Therapie der pulmonal arteriellen Hypertonie

Zusammenfassung

Die pulmonale Hypertonie (PH) gliedert sich nach der 5. Weltkonferenz in Nizza in fünf Gruppen. Die pulmonal arterielle Hypertonie (PAH; Gruppe 1) umfasst neben der idiopathischen PAH genetisch und medikamentös bedingte Formen sowie die assoziierte PAH. Bewiesen oder ausgeschlossen werden kann die Diagnose einer PH nur durch die Rechtsherzkatheteruntersuchung. Ohne Diagnosestellung mittels Rechtsherzkatheters sollte keine gezielte Therapie begonnen werden. Neben allgemeinen und supportiven Maßnahmen existieren aktuell vier Gruppen von Medikamenten, die für die gezielte Behandlung der PAH zugelassen sind. Kombinationstherapien, entweder sequenziell oder initial („up-front“), gewinnen an Bedeutung in der Behandlung der PAH. Therapieziele zur Steuerung der Behandlung und Abschätzung des individuellen Patientenrisikos wurden definiert. Trotz aller Innovationen ist ein kurativer Therapieansatz bei der Behandlung der PAH noch in weiter Ferne. Daher stellt nach Ausschöpfung der derzeit verfügbaren medikamentösen und supportiven Maßnahmen die Lungentransplantation eine wichtige Therapieoption dar.

Abstract

Pulmonary hypertension (PH) is classified into five distinct groups according to the fifth world conference in Nice 2013. Pulmonary arterial hypertension (PAH) comprises idiopathic PAH, hereditary PAH, drug-induced and associated PAH. Right heart catheterization is essential for the diagnosis of PH and should precede initiation of a targeted PAH therapy. Besides general measures and supportive therapy, four different classes of targeted drugs have been approved for the treatment of PAH. Combination therapy, either sequential or initial (up-front), is increasingly gaining recognition. Risk stratification and treatment goals have been defined to guide therapeutic decisions. However, cure is still far from reach and lung transplantation is an important treatment option for patients with end-stage disease under optimal supportive and targeted drug therapy.

Kernaussagen

Die Therapie von Patienten mit PAH ist vielschichtig und erfordert ein erfahrenes Behandlungsteam. Jeder Patient mit PAH sollte in einem auf PH spezialisierten Zentrum diagnostiziert und therapiert werden. Die Therapie umfasst neben allgemeinen und supportiven Maßnahmen aktuell vier Gruppen von gezielten Medikamenten. Die Kombinationstherapie gewinnt zunehmend an Bedeutung. Nach Einleitung einer gezielten PAH-Therapie ist eine regelmäßige Überwachung des Therapieerfolgs sowie der Verträglichkeit obligat. Die Behandlung sollte sich in strukturierter Form an den definierten Therapiezielen orientieren. Patienten, welche diese Ziele unter einer gezielten PAH-Therapie nicht erreichen, haben in der Regel eine schlechtere Prognose. Bei unzureichender klinischer Wirksamkeit der maximalen medikamentösen und supportiven Therapie stellt die Lungentransplantation für Patienten mit PAH eine wichtige Therapieoption dar.

