ERJ Express. Published on April 21, 2015 as doi: 10.1183/09031936.00217614
|
ORIGINAL ARTICLE IN PRESS | CORRECTED PROOF
Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry Jürgen Behr1, Michael Kreuter1, Marius M. Hoeper1, Hubert Wirtz1, Jens Klotsche1, Dirk Koschel, Stefan Andreas, Martin Claussen, Christian Grohé, Henrike Wilkens, Winfried Randerath, Dirk Skowasch, F. Joachim Meyer, Joachim Kirschner, Sven Gläser, Felix J.F. Herth, Tobias Welte, Rudolf Maria Huber, Claus Neurohr, Martin Schwaiblmair, Martin Kohlhäufl, Gert Höffken, Matthias Held, Andrea Koch, Thomas Bahmer and David Pittrow1 Affiliation: For the authors' affiliations, see the Acknowledgements. 1Study steering committee members. Correspondence: Jürgen Behr, Medizinische Klinik und Poliklinik V, Klinikum der Ludwig-MaximiliansUniversität München Asklepios Fachkliniken München-Gauting, Comprehensive Pneumology Center Munich (CPC-M). Mitglied des DZL, Marchioninistr. 15, D-81377 München, Germany. E-mail: [email protected]
ABSTRACT After introduction of the new international guidelines on idiopathic pulmonary fibrosis (IPF) in 2011, we investigated clinical management practices for patients with IPF according to physicians’ diagnoses. A prospective, multicenter, noninterventional study with comprehensive quality measures including on-site source data verification was performed in Germany. 502 consecutive patients (171 newly diagnosed, 331 prevalent; mean±SD age 68.7±9.4 years, 77.9% males) with a mean disease duration of 2.3±3.5 years were enrolled. IPF diagnosis was based on clinical assessments and high-resolution computed tomography (HRCT) in 90.2%, and on surgical lung biopsy (SLB) combined with histology in 34.1% (lavage in 61.8%). The median 6-min walk distance was 320 m (mean 268±200 m). The mean forced vital capacity was 72±20% pred and diffusing capacity of the lung for carbon monoxide was 35±15% pred. No drugs were administered in 17.9%, oral steroids in 23.7%, N-acetylcysteine (NAC) in 33.7%, pirfenidone in 44.2% and other drugs in 4.6% of patients. Only 2.8% of the cohort was listed for lung transplantation. IPF patients were diagnosed in line with the new guidelines. They had more severe disease than those enrolled in recent randomised controlled trials (RCTs). In addition to HRCT, the frequency of lung biopsies was surprisingly high. Treatment patterns varied substantially.
@ERSpublications This largest published registry of IPF patients shows surprising disease severity and treatment variation http://ow.ly/JbWRn
This article has supplementary material available from erj.ersjournals.com Received: May 07 2014 | Accepted after revision: Feb 03 2015 Clinical trial: This study is registered at www.clinicaltrials.gov with identifier number NCT01695408. Support statement: Boehringer Ingelheim AG & Co. KG, Germany, funded the study with an unrestricted educational grant. Boehringer Ingelheim did not influence the study design, analysis or interpretation of the study. The open access for this article was paid for by Boehringer Ingelheim. Funding information for this article has been deposited with FundRef. Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com Copyright ©ERS 2015 ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.
Eur Respir J 2015; in press | DOI: 10.1183/09031936.00217614
Copyright 2015 by the European Respiratory Society.
1
IDIOPATHIC PULMONARY FIBROSIS | J. BEHR ET AL.
