Gezielte Therapie der pulmonal arteriellen Hypertonie: Empfehlungen der Kölner Konsensuskonferenz 2016

Zusammenfassung

Die 2015 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 2016 fand in Köln eine Konsensus-Konferenz statt, die von den Arbeitsgruppen 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 der gezielten Therapie der pulmonal arteriellen Hypertonie (PAH) widmete. Die Ergebnisse und Empfehlungen dieser Arbeitsgruppe werden in dem vorliegenden Manuskript detailliert beschrieben.

Abstract

The 2015 European Guidelines on Diagnosis and Treatment of Pulmonary Hypertension are also valid for Germany. The guidelines contain detailed recommendations for the targeted 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 2016, 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 targeted therapy of PAH. This article summarizes the results and recommendations of the working group on targeted treatment of PAH.

Schlüsselwörter

pulmonale Hypertonie - pulmonal arterielle Hypertonie - Therapie - Endothelin-Rezeptor-Antagonisten - Phosphodiesterase-5-Inhibitoren - Prostacyclin-Analoga - sGC-Stimulatoren

Keywords

pulmonary hypertension - pulmonary arterial hypertension - treatment - endothelin receptor antagonists - phosphodiesterase-5 inhibitors - prostacyclin analogues - sGC stimulators

• Literatur

• 1 Barst RJ, Beghetti M, Pulido T et al. STARTS-2: Long-Term Survival With Oral Sildenafil Monotherapy in Treatment-Naive Pediatric Pulmonary Arterial Hypertension. Circulation 2014; 129: 1914-1923
• 2 Barst RJ, Ivy DD, Gaitan G et al. A randomized, double-blind, placebo-controlled, dose-ranging study of oral sildenafil citrate in treatment-naive children with pulmonary arterial hypertension. Circulation 2012; 125: 324-334
• 3 Barst RJ, Rubin LJ, Long WA 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
• 4 Baruteau AE, Belli E, Boudjemline Y et al. Palliative Potts shunt for the treatment of children with drug-refractory pulmonary arterial hypertension: updated data from the first 24 patients. Eur J Cardiothorac Surg 2015; 47: e105-110
• 5 Beghetti M, Haworth SG, 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 Beghetti M, Hoeper MM, Kiely DG et al. Safety experience with bosentan in 146 children 2-11 years old with pulmonary arterial hypertension: results from the European Postmarketing Surveillance program. Pediatr Res 2008; 64: 200-204
• 7 de Perrot M, Granton JT, McRae K et al. Impact of extracorporeal life support on outcome in patients with idiopathic pulmonary arterial hypertension awaiting lung transplantation. J Heart Lung Transplant 2011; 30: 997-1002
• 8 Esch JJ, Shah PB, Cockrill BA et al. Transcatheter Potts shunt creation in patients with severe pulmonary arterial hypertension: initial clinical experience. J Heart Lung Transplant 2013; 32: 381-387
• 9 Ewert R, Halank M, Bruch L et al. A case series of patients with severe pulmonary hypertension receiving an implantable pump for intravenous prostanoid therapy. Am J Respir Crit Care Med 2012; 186: 1196-1198
• 10 Galie N, Barbera JA, Frost AE et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med 2015; 373: 834-844
• 11 Galie N, Beghetti M, Gatzoulis MA et al. Bosentan therapy in patients with Eisenmenger syndrome: a multicenter, double-blind, randomized, placebo-controlled study. Circulation 2006; 114: 48-54
• 12 Galie N, Brundage BH, Ghofrani HA et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119: 2894-2903
• 13 Galie N, Ghofrani HA, Torbicki A et al. Sildenafil Citrate Therapy for Pulmonary Arterial Hypertension. N Engl J Med 2005; 353: 2148-2157
• 14 Galie N, Humbert M, Vachiery JL et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint 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: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Respir J 2015; 46: 903-975
• 15 Galie N, Humbert M, Vachiery JL et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J 2016; 37: 67-119
• 16 Galie N, Muller K, Scalise AV et al. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur Respir J 2015; 45: 1314-1322
• 17 Galie N, Neuser D, Muller K et al. A placebo-controlled, double-blind, phase II interaction study to vealuate blood pressure following addition of riociguat to patients with symptomatic pulmonary arterial hypertension receiving sildenafil. Am J Resp Crit Care Med 2013; 187: A3530
• 18 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
• 19 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
• 20 Ghofrani HA, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369: 330-340
• 21 Ghofrani HA, Grimminger F, Grunig E et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med 4: 361-371
• 22 Ghofrani HA, Morrell NW, Hoeper MM et al. Imatinib in pulmonary arterial hypertension patients with inadequate response to established therapy. Am J Respir Crit Care Med 2010; 182: 1171-1177
• 23 Gomberg-Maitland M, Tapson VF, Benza RL et al. Transition from Intravenous Epoprostenol to Intravenous Treprostinil in Pulmonary Hypertension. Am J Respir Crit Care Med 2005; 172: 1586-1589
• 24 Hassoun PM, Zamanian RT, Damico R et al. Ambrisentan and Tadalafil Up-front Combination Therapy in Scleroderma-associated Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2015; 192: 1102-1110
• 25 Hoeper MM, Barst RJ, Bourge RC et al. Imatinib mesylate as add-on therapy for pulmonary arterial hypertension: results of the randomized IMPRES study. Circulation 2013; 127: 1128-1138
