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DOI: 10.1055/s-0043-123035
German Guideline for Idiopathic Pulmonary Fibrosis – Update on Pharmacological Therapies 2017
S2k-Leitlinie Idiopathische Lungenfibrose – Update zur medikamentösen Therapie 2017Publication History
Publication Date:
16 January 2018 (online)
![](https://www.thieme-connect.de/media/pneumologie/201802/lookinside/thumbnails/885_10-1055-s-0043-123035-1.jpg)
Abstract
Idiopathic pulmonary fibrosis (IPF) is a severe and often fatal disease with a median survival of 2 – 4 years after diagnosis. Since the publication of the German IPF guideline in 2013 new treatment trials have been published, necessitating an update of the pharmacological therapy of IPF. Different from the previous guideline, the GRADE system was discarded and replaced by the Oxford evidence classification system which allows a more differentiated judgement. The following pharmacological therapies were rated not suitable for the treatment of IPF patients (recommendation A; evidence 1-b): triple therapy with prednisolone, azathioprine and acetyl-cysteine; imatinib; ambrisentan; bosentan; macitentan. A less clear but still negative recommendation (B, 1-b) was attributed to the treatment of IPF with the phosphodiesterase-5-inhibitor sildenafil and acetyl-cysteine monotherapy. In contrast to the international guideline antacid therapy as a general treatment for IPF was rated negative, based on conflicting results of recent analyses (recommendation C; evidence 4). An unanimous positive recommendation was granted for the antifibrotic drugs nintedanib and pirfenidone for the treatment of IPF (A, 1-a). For some open questions in the management of IPF patients for which firm evidence is lacking the guideline also offers recommendations based on expert consensus.
Zusammenfassung
Die idiopathische Lungenfibrose (idiopathische pulmonale Fibrose, IPF) ist eine schwerwiegende Lungenerkrankung, die häufig innerhalb von zwei bis vier Jahren nach Diagnosestellung zum Tod führt. Seit Veröffentlichung der deutschen IPF-Leitlinie im Jahr 2013 liegen neue Therapiestudien vor, die eine Neubewertung der Behandlungsstrategien erfordern. Abweichend von der Vorgängerleitlinie wurde in der aktuellen Überarbeitung nicht mehr das GRADE-System sondern die Oxford Evidenzsystematik mit drei Empfehlungsgraden (A, B, C) verwendet, weil dieses System eine differenziertere Betrachtung erlaubt. Folgende Medikamente wurden mit dem Empfehlungsgrad A und dem Evidenzgrad 1-b als nicht geeignet für die Behandlung der IPF klassifiziert: Triple-Therapie aus Prednisolon, Azathioprin und Acetylcystein; Antikoagulation mit Vitamin-K-Antagonisten; Imatinib; Ambrisentan; Bosentan; Macitentan. Weniger eindeutig ist die negative Bewertung des Phosphodiesterase-5-Inhibitors Sildenafil und der Acetylcystein-Monotherapie (Empfehlungsgrad B, Evidenzgrad 2-b). Eindeutig positiv fiel die Empfehlung für Nintedanib und Pirfenidon zur Behandlung von IPF-Patienten aus (Empfehlungsgrad A, Evidenzgrad 1-a). Mit Empfehlungsgrad C und Evidenzgrad 4 wurde der generelle Einsatz von Antazida zur Behandlung der IPF als nicht zu empfehlen bewertet, da die Datenlage widersprüchlich ist; hier weicht die deutsche Leitlinie auch am deutlichsten von der internationalen Leitlinie ab. Am Ende der Leitlinie wird aus Expertensicht zu offenen Fragen in der Therapie der IPF Stellung genommen, für die bisher keine ausreichende Evidenzbasis existiert.