Introduction Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause that is limited to the lungs [1]. The disease is characterised by progressive worsening of lung function and carries a prognosis that is worse than that of many cancers. According to revised guidelines of the European Respiratory Society (ERS), the American Thoracic Society (ATS) and other societies [1], revised in 2011, and an update of the ATS/ERS classification of idiopathic interstitial pneumonias in 2013 [2], the diagnosis of IPF requires exclusion of other known causes of interstitial lung disease (ILD), the presence of a usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) in patients not subjected to SLB, and specific combinations of HRCT and SLB patterns in patients subjected to SLB. IPF predominantly presents in older individuals, with preponderance in men and previous or current smokers. Patients typically have unexplained, chronic and worsening exertional dyspnoea, and commonly exhibit unproductive cough, bibasilar inspiratory crackles and finger clubbing. Currently, substantial efforts are being made to investigate the efficacy and safety of new drugs for IPF in controlled clinical trials [3]. Meanwhile, however, observational data on the characteristics of patients with IPF outside clinical studies, their management under clinical practice conditions and their long-term outcomes are sparse. In repeated calls for action to establish IPF registries, various authors underlined that improved management of this disease is dependent on better understanding of its epidemiology and diagnostic spectrum, and an analysis of outcomes from emerging therapies [4–6]. Registry data can serve further purposes; for example, they can complement the data from RCTs, provide much-needed information on drug utilisation (of particular importance during the introduction of new therapies) and evaluate to what extent guidelines are followed in practice [7, 8]. The contemporary Investigating Significant Health Trends in Idiopathic Pulmonary Fibrosis (INSIGHTS-IPF) registry was implemented to prospectively and comprehensively assess the characteristics, diagnostic procedures, treatment patterns, quality of life and long-term outcomes of patients with IPF under clinical practice conditions in Germany. Here, the baseline data of a large cohort of >500 patients, which in contrast to clinical trials were not pre-selected, is presented.
Methods The rationale and design of the INSIGHTS-IPF registry have been described previously in detail [9, 10]. In short, INSIGHTS-IPF is a multicentre, noninterventional study (registry) that documents patients with IPF in routine care. The study was initiated in November 2012 and continues to enrol patients (www.clinicaltrials.gov identifier number NCT01695408). The study materials were approved by the Ethics Committee of the Medical Faculty, Technical University of Dresden, Dresden, Germany, on September 15, 2012, and by further local ethics committees as per local requirements. The Gesellschaft für Wissenschaftstransfer (GWT-TUD GmbH), a 100% subsidiary of the Technical University of Dresden, sponsored the study. The study was designed and is being supervised by an interdisciplinary steering committee (see author list). In order to ensure adequate patient numbers per centre and high quality of data, the focus of the study is on specialised lung centres or practices. Currently, 19 pulmonary specialist centres in all parts of Germany are entering data into the registry. Patients are eligible for documentation if they are aged ⩾18 years, have IPF diagnosed by a physician who follows current international or German national guidelines, and have provided written informed consent. To avoid selection of patients and, thus, violation of the “real-life” principle, no explicit noneligibility criteria were defined. Patients were included in a consecutive manner at each site in order to avoid selection bias. At baseline, data on demographics, risk factors and comorbidities are collected. Detailed information on IPF as defined in our study is comprised of disease history, diagnostic procedures, and prior and current drug and non-drug treatment. At follow-up visits, every 6±3 months, events such as hospitalisation, disease exacerbation or death are recorded, as well as current management practice. Predicted percentage values for lung function were calculated on the basis of lung function test results, according to the following established formulas: for total lung capacity and diffusing capacity of the lung for carbon monoxide (DLCO), formulas by CRAPO et al. [11] from 1981 were used; for inspiratory vital capacity (IVC), the formula by QUANJER et al. [12] from 1993 was used; and for forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC, formulas by QUANJER and co-workers [12, 13] from 1993 and 2012 were applied. In terms of reference values, between 1978 and 2009, no secular trends were observed, and differences between datasets comprising >1000 subjects were small [14].
2
DOI: 10.1183/09031936.00217614
IDIOPATHIC PULMONARY FIBROSIS | J. BEHR ET AL.
Further, in yearly intervals, patient-related outcomes are being documented, including the San Diego Shortness of Breath Questionnaire [15, 16] and the St George’s Respiratory Questionnaire (SGRQ) [17]. Scores on the latter range from 0 to 100, with higher scores indicating more limitations (suggested minimally important difference for patients with IPF has been estimated at 5–8 points) [18]. The GAP point-scoring system (GAP index) is a clinical prediction tool for the prognosis of patients with IPF using gender, age, and two lung physiology variables, FVC and DLCO. Patients were categorised as stage I, II or III, corresponding to an estimated 1-year mortality of 6%, 16% and 39%, respectively [19]. Data collection and statistical analysis Data collection is performed using an Internet-based case report form (electronic case report form) with automated plausibility checks. On-site monitoring with source data verification is performed in ⩾20% of centres. Sample size was determined by feasibility aspects and no formal sample size calculation was made. The study uses a non-probability sampling approach. Categorical data are displayed as absolute and relative frequencies. For continuously distributed data, data following an approximately normal distribution are reported as mean and standard deviation; otherwise, median and interquartile range (IQR) are shown. The analysis was mainly performed descriptively. Characteristics of patients who were enrolled in INSIGHTS-IPF were compared with those in randomised controlled clinical trials (table S1) by a Chi-squared test for categorical variables and a t-test for continuously distributed variables. Data were analysed with STATA 12.1 (StataCorp, College Station, TX, USA).
