Therapie der pulmonal arteriellen Hypertonie (PAH)

Zusammenfassung

Die 2009 veröffentlichen Europäischen Leitlinien zur Diagnostik und Therapie der pulmonalen Hypertonie sind nunmehr auch in Deutschland gültig. Die Leitlinien befassen sich eingehend mit der Therapie der pulmonal arteriellen Hypertonie (PAH). Für die praktische Umsetzung der Europäischen Leitlinien in Deutschland sind jedoch zahlreiche für Deutschland spezifische Gesichtspunkte und bereits wieder neue Daten bedeutsam, die eine ausführliche Kommentierung der Leitlinien und in einigen Punkten eine Aktualisierung notwendig machen. Im Juni 2010 fand in Köln eine Konsensuskonferenz statt, die von den Arbeitsgruppe PH der Deutschen Gesellschaften für Kardiologie (DGK), Pneumologie (DGP) und Pädiatrische Kardiologie (DGPK) organisiert wurde. Die Konferenz befasste sich mit der Umsetzung der Europäischen Leitlinien in Deutschland. Dazu wurden verschiedene Arbeitsgruppen eingesetzt, von denen sich eine gezielt der Therapie der pulmonal arteriellen Hypertonie (PAH) widmete. Die Ergebnisse und Empfehlungen dieser Arbeitsgruppe werden in dem vorliegenden Manuskript detailliert beschrieben.

Abstract

The 2009 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension have been adopted for Germany. The guidelines contain detailed recommendations for the treatment of pulmonary arterial hypertension (PAH). However, the practical implementation of the European Guidelines in Germany requires the consideration of several country-specific issues and already existing novel data. This requires a detailed commentary to the guidelines, and in some aspects an update already appears necessary. In June 2010, a Consensus Conference organized by the PH working groups of the German Society of Cardiology (DGK), the German Society of Respiratory Medicine (DGP) and the German Society of Pediatric Cardiology (DGPK) was held in Cologne, Germany. This conference aimed to solve practical and controversial issues surrounding the implementation of the European Guidelines in Germany. To this end, a number of working groups was initiated, one of which was specifically dedicated to the treatment of PAH. This commentary summarizes the results and recommendations of the working group on treatment of PAH.

Schlüsselwörter

Pulmonal arterielle Hypertonie (PAH) - Therapie - Prostanoide - Endothelin-Rezeptor-Antagonisten - Phosphodiesterase-5-Inhibitoren

Keywords

pulmonary arterial hypertension (PAH) - treatment - prostanoids - endothelin receptor antagonists - phosphodiesterase type 5 inhibitors

