13993003.00879-2022.full.pdf

EUROPEAN RESPIRATORY JOURNAL ERS OFFICIAL DOCUMENTS M. HUMBERT ET AL. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Developed by the task force for the diagnosis and treatment of pulmonary hypertension of the European Society of Cardiology (ESC) and the European...

EUROPEAN RESPIRATORY JOURNAL ERS OFFICIAL DOCUMENTS M. HUMBERT ET AL. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Developed by 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 for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG) Marc Humbert1,2, Gabor Kovacs3,4, Marius M. Hoeper5,6, Roberto Badagliacca7,8, Rolf M.F. Berger9, Margarita Brida10,11, Jørn Carlsen12,13, Andrew J.S. Coats14,15, Pilar Escribano-Subias16,17,18, Pisana Ferrari19,20, Diogenes S. Ferreira21, Hossein Ardeschir Ghofrani22,23,24, George Giannakoulas25, David G. Kiely26,27,28, Eckhard Mayer29, Gergely Meszaros19,30, Blin Nagavci31, Karen M. Olsson32, Joanna Pepke-Zaba33, Jennifer K. Quint34, Göran Rådegran35,36, Gerald Simonneau37,38, Olivier Sitbon2,37,39, Thomy Tonia40, Mark Toshner41, Jean-Luc Vachiery42, Anton Vonk Noordegraaf43, Marion Delcroix44,46, Stephan Rosenkranz45,46 and the ESC/ERS Scientific Document Group 1 Faculty of Medicine, Université Paris-Saclay, Le Kremlin-Bicêtre, France, Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France. 2 INSERM UMR_S 999, Hôpital Marie-Lannelongue, Le Plessis-Robinson, France. 3University Clinic of Internal Medicine, Division of Pulmonology, Medical University of Graz, Graz, Austria. 4Ludwig Boltzmann Institute for Lung Vascular Research, Graz, Austria. 5 Respiratory Medicine, Hannover Medical School, Hanover, Germany. 6Biomedical Research in End-stage and Obstructive Lung Disease (BREATH), member of the German Centre of Lung Research (DZL), Hanover, Germany. 7Dipartimento di Scienze Cliniche Internistiche, Anestesiologiche e Cardiovascolari, Sapienza Università di Roma, Roma, Italy. 8Dipartimento Cardio-Toraco-Vascolare e Chirurgia dei Trapianti d’Organo, Policlinico Umberto I, Roma, Italy. 9Center for Congenital Heart Diseases, Beatrix Children’s Hospital, Dept of Paediatric Cardiology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 10Department of Sports and Rehabilitation Medicine, Medical Faculty University of Rijeka, Rijeka, Croatia. 11Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton and Harefield Hospitals, Guys and St Thomas’s NHS Trust, London, UK. 12 Department of Cardiology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. 13Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 14Faculty of Medicine, University of Warwick, Coventry, UK. 15Faculty of Medicine, Monash University, Melbourne, Australia. 16Pulmonary Hypertension Unit, Cardiology Department, Hospital Universitario 12 de Octubre, Madrid, Spain. 17CIBER-CV (Centro de Investigaciones Biomédicas En Red de enfermedades CardioVasculares), Instituto de Salud Carlos III, Madrid, Spain. 18Facultad de Medicina, Universidad Complutense, Madrid, Spain. 19ESC Patient Forum, Sophia Antipolis, France. 20AIPI, Associazione Italiana Ipertensione Polmonare, Bologna, Italy. 21 Alergia e Imunologia, Hospital de Clinicas, Universidade Federal do Parana, Curitiba, Brazil. 22Department of Internal Medicine, University Hospital Giessen, Justus-Liebig University, Giessen, Germany. 23Department of Pneumology, Kerckhoff Klinik, Bad Nauheim, Germany. 24Department of Medicine, Imperial College London, London, UK. 25Cardiology Department, Aristotle University of Thessaloniki, AHEPA University Hospital, Thessaloniki, Greece. 26Department of Infection, Immunity and Cardiovascular Disease, University of Sheffield, Sheffield, UK. 27Sheffield Pulmonary Vascular Disease Unit, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK. 28Insigneo Institute, University of Sheffield, Sheffield, UK. 29Thoracic Surgery, Kerckhoff Clinic, Bad Nauheim, Germany. 30 European Lung Foundation (ELF), Sheffield, UK. 31Institute for Evidence in Medicine, Faculty of Medicine and Medical Center, University of Freiburg, Freiburg, Germany. 32Clinic of Respiratory Medicine, Hannover Medical School, member of the German Center of Lung Research (DZL), Hannover, Germany. 33Pulmonary Vascular Diseases Unit, Royal Papworth Hospital, Cambridge, UK. 34NHLI, Imperial College London, London, UK. 35Department of Cardiology, Clinical Sciences Lund, Faculty of Medicine, Lund, Sweden. 36The Haemodynamic Lab, The Section for Heart Failure and Valvular Disease, VO. Heart and Lung Medicine, Skåne University Hospital, Lund, Sweden. 37Faculté Médecine, Université Paris Saclay, Le Kremlin-Bicêtre, France. 38Centre de Référence de l’Hypertension Pulmonaire, Hopital Marie-Lannelongue, Le Plessis-Robinson, France. 39Service de Pneumologie et Soins Intensifs Respiratoires, Centre de Référence de l’Hypertension Pulmonaire, Hôpital Bicêtre, Assistance Publique Hôpitaux de Paris, Le Kremlin-Bicêtre, France. 40 Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland. 41Dept of Medicine, Heart Lung Research Institute, University of Cambridge, Royal Papworth NHS Trust, Cambridge, UK. 42Department of Cardiology, Pulmonary Vascular Diseases and Heart Failure Clinic, HUB Hôpital Erasme, Brussels, Belgium. 43Pulmonology, Amsterdam UMC, Amsterdam, The Netherlands. 44Clinical Department of Respiratory Diseases, Centre of Pulmonary Vascular Diseases, University Hospitals of Leuven, Leuven, Belgium. 45Clinic III for Internal Medicine (Department of Cardiology, Pulmonology and Intensive Care Medicine), and Cologne Cardiovascular Research Center (CCRC), Heart Center at the University Hospital Cologne, Köln, Germany. 46The two chairpersons (M. Delcroix and S. Rosenkranz) contributed equally to the document and are joint corresponding authors. Corresponding authors: Stephan Rosenkranz ([email protected]) and Marion Delcroix ([email protected]) https://doi.org/10.1183/13993003.00879-2022 Eur Respir J 2022; in press: 2200879 EUROPEAN RESPIRATORY JOURNAL ESC/ERS GUIDELINES | M. HUMBERT ET AL. Table of contents 1. Preamble ....................................................................................... 2. Introduction .................................................................................. 2.1. What is new ........................................................................... 2.2. Methods ............................................................................... 3. Definitions and classifications ................................................. 3.1. Definitions ........................................................................... 3.2. Classifications ...................................................................... 4. Epidemiology and risk factors ................................................. 4.1. Group 1, pulmonary arterial hypertension ..................... 4.2. Group 2, pulmonary hypertension associated with left heart disease ....................................................................... 4.3. Group 3, pulmonary hypertension associated with lung diseases and/or hypoxia .................................................. 4.4. Group 4, pulmonary hypertension associated with chronic pulmonary artery obstruction .................................... 4.5. Group 5, pulmonary hypertension with unclear and/ or multifactorial mechanisms .................................................. 