Background
Idiopathic pulmonary fibrosis (IPF) is the most common type of the idiopathic interstitial pneumonias (IIP) characterized by a progressive fibrosis and loss of lung function [
1]. Idiopathic pulmonary fibrosis is diagnosed by a typical radiological finding of usual interstitial pneumonia (UIP) on high resolution computed tomography (HRCT) or, in some cases, by a histological investigation of lung biopsy [
1]. Two drugs (pirfenidone and nintedanib) have shown to slow down the decline of lung function in IPF patients, and combined treatments are currently under clinical investigation [
2,
3]. In addition to drug treatment, early integration of supportive care and possible lung transplant evaluation are recommended [
4,
5].
During the last few years, national registries collecting clinical data from IPF patients have been established [
6‐
9]. These registries enable prospective follow up of real-life IPF patients’ disease course. The IPF registry (FinnishIPF) in Finland was started in 2011 [
10] and currently includes nearly 700 patients. Previous studies on the Finnish IPF registry revealed that Finnish IPF patients are diagnosed at an early stage of the disease with mild or moderate loss of lung function [
11]. The Swedish IPF registry was started in 2014 and data on diagnostic evaluations, demographics, lung function, laboratory tests and quality of life have been successfully collected since then [
7].
There are no previous comparative studies on the real-life clinical presentation and management of IPF in the Nordic countries. Finland and Sweden are neighboring countries with many similarities. Furthermore, there is a close collaboration between the countries and specialists from the main university hospitals, and a shared position paper on the diagnosis and treatment of IPF was recently published as a first attempt to optimize and uniform health care for IPF patients in the Nordic countries [
12].
This cohort study was performed to assess whether IPF shares common presentation in two neighboring European countries, and whether patients have the same opportunities in terms of access to health care and treatment. We compared the main clinical presentation, demographics, lung function and access to specific treatments in Finland and Sweden using the respective national registries as source of data.
Methods
The National IPF registries
The Finnish IPF registry was created in 2011 on a web-based platform (Granitics Unify Med, Granitics Ltd., Espoo, Finland) and collects today patients from 27 different hospitals across the country. Inclusion criteria to the registry are patients diagnosed with IPF [
10]. In 2014, the same platform was chosen and adapted for the Swedish data collection to become the Swedish IPF registry [
7]. Patients are currently enrolled from 22 different hospitals across Sweden. The inclusion of IPF patients in both registries is based on the fulfillment of the main international diagnostic criteria [
1], and informed consent is signed in both countries upon inclusion.
Demographics, clinical data such as lung function, comorbidities, radiology, histopathology, prescribed treatments and outcomes are reported in both registries [
7,
13]. All these variables are duly updated in both registries by the investigators at site and by two research nurses in the respective headquarters (Helsinki in Finland and Stockholm in Sweden) at the time of inclusion and after every clinical visit usually between every 3–6 months.
For the aims of this study, only patients included in the two registries with a diagnosis of IPF from January 1, 2014 to December 31, 2016 were considered. Patients who received another diagnosis than IPF during the course of their disease were excluded from this study. Furthermore, patients treated with antifibrotic drugs before January 1, 2014 were excluded from the study.
Data collection
Data on age, sex, body mass index (BMI), smoking habits (smoking status, pack/years), forced vital capacity (FVC, liters and % of predicted), forced expiratory volume (FEV
1, liters and % of predicted) and diffusing capacity for carbon monoxide (DL
CO, % of predicted) at the time of inclusion were extracted from the registries. Percent of predicted values for lung function were reported with the Finnish reference values from 1982 [
14] in the Finnish registry and with the Swedish reference values in the Swedish registry [
15,
16].
Follow up-data were collected during the study period (January 1, 2014 - December 31, 2016). Information regarding the prescription of antifibrotic treatments and the time between inclusion and start of treatment (weeks) were collected during this period, as well as data on outcomes (death and lung transplantation).
Statistical analysis
Gender distribution and smoking habits were presented as proportions and compared with Chi-squared test between the Finnish and Swedish cohorts. Data on age, sex, BMI, smoking habit, FVC, FVC %, FEV1, FEV1%, DLCO % and time from inclusion to treatment with antifibrotic drugs were presented as mean and standard deviation (SD). Parametric and non-parametric statistical tests (Mann-Whitney test) were used when appropriate to compare means between the two cohorts.
The nominal data on prescribing a treatment with antifibrotic drugs during the study period (yes or no) was assessed as proportions for the two groups and compared with Chi-squared test. An univariate analysis was performed to assess differences between patients receiving and not receiving a treatment with antifibrotic drugs. To assess the influence of potential independent factors (gender, age, lung function, country, type of hospital) on the starting of treatment with antifibrotic drugs a logistic regression analysis was performed.
