An update of the official clinical practice guideline of the American Thoracic Society (ATS), the European Respiratory Society (ERS), the Japanese Respiratory Society (JRS), and the Latin American Thoracic Association (ALAT) summarizing all available evidence on treatment of idiopathic pulmonary fibrosis (IPF) provided conditional recommendations for treatment with novel agents such as pirfenidone and nintedanib for patients with IPF in 2015. The use of nintedanib to treat IPF was based on three randomized controlled trials (phase 2 trial by Richeldi L et al., IMPULSIS-1, and IMPULSIS-2 trials [Tables 1 and 2]). Pooled analysis of these three trials showed a relative risk (RR) of 0.70 (95% CI, 0.47 to 1.03; moderate confidence) for mortality and a hazard ratio (HR) of 0.47 (95% CI, 0.17 to 1.29; low confidence) for acute exacerbations. A benefit was seen with nintedanib for the outcome number of patients with more than 10% absolute decline in forced vital capacity (RR, 1.15; 95% CI, 1.06 to 1.25; moderate confidence). The rate of reported adverse events was significantly higher in patients treated with nintedanib (high confidence), but not for serious adverse events (high confidence). [1]
Pirfenidone was also suggested in patients with IPF (conditional recommendation, moderate confidence in estimates of effect) based on the CAPACITY trial (Table 3.), the combined results of two large-scale RCTs, and the ASCEND trial (Table 4; with the stricter patient selection criteria compared to the CAPACITY trial). The pooled results from these trials suggested improved mortality with pirfenidone (RR, 0.70; 95% CI, 0.47 to 1.02; moderate confidence). Pirfenidone reduced the rate of forced vital capacity (FVC) decline (standardized mean difference, 0.23; 95% CI, 0.06 to 0.41; high confidence). Overall, both nintedanib and pirfenidone were suggested in patients with IPF (conditional recommendation, moderate confidence in estimates of effect). Recommendations regarding the regular antiacid treatment for patients with IPF were limited to the conditional recommendation with very low confidence in estimates of effect. The guidelines do not generally recommend using imatinib, combination therapy of N-acetylcysteine (NAC), azathioprine, and prednisone, ambrisentan (regardless of the presence or absence of pulmonary hypertension), sildenafil, and bosentan in managing IPF. [1]
A 2019 review article from the American Journal of Managed Care provided a brief overview of idiopathic pulmonary fibrosis (IPF) and available pharmacological agents. Idiopathic pulmonary fibrosis is a chronic, progressive-fibrosing interstitial lung disease of unknown origin with a highly variable disease course. The management of IPF includes alleviating symptoms, improving health status, preserving lung function, maintaining adequate oxygenation with supplemental oxygen, minimizing adverse events, and reducing the frequency of acute exacerbations. Nintedanib and pirfenidone are two FDA-approved agents recommended by the guidelines in treating IPF. Both treatments have been shown to slow disease progression and impact survival, although neither agent is indicated to be curative. [2]
Nintedanib is an intracellular inhibitor that targets multiple tyrosine kinase receptors that appeared to be involved in lung fibrosis, including the vascular endothelial growth factor, fibroblast growth factor, and platelet-derived growth factor receptors. The data from the INPULSIS trials (Table 1 and Table 2.) demonstrated the efficacy of nintedanib in slowing the annual rate of decline of forced vital capacity (FVC) compared with placebo. Several well-recognized warnings and precautions include the potential of drug-induced liver injury, embryo-fetal toxicity, bleeding, arterial thromboembolic events, and gastrointestinal perforation. [2]
Pirfenidone is an orally bioavailable antifibrotic agent approved for the treatment of IPF. Based on the results from the phase 3 ASCEND (Table 3.) and CAPACITY (Table 4.) trials, 2,403 mg/day of pirfenidone significantly reduced the decline in FVC, improved progression-free survival time, and increased the 6-minute walk test distance compared with placebo among patients with IPF. [2]
The use of pirfenidone as add-on therapy to nintedanib was compared with nintedanib alone in an open-label randomized trial. After 12 weeks of treatment, the combination therapy resulted in significantly less decline in mean FVC from baseline compared with nintedanib alone (-13.3 mL vs. -40.9 mL), and the incidence of gastrointestinal adverse events was higher in the nintedanib with add-on pirfenidone group (69.8%) than nintedanib alone (52.9%). The author emphasizes that more evidence supporting the combination therapy is required given the exploratory nature of this analysis, and the potential for adverse events must also be weighed against the benefits of these agents. [3]
A 2016 meta-analysis evaluating the effectiveness and safety of pirfenidone, nintedanib, and N-acetylcysteine (NAC) in the treatment of IPF included a total of 10 trials (N= 3,847 treated n= 2,254; placebo n= 1,593). Study results indicated that both pirfenidone (0.26, 95% confidence interval [CI] 0.15 to 0.37; p<0.001) and nintedanib (0.37, 95% CI 0.26 to 0.48; p<0.001) were associated with significant improvement in the standard mean difference (SMD) of change from baseline in forced vital capacity (FVC) but not NAC (0.10, 95% CI -0.11 to 0.30; p> 0.05). The risk difference (RD) of FVC decline ≥ 10% was also significantly improved in pirfenidone (-0.10, 95%CI -0.14 to -0.06; p<0.001) and nintedanib (-0.12, 95% CI -0.21 to -0.03; p<0.05), but not NAC (-0.06, 95%CI -0.20 to 0.08; p> 0.05), compared with placebo. Additionally, the use of nintedanib resulted in a significant reduction of acute exacerbation (RD -0.05, 95%CI -0.10 to -0.01; p<0.05) compared with placebo. The authors concluded that head-to-head comparative trials between the approved doses of pirfenidone and nintedanib were necessary to confirm the rank of effectiveness emerging from this meta-analysis. The role of NAC in specific clusters of IPF patients needed to be further explored in trials with combined, sequential, or adjunctive treatment regimens. [4]
A 2021 systematic review and meta-analysis including phase 2 and phase 3 randomized controlled trials (N= 6 RCTs) in adults (aged ≥ 18 years) with idiopathic pulmonary fibrosis (IPF), compared the efficacy of pirfenidone, nintedanib, and pamrevlumab in slowing the rate of forced vital capacity (FVC) decline and mortality in patients with idiopathic pulmonary fibrosis (IPF) versus placebo.The three drugs were more effective than placebo in reducing the rate of FVC (pirfenidone: d= 3.30%, 95% Confidence interval [CI] 2.15 to 4.45; nintedanib: d= 3.15%, 95% CI 2.35 to 3.95; pamrevlumab: d= 4.30%, 95% CI 0.45 to 8.15). While these results align with those results relating to change from baseline FVC in liters, each drug showed efficacy on 10% reduction in FVC (pirfenidone: odds ratio [OR] 0.57, 95% CI 0.45 to 0.74; nintedanib: OR 0.66, 95% CI 0.51 to 0.85; pamrevlumab: OR 0.24, 95% CI 0.08 to 0.73). Of note, only pirfenidone showed an effect on all-cause mortality (OR 0.50; 95% CI 0.31 to 0.83). Overall, the authors concluded that pamrevlumab offers efficacy in slowing the decline in FVC compared with pirfenidone and nintedanib which makes it a potential IPF treatment in phase 3 studies; however, the meta-analysis was subject to publication bias since it excluded non-English studies. Additionally, the treatment duration varied from 48 weeks to 52 weeks which may have affected the results. [5]