5. Pulmonary hypertension diagnosis ........................................ 5.1. Diagnosis ............................................................................. 5.1.1. Clinical presentation ................................................... 5.1.2. Electrocardiogram ....................................................... 5.1.3. Chest radiography ....................................................... 5.1.4. Pulmonary function tests and arterial blood gases ........................................................................................ 5.1.5. Echocardiography ........................................................ 5.1.6. Ventilation/perfusion lung scan ................................ 5.1.7. Non-contrast and contrast-enhanced chest computed tomography examinations, and digital subtraction angiography ....................................................... 5.1.8. Cardiac magnetic resonance imaging ...................... 5.1.9. Blood tests and immunology .................................... 5.1.10. Abdominal ultrasound .............................................. 5.1.11. Cardiopulmonary exercise testing ........................... 5.1.12. Right heart catheterization, vasoreactivity, exercise, and fluid challenge ................................................ 5.1.12.1. Right heart catheterization ............................... 5.1.12.2. Vasoreactivity testing ......................................... 5.1.12.3. Exercise right heart catheterization ................. 5.1.12.4. Fluid challenge ................................................... 5.1.13. Genetic counselling and testing .............................. 5.2. Diagnostic algorithm .......................................................... 5.2.1 Step 1 (suspicion) ......................................................... 5.2.2. Step 2 (detection) ........................................................ 5.2.3. Step 3 (confirmation) .................................................. 5.3. Screening and early detection .......................................... 5.3.1. Systemic sclerosis ........................................................ 5.3.2. BMPR2 mutation carriers ............................................ 5.3.3. Portal hypertension ..................................................... 5.3.4. Pulmonary embolism .................................................. 6. Pulmonary arterial hypertension (group 1) ........................... 6.1. Clinical characteristics ....................................................... 6.2. Severity and risk assessment ............................................ 6.2.1. Clinical parameters ..................................................... 6.2.2. Imaging ......................................................................... 6.2.2.1. Echocardiography ................................................. 6.2.2.2. Cardiac magnetic resonance imaging ............... 6.2.3. Haemodynamics .......................................................... 6.2.4. Exercise capacity ......................................................... 6.2.5. Biochemical markers .................................................. 6.2.6. Patient-reported outcome measures ........................ 6.2.7. Comprehensive prognostic evaluation, risk assessment, and treatment goals ....................................... 6.3. Therapy ................................................................................ 6.3.1. General measures ........................................................ 6.3.1.1. Physical activity and supervised rehabilitation https://doi.org/10.1183/13993003.00879-2022 5 9 9 19 20 20 21 22 24 24 24 25 25 25 25 25 25 25 25 26 29 31 31 31 32 32 32 32 32 33 34 35 35 35 35 35 39 40 40 41 41 42 42 42 42 42 43 44 44 45 46 47 47 49 51 51 6.3.1.2. Anticoagulation ..................................................... 6.3.1.3. Diuretics ................................................................. 6.3.1.4. Oxygen ................................................................... 6.3.1.5. Cardiovascular drugs ........................................... 6.3.1.6. Anaemia and iron status ..................................... 6.3.1.7. Vaccination ............................................................ 6.3.1.8. Psychosocial support ........................................... 6.3.1.9. Adherence to treatments ..................................... 6.3.2. Special circumstances ................................................. 6.3.2.1. Pregnancy and birth control ............................... 6.3.2.1.1. Pregnancy ...................................................... 6.3.2.1.2. Contraception ............................................... 6.3.2.2. Surgical procedures ............................................. 6.3.2.3. Travel and altitude ............................................... 6.3.3. Pulmonary arterial hypertension therapies ............. 6.3.3.1. Calcium channel blockers ................................... 6.3.3.2. Endothelin receptor antagonists ........................ 6.3.3.2.1. Ambrisentan .................................................. 6.3.3.2.2. Bosentan ........................................................ 6.3.3.2.3. Macitentan ..................................................... 6.3.3.3. Phosphodiesterase 5 inhibitors and guanylate cyclase stimulators .......................................... 6.3.3.3.1. Sildenafil ........................................................ 6.3.3.3.2. Tadalafil ......................................................... 6.3.3.3.3. Riociguat ........................................................ 6.3.3.4. Prostacyclin analogues and prostacyclin receptor agonists ............................................................... 6.3.3.4.1. Epoprostenol ................................................. 6.3.3.4.2. Iloprost ........................................................... 6.3.3.4.3. Treprostinil .................................................... 6.3.3.4.4. Beraprost ....................................................... 6.3.3.4.5. Selexipag ........................................................ 6.3.4. Treatment strategies for patients with idiopathic, heritable, drug-associated, or connective tissue disease-associated pulmonary arterial hypertension ........................................................................... 6.3.4.1. Initial treatment decision in patients without cardiopulmonary comorbidities ........................ 6.3.4.2. Treatment decisions during follow-up in patients without cardiopulmonary comorbidities ........ 6.3.4.3. Pulmonary arterial hypertension with cardiopulmonary comorbidities ...................................... 6.3.5. Drug interactions ......................................................... 6.3.6. Interventional therapy ................................................ 6.3.6.1. Balloon atrial septostomy and Potts shunt ...... 6.3.6.2. Pulmonary artery denervation ........................... 6.3.7. Advanced right ventricular failure ............................. 6.3.7.1. Intensive care unit management ....................... 6.3.7.2. Mechanical circulatory support .......................... 6.3.8. Lung and heart–lung transplantation ...................... 6.3.9. Evidence-based treatment algorithm ....................... 