Gezielte medikamentöse Therapie der pulmonalarteriellen Hypertonie bei Patient*innen ohne Komorbiditäten

Zusammenfassung

Die neuen Leitlinien der European Society of Cardiology (ESC) und European Respiratory Society (ERS) von 2022 zur pulmonalen Hypertonie fassen die aktuelle Evidenz zusammen und legen Therapiestrategien dar. Um der veränderten klinischen Präsentation der Patient*innen, bei denen eine pulmonalarterielle Hypertonie (PAH) in Europa diagnostiziert und behandelt wird, Rechnung zu tragen, werden Behandlungsempfehlungen für Patient*innen mit und ohne kardiopulmonale Komorbiditäten unterschieden. Dieser Artikel stellt die gezielte Therapie der PAH bei Patient*innen ohne kardiopulmonale Komorbiditäten vor und konzentriert sich auf Patient*innen mit idiopathischer, hereditärer, medikamenten-/toxinassoziierter oder mit Bindegewebserkrankungen-assoziierter PAH. Bei diesen Patient*innen orientiert sich die Therapieeinleitung und Anpassung im Krankheitsverlauf an einer multiparametrischen Bewertung des Mortalitätsrisikos. Für Patient*innen mit niedrigem oder intermediärem Risiko wird eine initiale, orale Kombinationstherapie (Phosphodiesterase-5-Inhibitor und Endothelin-Rezeptor-Antagonist) empfohlen. Bei Patient*innen mit hohem Risiko sollte eine Dreifach-Kombinationstherapie mit einem i. v./s. c. Prostazyklin-Analogon in Betracht gezogen werden. Wenn unter der Therapie ein niedriger Risikostatus nicht erreicht wird, sollte eine sequentielle Therapieerweiterung mit einem Prostazyklin-Rezeptor-Agonisten oder einem Prostazyklin-Analogon in Betracht gezogen werden. Alternativ kann eine Umstellung des Phosphodiesterase-5-Inhibitors auf einen Guanylatzyklase-Stimulator erwogen werden.

Abstract

The 2022 guidelines on pulmonary hypertension from the European Society of Cardiology (ESC) and the European Respiratory Society (ERS) provide therapeutic strategies that account for the variability in the clinical presentation of newly diagnosed patients. We summarize treatment recommendations for pulmonary arterial hypertension (PAH) in patients without significant comorbidities, particularly for idiopathic, hereditary, drug/toxin-induced, or connective tissue disease-associated PAH. In this group of patients, multidimensional assessments for short-term mortality risk guide initial treatment decisions and treatment decisions during follow-up. Upfront dual combination therapy (phosphodiesterase type-5 inhibitor and endothelin receptor antagonist) is recommended for low- and intermediate-risk patients, and triple therapy including a parenteral prostacyclin should be considered in high- or intermediate-high-risk patients. If a low or intermediate-low-risk profile cannot be achieved during therapy, sequential add-on therapy escalation with parenteral prostacyclin or a prostacyclin receptor agonist should be considered, and switching from a phosphodiesterase type-5 inhibitor to a guanylate cyclase stimulator may also be considered.

Schlüsselwörter

pulmonalarteriellen Hypertonie - Kalziumkanalblocker - Endothelin-Rezeptor-Antagonisten - Phosphodiesterase-5-Inhibitoren - Guanylatzyklase-Stimulatoren - Prostazyklin-Analoga - Prostazyklin-Rezeptor-Agonisten - Therapiestrategie

Keywords

pulmonary arterial hypertension - calcium channel blockers - endothelin receptor antagonists, Phosphodiesterase 5 inhibitors - soluble guanylate cyclase stimulators - prostazyklin analogues - prostazyklin - treatment strategies

