Background
Idiopathic pulmonary fibrosis (IPF) is a chronic, debilitating, irreversible, and progressive lung disease characterized by exertional dyspnea and cough [
1,
2]. Patients with IPF have a poor prognosis, with median survival following diagnosis previously reported as lower than that for many common types of cancer at between 2 and 5 years [
1‐
8].
The reported incidence of IPF has been estimated to range from 2.8 to 9.3 cases per 100,000 population per year, in Europe and North America [
9]. The prevalence of IPF in Europe is thought to range from 1.25 to 23.4 cases per 100,000 population [
10]. There is evidence that the incidence, prevalence, and number of deaths from IPF may be increasing [
9,
11‐
13].
Two antifibrotic drugs, pirfenidone and nintedanib, are approved by the European Medicines Agency and the US Food and Drug Administration for the treatment of IPF, and both are recommended in international treatment guidelines [
14]. In the Phase III ASCEND and CAPACITY trials, pirfenidone significantly reduced the risk of disease progression or death compared with placebo [
15,
16]. In the Phase III INPULSIS trials, nintedanib reduced the risk of disease progression versus placebo in patients with IPF [
17].
Following the approval and recommendation of pirfenidone and nintedanib for the treatment of IPF, we conducted a patient chart audit using an online physician survey to investigate pharmacological treatment patterns, understand antifibrotic prescribing, and identify unmet needs in IPF treatment practice in Europe.
Discussion
Our results show that approximately 40% of European patients with confirmed IPF do not receive antifibrotic treatment despite the regulatory approval of two antifibrotic therapies and the recommendation in international guidelines that the majority of individuals with IPF should be offered antifibrotic treatment. Indeed, at the time of the survey, antifibrotic therapy had been available for at least 2 years in all the countries surveyed, and it is therefore important to consider reasons for the observed treatment pattern.
Treatment requires a confident diagnosis of IPF, and it may be that a lack of awareness about IPF as a potential diagnosis and/or a lack of referral to specialist centers for MDT diagnostic assessment have an impact upon treatment practices. Our results show that a higher proportion of untreated patients had suspected IPF than treated patients and a lower proportion of untreated patients had an MDT evaluation at diagnosis. Uncertain diagnosis is also a key barrier to treatment in patients with suspected IPF, which will potentially be addressed by two clinical trials currently investigating the efficacy of antifibrotics in non-IPF interstitial lung diseases (NCT03099187 and NCT02999178).
In our analysis of treatment patterns in expert versus non-expert centers, more patients had a confirmed diagnosis of IPF at expert centers. In addition, a higher proportion of patients in the untreated population did not have an FVC (12% vs 8%), DLco (23% vs 15%), or 6MWD (57% vs 36%) measurement at baseline compared with the treated population. These differences between the untreated and treated populations could reflect a number of issues, including difficulty with interpreting dynamic changes in pulmonary function or reduced monitoring in patients considered to be unsuitable for treatment by their physician.
Previous studies have shown that patients often visit several healthcare professionals before being diagnosed with IPF, with the process of obtaining a confirmed diagnosis taking in excess of 1 year in the majority of cases [
19,
20]. Misdiagnosis and a lack of knowledge about IPF in primary care are cited as key reasons for delayed referral to specialist centers [
20,
21]. Our data suggest that referral to a non-specialist pulmonologist may be another barrier to diagnosis and treatment access. Patients in several areas across the EU have reported limited access to a full MDT to facilitate diagnosis [
21]. Once a diagnosis has been made, areas of unmet needs include a lack of awareness of available approved antifibrotic therapy and/or information and resources on pulmonary fibrosis from both a patient and a healthcare professional perspective [
22‐
24]. Indeed, in our experience, informed patients with a good knowledge of their condition and the available treatments are more likely to request referral to specialist care and/or access to treatment than those with less knowledge about their condition. Similar factors were highlighted in the European IPF Patient Charter [
21] and may contribute to the delayed diagnosis and treatment of IPF.