All the analyses were performed using the statistical software SPSS 20.0 (IBM Corp, Armonk, NY, USA).
Discussion
Our study demonstrates significant differences in the clinical characteristics and initiation of treatment with antifibrotic drugs in IPF in two neighboring Nordic countries based on those subjects included into the IPF-registries. Finnish IPF patients were older, had better lung function, were less likely to have smoked and were prescribed less antifibrotic drugs compared to Sweden.
The better lung function in Finnish patients at the point of inclusion may be a result of diagnosis at an earlier stage of the disease compared to Swedish patients. The proportion of ex- or current- smokers in both countries was lower than what was previously shown with e.g. Danish patients, where a cohort study showed that 81% of the patients were ex- or current- smokers [
17].
A previous study showed that organization of specific services can vary among different Nordic countries and within countries, depending on resources and local guidelines [
18]. Finland and Sweden are neighboring countries with many similarities but also marked differences in health care systems. It is shown that there are significant genetic differences between these two populations but also within Finland between subpopulations in Eastern and Western Finland [
19,
20].
Our study shows that there are differences in how patients are treated with antifibrotic drugs in Finland and Sweden. Close to 30% of Finnish patients started treatment compared to nearly 70% of the patients in Sweden. Although nintedanib reached the markets in 2015, there was no difference in the availability of drugs in the two countries during the study period; pirfenidone was introduced in Sweden in 2011 and in Finland in 2013, way before our study started. However, nor of the registries have a full coverage of the IPF population in each country, and therefore the bias of selection of the patients may have some effect to the results. It is to note, anyway, that all the university hospitals and all the main peripheral hospitals are actively reporting patients in Finland and Sweden.
Therefore, we report a consistent and significant difference in the use of antifibrotic drugs in Finland and Sweden, not explained by the availability of the drugs on the market. Differences in reimbursement systems between these two countries could account for this difference. The prescription of drugs in Finland is regulated by the social insurance institution of Finland. Patients with IPF are required to have a FVC % value between 50 and 90% to receive the drugs at lower costs, but still need to pay an annual cost of over six hundred Euros. Furthermore, until 2015, the upper limit for FVC % was 80% which means that once reached the markets, antifibrotic drugs was not an option for patients with FVC % over 80% for at least two years. The reimbursement is applied for every patient and the processing time for applications can vary between 2 and 6 weeks. On the other hand, the antifibrotic drugs are included in the general high-cost protection in Sweden and, therefore, there is no need to apply for reimbursement, patients can purchase drugs as soon as a physician has made a decision on drug initiation. A Swedish patient pays no more than around 230 Euros for drugs entitled to high-cost protection within a year. Furthermore, since 2012, antifibrotic drugs can be prescribed in Sweden regardless of the lung function values.
Previous studies show benefits of treating patients with mild to moderate loss of lung function [
5,
21,
22]. This study revealed common tendencies of drug prescription in both countries; Firstly, a lower FVC % seems to favor treatment, as it does a younger age. Limited studies on the treatment of patients at the extremes of lung function (well preserved or severely impaired) and regional guidelines (allocating resources and priorities at a local level) are probably two of many reasons affecting the decision to treat with antifibrotic drugs. However, recent studies show that both patients with preserved lung function and with a severe loss of lung function may benefit from treatment [
23‐
25].
During the study period, no significant difference in disease outcomes was shown. However, we consider the period as too short and the cohort size as too small to make any conclusions; a longer follow up period and larger cohort sizes are needed to show some potential differences in either lung function decline or mortality, even in consideration of the differences in the prescription of the treatment.
There are some possible limitations when working with two independent registries which could contribute to the differences. We cannot exclude a bias in the recruitment of patients to the registries in the two countries, i.e. patients could be recruited in Sweden mostly in university- or reference centers and they could be more prone to be treated than in peripheral hospitals in Finland. On the other hand, the comparison between the university and peripheral hospitals revealed no difference for what concerns treatment with antifibrotic drugs between these two cohorts.
Finland and Sweden are using different, local reference values for the lung function tests which could contribute to the differences in the observed lung function in per cent of predicted. However, we investigated in this study which factors did support the decision to treat with antifibrotic drugs in real-life practice in the two countries; the real-life reported value of the FVC % of the predicted value was the main index used by physicians in both countries, and our study clearly shows that patients in Finland and Sweden are treated when a big proportion of lung function is already lost. These findings should stimulate the discussion about the need of an early diagnosis and treatment of IPF.
None of the patients included in the Finnish and Swedish registries were enrolled in ongoing clinical trials during the study period. This is an important information, as the participation of clinical centers in ongoing trials could have potentially increased the number of patients receiving drugs, regardless of local regulations.
Acknowledgements
We thank all patients that consented to participate in the national IPF registries in Finland and Sweden and the colleagues that have provided help in patient recruitment for the registries in Finland and Sweden.