• Literatur

• 1 Galie N, Hoeper MM, 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 Respir J 2009; 34: 1219-1263
• 2 Grunig E, Ehlken N, Hohenforst-Schmidt W et al. [Supportive therapy in pulmonary arterial hypertension]. Dtsch Med Wochenschr 2014; 139 (Suppl. 04) S136-141
• 3 Galie N, Corris PA, Frost A et al. Updated treatment algorithm of pulmonary arterial hypertension. J Am Coll Cardiol 2013; 62: D60-72
• 4 Galie N, Hoeper MM, 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
• 5 Klose H, Opitz C, Bremer H et al. [Targeted therapy of pulmonary arterial hypertension (PAH)]. Dtsch Med Wochenschr 2014; 139 (Suppl. 04) S142-150
• 6 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
• 7 McLaughlin VV, Gaine SP, Howard LS et al. Treatment goals of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D73-81
• 8 Lowe B, Grafe K, Ufer C et al. Anxiety and depression in patients with pulmonary hypertension. Psychosomatic Medicine 2004; 66: 831-836
• 9 Harzheim D, Klose H, Pinado FP et al. Anxiety and depression disorders in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Respir Res 2013; 14: 104
• 10 Halank M, Einsle F, Lehman S et al. Exercise capacity affects quality of life in patients with pulmonary hypertension. Lung 2013; 191: 337-343
• 11 Ladwig KH, Lederbogen F, Albus C et al. Position paper on the importance of psychosocial factors in cardiology: Update 2013. German medical science: GMS e-journal 2014; 12: Doc09
• 12 Larisch A, Neeb C, de Zwaan M et al. [Mental distress and wish for psychosomatic treatment of patients with pulmonary hypertension]. Psychother Psych Med 2014; 64: 384-389
• 13 Frank H, Mlczoch J, Huber K et al. The effect of anticoagulant therapy in primary and anorectic drug-induced pulmonary hypertension. Chest 1997; 112: 714-721
• 14 Olsson KM, Delcroix M, Ghofrani HA et al. Anticoagulation and survival in pulmonary arterial hypertension: results from the Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension (COMPERA). Circulation 2014; 129: 57-65
• 15 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
• 16 Olsson KM, Nickel NP, Tongers J et al. Atrial flutter and fibrillation in patients with pulmonary hypertension. Int J Cardiol 2013; 167: 2300-2305
• 17 Nickel N, Golpon H, Greer M et al. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2012; 39: 589-596
• 18 Mathai SC, Bueso M, Hummers LK et al. Disproportionate elevation of N-terminal pro-brain natriuretic peptide in scleroderma-related pulmonary hypertension. Eur Respir J 2010; 35: 95-104
• 19 Simonneau G, Gatzoulis MA, Adatia I et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D34-41
• 20 Hoeper MM, Bogaard HJ, Condliffe R et al. Definitions and diagnosis of pulmonary hypertension. J Am Coll Cardiol 2013; 62: D42-50
• 21 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
• 22 Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896-903
• 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 Humbert M, Segal ES, Kiely DG et al. Results of European post-marketing surveillance of bosentan in pulmonary hypertension. Eur Respir J 2007; 30: 338-344
• 25 Galie N, Olschewski H, Oudiz RJ 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
• 26 Ben-Yehuda O, Pizzuti D, Brown A et al. Long-term hepatic safety of ambrisentan in patients with pulmonary arterial hypertension. J Am Coll Cardiol 2012; 60: 80-81
• 27 Kummer O, Haschke M, Hammann F et al. Comparison of the dissolution and pharmacokinetic profiles of two galenical formulations of the endothelin receptor antagonist macitentan. Eur J Pharm Sci 2009; 38: 384-388
• 28 Pulido T, Adzerikho I, Channick RN et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369: 809-818
• 29 Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995; 333: 214-221
• 30 Galie N, Ghofrani HA, Torbicki A et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 2148-2157
• 31 Rubin LJ, Badesch DB, Fleming TR et al. Long-term treatment with sildenafil citrate in pulmonary arterial hypertension: the SUPER-2 study. Chest 2011; 140: 1274-1283
• 32 Simonneau G, Rubin LJ, 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
• 33 Galie N, Brundage BH, Ghofrani HA et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119: 2894-2903
• 34 Ghofrani HA, Grimminger F. Soluble guanylate cyclase stimulation: an emerging option in pulmonary hypertension therapy. Eur Respir Rev 2009; 18: 35-41
• 35 Ghofrani HA, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369: 330-340
• 36 Rubin LJ, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J 2015; 45: 1303-1313