Results At interim analysis database lock (October 27, 2014), 19 centres had entered data for 502 patients. All results reported in this article were entered at the time of inclusion of the patients (baseline visit). Demographics Baseline characteristics are presented in table 1. All but two patients were Caucasian (99.6%). Substantially more men than women were documented (77.9% versus 22.1%) and patients were predominantly older (mean age 68.7 years). In accordance with the age pattern, the majority of patients were retired (80.0%). Risk factors and comorbidities Environmental exposure was reported in 136 patients (27.1% of total). Among those, types of exposure included asbestos in 56 patients, metal dusts in 25, raising birds in 19, wood dusts in 16 and solvents in
TABLE 1 Patient characteristics and risk factors in the total cohort by idiopathic pulmonary fibrosis (IPF) disease duration Patients
Patients Males Age years Body mass index kg·m−2 Smoking status Never Previous Current 6-min walk distance m Symptom duration months Disease duration months Risk factors Environmental exposure Gastro-oesophageal reflux Genetic predisposition Exposure to drugs associated with IPF
502 502 502 502
502 458 498 502
Total cohort
Subgroups Prevalent IPF#
Incident IPF¶
502 391 (77.9) 68.7±9.4 27.6±4.1
331 243 (73.4) 67.5±9.8 27.4±4.2
171 148 (86.6) 71.0±8.0 28.2±3.8
195 (38.8) 302 (60.2) 5 (1.0) 267.6±199.7 46.9±52.5 27.6±41.9
140 (42.3) 188 (56.8) 3 (0.9) 266.7±198.7 57.6±54.4 41.3±46.2
55 (32.2) 114 (66.7) 2 (1.2) 269.4±202.1 27.2±42.3 1.4±2.0
0.886
|
ORIGINAL ARTICLE IN PRESS | CORRECTED PROOF
Management of patients with idiopathic pulmonary fibrosis in clinical practice: the INSIGHTS-IPF registry Jürgen Behr1, Michael Kreuter1, Marius M. Hoeper1, Hubert Wirtz1, Jens Klotsche1, Dirk Koschel, Stefan Andreas, Martin Claussen, Christian Grohé, Henrike Wilkens, Winfried Randerath, Dirk Skowasch, F. Joachim Meyer, Joachim Kirschner, Sven Gläser, Felix J.F. Herth, Tobias Welte, Rudolf Maria Huber, Claus Neurohr, Martin Schwaiblmair, Martin Kohlhäufl, Gert Höffken, Matthias Held, Andrea Koch, Thomas Bahmer and David Pittrow1 Affiliation: For the authors' affiliations, see the Acknowledgements. 1Study steering committee members. Correspondence: Jürgen Behr, Medizinische Klinik und Poliklinik V, Klinikum der Ludwig-MaximiliansUniversität München Asklepios Fachkliniken München-Gauting, Comprehensive Pneumology Center Munich (CPC-M). Mitglied des DZL, Marchioninistr. 15, D-81377 München, Germany. E-mail: [email protected]
ABSTRACT After introduction of the new international guidelines on idiopathic pulmonary fibrosis (IPF) in 2011, we investigated clinical management practices for patients with IPF according to physicians’ diagnoses. A prospective, multicenter, noninterventional study with comprehensive quality measures including on-site source data verification was performed in Germany. 502 consecutive patients (171 newly diagnosed, 331 prevalent; mean±SD age 68.7±9.4 years, 77.9% males) with a mean disease duration of 2.3±3.5 years were enrolled. IPF diagnosis was based on clinical assessments and high-resolution computed tomography (HRCT) in 90.2%, and on surgical lung biopsy (SLB) combined with histology in 34.1% (lavage in 61.8%). The median 6-min walk distance was 320 m (mean 268±200 m). The mean forced vital capacity was 72±20% pred and diffusing capacity of the lung for carbon monoxide was 35±15% pred. No drugs were administered in 17.9%, oral steroids in 23.7%, N-acetylcysteine (NAC) in 33.7%, pirfenidone in 44.2% and other drugs in 4.6% of patients. Only 2.8% of the cohort was listed for lung transplantation. IPF patients were diagnosed in line with the new guidelines. They had more severe disease than those enrolled in recent randomised controlled trials (RCTs). In addition to HRCT, the frequency of lung biopsies was surprisingly high. Treatment patterns varied substantially.