Our results indicate that many patients with IPF that is perceived to be ‘mild’ or ‘stable’ by their physician were not treated with an antifibrotic, suggesting physicians were adopting a ‘watch and wait’ approach. Indeed, a large group of patients who did not receive an antifibrotic received no treatment at all, with the most common reasons for this being lack of symptoms and/or lack of disease progression. The data gathered in this survey suggest that treated patients had more severe disease than untreated patients: they were more likely to have an FVC < 70% at diagnosis and follow-up, they were more likely to have disease rated as ‘moderate’ by their physician, they tended to have more acute exacerbations than untreated patients, and they were more likely to be candidates for lung transplantation (although it should be acknowledged that this may have been because they were younger and/or had fewer comorbidities than untreated patients, rather than reflecting more severe disease).
One possible explanation for patients with ‘mild’ or ‘stable’ IPF remaining untreated is a lack of physician confidence in the evidence base. The limitations of our survey design prevented further investigation of this possibility; however, a survey of respiratory physicians has previously reported that physicians who waited for disease progression before initiating antifibrotic therapy were less likely to agree that antifibrotics can significantly slow disease progression compared with physicians who treated within 4 months of diagnosis [
25]. However, the available evidence increasingly points toward early intervention in this progressive, unpredictable, irreversible, and fatal disease [
1,
26‐
31], especially as experience from other lung diseases suggests that physicians tend to underestimate the severity of disease [
32,
33]. Antifibrotic treatment in patients with limited lung function impairment has been demonstrated to reduce FVC decline compared with placebo [
28,
30,
31], and patients who progress on antifibrotic therapy still appear to benefit from continued therapy [
34]. Furthermore, in a post-hoc analysis of data from the pooled ASCEND and CAPACITY population, pirfenidone showed similar efficacy in patients with more-preserved and less-preserved baseline lung function [
27], a finding that has also been reported with nintedanib in a post-hoc subgroup analysis of data from the INPULSIS trials [
29]. These data suggest that earlier treatment with antifibrotics may help to preserve lung function at higher levels if started in the early stages of the disease.
Goals for patient care may also have influenced treatment decisions. Overall, the three most important goals given by physicians were to prolong survival or reduce the risk of mortality, improve quality of life, and stabilize disease. However, the importance placed on these goals differed in treated and untreated patients, with improvement and/or stabilization in quality of life being more frequent for untreated patients (78%) than treated patients (68%). There may be a perception among physicians that antifibrotic treatment might have a detrimental effect on quality of life, possibly via the common side effects associated with treatment, and that the potential risks outweigh the benefit of treatment, particularly in patients with preserved lung function. Validating IPF-specific quality-of-life endpoints is still a work in progress and, so far, findings have been inconsistent with the treatment response (as measured with clinical endpoints) [
35]. However, the available evidence from clinical trials suggests antifibrotic treatment results in statistically non-significant improvements in quality-of-life endpoints or has no net effect on these endpoints [
15,
17,
36].
Access to IPF treatment differs in each country, for example because of reimbursement restrictions, and this may also have resulted in some differences in treatment practices. In Italy, patients must have a DLco > 35% and be < 80 years of age to be eligible for treatment reimbursement, while patients in the UK and in several regions in Spain must have an FVC < 80%. Interpretation of our data is limited because the survey did not specifically ask about access restrictions; however, the proportion of patients in the UK with ‘mild’ disease who were untreated was higher (51.4%) compared with countries without an upper FVC limit, such as France and Germany (41.1 and 40.4%, respectively). Overall, a greater proportion of the untreated population had an FVC > 80% compared with treated patients, both at diagnosis (17.9% vs 11.4%) and at last check up (13.1% vs 4.7%).