6.3.10. Diagnosis and treatment of pulmonary arterial hypertension complications ................................................. 6.3.10.1. Arrhythmias ......................................................... 6.3.10.2. Haemoptysis ........................................................ 6.3.10.3. Mechanical complications ................................. 6.3.11. End-of-life care and ethical issues .......................... 6.3.12. New drugs in advanced clinical development ( phase 3 studies) ................................................................... 7. Specific pulmonary arterial hypertension subsets ............... 7.1. Pulmonary arterial hypertension associated with drugs and toxins ........................................................................ 7.2. Pulmonary arterial hypertension associated with connective tissue disease ......................................................... 7.2.1. Epidemiology and diagnosis ...................................... 51 51 52 52 52 52 52 52 53 53 53 53 53 54 55 55 56 57 57 57 57 57 57 57 57 57 58 58 58 58 58 59 60 62 63 63 63 63 64 64 64 64 65 65 65 66 66 66 67 67 67 68 68 2 EUROPEAN RESPIRATORY JOURNAL 7.2.2. Therapy ......................................................................... 7.3. Pulmonary arterial hypertension associated with human immunodeficiency virus infection .......................... 7.3.1. Diagnosis ...................................................................... 7.3.2. Therapy ......................................................................... 7.4. Pulmonary arterial hypertension associated with portal hypertension ................................................................... 7.4.1. Diagnosis ...................................................................... 7.4.2. Therapy ......................................................................... 7.4.2.1. Liver transplantation ............................................ 7.5. Pulmonary arterial hypertension associated with adult congenital heart disease ................................................ 7.5.1. Diagnosis and risk assessment .................................. 7.5.2. Therapy ......................................................................... 7.6. Pulmonary arterial hypertension associated with schistosomiasis .......................................................................... 7.7. Pulmonary arterial hypertension with signs of venous/capillary involvement .................................................. 7.7.1. Diagnosis ...................................................................... 7.7.2. Therapy ......................................................................... 7.8. Paediatric pulmonary hypertension ................................ 7.8.1. Epidemiology and classification ................................ 7.8.2. Diagnosis and risk assessment .................................. 7.8.3. Therapy ......................................................................... 8. Pulmonary hypertension associated with left heart disease (group 2) ........................................................................... 8.1. Definition, prognosis, and pathophysiology ................... 8.2. Diagnosis ............................................................................. 8.2.1. Diagnosis and control of the underlying left heart disease .......................................................................... 8.2.2. Evaluation of pulmonary hypertension and patient phenotyping .............................................................. 8.2.3. Invasive assessment of haemodynamics ................. 8.3. Therapy ................................................................................ 8.3.1. Pulmonary hypertension associated with leftsided heart failure ................................................................. 8.3.1.1. Heart failure with reduced ejection fraction .... 8.3.1.2. Heart failure with preserved ejection fraction . 8.3.1.3. Interatrial shunt devices ...................................... 8.3.1.4. Remote pulmonary arterial pressure monitoring in heart failure ............................................... 8.3.2. Pulmonary hypertension associated with valvular heart disease ........................................................... 8.3.2.1. Mitral valve disease .............................................. 8.3.2.2. Aortic stenosis ....................................................... 8.3.2.3. Tricuspid regurgitation ........................................ 8.3.3. Recommendations on the use of drugs approved for PAH in PH-LHD ............................................... 9. Pulmonary hypertension associated with lung diseases and/or hypoxia (group 3) ............................................................. 9.1. Diagnosis ............................................................................. 9.2. Therapy ................................................................................ 9.2.1. Pulmonary hypertension associated with chronic obstructive pulmonary disease or emphysema .. 9.2.2. Pulmonary hypertension associated with interstitial lung disease ......................................................... 9.2.3. Recommendations on the use of drugs approved for PAH in PH associated with lung disease .... 10. Chronic thrombo-embolic pulmonary hypertension (group 4) ......................................................................................... 10.1. Diagnosis ........................................................................... 10.2. Therapy .............................................................................. 10.2.1. Surgical treatment ..................................................... 10.2.2. Medical therapy ......................................................... 10.2.3. Interventional treatment .......................................... 10.2.4. Multimodal treatment ............................................... 10.2.5. Follow-up .................................................................... https://doi.org/10.1183/13993003.00879-2022 ESC/ERS GUIDELINES | M. HUMBERT ET AL. 68 69 69 70 70 71 71 71 72 73 73 75 76 76 76 77 77 77 79 81 81 82 84 84 84 84 85 85 85 86 86 86 86 86 86 87 87 89 89 90 90 90 91 91 93 93 94 95 96 96 10.3. Chronic thrombo-embolic pulmonary hypertension team and experience criteria ................................................... 96 11. Pulmonary hypertension with unclear and/or multifactorial mechanisms (group 5) ......................................... 98 11.1. Haematological disorders ............................................... 98 11.2. Systemic disorders ........................................................... 99 11.3. Metabolic disorders .......................................................... 99 11.4. Chronic kidney failure ...................................................... 99 11.5. Pulmonary tumour thrombotic microangiopathy ....... 99 11.6. Fibrosing mediastinitis ................................................... 100 12. Definition of a pulmonary hypertension centre ................ 100 12.1. Facilities and skills required for a pulmonary hypertension centre ................................................................ 100 12.2. European Reference Network ....................................... 102 12.3. Patient associations and patient empowerment ....... 