Literatur

• 1 Barst R J, Ivy D, Dingemanse J, Widlitz A. et al . Pharmacokinetics, safety and efficacy of bosentan in pediatric patients with pulmonary arterial hypertension.  Clin Pharmacol Ther. 2003;  73 372-382
• 2 Barst R J, Langleben D, Badesch D. et al . Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan.  J Am Coll Cardiol. 2006;  47 2049-2056
• 3 Barst R J, Langleben D, Frost A. et al . Sitaxsentan therapy for pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2004;  169 441-447
• 4 Barst R J, Rubin L J, Long W A. et al . A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group.  N Engl J Med. 1996;  334 296-302
• 5 Beghetti M, Haworth S G, Bonnet D. et al . Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study.  Br J Clin Pharmacol. 2009;  68 948-955
• 6 Bull T M, Fagan K A, Badesch D B. Pulmonary vascular manifestations of mixed connective tissue disease.  Rheum Dis Clin North Am. 2005;  31 451-464, vi
• 7 Carlsen J, Kjeldsen K, Gerstorft J. Sildenafil as a successful treatment of otherwise fatal HIV-related pulmonary hypertension.  AIDS. 2002;  16 1568-1569
• 8 Channick R N, Simonneau G, Sitbon O. et al . Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study.  Lancet. 2001;  358 1119-1123
• 9 Chau E M, Fan K Y, Chow W H. Effects of chronic sildenafil in patients with Eisenmenger syndrome versus idiopathic pulmonary arterial hypertension.  Int J Cardiol. 2007;  120 301-305
• 10 Degano B, Yaici A, Le Pavec J. et al . Long-term effects of bosentan in patients with HIV-associated pulmonary arterial hypertension.  Eur Respir J. 2009;  33 92-98
• 11 De Man F S, Handoko M L, Groepenhoff H. et al . Effects of exercise training in patients with idiopathic pulmonary arterial hypertension.  Eur Respir J. 2009;  34 669-675
• 12 Dimopoulos K, Inuzuka R, Goletto S. et al . Improved survival among patients with Eisenmenger syndrome receiving advanced therapy for pulmonary arterial hypertension.  Circulation. 2010;  121 20-25
• 13 Dupuis J, Hoeper M M. Endothelin receptor antagonists in pulmonary arterial hypertension.  Eur Respir J. 2008;  31 407-414
• 14 Evgenov O V, Pacher P, Schmidt P M. et al . NO-independent stimulators and activators of soluble guanylate cyclase: discovery and therapeutic potential.  Nat Rev Drug Discov. 2006;  5 755-768
• 15 Fernandes S M, Newburger J W, Lang P. et al . Usefullness of epoprostenol therapy in the severly ill adolescent/adult with Eisenmenger physiology.  Am J Cardiol. 2003;  91 632-635
• 16 Galie N, Beghetti M, Gatzoulis M A. et al . Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study.  Circulation. 2006;  114 48-54
• 17 Galie N, Brundage B H, Ghofrani H A. et al . Tadalafil therapy for pulmonary arterial hypertension.  Circulation. 2009;  119 2894-2903
• 18 Galie N, Ghofrani H A, Torbicki A. et al . Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension.  N Engl J Med. 2005;  353 2148-2157
• 19 Galiè N, Hoeper M M, Humbert M. et al . Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT).  Eur Heart J. 2009;  30 2493-2537
• 20 Galiè N, Hoeper M M, Humber M. et al . Guidelines for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT).  Eur Respir J. 2009;  34 1219-1263
• 21 Galie N, Manes A, Negro L. et al . A meta-analysis of randomized controlled trials in pulmonary arterial hypertension.  Eur Heart J. 2009;  30 394-403
• 22 Galie N, Olschewski H, Oudiz R J. et al . Ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2.  Circulation. 2008;  117 3010-3019
• 23 Galie N, Rubin L, Hoeper M. et al . Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial.  Lancet. 2008;  371 2093-2100
• 24 Ghofrani H A, Grimminger F. Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy.  Eur Respir Rev. 2009;  18 35-41
• 25 Ghofrani H A, Hoeper M M, Halank M. et al . Riociguat for chronic thromboembolic pulmonary hypertension and pulmonary arterial hypertension: a phase II study.  Eur Respir J. 2010a (in press); 
• 26 Ghofrani H A, Morrell N W, Hoeper M M. et al . Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy.  Am J Respir Crit Care Med. 2010b ;  DOI: 10.1164/rccm.201001–0123OC
• 27 Grannas G, Neipp M, Hoeper M M. et al . Indications for and Outcomes After Combined Lung and Liver Transplantation: A Single-Center Experience on 13 Consecutive Cases.  Transplantation. 2008;  85 524-531
• 28 Haworth S G, Hislop A A. Treatment and survival in children with pulmonary arterial hypertension: the UK Pulmonary Hypertension Service for Children 2001 – 2006.  Heart. 2009;  95 312-317
• 29 Hoeper M M, Gall H, Seyfarth H J. et al . Long-term outcome with intravenous iloprost in pulmonary arterial hypertension.  Eur Respir J. 2009;  34 132-137
• 30 Hoeper M M, Ghofrani H A, Gorenflo M. et al . Diagnostik und Therapie der pulmonalen Hypertonie: Europäische Leitlinien 2009.  Pneumologie. 2010;  64 401-414
