ILD-IPF Update: Issue 14

Pirfenidone Reduces Lung Function Decline in Moderate to Severe IPF Patients: Results from Italian Study

The decline in forced vital capacity (FVC) of 5-10% or more from baseline over a period of six months is associated with an increased risk of a poorer prognosis in patients with idiopathic pulmonary fibrosis (IPF). Although pirfenidone preserves the lung functionality and improves progression-free survival as compared to placebo in patients with early-stage IPF, the effects of pirfenidone are uncertain in patients with advanced-stage IPF. In a retrospective Italian study by Harari et al from IRCCS, Italy, involving 128 patients diagnosed with mild, moderate or severe IPF, compared the decline in lung function monitored during the one-year pirfenidone treatment with the decline measured during the one-year pre-treatment period.

The mean percentage forced vital capacity (FVC) was 75% of predicted, and the mean percentage diffuse lung capacity (DLCO) was 47% (17-120%) of predicted at the baseline. Around 37.5% (n=48) had mild disease (GAP index stage I), 50% (n=64) had moderate IPF (stage II), and 6.3% (n=8) had severe IPF (stage III).

As compared to the pre-treatment period, pirfenidone attenuated the decline in FVC (p = 0.065), but did not influence the decline in DLCO (p = 0.355). When the patients were grouped into mild and severe disease groups based on %FVC level at baseline (>75% and ≤75%), the attenuation of decline in FVC (p = 0.002) was more pronounced in second group of patients. The attenuation of decline in lung function was more pronounced in patients with more severe disease when stratified as per the GAP index at baseline (stage I vs. II/III).

Pirfenidone reduced the rate of annual FVC decline (p = 0.065) especially providing significant treatment benefit for patients with moderate-severe disease. Thus, the drug may also be effective in patients with more advanced disease.

Respir Med. 2015 Jul; 109(7):904-13.

An Update of 2011 Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and debilitating disease which involves fibrosing of interstitial pneumonia in adults due to unknown cause. The American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society (JRS)/Latin American Thoracic Association (LATA) updated the 2011 guideline on IPF treatment after assessing the confidence in effect estimates, the importance of studied outcomes, desirable and undesirable results of treatment, cost, feasibility, acceptability of the intervention, and implications to health equity. Several recommendations were made for or against specific treatment interventions as compared to the previous guideline.

The guideline suggests that the clinicians should use pirfenidone or nintedanib in IPF with a ‘conditional’ or ‘weak’ recommendation. The use of antiacid in IPF patients are also ‘weakly’ recommended which has remained unchanged from the previous guideline. On the other hand, anticoagulation (warfarin) and the triple drug therapy (combination of prednisone, azathioprine and N-acetyl cysteine) were recommended against its use in IPF which shifted from a ‘weak recommendation in 2011 guideline to a ‘strong’ recommendation in current guideline. The clinicians are also suggested not to use imatinib and selective endothelin receptor antagonist (ambrisentan) with a ‘strong’ recommendation in IPF patients.

The guideline suggests not to use phosphodiesterase-5 inhibitor (sildenafil), dual endothelin receptor antagonists (macitentan, bosentan) in IPF with a ‘conditional’ recommendation which were not addressed in 2011 guideline. The guideline still suggests against the use of N-acetylcysteine monotherapy in IPF with ‘conditional’ recommendation.

The committee however, did not make a recommendation regarding treatment of pulmonary hypertension in patients with IPF and the decision was deferred until the next update. Recommendations for multiple other interventions that were addressed in the 2011 guideline (e.g., treatment of acute exacerbation of IPF with corticosteroids, oxygen supplementation, mechanical ventilation, pulmonary rehabilitation, and lung transplantation in general) were not prioritized for an update in this guideline.

In conclusion, the guideline committee hopes to halt the disease progression and ultimately cure the disease with continued high-level and collaborative clinical and basic science research, dedicated efforts and adequate resources and funds.

Am J RespirCrit Care Med July 2015; 192 (2): e3–e19

Real-world Benefit of Pirfenidone Treatment in Everyday Clinical Practice: A Retrospective Cohort Analysis of 63 Patients from Belgium and the Netherlands

Pirfenidone has been evaluated in 4 phase III clinical trials, namely 3 multinational studies (CAPACITY 004, CAPACITY 006 and ASCEND) and a Japanese study. In comparison with placebo group, pirfenidone treatment showed significant reductions in declines in forced vital capacity (FVC) and 6-min walk test distance and increase in progression free survival. Although a classic phase III clinical trial is well defined, the questions are always raised about the applicability of results from clinical trials to daily clinical practice. In order to fill the lack of pertaining information available for health-care professionals, Wijsenbeeket al. have recently published the early clinical experiences of management in IPF patients receiving pirfenidone treatment across three centers (2 in the Netherlands and 1 in Belgium) between April 2011 and October 2013. Their results evaluating safety and effectiveness profile of oral pirfenidone (2403 mg/day) are in agreement with those of ASCEND clinical study.

Although many patient characteristics were similar to ASCEND, the selected patients did have co-morbidities and concomitant medications due to adoption of more realistic approach in daily clinic practice. Furthermore, only 69.8% of patients had a definite usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) compared to 95.7% in ASCEND. The pulmonary function analysis revealed that the mean decline in % FVC was 4.8% from -6 months to baseline and 0.8% after 6 months into therapy. The similar trend of lesser decline was observed in another parameter, diffusing capacity of the lungs for carbon monoxide (DL_CO). More than half (57.1%) of patients encountered treatment-related adverse events (AEs).The estimated progression free survival rate was 0.78. Finally, IPF was concluded to be cause of death in 5 (7.9%) patients.

In conclusion, these results indicate a positive effectiveness profile of pirfenidone in real-world daily clinical practice, congruous with the favorable effects noted in clinical trials. The study also recommends a flexible approach for dose adjustment established on severity of observed AEs and patient’s reaction to dose-alteration.

AdvTher. 2015; 32(7): 691–704