@ERSpublications This largest published registry of IPF patients shows surprising disease severity and treatment variation http://ow.ly/JbWRn
This article has supplementary material available from erj.ersjournals.com Received: May 07 2014 | Accepted after revision: Feb 03 2015 Clinical trial: This study is registered at www.clinicaltrials.gov with identifier number NCT01695408. Support statement: Boehringer Ingelheim AG & Co. KG, Germany, funded the study with an unrestricted educational grant. Boehringer Ingelheim did not influence the study design, analysis or interpretation of the study. The open access for this article was paid for by Boehringer Ingelheim. Funding information for this article has been deposited with FundRef. Conflict of interest: Disclosures can be found alongside the online version of this article at erj.ersjournals.com Copyright ©ERS 2015 ERJ Open articles are open access and distributed under the terms of the Creative Commons Attribution Non-Commercial Licence 4.0.
Eur Respir J 2015; in press | DOI: 10.1183/09031936.00217614
Copyright 2015 by the European Respiratory Society.
1
IDIOPATHIC PULMONARY FIBROSIS | J. BEHR ET AL.
Introduction Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause that is limited to the lungs [1]. The disease is characterised by progressive worsening of lung function and carries a prognosis that is worse than that of many cancers. According to revised guidelines of the European Respiratory Society (ERS), the American Thoracic Society (ATS) and other societies [1], revised in 2011, and an update of the ATS/ERS classification of idiopathic interstitial pneumonias in 2013 [2], the diagnosis of IPF requires exclusion of other known causes of interstitial lung disease (ILD), the presence of a usual interstitial pneumonia (UIP) pattern on high-resolution computed tomography (HRCT) in patients not subjected to SLB, and specific combinations of HRCT and SLB patterns in patients subjected to SLB. IPF predominantly presents in older individuals, with preponderance in men and previous or current smokers. Patients typically have unexplained, chronic and worsening exertional dyspnoea, and commonly exhibit unproductive cough, bibasilar inspiratory crackles and finger clubbing. Currently, substantial efforts are being made to investigate the efficacy and safety of new drugs for IPF in controlled clinical trials [3]. Meanwhile, however, observational data on the characteristics of patients with IPF outside clinical studies, their management under clinical practice conditions and their long-term outcomes are sparse. In repeated calls for action to establish IPF registries, various authors underlined that improved management of this disease is dependent on better understanding of its epidemiology and diagnostic spectrum, and an analysis of outcomes from emerging therapies [4–6]. Registry data can serve further purposes; for example, they can complement the data from RCTs, provide much-needed information on drug utilisation (of particular importance during the introduction of new therapies) and evaluate to what extent guidelines are followed in practice [7, 8]. The contemporary Investigating Significant Health Trends in Idiopathic Pulmonary Fibrosis (INSIGHTS-IPF) registry was implemented to prospectively and comprehensively assess the characteristics, diagnostic procedures, treatment patterns, quality of life and long-term outcomes of patients with IPF under clinical practice conditions in Germany. Here, the baseline data of a large cohort of >500 patients, which in contrast to clinical trials were not pre-selected, is presented.
