from “against” to “for” use [4]. These substantial variations after only 4 years, explained by the findings of recent RCTs, indicate that advances have been made in the clinical management of IPF since the 2011, and that well designed RCTs may provide the rationale for reversing previous recommendations.

In view of the lack of head-to-head RCTs of treatment interventions, considering the confounding findings resulting from a plethora of reviews and meta-analysis on IPF therapy [5], [6], [7], [8], [9], [10], [11], and also the recent positive evidences on combination therapy including NAC [12], we have carried out a treatment comparison by systematic review and synthesis of the available clinical variables to evaluate the effectiveness and safety of pirfenidone, nintedanib and NAC for IPF treatment vs. placebo, with unbiased analyses that incorporated exclusively the data from high quality RCTs lasting at least 6 months.