102 13. Key messages ......................................................................... 102 14. Gaps in evidence ................................................................... 103 14.1. Pulmonary arterial hypertension (group 1) ................ 103 14.2. Pulmonary hypertension associated with left heart disease (group 2) ..................................................................... 104 14.3. Pulmonary hypertension associated with lung diseases and/or hypoxia (group 3) ....................................... 104 14.4. Chronic thrombo-embolic pulmonary hypertension (group 4) ................................................................................... 104 14.5. Pulmonary hypertension with unclear and/or multifactorial mechanisms (group 5) ................................... 104 15. ‘What to do’ and ‘What not to do’ messages from the Guidelines ..................................................................................... 104 16. Quality indicators .................................................................. 109 17. Supplementary data ............................................................. 110 18. Data availability statement .................................................. 110 19. Other information and notes ............................................... 110 20. Appendix ................................................................................. 111 21. References .............................................................................. 112 Tables of Recommendations RECOMMENDATION TABLE 1 — Recommendations for right heart catheterization and vasoreactivity testing ....................... RECOMMENDATION TABLE 2 — Recommendations for diagnostic strategy ......................................................................... RECOMMENDATION TABLE 3 — Recommendations for screening and improved detection of pulmonary arterial hypertension and chronic thrombo-embolic pulmonary hypertension ................................................................................... RECOMMENDATION TABLE 4 — Recommendations for evaluating the disease severity and risk of death in patients with pulmonary arterial hypertension ........................ RECOMMENDATION TABLE 5 — Recommendations for general measures and special circumstances ........................... RECOMMENDATION TABLE 6 — Recommendations for women of childbearing potential ................................................ RECOMMENDATION TABLE 7 — Recommendations for the treatment of vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension ................................................................................... RECOMMENDATION TABLE 8A — Recommendations for the treatment of non-vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension who present without cardiopulmonary comorbiditiesa ................................................................................ RECOMMENDATION TABLE 8B — Recommendations for the treatment of non-vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension who present without cardiopulmonary comorbiditiesa ................................................................................ 34 39 41 49 54 54 55 59 60 3 EUROPEAN RESPIRATORY JOURNAL RECOMMENDATION TABLE 9 — Recommendations for initial oral drug combination therapy for patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension without cardiopulmonary comorbidities ........... RECOMMENDATION TABLE 10 — Recommendations for sequential drug combination therapy for patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension ................................................................................... RECOMMENDATION TABLE 11 — Recommendations for the treatment of non-vasoreactive patients with idiopathic, heritable, or drug-associated pulmonary arterial hypertension who present with cardiopulmonary comorbiditiesa ................................................................................ RECOMMENDATION TABLE 12 — Recommendations for intensive care management for pulmonary arterial hypertension ................................................................................... RECOMMENDATION TABLE 13 — Recommendations for lung transplantation ...................................................................... RECOMMENDATION TABLE 14 — Recommendations for pulmonary arterial hypertension associated with drugs or toxins ............................................................................................... RECOMMENDATION TABLE 15 — Recommendations for pulmonary arterial hypertension associated with connective tissue disease ............................................................. RECOMMENDATION TABLE 16 — Recommendations for pulmonary arterial hypertension associated with human immunodeficiency virus infection ............................................... RECOMMENDATION TABLE 17 — Recommendations for pulmonary arterial hypertension associated with portal hypertension ................................................................................... RECOMMENDATION TABLE 18 — Recommendations for shunt closure in patients with pulmonary–systemic flow ratio >1.5:1 based on calculated pulmonary vascular resistance ........................................................................................ RECOMMENDATION TABLE 19 — Recommendations for pulmonary arterial hypertension associated with adult congenital heart disease ............................................................... RECOMMENDATION TABLE 20 — Recommendations for pulmonary arterial hypertension with signs of venous/ capillary involvement .................................................................... RECOMMENDATION TABLE 21 — Recommendations for paediatric pulmonary hypertension ............................................ RECOMMENDATION TABLE 22A — Recommendations for pulmonary hypertension associated with left heart disease .. RECOMMENDATION TABLE 22B — Recommendations for pulmonary hypertension associated with left heart disease .. RECOMMENDATION TABLE 23A — Recommendations for pulmonary hypertension associated with lung disease and/ or hypoxia ....................................................................................... RECOMMENDATION TABLE 23B — Recommendations for pulmonary hypertension associated with lung disease and/ or hypoxia ....................................................................................... RECOMMENDATION TABLE 24A — Recommendations for chronic thrombo-embolic pulmonary hypertension and chronic thrombo-embolic pulmonary disease without pulmonary hypertension .............................................................. RECOMMENDATION TABLE 24B — Recommendations for chronic thrombo-embolic pulmonary hypertension and chronic thrombo-embolic pulmonary disease without pulmonary hypertension .............................................................. RECOMMENDATION TABLE 25 — Recommendations for pulmonary hypertension centres .............................................. ESC/ERS GUIDELINES | M. HUMBERT ET AL. 60 61 63 64 65 67 69 70 71 75 75 76 81 87 19 20 20 20 22 24 27 28 30 33 33 36 38 44 45 46 48 56 65 72 80 85 98 87 91 91 97 97 102 List of tables TABLE 1 Strength of the recommendations according to GRADE .............................................................................................. 