Methods The rationale and design of the INSIGHTS-IPF registry have been described previously in detail [9, 10]. In short, INSIGHTS-IPF is a multicentre, noninterventional study (registry) that documents patients with IPF in routine care. The study was initiated in November 2012 and continues to enrol patients (www.clinicaltrials.gov identifier number NCT01695408). The study materials were approved by the Ethics Committee of the Medical Faculty, Technical University of Dresden, Dresden, Germany, on September 15, 2012, and by further local ethics committees as per local requirements. The Gesellschaft für Wissenschaftstransfer (GWT-TUD GmbH), a 100% subsidiary of the Technical University of Dresden, sponsored the study. The study was designed and is being supervised by an interdisciplinary steering committee (see author list). In order to ensure adequate patient numbers per centre and high quality of data, the focus of the study is on specialised lung centres or practices. Currently, 19 pulmonary specialist centres in all parts of Germany are entering data into the registry. Patients are eligible for documentation if they are aged ⩾18 years, have IPF diagnosed by a physician who follows current international or German national guidelines, and have provided written informed consent. To avoid selection of patients and, thus, violation of the “real-life” principle, no explicit noneligibility criteria were defined. Patients were included in a consecutive manner at each site in order to avoid selection bias. At baseline, data on demographics, risk factors and comorbidities are collected. Detailed information on IPF as defined in our study is comprised of disease history, diagnostic procedures, and prior and current drug and non-drug treatment. At follow-up visits, every 6±3 months, events such as hospitalisation, disease exacerbation or death are recorded, as well as current management practice. Predicted percentage values for lung function were calculated on the basis of lung function test results, according to the following established formulas: for total lung capacity and diffusing capacity of the lung for carbon monoxide (DLCO), formulas by CRAPO et al. [11] from 1981 were used; for inspiratory vital capacity (IVC), the formula by QUANJER et al. [12] from 1993 was used; and for forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC, formulas by QUANJER and co-workers [12, 13] from 1993 and 2012 were applied. In terms of reference values, between 1978 and 2009, no secular trends were observed, and differences between datasets comprising >1000 subjects were small [14].
2
DOI: 10.1183/09031936.00217614
IDIOPATHIC PULMONARY FIBROSIS | J. BEHR ET AL.
Further, in yearly intervals, patient-related outcomes are being documented, including the San Diego Shortness of Breath Questionnaire [15, 16] and the St George’s Respiratory Questionnaire (SGRQ) [17]. Scores on the latter range from 0 to 100, with higher scores indicating more limitations (suggested minimally important difference for patients with IPF has been estimated at 5–8 points) [18]. The GAP point-scoring system (GAP index) is a clinical prediction tool for the prognosis of patients with IPF using gender, age, and two lung physiology variables, FVC and DLCO. Patients were categorised as stage I, II or III, corresponding to an estimated 1-year mortality of 6%, 16% and 39%, respectively [19]. Data collection and statistical analysis Data collection is performed using an Internet-based case report form (electronic case report form) with automated plausibility checks. On-site monitoring with source data verification is performed in ⩾20% of centres. Sample size was determined by feasibility aspects and no formal sample size calculation was made. The study uses a non-probability sampling approach. Categorical data are displayed as absolute and relative frequencies. For continuously distributed data, data following an approximately normal distribution are reported as mean and standard deviation; otherwise, median and interquartile range (IQR) are shown. The analysis was mainly performed descriptively. Characteristics of patients who were enrolled in INSIGHTS-IPF were compared with those in randomised controlled clinical trials (table S1) by a Chi-squared test for categorical variables and a t-test for continuously distributed variables. Data were analysed with STATA 12.1 (StataCorp, College Station, TX, USA).
Results At interim analysis database lock (October 27, 2014), 19 centres had entered data for 502 patients. All results reported in this article were entered at the time of inclusion of the patients (baseline visit). Demographics Baseline characteristics are presented in table 1. All but two patients were Caucasian (99.6%). Substantially more men than women were documented (77.9% versus 22.1%) and patients were predominantly older (mean age 68.7 years). In accordance with the age pattern, the majority of patients were retired (80.0%). Risk factors and comorbidities Environmental exposure was reported in 136 patients (27.1% of total). Among those, types of exposure included asbestos in 56 patients, metal dusts in 25, raising birds in 19, wood dusts in 16 and solvents in
TABLE 1 Patient characteristics and risk factors in the total cohort by idiopathic pulmonary fibrosis (IPF) disease duration Patients
Patients Males Age years Body mass index kg·m−2 Smoking status Never Previous Current 6-min walk distance m Symptom duration months Disease duration months Risk factors Environmental exposure Gastro-oesophageal reflux Genetic predisposition Exposure to drugs associated with IPF
502 502 502 502
502 458 498 502
Total cohort
Subgroups Prevalent IPF#
Incident IPF¶
502 391 (77.9) 68.7±9.4 27.6±4.1
331 243 (73.4) 67.5±9.8 27.4±4.2
171 148 (86.6) 71.0±8.0 28.2±3.8
195 (38.8) 302 (60.2) 5 (1.0) 267.6±199.7 46.9±52.5 27.6±41.9
140 (42.3) 188 (56.8) 3 (0.9) 266.7±198.7 57.6±54.4 41.3±46.2
55 (32.2) 114 (66.7) 2 (1.2) 269.4±202.1 27.2±42.3 1.4±2.0
0.886