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References
- 1 Behr J, Günther A, Ammenwerth W. et al. S2K-Leitlinie zur Diagnostik und Therapie der idiopathischen Lungenfibrose. Pneumologie 2013; 67: 81-111
- 2 Raghu G, Rochwerg B, Zhang Y. et al. An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med 2015; 192: e3-e19
- 3 Cantin AM, Hubbard RC, Crystal RG. Glutathione deficiency in the epithelial lining fluid of the lower respiratory tract in idiopathic pulmonary fibrosis. Am Rev Respir Dis 1989; 139: 370-372
- 4 Behr J, Maier K, Degenkolb B. et al. Antioxidative and clinical effects of high-dose N-acetylcysteine in fibrosing alveolitis: adjunctive therapy to maintenance immunosuppression. Am J Respir Crit Care Med 1997; 156: 1897-1901
- 5 Demedts M, Behr J, Buhl R. et al. IFIGENIA Study Group. High-dose acetylcysteine in idiopathic pulmonary fibrosis. N Engl JMed 2005; 353: 2229-2242
- 6 Hunninghake GW. Antioxidant therapy for idiopathic pulmonary fibrosis. N Engl J Med 2005; 353: 2285-2287
- 7 Wells AU. Antioxidant therapy in idiopathic pulmonary fibrosis: hope is kindled. Eur Respir J 2006; 27: 664-666
- 8 The Idiopathic Pulmonary Fibrosis Clinical Research Network. Prednisone, Azathioprine, and N-Acetylcysteine for pulmonary fibrosis. N Engl J Med 2012; 366: 1968-1977
- 9 Idiopathic Pulmonary Fibrosis Clinical Research. Randomized trial of acetylcysteine in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2093-2101
- 10 Oldham JM, Ma SF, Martinez FJ. et al. TOLLIP, MUC5B, and the Response to N-Acetylcysteine among Individuals with Idiopathic Pulmonary Fibrosis. American journal of respiratory and critical care medicine 2015; 192: 1475-82
- 11 Hubbard RB, Smith C, Le JeuneI. et al. The association between idiopathic pulmonary fibrosis and vascular disease: a population-based study. Am J Respir Crit Care Med 15.12.2008; 178: 1257-1261
- 12 Sode BF, Dahl M, Nielsen SF. et al. Venous thromboembolism and risk of idiopathic interstitial pneumonia: a nationwide study. Am J Respir Crit Care Med 15.05.2010; 181: 1085-1092
- 13 Kubo H, Nakayama K, Yanai M. et al. Anticoagulant therapy for idiopathic pulmonary fibrosis. Chest 09/2005; 128: 1475-1482
- 14 Noth I, Anstrom KJ, Calvert SB. et al. A Placebo-Controlled Randomized Trial of Warfarin in Idiopathic Pulmonary Fibrosis. Am J Respir Crit Care Med 01.07.2012; 186: 88-95
- 15 Kreuter M, Wijsenbeek MS, Vasakova M. et al. Unfavourable effects of medically indicated oral anticoagulants on survival in idiopathic pulmonary fibrosis. Eur Respir J 06/2016; 47: 1776-1784
- 16 Hyldgaard C, Hilberg O, Muller A. et al. A cohort study of interstitial lung diseases in central Denmark. Respir Med 2014; 108: 793-799
- 17 Tomassetti S, Ruy JH, Gurioli EtAl C. The effect of anticoagulant therapy for idiopathic pulmonary fibrosis in real life practice. Sarcoidosis Vasc Diffuse Lung Dis 2013; 30: 121-127
- 18 Daniels CE, Lasky JA, Limper AH. et al. Imatinib treatment for idiopathic pulmonary fibrosis: Randomized placebo-controlled trial results. Am J Respir Crit Care Med 15.03.2010; 181: 604-610
- 19 Park SH, Saleh D, Giaid A. et al. Increased endothelin-1 in bleomycin-induced pulmonary fibrosis and the effect of an endothelin receptor antagonist. Am J Respir Crit Care Med 1997; 156: 600-608
- 20 Raghu G, Behr J, Brown KK. et al. Treatment of idiopathic pulmonary fibrosis with ambrisentan: a parallel, randomized trial. Annals of internal medicine 07.05.2013; 158: 641-649
- 21 King TE Jr, Behr J, Brown KK. et al. BUILD-1: a randomized placebo-controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2008; 177: 75-81
- 22 King TE Jr, Brown KK, Raghu G. et al. BUILD-3: a randomized, controlled trial of bosentan in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184: 92-99
- 23 Raghu G, Million-Rousseau R, Morganti A. et al. Macitentan for the treatment of idiopathic pulmonary fibrosis: the randomised controlled MUSIC trial. Eur Respir J 2013; 42: 1622-1632
- 24 Jackson RM, Glassberg MK, Ramos CF. et al. Sildenafil therapy and exercise tolerance in idiopathic pulmonary fibrosis. Lung 2010; 188: 115-123
- 25 Zisman DA, Schwarz M, Anstrom KJ. et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med 2010; 363: 620-628
- 26 Han MK, Bach DS, Hagan PG. et al. Sildenafil preserves exercise capacity in patients with idiopathic pulmonary fibrosis and rightsided ventricular dysfunction. Chest 2013; 143: 1699-1708
- 27 Richeldi L. et al. Efficacy of a tyrosine kinase inhibitor in idiopathic pulmonary fibrosis. N Engl J Med 2011; 365: 1079-1087
- 28 Richeldi L, du Bois RM, Raghu G. et al. Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2071-2082
- 29 Richeldi L, du Bois RM, Raghu G. et al. Online supplement to: Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med DOI: 10.1056/NEJMoa1402584.