19 https://doi.org/10.1183/13993003.00879-2022 TABLE 2 Quality of evidence grades and their definitions [5] ..................................................................................................... TABLE 3 Classes of recommendations ........................................ TABLE 4 Levels of evidence .......................................................... TABLE 5 Haemodynamic definitions of pulmonary hypertension ................................................................................... TABLE 6 Clinical classification of pulmonary hypertension ..... TABLE 7 Drugs and toxins associated with pulmonary artery hypertension ....................................................................... TABLE 8 Electrocardiogram abnormalities in patients with pulmonary hypertension .............................................................. TABLE 9 Radiographic signs of pulmonary hypertension and concomitant abnormalities .................................................. TABLE 10 Additional echocardiographic signs suggestive of pulmonary hypertensiona ............................................................. TABLE 11 Haemodynamic measures obtained during right heart catheterization ..................................................................... TABLE 12 Route of administration, half-life, dosages, and duration of administration of the recommended test compounds for vasoreactivity testing in pulmonary arterial hypertension ................................................................................... TABLE 13 Phenotypic features associated with pulmonary arterial hypertension mutations .................................................. TABLE 14 Characteristic diagnostic features of patients with different forms of pulmonary hypertension ..................... TABLE 15 World Health Organization classification of functional status of patients with pulmonary hypertension ... TABLE 16 Comprehensive risk assessment in pulmonary arterial hypertension (three-strata model) ................................ TABLE 17 Suggested assessment and timing for the follow-up of patients with pulmonary arterial hypertension .. TABLE 18 Variables used to calculate the simplified four-strata risk-assessment tool .................................................. TABLE 19 Dosing of pulmonary arterial hypertension medications in adults .................................................................... TABLE 20 Criteria for lung transplantation and listing in patients with pulmonary arterial hypertension ........................ TABLE 21 Clinical classification of pulmonary arterial hypertension associated with congenital heart disease .......... TABLE 22 Use of pulmonary arterial hypertension therapies in children ....................................................................................... TABLE 23 Patient phenotyping and likelihood for left heart disease as cause of pulmonary hypertension ........................... TABLE 24 Pulmonary hypertension with unclear and/or multi-factorial mechanisms .......................................................... List of figures FIGURE 1 Central illustration ........................................................ FIGURE 2 Symptoms in patients with pulmonary hypertension ................................................................................... FIGURE 3 Clinical signs in patients with pulmonary hypertension ................................................................................... FIGURE 4 Transthoracic echocardiographic parameters in the assessment of pulmonary hypertension ............................. FIGURE 5 Echocardiographic probability of pulmonary hypertension and recommendations for further assessment . FIGURE 6 Diagnostic algorithm of patients with unexplained dyspnoea and/or suspected pulmonary hypertension ................................................................................... FIGURE 7 Pathophysiology and current therapeutic targets of pulmonary arterial hypertension (group 1) .......................... FIGURE 8 Vasoreactivity testing algorithm of patients with presumed diagnosis of idiopathic, heritable, or drug-associated pulmonary arterial hypertension .................... FIGURE 9 Evidence-based pulmonary arterial hypertension treatment algorithm for patients with idiopathic, heritable, 23 26 27 29 30 37 43 48 4 EUROPEAN RESPIRATORY JOURNAL ESC/ERS GUIDELINES | M. HUMBERT ET AL. drug-associated, and connective tissue disease-associated pulmonary arterial hypertension ................................................. FIGURE 10 Neonatal and paediatric versus adult pulmonary hypertension ................................................................................... FIGURE 11 Pathophysiology of pulmonary hypertension associated with left heart disease (group 2) ............................. FIGURE 12 Pathophysiology of pulmonary hypertension associated with lung disease (group 3) ...................................... 50 78 83 88 FIGURE 13 Diagnostic strategy in chronic thrombo-embolic pulmonary hypertension .............................................................. FIGURE 14 Management strategy in chronic thrombo-embolic pulmonary hypertension ............................... FIGURE 15 Overlap in treatments/multimodality approaches in chronic thrombo-embolic pulmonary hypertension ................................................................................... FIGURE 16 Pulmonary hypertension centre schematic .......... 92 94 95 101 Shareable abstract (@ERSpublications) 2022 ESC/ERS pulmonary hypertension guidelines incorporate changes and adaptations focusing on clinical management https://bit.ly/3QtUvb4 Cite this article as: Humbert M, Kovacs G, Hoeper MM, et al. 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Respir J 2022; in press: 2200879 [DOI: 10.1183/13993003.00879-2022]. Copyright © the European Society of Cardiology and the European Respiratory Society 2022. All rights reserved. 1. Preamble Guidelines summarize and evaluate available evidence, with the aim of assisting health professionals in proposing the best management strategies for an individual patient with a given condition. Guidelines and their recommendations should facilitate decision-making of health professionals in their daily practice. However, guidelines are not a substitute for the patient’s relationship with their practitioner. The final decisions concerning an individual patient must be made by the responsible health professional(s), based on what they consider to be the most appropriate in the circumstances. These decisions are made in consultation with the patient and caregiver as appropriate. Guidelines are intended for use by health professionals. To ensure that all physicians have access to the most recent recommendations, both the European Society of Cardiology (ESC) and European Respiratory Society (ERS) make their guidelines freely available in their own journals. The ESC and ERS warn non-medical readers that the technical language may be misinterpreted and decline any responsibility in this respect. Many Guidelines have been issued in recent years by the ESC and ERS. Because of their impact on clinical practice, quality criteria for the development of guidelines have been established in order to make all decisions transparent to the user. The