• 31 Hoeper M M, Markevych I, Spiekerkoetter E, Welte T, Niedermeyer J. Goal-oriented treatment and combination therapy for pulmonary arterial hypertension.  Eur Respir J. 2005;  26 858-863
• 32 Hoeper M M, Seyfarth H J, Hoeffken G. et al . Experience with inhaled iloprost and bosentan in portopulmonary hypertension.  Eur Respir J. 2007;  30 1096-1102
• 33 Krasuski R A, Hart S A, Smith B. et al . Association of anemia and long-term survival in patients with pulmonary hypertension.  Int J Cardiol. 2010 (in press); 
• 34 Ladwig K H, Baumert J, Marten M. et al . Posttraumatic stress symptoms and predicted mortality in patients with implantable cardioverter-defibrillators: results from the prospective living with an implanted cardioverter-defibrillator study.  Arch Gen Psychiatry. 2008;  65 1324-1330
• 35 McLaughlin V V, Benza R L, Rubin R J. et al . Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension.  J Am Coll Cardiol. 2010;  55 1915-1922
• 36 McLaughlin V V, Oudiz R J, Frost A. et al . Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2006;  174 1257-1263
• 37 Mereles D, Ehlken N, Kreuscher S. et al . Exercise and respiratory training improve exercise capacity and quality of life in patients with severe chronic pulmonary hypertension.  Circulation. 2006;  114 1482-1489
• 38 Moledina S, Hislop A A, Foster H, Schulze-Neick I, Haworth S G. Childhood idiopathic pulmonary arterial hypertension: a national cohort study.  Heart. 2010;  (Epub ahead of print)
• 39 Mukerjee D, St G eorge D, Coleiro B. et al . Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach.  Ann Rheum Dis. 2003;  62 1088-1093
• 40 Mukhopadhyay S, Sharma M, Ramakrishnan S. et al . Phosphodiesterase-5 inhibitor in Eisenmenger syndrome: a preliminary observational study.  Circulation. 2006;  114 1807-1810
• 41 Olschewski H, Gomberg-Maitland M. Prostacyclin therapies for the treatment of pulmonary arterial hypertension.  Eur Respir J. 2008;  31 801-901
• 42 Olschewski H, Simonneau G, Galie N. et al . Inhaled iloprost for severe pulmonary hypertension.  N Engl J Med. 2002;  347 322-329
• 43 Oudiz R J, Galie N, Olschewski H. et al . Long-term ambrisentan therapy for the treatment of pulmonary arterial hypertension.  J Am Coll Cardiol. 2009;  54 1971-1981
• 44 Perros F, Montani D, Dorfmüller P. et al . Platelet-derived growth factor expression and function in idiopathic pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2008;  178 81-88
• 45 Reichenberger F, Voswinckel R, Steveling E. et al . Sildenafil treatment for portopulmonary hypertension.  Eur Respir J. 2006;  28 563-567
• 46 Rosenzweig E B, Ivy D D, Wildlitz A. et al . Effects of long-term bosentan in children with pulmonary arterial hypertension.  J Am Coll Cardiol. 2005;  46 697-704
• 47 Rubin L J, Badesch D B, Barst R J. et al . Bosentan therapy for pulmonary arterial hypertension.  N Engl J Med. 2002;  346 896-903
• 48 Schermuly R T, Dony E, Ghofrani H A. et al . Reversal of experimental pulmonary hypertension by PDGF inhibition.  J Clin Invest. 2005;  115 2811-2821
• 49 Schumacher Y O, Zdebik A, Huonker M, Kreisel W. Sildenafil in HIV-related pulmonary hypertension.  AIDS. 2001;  15 1747-1748
• 50 Simonneau G, Barst R J, Galie N. et al . Continuous subcutaneous infusion of treprostinil, a prostacyclin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial.  Am J Respir Crit Care Med. 2002;  165 800-804
• 51 Simonneau G, Rubin L J, Galie N. et al . Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial.  Ann Intern Med. 2008;  149 521-530
• 52 Sitbon O, Gressin V, Speich R. et al . Bosentan for the treatment of human immunodeficiency virus-associated pulmonary arterial hypertension.  Am J Respir Crit Care Med. 2004;  170 1212-1217
• 53 Sitbon O, Humbert M, Jais X. et al . Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension.  Circulation. 2005;  111 3105-3111
• 54 Sitbon O, Lascoux-Combe C, Delfraissy J F. et al . Prevalence of HIV-related pulmonary arterial hypertension in the current antiretroviral therapy era.  Am J Respir Crit Care Med. 2008;  177 108-113
• 55 Thamm M, Voswinckel R, Gall H. et al . Air travel is safe and well tolerated in clinically stable patients with stable pulmonary hypertension. ATS PH patients.  Am J Respir Crit Care Med. 2009;  179 A3371 (Abstract)
• 56 Tongers J, Schwerdtfeger B, Klein G. et al . Incidence and clinical relevance of supraventricular tachyarrhythmias in pulmonary hypertension.  Am Heart J. 2007;  153 127-132
• 57 Whooley M A, Simon G E. Managing depression in medical outpatients.  N Engl J Med. 2000;  343 1942-1950
• 58 Wilkins M R, Wharton J, Grimminger F, Ghofrani H A. Phosphodiesterase inhibitors for the treatment of pulmonary hypertension.  Eur Respir J. 2008;  32 198-209