Both pirfenidone and nintedanib are associated with a number of adverse events, which may limit tolerability or result in treatment discontinuation due to potentially harmful events, e.g., rare elevations in liver enzymes [
37,
38]. Patients may occasionally be prevented from taking specific antifibrotics due to contraindications [
37,
38]. Although emphysema and lung cancer are not direct contraindications to antifibrotic treatment, untreated patients in our analysis were more likely to have these comorbidities. The results suggest that physicians are reluctant to treat patients with other lung diseases, perhaps due to a perception that these individuals may be more susceptible to adverse effects from treatment, or concerns about the benefit of treating fibrosis in individuals who may have other life-limiting disease. It should be noted, however, that patients with some degree of emphysema were included in the CAPACITY and INPULSIS trials [
15,
17].
In Europe, pirfenidone is indicated for the treatment of ‘mild to moderate’ IPF [
37], thereby excluding patients with ‘severe’ disease, often considered to be those with FVC < 50%. In fact, a minority of treated patients in our analysis had an FVC < 50%, and this proportion was similar in the untreated population. Other reasons for non-treatment could include patient choice, particularly in those with ‘mild disease’, or lack of adherence to treatment due to social or personal circumstances.
The focus of the current analysis was to investigate antifibrotic treatment patterns; however, in general, many patients in our analysis appeared to receive inadequate additional symptom management measures. Treatment guidelines recommend oxygen supplementation and other therapies for symptom control and management of comorbidities [
2]; however, oxygen therapy and supportive treatments, such as anti-cough treatments, vaccines, etc., were used in only half of patients overall and in approximately a quarter of patients in the treated population. Supportive treatments for comorbidities, symptom control, or side-effect management may help with adherence to antifibrotic therapy and also improve patients’ perceptions of treatment. Furthermore, only 59/1783 patients (3%) overall received palliative care (46 patients were reported as having received palliative care only ± oxygen and a further 13 were reported as receiving no drug treatment and palliative care only ± oxygen). Amongst patients with IPF considered ‘severe’ by their doctor, only 10% were receiving palliative care. This is similar to previous findings, which highlighted poor or variable access and ineffective utilization of palliative care services, despite increasing evidence that access to palliative care services or having end-of-life discussions early in the course of IPF is desired by patients and can also improve quality of life, symptom control, and mood [
21,
39‐
41]. Variable information regarding the disease and treatment, and access to other aspects of IPF management, such as supplementary oxygen, comorbidities, and palliative care, have been identified as unmet needs in the IPF Patient Charter; our observations support the findings of the Charter and suggest improvements in IPF awareness are still needed [
21].
The conclusions from this study are limited by the nature of questionnaire-based research, which may have introduced bias. Furthermore, the quality of the data collected in this survey was reliant upon case notes recorded by physicians during patient consultations prior to their awareness of the survey. Physicians might not have reported on consecutive patients as directed, and may instead have selected cases that they considered representative of their medical decision making. The number of acute exacerbations resulting in hospitalization or an emergency room visit in the previous year (40–47%) was much higher than expected when compared with an annual acute exacerbation rate of 5–10% in the published literature [
42‐
44], suggesting that these data are limited by the subjective acute exacerbation diagnoses made by individual physicians and the lack of specific criteria defining acute exacerbations in the survey. There is also no consensus on how to categorize disease severity or disease progression in IPF, and our analysis is limited by the subjective determination made by individual physicians as to whether disease was ‘mild’, ‘moderate’, or ‘severe’, or whether the patient had stable or worsening disease. We recognize that there is an unmet need for an objective severity staging system to capture the nature and progression of IPF. In particular, ‘mild’ is an inadequate description of a disease that can impair quality of life and undergo periods of acute exacerbation even in its early stages, and other classifications including ‘subclinical IPF’ may become more appropriate in the future. Finally, this analysis focused on five European countries (France, Germany, Italy, Spain, and the UK); therefore, the results may not be comparable in the rest of the world.
Treatment patterns in IPF will require further evaluation in future studies as more evidence is presented regarding available pharmacological treatments. The impact of early intervention and the potential for combining antifibrotics need further investigation [
45,
46].