ERS and ESC guidance and procedure to formulate and issue clinical practice recommendations can be found on the societies’ relevant website or journal (https://www. escardio.org/Guidelines and https://openres.ersjournals.com/content/8/1/00655-2021). The ESC and ERS Guidelines represent the official position of the ESC and ERS on a given topic and are regularly updated. The panel of experts of these specific guidelines comprised an equal number of ERS and ESC members, including representatives from relevant subspecialty groups involved in the medical care of patients with this pathology. The experts of the writing and reviewing panels provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest. Their declarations of interest were reviewed according to the ESC declaration of interest rules and can be found on the ESC website (http://www.escardio.org/Guidelines). They have been compiled in a report and co-published in a supplementary document of the guidelines. This process ensures transparency and prevents potential biases in the development and review processes. Any changes in declarations of interest that arose during the writing period were notified to the ESC and updated. The Task Force received its entire financial support from the ESC and ERS without any involvement from the health care industry. The ESC Clinical Practice Guidelines (CPG) Committee and the ERS Guidelines Director reporting to the ERS Science Council supervise and co-ordinate the preparation of new guidelines. These Guidelines underwent extensive review by the ESC CPG Committee, the ERS Guidelines Working Group, and external experts. The guidelines were developed after careful consideration of the scientific and medical knowledge and the evidence available at the time of drafting. After appropriate revisions, the guidelines were signed off by all the experts in the Task Force. The finalized document was signed off by the ESC CPG Committee and endorsed by the ERS Executive Committee before being simultaneously published in the European Heart Journal (EHJ) and the European Respiratory Journal (ERJ). The decision to publish the guidelines in both journals was made to ensure adequate dissemination of the recommendations in both the cardiology and respiratory fields. https://doi.org/10.1183/13993003.00879-2022 5 EUROPEAN RESPIRATORY JOURNAL ESC/ERS GUIDELINES | M. HUMBERT ET AL. BOX 1 Abbreviations and acronyms 6MWD 6MWT ABG ACEi ALAT ARB ARNI ASAT ASIG BNP BPA BPD CAMPHOR CCB CDH cGMP CHD CI cMRI CO COMPERA COPD CpcPH CPET CPFE CT CTD CTEPD CTEPH CTPA DECT DLCO DPAH dPAP DPG DSA ECG ECMO EHJ EMA EOV ERA ERJ ERN ERN-LUNG ERS ESC EtD FPHR FVC GRADE HAART Hb HF HFpEF HIV HPAH HPS HR HR-QoL ICU 6-minute walking distance 6-minute walking test Arterial blood gas analysis Angiotensin-converting enzyme inhibitor Alanine aminotransferase Angiotensin receptor blocker Angiotensin receptor–neprilysin inhibitor Aspartate aminotransferase Australian Scleroderma Interest Group Brain natriuretic peptide Balloon pulmonary angioplasty Bronchopulmonary dysplasia Cambridge Pulmonary Hypertension Outcome Review Calcium channel blocker Congenital diaphragmatic hernia Cyclic guanosine monophosphate Congenital heart disease Cardiac index; Confidence interval Cardiac magnetic resonance imaging Cardiac output Comparative, Prospective Registry of Newly Initiated Therapies for PH Chronic obstructive pulmonary disease Combined post- and pre-capillary pulmonary hypertension Cardiopulmonary exercise testing Combined pulmonary fibrosis and emphysema Computed tomography Connective tissue disease Chronic thrombo-embolic pulmonary disease Chronic thrombo-embolic pulmonary hypertension Computed tomography pulmonary angiography Dual-energy computed tomography Lung diffusion capacity for carbon monoxide Drug- or toxin-associated pulmonary arterial hypertension Diastolic pulmonary arterial pressure Diastolic pressure gradient Digital subtraction angiography Electrocardiogram Extracorporeal membrane oxygenation European Heart Journal European Medicines Agency Exercise oscillatory ventilation Endothelin receptor antagonist European Respiratory Journal European Reference Network European Reference Network on rare respiratory diseases European Respiratory Society European Society of Cardiology Evidence to Decision French Pulmonary Hypertension Registry Forced vital capacity Grading of Recommendations, Assessment, Development, and Evaluations Highly active antiretroviral therapy Haemoglobin Heart failure Heart failure with preserved ejection fraction Human immunodeficiency virus Heritable pulmonary arterial hypertension Hepatopulmonary syndrome Hazard ratio Health-related quality of life Intensive care unit Continued https://doi.org/10.1183/13993003.00879-2022 6 EUROPEAN RESPIRATORY JOURNAL ESC/ERS GUIDELINES | M. HUMBERT ET AL. BOX 1 Continued IgG4 ILD IPAH IpcPH IP receptor ISWT i.v. LA LAS LHD LTx LV LVAD mPAP MR MRI NOAC NT-proBNP OR PA PAC PaCO2 PADN PAH PAH-CTD PAH-SSc PAH-SYMPACT PaO2 PAP PAVM PAWP PCH PDE5i PE PEA PET PETCO2 PFT PH PH-LHD PICO PoPH PPHN PROM PVD PVOD PVR PVRI QI Qp/Qs RA RAP RCT REVEAL RHC RR RV RVEF RV-FAC RVOT AT SaO2 s.c. Immunogolobulin G4 Interstitial lung disease Idiopathic pulmonary arterial hypertension Isolated post-capillary pulmonary hypertension Prostacyclin I2 receptor Incremental shuttle walking test Intravenous Left atrium/left atrial Lung allocation score Left heart disease Lung transplantation Left ventricle/left ventricular Left ventricular assist device Mean pulmonary arterial pressure Magnetic resonance Magnetic resonance imaging Novel oral anticoagulant N-terminal pro-brain natriuretic peptide Odds ratio Pulmonary artery Pulmonary arterial compliance Partial pressure of arterial carbon dioxide Pulmonary artery denervation Pulmonary arterial hypertension Pulmonary arterial hypertension associated with connective tissue disease Pulmonary arterial hypertension associated with systemic sclerosis Pulmonary Arterial Hypertension-Symptoms and Impact Partial pressure of arterial oxygen Pulmonary arterial pressure Pulmonary arteriovenous malformation Pulmonary arterial wedge pressure Pulmonary capillary haemangiomatosis Phosphodiesterase 5 inhibitor Pulmonary embolism Pulmonary endarterectomy Positron emission tomography End-tidal partial pressure of carbon dioxide Pulmonary function test Pulmonary hypertension Pulmonary hypertension associated with left heart disease Population, Intervention, Comparator, Outcome Porto-pulmonary hypertension Persistent pulmonary hypertension of the newborn Patient-reported outcome measure Pulmonary vascular disease Pulmonary veno-occlusive disease Pulmonary vascular resistance Pulmonary vascular resistance index Quality indicator Pulmonary blood flow/systemic blood flow Right atrium/right atrial Right atrial pressure Randomized controlled trial Registry to Evaluate Early and Long-Term PAH Disease Management Right heart catheterization Relative risk Right ventricle/right ventricular Right ventricular ejection fraction Right ventricular fractional area change Right ventricular outflow tract acceleration time Arterial oxygen saturation Subcutaneous Continued https://doi.org/10.1183/13993003.00879-2022 7 EUROPEAN RESPIRATORY JOURNAL ESC/ERS GUIDELINES | M. HUMBERT ET AL. BOX 1 Continued SCD sGC SGLT-2i SLE SPAHR sPAP SPECT SSc SV SVI SvO2 TAPSE TGF-β