- 30 Richeldi L, Cottin V, du Bois RM. et al. nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS(®) trials. Respir Med 2016; 113: 74-79
- 31 Costabel U, Inoue Y, Richeldi L. et al. Efficacy of nintedanib in Idiopathic Pulmonary Fibrosis across prespecified subgroups in INPULSIS. Am J Respir Crit Care Med 2016; 193: 178-185
- 32 Taniguchi H, Xu Z, Azuma A. et al. Subgroup analysis of Asian patients in the INPULSIS® trials of nintedanib in idiopathic pulmonary fibrosis. Respirology 2016; 21: 1425-1430
- 33 Wuyts WA, Kolb M, Stowasser S. et al. First data on efficacy and safety of nintedanib in patients with idiopathic pulmonary fibrosis and forced vital capacity of ≤50 % of Predicted Value. Lung 2016; 194: 739-743
- 34 Raghu G, Wells AU, Nicholson AG. et al. Effect of nintedanib in subgroups of idiopathic pulmonary fibrosis by diagnostic criteria. Am J Respir Crit Care Med 2017; 195: 78-85
- 35 Kolb M, Richeldi L, Behr J. et al. nintedanib in patients with idiopathic pulmonary fibrosis and preserved lung volume. Thorax 26.09.2016; DOI: 10.1136/thoraxjnl-2016-208710. pii: thoraxjnl-2016-208710. [Epub ahead of print] PMID: 27672117.
- 36 Bonella F, Kreuter M, Hagmeyer L. et al. Insights from the German compassionate use program of nintedanib for the treatment of idiopathic pulmonary fibrosis. Respiration 2016; 92: 98-106
- 37 Canestaro WJ, Forrester SH, Raghu G. et al. Drug treatment of idiopathic pulmonary fibrosis: Systematic review and network meta-analysis. Chest 2016; 149: 756-766
- 38 Rochwerg B, Neupane B, Zhang Y. et al. Treatment of idiopathic pulmonary fibrosis: a network meta-analysis. BMC Med 2016; 14: 18
- 39 Rogliani P, Calzetta L, Cavalli F. et al. Pirfenidone, nintedanib and N-acetylcysteine for the treatment of idiopathic pulmonary fibrosis: A systematic review and meta-analysis. Pulm Pharmacol Ther 2016; 40: 95-103
- 40 Nakazato H, Oku H, Yamane S. et al. A novel antifibrotic agent pirfenidone suppresses tumor necrosis factor-alpha at the translational level. Eur J Pharmacol 2002; 446: 177-185
- 41 Iyer SN, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on transforming growth factor-beta gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999; 291: 367-373
- 42 Iyer SNGG, Gurujeyalakshmi G, Giri SN. Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis. J Pharmacol Exp Ther 1999; 289: 211-218
- 43 Oku H, Shimizu T, Kawabata T. et al. Antifibrotic action of pirfenidone and prednisolone: different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol 2008; 590: 400-408
- 44 Raghu G, Johnson WC, Lockhart D. et al. Treatment of idiopathic pulmonary fibrosis with a new antifibrotic agent, pirfenidone: results of a prospective, open-label phase II study. Am J Respir Crit Care Med 1999; 159: 1061-1069
- 45 Azuma A, Nukiwa T, Tsuboi E. et al. Double-blind, placebo-controlled trial of pirfenidone in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2005; 171: 1040-1047
- 46 Taniguchi H, Ebina M, Kondoh Y. et al. Pirfenidone Clinical Study Group in Japan. Pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2010; 35: 821-829
- 47 Noble PW, Albera C, Bradford WZ. et al. CAPACITY Study Group. Pirfenidone in patients with idiopathic pulmonary fibrosis (CAPACITY): two randomised trials. Lancet 2011; 377: 1760-1769
- 48 King TE Jr, Bradford WZ, Castro-Bernardini S. et al. ASCEND Study Group. A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med 2014; 370: 2083-2092
- 49 Noble PW, Albera C, Bradford WZ. et al. Pirfenidone for idiopathic pulmonary fibrosis: analysis of pooled data from three multinational phase 3 trials. Eur Respir J 2016; 47: 243-253
- 50 Lancaster L, Albera C, Bradford WZ. et al. Safety of pirfenidone in patients with idiopathic pulmonary fibrosis: integrated analysis of cumulative data from 5 clinical trials. BMJ open respiratory research 2016; 3: e000105
- 51 Albera C. et al. Efficacy of pirfenidone in patients with idiopathic pulmonary fibrosis with more preserved lung function. Eur Respir J 09/2016; 48: 843-851
- 52 Bonella F, Wessendorf TE, Costabel U. Clinical experience with pirfenidone for the treatment of idiopathic pulmonary fibrosis. Dtsch Med Wochenschr 03/2013; 138: 518-523
