Discussion
The PROOF registry collects data from a real-world cohort of patients with IPF in Europe. Unlike clinical trials, which have strict inclusion/exclusion criteria relating to disease severity, comorbidities and prescribed medications, the PROOF registry provides an opportunity to characterise a real-world population of patients. Compared with clinical trials, registry data are more likely to reflect the range of disease severities and complex medical histories that clinicians observe in clinical practice. In the present manuscript, we report a comprehensive summary of baseline data from patients enrolled in the PROOF registry, including patient demographics and clinical data such as lung function and HRQoL. In addition, we present data demonstrating the high burden of comorbidities and prescribed medication in this population.
Further to providing comprehensive clinical data, the PROOF registry also provides an opportunity to collect information on the diagnosis of IPF in a real-world population. In the PROOF registry, the median length of time between the appearance of the first symptoms of IPF and subsequent diagnosis was 281 days. Delays in the diagnosis of IPF have been reported elsewhere, with a qualitative European survey of patients with IPF reporting that 87% of patients waited more than 1 year to receive a diagnosis.5 In Belgium and Luxembourg, the patient journey to diagnosis can be relatively rapid once patients are referred to specialist centres. However, it is well known that the lack of awareness regarding IPF among primary care physicians and difficulty accessing specialist centres can lead to delays in referral and diagnosis,5 24 although this cannot be evaluated using registry data such as those from PROOF. Misdiagnosis with other respiratory disorders has also been identified as a key reason for delayed diagnosis of IPF.5 Indeed, in the PROOF registry, the non-specific symptoms of cough and breathlessness were present at baseline in 66.8% and 67.9% of patients, respectively. However, Velcro rales, which are a common but non-specific early feature of IPF,25 were the most common finding present at the baseline visit of PROOF, recorded in 78% of patients. Although we could not confirm if this feature of IPF was present at the beginning of the diagnostic process for patients included in the PROOF registry, it is possible that targeting education on Velcro rales to primary care physicians could help to reduce delays in referral and diagnosis.
Once patients with suspected ILD are referred to a specialist centre, international treatment guidelines recommend that a diagnosis of IPF be made based on the presence of a usual interstitial pattern (UIP) on HRCT images of the chest.2 In patients without clear UIP, a biopsy may be required to confirm a diagnosis of IPF.2 Almost a third of patients in the PROOF registry underwent lung biopsy (open surgical, VATS or cryobiopsy) as part of the IPF diagnostic process, which is a greater proportion compared with observations from other IPF registries. For example, in the Finnish IPF registry, the Australian IPF registry and the Swedish IPF registry, the rate of lung biopsy was approximately 20%.26–28 The high biopsy rate observed in the PROOF registry may be partially explained by evidence suggesting that patients with less advanced IPF are less likely to demonstrate definite UIP on HRCT at the time of diagnosis.29 The potential relationship between less advanced disease and the likelihood of definite UIP on HRCT is relevant because many patients in the PROOF registry had relatively preserved lung function, with 39% of patients in GAP stage I and mean per cent predicted FVC of 80.6% at baseline. Another factor to be considered, which may partially explain the high biopsy rate observed in the PROOF registry, is the time period at which patients were enrolled compared with other IPF registries. Practices used in biopsy and HRCT during the diagnosis of IPF are ever evolving, for example, the Fleischner Society White Paper outlines the process of forming working diagnoses in patients with a probable UIP pattern and a consistent clinical context. In these cases, a surgical lung biopsy is not required.30 However, the 2018 international diagnostic guidelines provide a conditional recommendation for surgical lung biopsy in patients with probable UIP, a recommendation that has provoked much discussion.31 32 These changes in diagnostic practice over time and variations in interpretation are likely to affect comparisons between real-world populations, particularly in countries including Belgium where diagnosis of IPF with a high CI is necessary (and was necessary at the time of enrolment in the PROOF registry) for reimbursement of antifibrotics. Going forward, uptake and application of the new recommendations may not be immediate or uniform and may be one factor behind inter-registry variations in the proportions of patients undergoing biopsies.
The observation that patients in the PROOF registry had relatively preserved lung function is similar compared with other IPF registries across the world, which have reported mean FVC values between 68% and 81%.26–28 33–35 Similarly, although patients enrolled in PROOF reported impaired HRQoL, as would be expected in a population of patients with IPF, the majority of patients described their health as ‘fair’ or ‘good’ based on the results of the SGRQ. Data from the German INSIGHTS-IPF (INvestigating SIGnificant Health TrendS in idiopathic pulmonary fibrosis) registry have previously demonstrated that FVC and GAP Index are significantly associated with HRQoL in patients with IPF.36 Similarly, in the PROOF registry, lung function and HRQoL were both relatively preserved.
Another significant predictor of impaired HRQoL in patients with IPF is the presence of comorbidities, with an increasing number of comorbidities associated with greater impairment reported using the SGRQ total score.36 In the PROOF registry, a wide range of comorbidities were reported at baseline. The most prevalent comorbidities were gastrointestinal disorders, in particular GERD, which was present in nearly half of all patients enrolled in PROOF. Other prevalent conditions included metabolism and nutrition disorders and vascular disorders. These results are similar to those from other IPF registries, with GERD and vascular disorders shown to be prevalent among patients enrolled in both the Australian IPF registry and the INSIGHTS-IPF registry.28 33 Interestingly, the prevalence of pulmonary hypertension appeared to be lower in the PROOF registry compared with other real-world registries. For example, in both the Australian IPF registry and the INSIGHTS-IPF registry, pulmonary hypertension at baseline was suspected or confirmed in nearly 20% of patients compared with only 4% in PROOF.28 33 It is possible that the observed differences in the prevalence of pulmonary hypertension might be partially explained by a combination of patients having less advanced disease in the PROOF registry compared with other registries, the use of different data collection modalities, for example, self-reported patient questionnaires used to collect comorbidity data in the Australian IPF registry, or differences in diagnostic technique, for example, differences in the routine performance of echocardiography and availability of right heart catheterisation and underdetection due to differences in the sensitivity of the diagnostic modality used.