TPR TR TRPG TRV TSH V/Q VE/VCO2 VKA VO2 VO2/HR VTE WHO-FC WSPH WU Sickle cell disease Soluble guanylate cyclase Sodium–glucose cotransporter-2 inhibitor Systemic lupus erythematosus Swedish Pulmonary Arterial Hypertension Registry Systolic pulmonary arterial pressure Single-photon emission computed tomography Systemic sclerosis Stroke volume Stroke volume index Mixed venous oxygen saturation Tricuspid annular plane systolic excursion Transforming growth factor-β Total pulmonary resistance Tricuspid regurgitation Tricuspid regurgitation pressure gradient Tricuspid regurgitation velocity Thyroid-stimulating hormone Ventilation perfusion Ventilatory equivalent for carbon dioxide Vitamin K antagonist Oxygen uptake Oxygen pulse Venous thrombo-embolism World Health Organization functional class World Symposium on Pulmonary Hypertension Wood units The task of developing the ESC/ERS Guidelines also included creating educational tools and implementation programmes for the recommendations, including condensed pocket guidelines versions, summary slides, a lay summary, and an electronic version for digital applications (smartphones, etc.). These versions are abridged and thus, for more detailed information, the user should always access the full-text version of the guidelines, which is freely available via the ESC and ERS websites, and hosted on the EHJ and ERJ websites. The National Cardiac Societies of the ESC are encouraged to endorse, adopt, translate, and implement all ESC Guidelines. Pulmonary national societies are also encouraged to share these guidelines with their members and develop a summary or editorials in their own language, if appropriate. Implementation programmes are needed because it has been shown that the outcome of disease may be favourably influenced by the thorough application of clinical recommendations. Health professionals are encouraged to take the ESC/ERS Guidelines fully into account when exercising their clinical judgement, as well as in determining and implementing preventive, diagnostic, or therapeutic medical strategies. However, the ESC/ERS Guidelines do not override, in any way, the individual responsibility of health professionals to make appropriate and accurate decisions in considering each patient’s health condition and in consulting with that patient or the patient’s caregiver where appropriate and/or necessary. It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time of prescription and, where appropriate, to respect the ethical rules of their profession in each country. Off-label use of medication may be presented in these guidelines if a sufficient level of evidence shows that it can be considered medically appropriate to a given condition and if patients could benefit from the recommended therapy. However, the final decisions concerning an individual patient must be made by the responsible health professional, giving special consideration to: • The specific situation of the patient. In this respect, it is specified that, unless otherwise provided for by national regulations, off-label use of medication should be limited to situations where it is in the patient’s interest to do so, with regards to the quality, safety, and efficacy of care, and only after the patient has been fully informed and provided consent. • Country-specific health regulations, indications by governmental drug regulatory agencies, and the ethical rules to which health professionals are subject, where applicable. https://doi.org/10.1183/13993003.00879-2022 8 EUROPEAN RESPIRATORY JOURNAL ESC/ERS GUIDELINES | M. HUMBERT ET AL. 2. Introduction Pulmonary hypertension (PH) is a pathophysiological disorder that may involve multiple clinical conditions and may be associated with a variety of cardiovascular and respiratory diseases. The complexity of managing PH requires a multifaceted, holistic, and multidisciplinary approach, with active involvement of patients with PH in partnership with clinicians. Streamlining the care of patients with PH in daily clinical practice is a challenging but essential requirement for effectively managing PH. In recent years, substantial progress has been made in detecting and managing PH, and new evidence has been timeously integrated in this fourth edition of the ESC/ ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Reflecting the multidisciplinary input into managing patients with PH and interpreting new evidence, the Task Force included cardiologists and pneumologists, a thoracic surgeon, methodologists, and patients. These comprehensive clinical practice guidelines cover the whole spectrum of PH, with an emphasis on diagnosing and treating pulmonary arterial hypertension (PAH) and chronic thrombo-embolic pulmonary hypertension (CTEPH). 2.1. What is new One of the most important proposals from the 6th World Symposium on Pulmonary Hypertension (WSPH) was to reconsider the haemodynamic definition of PH [1]. After careful evaluation, the new definitions of PH have been endorsed and expanded in these guidelines, including a revised cut-off level for pulmonary vascular resistance (PVR) and a definition of exercise PH. The classification of PH has been updated, including repositioning of vasoreactive patients with idiopathic pulmonary arterial hypertension (IPAH) and a revision of group 5 PH, including repositioning of PH in lymphangioleiomyomatosis in group 3. Concerning the diagnosis of PH, a new algorithm has been developed aiming at earlier detection of PH in the community. In addition, expedited referral is recommended for high-risk or complex patients. Screening strategies are also proposed. The risk-stratification table has been expanded to include additional echocardiographic and cardiac magnetic resonance imaging (cMRI) prognostic indicators. The recommendations for initial drug therapies have been simplified, building on this revised, three-strata, multiparametric risk model to replace functional classification. At follow-up, a four-strata risk-assessment tool is now proposed based on refined cut-off levels for World Health Organization functional class (WHO-FC), 6-minute walking distance (6MWD), and N-terminal pro-brain natriuretic peptide (NT-proBNP), categorizing patients as low, intermediate–low, intermediate–high, or high risk. The PAH treatment algorithm has been modified, highlighting the importance of cardiopulmonary comorbidities, risk assessment both at diagnosis and follow-up, and the importance of combination therapies. Treatment strategies during follow-up have been based on the four-strata model intended to facilitate more granular decision-making. The recommendations for managing PH associated with left heart disease (PH-LHD) and lung disease have been updated, including a new haemodynamic definition of severe PH in patients with lung disease. In group 4 PH, the term chronic thrombo-embolic pulmonary disease (CTEPD) with or without PH has been introduced, acknowledging the presence of similar symptoms, perfusion defects, and organized fibrotic obstructions in patients with or without PH at rest. Interventional treatment by balloon pulmonary angioplasty (BPA) in combination with medical therapy has been upgraded in the therapeutic algorithm of CTEPH. New standards for PH centres have been presented and, for the first time, patient representatives were actively involved in developing these