- 53 Oltmanns U, Kahn N, Palmowski K. et al. Pirfenidone in idiopathic pulmonary fibrosis: real-life experience from a German tertiary referral center for interstitial lung diseases. Respiration 2014; 88: 199-207
- 54 Loeh B. et al. Intraindividual response to treatment with pirfenidone in idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2015; 191: 110-113
- 55 Raghu G, Amatto VC, Behr J. et al. Comorbidities in idiopathic pulmonary fibrosis patients: a systematic literature review. Eur Respir J 2015; 46: 1113-1130
- 56 Lee JS, Ryu JH, Elicker BM. et al. Gastroesophageal reflux therapy is associated with longer survival in patients with idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2011; 184: 1390
- 57 Kreuter M, Ehlers-Tenenbaum S, Palmowski K. et al. Impact of Comorbidities on Mortality in Patients with Idiopathic Pulmonary Fibrosis. PLoS One 29.03.2016; 11: e0151425
- 58 Allaix ME, Fisichella PM, Noth I. et al. The Pulmonary Side of Reflux Disease: from Heartburn to Lung Fibrosis. J Gastrointest Surg 2013; 17: 1526-1535
- 59 Lee JS, Song JW, Wolters PJ. et al. Bronchoalveolar lavage pepsin in acute exacerbation of idiopathic pulmonary fibrosis. Eur Respir J 2012; 39: 352-358
- 60 Raghu G. Idiopathic pulmonary fibrosis: increased survival with “gastroesophageal reflux therapy”: fact or fallacy?. Am J Respir Crit Care Med 2011; 184: 1330-1332
- 61 Lee JS, Collard HR, Anstrom KJ. et al. Anti-acid treatment and disease progression in idiopathic pulmonary fibrosis: an analysis of data from three randomised controlled trials. Lancet Respir Med 2013; 1: 369-376
- 62 Raghu G, Freudenberger TD, Yang S. et al. High prevalence of abnormal acid gastro-oesophageal reflux in idiopathic pulmonary fibrosis. Eur Respir J 2006; 27: 136-142
- 63 Kreuter M, Wuyts W, Renzoni E. et al. Antacid therapy and disease outcomes in idiopathic pulmonary fibrosis: a pooled analysis. Lancet Respir Med 2016; 4: 381-389
- 64 Kreuter M, Spagnolo P, Wuyts W. et al. Antacid therapy and disease progression in patients with IPF who received pirfenidone. Respiration 2017; DOI: 10.1159/000468546.
- 65 Raghu G, Crestani B, Bailes Z. et al. Effect of anti-acid medication on reduction in FVC decline with nintedanib. Eur Respir J 2015; 46 (Suppl. 59) OA450
- 66 Costabel U, Albera C, Bradford WZ. et al. Analysis of lung function and survival in RECAP: an open-label extension study of pirfenidone in patients with idiopathic pulmonary fibrosis. Sarcoidosis Vasc Diffuse Lung Dis 2014; 31: 198-205
- 67 Cottin V, Maher T. Long-termclinical and real-world experiencewith pirfenidone in the treatment of idiopathic pulmonary fibrosis. Eur Respir Rev 2015; 24: 58-64
- 68 Okuda R, Hagiwara E, Baba T. et al. Safety and efficacy of pirfenidone in idiopathic pulmonary fibrosis in clinical practice. Respir Med 2013; 107: 1431-1437
- 69 Chaudhuri N, Duck A, Frank R. et al. Real world experiences: pirfenidone is well tolerated in patients with idiopathic pulmonary fibrosis. Respir Med 2014; 108: 224-226
- 70 Arai T, Inoue Y, Sasaki Y. et al. Predictors of the clinical effects of pirfenidone on idiopathic pulmonary fibrosis. Respir Investig 2014; 52: 136-143.31
- 71 Taguchi Y, Ebina M, Hashimoto S. et al. Efficacy of pirfenidone and disease severity of idiopathic pulmonary fibrosis: Extended analysis of phase III trial in Japan. Respir Investig 2015; 53: 279-87
- 72 King CS, Nathan SD. Practical considerations in the pharmacologic treatment of idiopathic pulmonary fibrosis. Curr Opin Pulm Med 2015; 21: 479-89
- 73 du Bois RM, Weycker D, Albera C. et al. Forced vital capacity in patients with idiopathic pulmonary fibrosis test properties and minimal clinically important difference. Am J Respir Crit Care Med 2011; 184: 1382-1389
- 74 Behr J, Bonella F, Bonnet R. et al. Position Paper: Significance of the Forced Vital Capacity in Idiopathic Pulmonary Fibrosis. Pneumologie 2015; 69: 455-458 Epub 2015 Jul 30. German. PubMed PMID: 26227628
- 75 Nathan SD. et al. Effect of continued treatment with pirfenidone following clinically meaningful declines in forced vital capacity: analysis of data from three phase 3 trials in patients with idiopathic pulmonary fibrosis. Thorax 2016; 71: 429-435 Epub 2016 Mar 11. PubMed PMID: 26968970; PubMed Central PMCID: PMC4862066.