Publication History

Article published online:
14 November 2023

• Literatur

• 1 Hoeper MM, Pausch C, Grünig E. et al. Idiopathic pulmonary arterial hypertension phenotypes determined by cluster analysis from the COMPERA registry. J Heart Lung Transplant 2020; 39: 1435-1444
• 2 Humbert M, Kovacs G, Hoeper MM. et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2023; 61: 2200879
• 3 Sitbon O, Humbert M, Jaïs X. et al. Long-term response to calcium channel blockers in idiopathic pulmonary arterial hypertension. Circulation 2005; 111: 3105-3111
• 4 Rich S, Kaufmann E, Levy PS. The effect of high doses of calcium-channel blockers on survival in primary pulmonary hypertension. N Engl J Med 1992; 327: 76-81
• 5 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
• 6 Clozel M, Maresta A, Humbert M. Endothelin receptor antagonists. Handb Exp Pharmacol 2013; 218: 199-227
• 7 Xing J, Cao Y, Yu Y. et al. In Vitro Micropatterned Human Pluripotent Stem Cell Test (µP-hPST) for Morphometric-Based Teratogen Screening. Sci Rep 2017; 7: 8491
• 8 Galiè 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
• 9 Rubin LJ, Badesch DB, Barst RJ. et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896-903
• 10 Giersbergen P vanL, Halabi A, Dingemanse J. Pharmacokinetic interaction between bosentan and the oral contraceptives norethisterone and ethinyl estradiol. Int J Clin Pharmacol Ther 2006; 44: 113-118
• 11 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
• 12 Weber C, Banken L, Birnboeck H. et al. Effect of the endothelin-receptor antagonist bosentan on the pharmacokinetics and pharmacodynamics of warfarin. J Clin Pharmacol 1999; 39: 847-854
• 13 Wrishko RE, Dingemanse J, Yu A. et al. Pharmacokinetic interaction between tadalafil and bosentan in healthy male subjects. J Clin Pharmacol 2008; 48: 610-618
• 14 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
• 15 Galiè N, Müller 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
• 16 Galiè N, Ghofrani HA, Torbicki A. et al. Sildenafil citrate therapy for pulmonary arterial hypertension. N Engl J Med 2005; 353: 2148-2157
• 17 Sastry BK, Narasimhan C, Reddy NK. et al. Clinical efficacy of sildenafil in primary pulmonary hypertension: a randomized, placebo-controlled, double-blind, crossover study. J Am Coll Cardiol 2004; 43: 1149-1153
• 18 Simonneau G, Rubin LJ, Galiè 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
• 19 Galiè N, Brundage BH, Ghofrani HA. et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation 2009; 119: 2894-2903
• 20 Schermuly RT, Janssen W, Weissmann N. et al. Riociguat for the treatment of pulmonary hypertension. Expert Opin Investig Drugs 2011; 20: 567-576
• 21 Ghofrani HA, Galiè N, Grimminger F. et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013; 369: 330-340
• 22 Jones DA, Benjamin CW, Linseman DA. Activation of thromboxane and Prostazyklin receptors elicits opposing effects on vascular smooth muscle cell growth and mitogen-activated protein kinase signaling cascades. Mol Pharmacol 1995; 48: 890-896
• 23 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. Am Heart J 2014; 167: 210-217
• 24 Barst RJ, Rubin LJ, Long WA. et al. A comparison of continuous intravenous epoprostenol (Prostazyklin) with conventional therapy for primary pulmonary hypertension. N Engl J Med 1996; 334: 296-301
• 25 Rubin LJ, Mendoza J, Hood M. et al. Treatment of primary pulmonary hypertension with continuous intravenous Prostazyklin (epoprostenol). Results of a randomized trial. Ann Intern Med 1990; 112: 485-491
• 26 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
• 27 Olschewski H, Simonneau G, Galiè N. et al. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002; 347: 322-329
• 28 Simonneau G, Barst RJ, Galie N. et al. Continuous subcutaneous infusion of treprostinil, a Prostazyklin analogue, in patients with pulmonary arterial hypertension: a double-blind, randomized, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165: 800-804
• 29 Bourge RC, Waxman AB, Gomberg-Maitland M. et al. Treprostinil Administered to Treat Pulmonary Arterial Hypertension Using a Fully Implantable Programmable Intravascular Delivery System: Results of the DelIVery for PAH Trial. Chest 2016; 150: 27-34
• 30 Richter MJ, Harutyunova S, Bollmann T. et al. Long-term safety and outcome of intravenous treprostinil via an implanted pump in pulmonary hypertension. J Heart Lung Transplant 2018; 37: 1235-1244
• 31 Sitbon O, Channick R, Chin KM. et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2015; 373: 2522-2533
• 32 Degering J, Egenlauf B, Harutyunova S. et al. Tolerability, safety and survival in patients with severe pulmonary arterial hypertension treated with intravenous epoprostenol (Veletri^®): a prospective, 6-months, open label, observational, non-interventional study. Respir Res 2023; 24: 18
• 33 Galiè N, Barberà JA, Frost AE. et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med 2015; 373: 834-844
• 34 Chin KM, Sitbon O, Doelberg M. et al. Three- Versus Two-Drug Therapy for Patients With Newly Diagnosed Pulmonary Arterial Hypertension. J Am Coll Cardiol 2021; 78: 1393-1403
• 35 Sitbon O, Jaïs X, Savale L. et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J 2014; 43: 1691-1697
• 36 D'Alto M, Badagliacca R, Argiento P. et al. Risk Reduction and Right Heart Reverse Remodeling by Upfront Triple Combination Therapy in Pulmonary Arterial Hypertension. Chest 2020; 157: 376-383
• 37 Boucly A, Savale L, Jaïs X. et al. Association between Initial Treatment Strategy and Long-Term Survival in Pulmonary Arterial Hypertension. Am J Respir Crit Care Med 2021; 204: 842-854
• 38 Weatherald J, Boucly A, Chemla D. et al. Prognostic Value of Follow-Up Hemodynamic Variables After Initial Management in Pulmonary Arterial Hypertension. Circulation 2018; 137: 693-704
• 39 Kylhammar D, Kjellström B, Hjalmarsson C. et al. A comprehensive risk stratification at early follow-up determines prognosis in pulmonary arterial hypertension. Eur Heart J 2018; 39: 4175-4181
• 40 Boucly A, Weatherald J, Humbert M. et al. Risk assessment in pulmonary arterial hypertension. Eur Respir J 2018; 51: 1800279
• 41 Hoeper MM, Kramer T, Pan Z. et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J 2017; 50: 1700740
• 42 Hoeper MM, Al-Hiti H, Benza RL. et al. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. Lancet Respir Med 2021; 9: 573-584
• 43 Hoeper MM, Badesch DB, Ghofrani HA. et al. Phase 3 Trial of Sotatercept for Treatment of Pulmonary Arterial Hypertension. N Engl J Med 2023; 388: 1478-1490