Real-World Study Analysing Progression and Survival of Patients with Idiopathic Pulmonary Fibrosis with Preserved Lung Function on Antifibrotic Treatment

In the UK, NICE has restricted access of antifibrotics to patients with IPF who have an FVC between 50% and 80% [16]. This decision is based on a complex health economic rationale with the assumption that patients with an FVC above 80% are considered to have a “milder” phenotype of IPF [17]. The aim of this real-world study was to assess baseline demographics and natural progression with respect to lung function and survival in patients with IPF who have an FVC value above 80%. A total of 128 (79.5%) patients in this study were able to access pirfenidone or nintedanib through a CUP. The remaining patients (33, 20.5%) were untreated either because the CUP treatment window had closed or patient choice. The important findings of this study highlight that patients with untreated IPF characterised as “mild” in phenotype with a baseline FVC of 100% and DLCO 54% have a significantly reduced median survival post diagnosis of 2.5 years. This is compared to a survival of 3.5, 3 and 3.75 years in a cohort of patients with IPF treated with pirfenidone, nintedanib and both treatments respectively. This reduced survival in the untreated cohort is despite the fact that the antifibrotic treated cohort of patients with IPF have lower baseline lung function compared to the untreated group.

In this study, there were no significant imbalances observed between the baseline demographics of the untreated and antifibrotic-treated cohorts. The majority of patients were male with an average age of 73 years. This was similar to the INPULSIS trials [6]; however, the average age in the CAPACITY studies [7] was lower at 68 and 66.8 years (study arm 004 and 006 respectively). Additionally, the patients were mostly former smokers with comorbidities such as hypertension, ischaemic heart disease and gastro-oesophageal reflux disease.

We reported similar profiles with respect to adverse effects and discontinuation rates compared to existing clinical trials. The most common adverse effect experienced by the pirfenidone cohort was loss of appetite (19.6%), fatigue (17.9%), indigestion (17.9%) and nausea/vomiting (12.5%). These are of lower frequency compared to the adverse effects noted in the CAPACITY trials: nausea (36%) and skin rash (32%) [8]. Similarly the most common adverse event experienced by the nintedanib cohort in our study was diarrhoea (33.8%); this again was less than those reported in the INPULSIS trials (61.5% and 63.2% in INPULSIS-1 and INPULSIS-2 respectively) [6]. Our adverse events frequencies were lower than those of clinical trials potentially because of reporter bias as clinical assessment and documentation perhaps would not be as robust as clinical trials. Among our patients, 21% permanently discontinued pirfenidone treatment; this rate was greater than that in the CAPACITY trial 006 (19.9%) [7]. Moreover, the discontinuation rate was greater in the patients who received both antifibrotics, as compared to patients receiving pirfenidone and nintedanib (27.8%, 21% and 21% respectively). The most common cause of termination in the case of both drugs was intolerable adverse effects. An average of about two separate adverse effects were reported per patient in the pirfenidone and nintedanib group, whilst about five adverse events were reported on average per patient in the category of patients who received both treatments.

The average baseline FVC in our untreated group was significantly higher than in both pirfenidone and nintedanib groups: 3.55 l (100%) vs 2.85 l (89.7%) pirfenidone (p = 0.012) vs 2.99 l (93.5%) nintedanib (p = 0.04) vs 3.10 (92.7%) both treatments (p = 0.07). One reasonable explanation for this could be the lack of randomisation regarding treatment options. Patients with higher FVC values may have had milder symptoms, and therefore may have declined treatment for this reason. The FVC decline was similar in the untreated group and in the groups receiving pirfenidone and nintedanib (Fig. 1); however, it is difficult to directly compare the groups as the untreated group in our study had a statistically higher baseline FVC, when compared to the treated groups. Patients treated with both antifibrotics had a statistically greater decline compared to those treated with single antifibrotic alone. Again this is because this group has a selection bias as the clinical decision to switch from one antifibrotic to another is based on the presence of an FVC decline of greater than 10%. This cohort of patients treated with both antifibrotics is therefore deemed to be more progressive in nature.

When comparing to existing trials, the 004 arm of the CAPACITY trial showed an 8% FVC decline in the pirfenidone group and a 12.4% decline in the untreated placebo group over 72 weeks [7]. In our study both our pirfenidone and untreated cohorts declined at a much slower rate, by 4.16% and 5.1% in 72 weeks respectively (2.77% and 3.72% per year). The baseline FVC and DLCO in the pirfenidone and placebo arms of the CAPACITY 004 trial were an FVC of 73% and 73.6% respectively and DLCO of 45.4% and 43.7% respectively [7]. This was in comparison to an FVC of 89.7% and DLCO 39.7% for the pirfenidone-treated group and FVC of 100.5% and DLCO 54.3% in the untreated group in our study. The higher baseline FVC in our cohort may explain the slower observed rate of decline in FVC compared to published clinical trials. When comparing to the INPULSIS-1 trial [6] our study had a similar rate of decline in the nintedanib-treated group (− 130.9 ml vs − 104.3 ml) but a slower decline in the untreated group (− 158.1 ml vs 239.9 ml). Again, this is likely to be because of higher baseline lung function in our cohort compared to those in the clinical trials.

A Kaplan–Meier analysis of survival showed similarities between all groups (p = 0.33), despite the treatment groups having a significantly lower baseline lung function (Fig. 2). We found that patients in the treatment groups had a longer median survival length post diagnosis when compared to our untreated group; (3.5 years pirfenidone, 3 years nintedanib, 3.75 years both treatment and 2.5 years untreated). This was despite all of the treatment groups having lower overall baseline FVC and DLCO values. Furthermore, in the untreated cohort, FVC continued to decline at a similar rate to treatment arms in clinical trials and one in five patients died within the time period, despite having a higher FVC and DLCO compared to treated groups in this study or patients with IPF in clinical trials. This leads to the important finding that a higher FVC at diagnosis does not correlate with a milder disease phenotype and that these patients would benefit from treatment. Furthermore, our study showed that receiving antifibrotic treatment was associated with an increased median survival post diagnosis regardless of having a lower FVC, thereby showing the beneficial effects these drugs have with respect to survival in patients with an FVC above 80%. Comparably, in an analysis from the Australian IPF registry, Jo et al. showed that whilst patients with preserved baseline lung function (FVC at least 80%) have a greater survival rate, their disease progression over time is similar to groups with lower FVC values [18]. This shows that the natural history of the disease is analogous, irrespective of baseline FVC, and these groups would benefit considerably from antifibrotic therapy.

Our study has a number of limitations. Firstly, this study is a single-centre retrospective non-randomised real-world study. As a result of its retrospective nature, patients did not have standardised records in their consultations regarding occurrence of adverse events. Furthermore, in the real-world setting patients have the autonomy to decline treatment, which would introduce bias in this study. There was no randomisation with regards to treatment choice. Lastly, we would endeavour for a larger sample size in the future which would increase the reliability of our results.