- 76 Richeldi L, Azuma A, Selman M. et al. Twenty-four week decline in forced vital capacity predicts mortality at week 52 in the INPULSIS® trials. Eur Respir J 2016; OA1814
- 77 Milger K, Kneidinger N, Neurohr C. et al. Switching to nintedanib after discontinuation of pirfenidone dueto adverse events in IPF. Eur Respir J 2015; 46: 1217-1221
- 78 Wuyts WA, Antoniou KM, Borensztajn K. et al. Combination therapy: the future of management for idiopathic pulmonary fibrosis?. Lancet Respir Med 2014; 2: 933-942
- 79 Behr J, Bendstrup E, Crestani B. et al. Safety and tolerability of acetylcysteine and pirfenidone combination therapy in idiopathic pulmonary fibrosis: a randomised, double-blind, placebo-controlled, phase 2 trial. Lancet Respir Med 2016; 4: 445-453
- 80 Ogura T, Taniguchi H, Azuma A. et al. Safety and pharmacokinetics of nintedanib and pirfenidone in idiopathic pulmonary fibrosis. Eur Respir J 2015; 45: 1382-1392
- 81 Raghu G, Collard HR, Egan JJ. et al. ATS/ERS/JRS/ALAT Committee on Idiopathic Pulmonary Fibrosis. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med 2011; 183: 788-824
- 82 Lettieri CJ, Veerappan GR, Helman DL. et al. Outcomes and safety of surgical lung biopsy for interstitial lung disease. Chest 2005; 127: 1600-1605
- 83 Park JH, Kim DK, Kim DS. et al. Mortality and risk factors for surgical lung biopsy in patients with idiopathic pulmonary fibrosis. Eur J Cardiothorac Surg 2007; 31: 1115-1119
- 84 Hutchinson JP, Fogarty AW, McKeever TM. et al. In-Hospital Mortality after Surgical Lung Biopsy for Interstitial Lung Disease in the United States. 2000 to 2011. Am J Respir Crit Care Med 2016; 193: 1161-1167
- 85 Casoni GL, Tomassetti S, Cavazza A. et al. Cryobiopsy in the diagnosis of fibrotic interstitial lung diseases. PLoS One 2014; 9 (02) e86716 doi:10.1371/journal.pone.0086716.eCollection2014
- 86 Tomassetti S, Wells AU, Costabel U. et al. Bronchoscopic lung cryobiopsy increases diagnostic confidence in the multidisciplinary diagnosis of idiopathic pulmonary fibrosis. Am J Respir Crit Care Med 2016; 193: 745-752
- 87 Ravaglia C, Bonifazi M, Wells AU. et al. Safety and diagnostic yield of transbronchial lung cryobiopsy in diffuse parenchymal lung diseases: A comparative study versus video-assisted thoracoscopic lung biopsy and a systematic review of the literature. Respiration 2016; 91: 215-227
- 88 Poletti V, Ravaglia C, Tomassetti S. Transbronchial cryobiopsy in diffuse parenchymal lung diseases. Curr Opin Pulm Med 2016; 22: 289-296
- 89 Poletti V, Ravaglia C, Gurioli C. et al. Invasive diagnostic techniques in idiopathic interstitial pneumonias. Respirology 2016; 21: 44-50