• 37 Olschewski H, Rose F, Grunig E et al. Cellular pathophysiology and therapy of pulmonary hypertension. J Lab Clin Med 2001; 138: 367-377
• 38 Olschewski H, Simonneau G, Galie N et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347: 322-329
• 39 Badesch DB, Tapson VF, McGoon MD et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132: 425-434
• 40 Rubin LJ, Mendoza J, Hood M et al. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin (epoprostenol). Results of a randomized trial. Ann Intern Med 1990; 112: 485-491
• 41 Barst RJ, Rubin LJ, Long WA et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334: 296-301
• 42 Sitbon O, Delcroix M, Bergot E et al. EPITOME-2: An open-label study assessing the transition to a new formulation of intravenous epoprostenol in patients with pulmonary arterial hypertension. American heart journal 2014; 167: 210-217
• 43 Simonneau G, Barst RJ, 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
• 44 Hiremath J, Thanikachalam S, Parikh K et al. Exercise improvement and plasma biomarker changes with intravenous treprostinil therapy for pulmonary arterial hypertension: a placebo-controlled trial. J Heart Lung Transplant 2010; 29: 137-149
• 45 Benza RL, Seeger W, McLaughlin VV et al. Long-term effects of inhaled treprostinil in patients with pulmonary arterial hypertension: the Treprostinil Sodium Inhalation Used in the Management of Pulmonary Arterial Hypertension (TRIUMPH) study open-label extension. J Heart Lung Transplant 2011; 30: 1327-1333
• 46 Tapson VF, Jing ZC, Xu KF et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C2 study): a randomized controlled trial. Chest 2013; 144: 952-958
• 47 Tapson VF, Torres F, Kermeen F et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOM-C study): a randomized controlled trial. Chest 2012; 142: 1383-1390
• 48 Jing ZC, Parikh K, Pulido T et al. Efficacy and safety of oral treprostinil monotherapy for the treatment of pulmonary arterial hypertension: a randomized, controlled trial. Circulation 2013; 127: 624-633
• 49 Simonneau G, Torbicki A, Hoeper MM et al. Selexipag: an oral, selective prostacyclin receptor agonist for the treatment of pulmonary arterial hypertension. Eur Respir J 2012; 40: 874-880
• 50 GRIPHON, (Prostacyclin (PGI2) Receptor agonist In Pulmonary arterial HypertensiON) was a randomized, multicenter, double-blind, placebo-controlled trial evaluating the long term efficacy and safety of oral selexipag in patients with pulmonary arterial hypertension. Actelion Pharmaceuticals Ltd. 2014. http://www1.actelion.com/en/scientists/development-pipeline/phase-3/selexipag.page
• 51 Bai Y, Sun L, Hu S et al. Combination therapy in pulmonary arterial hypertension: a meta-analysis. Cardiology 2011; 120: 157-165
• 52 Sitbon O, Jais X, Savale L et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J 2014; 43: 1691-1697
• 53 First-Line Combination of Ambrisentan and Tadalafil Reduces Risk of Clinical Failure Compared to Monotherapy in Pulmonary Arterial Hypertension Outcomes Study. Gilead Sciences Inc; 2014 http://www.gilead.com/news/press-releases/2014/9/firstline-combination-of-ambrisentan-and-tadalafil-reduces-risk-of-clinical-failure-compared-to-monotherapy-in-pulmonary-arterial-hypertension-outcomes-study Accessed 2014-10-13
• 54 de Perrot M, Granton JT, McRae K et al. Outcome of patients with pulmonary arterial hypertension referred for lung transplantation: a 14-year single-center experience. J Thorac Cardiovasc Surg 2012; 143: 910-918
• 55 Fadel E, Mercier O, Mussot S et al. Long-term outcome of double-lung and heart-lung transplantation for pulmonary hypertension: a comparative retrospective study of 219 patients. Eur J Cardiothorac Surg 2010; 38: 277-284
• 56 Christie JD, Edwards LB, Kucheryavaya AY et al. The Registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report-2012. J Heart Lung Transplant 2012; 31: 1073-1086
• 57 Fuehner T, Kuehn C, Hadem J et al. Extracorporeal membrane oxygenation in awake patients as bridge to lung transplantation. Am J Respir Crit Care Med 2012; 185: 763-768
• 58 Opitz CF, Blindt R, Blumberg F et al. [Pulmonary hypertension: hemodynamic evaluation: hemodynamic evaluation – recommendations of the Cologne Consensus Conference 2010]. Dtsch Med Wochenschr 2010; 135 (Suppl. 03) S78-86
• 59 Tapson VF, Gomberg-Maitland M, McLaughlin VV et al. Safety and efficacy of IV treprostinil for pulmonary arterial hypertension: a prospective, multicenter, open-label, 12-week trial. Chest 2006; 129: 683-688