As would be expected in a population of patients with a high burden of comorbidity, the majority of patients in the PROOF registry were prescribed one or more medications at baseline. The large proportion of patients in PROOF who were prescribed antithrombotics/anticoagulants or statins is of particular interest. Based on previous research investigating clinical outcomes in patients with IPF enrolled in the placebo arms of ASCEND or CAPACITY who were treated with anticoagulants or statins for non-IPF indications, these post-hoc analyses have suggested that while statins may have some beneficial effects on disease-related outcomes in patients with IPF,37 anticoagulants might be associated with an increased risk of IPF-related mortality over 52 weeks.38 In the absence of clinical trials investigating the use of multiple medications in patients with IPF, registries such as PROOF will provide an invaluable opportunity to study the relationship between prescribed medications and longitudinal outcomes in patients with IPF.
In the PROOF registry, a total of 69.3% of patients were treated with an antifibrotic at baseline, initiated prior to, or at the time of, registry inclusion. This is a higher proportion than has been previously reported in other registries, with 44.2% and 23.0% of patients receiving antifibrotic treatment at inclusion in the INSIGHTS-IPF registry and Australian IPF registry, respectively.28 33 Licensing and reimbursement criteria are key factors in influencing antifibrotic prescribing patterns across different regions. For example, in the PROOF registry, the higher proportion of patients prescribed pirfenidone versus nintedanib was largely driven by the fact that while pirfenidone was approved for the treatment of patients with IPF in Europe in 2011, nintedanib was not approved until 2015.7 8 In addition, enrolment into the PROOF registry began in 2013, at a time when pirfenidone treatment was reimbursed in patients with ‘mild to moderate’ IPF in Belgium and Luxembourg.
Although the most recent international consensus guidelines for the treatment of IPF recommend that the majority of patients with IPF should be considered for treatment with an antifibrotic,39 it is possible that many clinicians might be reluctant to prescribe antifibrotics in patients receiving multiple prescribed medications40 and with multiple comorbid conditions. In the absence of clinical trials, the PROOF registry provides a valuable opportunity to investigate the use of antifibrotics in a real-world population with a high level of comorbidity and prescribed medication. Of particular interest, we observed that many patients enrolled in the PROOF registry who were prescribed pirfenidone at the baseline visit were also prescribed other medications concomitantly. The most commonly co-prescribed medications in patients receiving pirfenidone were antihypertensives, statins and prophylactic antithrombotics/anticoagulants.
The PROOF registry provides valuable data from a real-world population of patients with IPF. However, the potential limitations of the PROOF registry should also be considered. For example, the PROOF registry enrolled a relatively small number of patients (N=277) across a limited geographical area. The global prescribing pattern of antifibrotics varies by geographical area depending on factors such as reimbursement or prescribing guidelines; for example, in Belgium, antifibrotic prescribing is limited to centres with a vast amount of experience in the clinical diagnosis and management of IPF. Therefore, it is possible that results from the PROOF registry may not be representative of populations of patients with IPF in different countries, thus limiting cross-registry comparisons. In addition, it may be the case that patients with comorbid life-threatening conditions, for example, lung cancer or advanced heart failure, or patients with more advanced disease, are not referred to centres of excellence for the treatment of IPF due to concerns regarding treatment tolerability or lack of reimbursement in patients with more advanced disease. These patients would not have been included in the PROOF registry and this could affect the comparison of results from PROOF with the real-world patient population. The diagnoses of the majority of patients included in the PROOF registry at one of three ‘expert centres’ could also be considered a limitation, as these centres had an experienced MDT present which may not be representative of the real world. In addition, we are restricted in evaluating how comparable the diagnoses of IPF in the PROOF registry are versus other real-world populations as we do not have further data regarding the breakdown of HRCT and lung biopsy patterns and subsequent diagnoses. A further limitation is that some patients participating in the PROOF registry were diagnosed with IPF prior to enrolment in the registry; therefore, some of the diagnostic data captured in the PROOF registry may have been retrospective. It should also be acknowledged that the PROOF registry is not designed as a clinical trial; therefore, patients were not randomised to receive treatments as per usual clinical practice, and so different treatments may not be comparable with respect to outcomes.
In conclusion, the PROOF registry provides valuable information on the characteristics of patients with IPF in a real-world setting. Baseline data collected from patients enrolled in the PROOF registry demonstrated modest delays in diagnosis, which were shorter than have been previously reported by patients within Europe, with relatively preserved lung function and HRQoL. A high burden of comorbidities and prescribed medications was evident in PROOF, with many patients receiving concomitant medications in addition to pirfenidone, most commonly antihypertensives and anticoagulants/antithrombotics. Whereas clinical trials have focused on patients with limited comorbidity, the PROOF registry will be able to provide data more representative of patients in clinical practice. Future analyses in this real-world cohort will investigate longitudinal outcomes in patients with IPF with a range of comorbidities and prescribed medications.