• 26 Hoeper MM, Humbert M, Souza R et al. A global view of pulmonary hypertension. Lancet Respir Med 2016; 4: 306-322
• 27 Hoeper MM, Huscher D, Ghofrani HA et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: Results from the COMPERA registry. Int J Cardiol 2013; 168: 871-880
• 28 Hoeper MM, Huscher D, Pittrow D. Incidence and prevalence of pulmonary arterial hypertension in Germany. Int J Cardiol 2016; 203: 612-613
• 29 Hoeper MM, Leuchte H, Halank M et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J 2006; 28: 691-694
• 30 Hoeper MM, McLaughlin VV, Dalaan AM et al. Treatment of pulmonary hypertension. Lancet Respir Med 2016; 4: 323-336
• 31 Hoeper MM, Meyer K, Rademacher J et al. Diffusion Capacity and Mortality in Patients With Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction. JACC Heart failure 2016; 4: 441-449
• 32 Hoeper MM, Opitz C, Olschewski H et al. [Imatinib for pulmonary arterial hypertension.]. Dtsch Med Wochenschr 2014; 139: S151-S154
• 33 Humbert M, Lau EM, Montani D et al. Advances in therapeutic interventions for patients with pulmonary arterial hypertension. Circulation 2014; 130: 2189-2208
• 34 Jing ZC, Jiang X, Han ZY et al. Iloprost for pulmonary vasodilator testing in idiopathic pulmonary arterial hypertension. Eur Respir J 2009; 33: 1354-1360
• 35 Kemp K, Savale L, O'Callaghan DS et al. Usefulness of first-line combination therapy with epoprostenol and bosentan in pulmonary arterial hypertension: an observational study. J Heart Lung Transplant 2012; 31: 150-158
• 36 Lajoie AC, Lauziere G, Lega JC et al. Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis. Lancet Respir Med 2016; 4: 291-305
• 37 Latus H, Apitz C, Moysich A et al. Creation of a functional Potts shunt by stenting the persistent arterial duct in newborns and infants with suprasystemic pulmonary hypertension of various etiologies. J Heart Lung Transplant 2014; 33: 542-546
• 38 McLaughlin V, Channick RN, Ghofrani HA et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J 2015; 46: 405-413
• 39 McLaughlin VV, Benza RL, Rubin LJ et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol 2010; 55: 1915-1922
• 40 McLaughlin VV, Oudiz RJ, 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
• 41 Montani D, Savale L, Natali D et al. Long-term response to calcium-channel blockers in non-idiopathic pulmonary arterial hypertension. Eur Heart J 2010; 31: 1898-1907
• 42 Mueller-Mottet S, Stricker H, Domenighetti G et al. Long-term data from the Swiss pulmonary hypertension registry. Respiration 2015; 89: 127-140
• 43 Olschewski H, Simonneau G, Galie N et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347: 322-329
• 44 Opitz CF, Hoeper MM, Gibbs JS et al. Pre-Capillary, Combined, and Post-Capillary Pulmonary Hypertension: A Pathophysiological Continuum. J Am Coll Cardiol 2016; 68: 368-378
• 45 Paul GA, Gibbs JS, Boobis AR et al. Bosentan decreases the plasma concentration of sildenafil when coprescribed in pulmonary hypertension. Br J Clin Pharmacol 2005; 60: 107-112
• 46 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
• 47 Rubin LJ, Badesch DB, Barst RJ et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896-903
• 48 Rubin LJ, Badesch DB, Fleming TR et al. Long-Term Treatment with Sildenafil Citrate in Pulmonary Arterial Hypertension: SUPER-2. Chest 2011; 140: 1274-1283
• 49 Shah AM, Campbell P, Rocha GQ et al. Effect of imatinib as add-on therapy on echocardiographic measures of right ventricular function in patients with significant pulmonary arterial hypertension. Eur Heart J 2015; 36: 623-632
• 50 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
• 51 Simonneau G, D'Armini AM, Ghofrani HA et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2). Eur Respir J 2015; 45: 1293-1302
• 52 Simonneau G, Rubin LJ, Galie N et al. Long-term sildenafil added to intravenous epoprostenol in patients with pulmonary arterial hypertension. J Heart Lung Transplant 2014; 33: 689-697
• 53 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
• 54 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
• 55 Sitbon O, Channick R, Chin KM et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. New England Journal of Medicine 2015; 373: 2522-2533
• 56 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
• 57 Sitbon O, Sattler C, Bertoletti L et al. Initial dual oral combination therapy in pulmonary arterial hypertension. Eur Respir J 2016; 47: 1727-1736
• 58 Speich R, Ulrich S, Domenighetti G et al. Efficacy and Safety of Long-Term Imatinib Therapy for Pulmonary Arterial Hypertension. Respiration 2015; 89: 515-524
• 59 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
• 60 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
• 61 Trip P, Nossent EJ, de Man FS et al. Severely reduced diffusion capacity in idiopathic pulmonary arterial hypertension: patient characteristics and treatment responses. Eur Respir J 2013; 42: 1575-1585
• 62 Tudorache I, Sommer W, Kuhn C et al. Lung transplantation for severe pulmonary hypertension-awake extracorporeal membrane oxygenation for postoperative left ventricular remodelling. Transplantation 2015; 99: 451-458
• 63 Weill D, Benden C, Corris PA et al. A consensus document for the selection of lung transplant candidates: 2014-An update from the Pulmonary Transplantation Council of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 2015; 34: 1-15