guidelines. Questions with direct consequences for clinical practitioners regarding each PH classification subgroup were selected and addressed, namely guidance on: initial treatment strategy for group 1 PH (Population, Intervention, Control, Outcome [PICO] I); use of oral phosphodiesterase 5 inhibitors (PDE5is) for the treatment of group 2 PH (PICO II); use of oral PDE5is for the treatment of group 3 PH (PICO III); and use of PH drugs prior to BPA for the treatment of group 4 PH (PICO IV). These questions were considered to be important because: most contemporary PH registries describe variable use of initial oral monotherapy and combination therapy; large case series show widespread use of PDE5is in group 2 PH, despite a class III recommendation in the 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension; large case series show widespread use of PDE5is in group 3 PH, despite a class III recommendation in the 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension; and there is no clear guidance for therapy with PH drugs in patients with inoperable CTEPH prior to BPA. https://doi.org/10.1183/13993003.00879-2022 9 EUROPEAN RESPIRATORY JOURNAL ESC/ERS GUIDELINES | M. HUMBERT ET AL. BOX 2 Selected revised recommendations (R) and new recommendations (N) New or revised Recommendation in 2015 version Classa Recommendation in 2022 version Right heart catheterization and vasoreactivity testing – Recommendation Table 1 N It is recommended that RHC comprises a complete set of haemodynamics and is performed following standardized protocols R Adenosine should be considered for performing IIa Inhaled nitric oxide, inhaled iloprost, or i.v. vasoreactivity testing as an alternative epoprostenol are recommended for performing Inhaled iloprost may be considered for performing vasoreactivity testing vasoreactivity testing as an alternative Diagnostic strategy – Recommendation Table 2 N It is recommended to assign an echocardiographic probability of PH, based on an abnormal TRV and the presence of other echocardiographic signs suggestive of PH (see Table 10) N It is recommended to maintain the current threshold for TRV (>2.8 m/s) for echocardiographic probability of PH according to the updated haemodynamic definition N Based on the probability of PH by echocardiography, further testing should be considered in the clinical context (i.e. symptoms and risk factors or associated conditions for PAH/CTEPH) N In symptomatic patients with intermediate echocardiographic probability of PH, CPET may be considered to further determine the likelihood of PH Screening and improved detection of pulmonary arterial hypertension and chronic thrombo-embolic pulmonary hypertension – Recommendation Table 3 N In patients with SSc, an annual evaluation of the risk of having PAH is recommended R Resting echocardiography is recommended as a I In adult patients with SSc of >3 years’ disease screening test in asymptomatic patients with SSc, duration, an FVC ⩾40%, and a DLCO <60%, the followed by annual screening with echocardiography, DETECT algorithm is recommended to identify DLCO, and biomarkers asymptomatic patients with PAH N In patients with SSc, where breathlessness remains unexplained following non-invasive assessment, RHC is recommended to exclude PAH N Assessing the risk of having PAH, based on an evaluation of breathlessness, in combination with echocardiogram or PFTs and BNP/NT-proBNP, should be considered in patients with SSc N Policies to evaluate the risk of having PAH should be considered in hospitals managing patients with SSc R RHC is recommended in all cases of suspected PAH I In symptomatic patients with SSc, exercise associated with CTD echocardiography or CPET, or CMR may be considered to aid decisions to perform RHC N In patients with CTD with overlap features of SSc, an annual evaluation of the risk of PAH may be considered R In PE survivors with exercise dyspnoea, CTEPH should IIa In patients with persistent or new-onset dyspnoea or be considered exercise limitation following PE, further diagnostic evaluation to assess for CTEPH/CTEPD is recommended N For symptomatic patients with mismatched perfusion lung defects beyond 3 months of anticoagulation for acute PE, referral to a PH/CTEPH centre is recommended after considering the results of echocardiography, BNP/NT-proBNP, and/or CPET Classa I I I I IIa IIb I I I IIa IIa IIb IIb I I Continued https://doi.org/10.1183/13993003.00879-2022 10 EUROPEAN RESPIRATORY JOURNAL ESC/ERS GUIDELINES | M. 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BOX 2 Continued New or revised Recommendation in 2015 version N Classa Recommendation in 2022 version Counselling regarding the risk of PAH, and annual screening is recommended in individuals who test positive for PAH-causing mutations and in first-degree relatives of patients with HPAH N In patients referred for liver transplantation, echocardiography is recommended as a screening test for PH N Further tests (echocardiography, BNP/NT-proBNP, PFTs, and/or CPET) should be considered in symptomatic patients with CTD, portal hypertension, or HIV to screen for PAH Evaluating the disease severity and risk of death in patients with pulmonary arterial hypertension – Recommendation Table 4 N For risk stratification at the time of diagnosis, the use of a three-strata model (low, intermediate, and high risk) is recommended, taking into account all available data including haemodynamics N For risk stratification during follow-up, the use of a four-strata model (low, intermediate–low, intermediate–high, and high risk) based on WHO-FC, 6MWD, and BNP/NT-proBNP is recommended, with additional variables taken into account as necessary IIa In some PAH aetiologies and in patients with R Achievement/maintenance of an intermediate-risk comorbidities, optimization of therapy should be profile should be considered an inadequate treatment considered on an individual basis while response for most patients with PAH acknowledging that a low-risk profile is not always achievable General measures and special circumstances – Recommendation Table 5 R Supervised exercise training should be considered in IIa Supervised exercise training is recommended in physically deconditioned PAH patients under medical patients with PAH under medical therapy therapy R Immunization of PAH patients against influenza and I Immunization of patients with PAH against pneumococcal infection is recommended SARS-CoV-2, influenza, and Streptococcus pneumoniae is recommended R Correction of anaemia and/or iron status may be IIb In the presence of iron-deficiency anaemia, correction considered in PAH patients of iron status is recommended in patients with PAH N In the absence of anaemia, iron repletion may be considered in patients with PAH with iron deficiency R Oral anticoagulant treatment may be considered in IIb Anticoagulation is not generally recommended in patients with IPAH, HPAH, and PAH due to use of patients with PAH but may be considered on an anorexigens individual basis III The use of ACEis, ARBs, ARNIs, SGLT-2is, beta-blockers, R The use of angiotensin-converting enzyme inhibitors, or ivabradine is not recommended in patients with angiotensin-2 receptor antagonists, beta-blockers, and PAH unless required by comorbidities (i.e. high ivabradine is not recommended in patients with PAH blood pressure, coronary arter