Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis

Abstract

BackgroundThe assessment of treatment response in idiopathic pulmonary fibrosis (IPF) is complicated by the variable clinical course. We examined the variability in the rate of disease progression and evaluated the effect of continued treatment with pirfenidone in patients who experienced meaningful progression during treatment.MethodsThe source population included patients enrolled in the ASCEND and CAPACITY trials (N=1247). Pearson's correlation coefficients were used to characterise the relationship between changes in FVC during consecutive 6-month intervals in the placebo population. Outcomes following a ≥10% decline in FVC were evaluated by comparing the proportion of patients in the pirfenidone and placebo groups who experienced a ≥10% decline in FVC or death during the subsequent 6 months.ResultsA weak negative correlation was observed between FVC changes during consecutive intervals in the placebo population (coefficient, −0.146, p<0.001), indicating substantial variability. Thirty-four (5.5%) and 68 (10.9%) patients in the pirfenidone and placebo groups, respectively, experienced a ≥10% decline in FVC by month 6. During the subsequent 6 months, fewer patients in the pirfenidone group compared with placebo experienced a ≥10% decline in FVC or death (5.9% vs 27.9%; relative difference, 78.9%). There was one (2.9%) death in the pirfenidone group and 14 (20.6%) deaths in the placebo group (relative difference, 85.7%).ConclusionsLongitudinal FVC data from patients with IPF showed substantial intrasubject variability, underscoring the inability to reliably assess therapeutic response using serial FVC trends. In patients who progressed during treatment, continued treatment with pirfenidone resulted in a lower risk of subsequent FVC decline or death.Trial registration numbersNCT01366209, NCT00287729, NCT00287716.

Evaluating disease severity in idiopathic pulmonary fibrosis

“…It seems that continued treatment with pirfenidone in those whose disease has progressed, defined as ⩾10% absolute decline in FVC during the first 6 months of treatment, can still be beneficial as reflected in a lower risk of subsequent FVC decline or death [36].…”

Physiology of the lung in idiopathic pulmonary fibrosis

“…Although the novel antifibrotic agents pirfenidone and nintedanib attenuate the progressive decline in lung function characteristic of IPF [1], reduce the risk of hospitalisation or exacerbation [2,3], and reduce the risk of death [3][4][5], IPF is a very severe disease where clinical decline is common. IPF is of particular interest to the lung physiologist because its clinical expression, which ranges from exertional dyspnoea occurring early in the disease to end-stage respiratory failure, is directly related to alterations in lung physiology.…”

When to start and when to stop antifibrotic therapies

“…Interestingly, only a few patients (5.9%) in the pirfenidone group experienced a further decline of ⩾10% in FVC during the subsequent 6 months, compared to 27.9% of patients in the placebo group, with only one death (2.9%) in the pirfenidone group versus 14 deaths (20.6%) in the placebo group. These data demonstrate that even patients with an initial decline in FVC of ⩾10% may also benefit from continued treatment with pirfenidone compared with placebo [32]. Accordingly, antifibrotic drugs should not be discontinued other than for safety issues.…”

“…What would have been the functional decline in the absence of treatment? A recent article by NATHAN et al [32] tried to answer these intriguing questions. They analysed data coming from the pooled pirfenidone clinical trials, focusing on patients who experienced a significant disease progression, both in the pirfenidone and placebo groups.…”