Hipertensiune Pulmonara

European Heart Journal Advance Access published October 21, 2015
European Heart Journal ESC/ERS GUIDELINES

doi:10.1093/eurheartj/ehv317
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
Downloaded from http://eurheartj.oxfordjournals.org/ by guest on December 7, 2015

Transplantation (ISHLT)
Authors/Task Force Members: Nazzareno Galiè* (ESC Chairperson) (Italy),
Marc Humbert* a (ERS Chairperson) (France), Jean-Luc Vachiery c (Belgium),
Simon Gibbs (UK), Irene Lang (Austria), Adam Torbicki (Poland), Gérald Simonneaua
(France), Andrew Peacocka (UK), Anton Vonk Noordegraafa (The Netherlands),
Maurice Beghettib (Switzerland), Ardeschir Ghofrania (Germany),
Miguel Angel Gomez Sanchez (Spain), Georg Hansmannb (Germany), Walter Klepetkoc
(Austria), Patrizio Lancellotti (Belgium), Marco Matuccid (Italy), Theresa McDonagh
(UK), Luc A. Pierard (Belgium), Pedro T. Trindade (Switzerland), Maurizio Zompatorie
(Italy) and Marius Hoepera (Germany)
* Corresponding authors: Nazzareno Galiè, Department of Experimental, Diagnostic and Specialty Medicine –DIMES, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy,
Tel: +39 051 349 858, Fax: +39 051 344 859, Email: nazzareno.galie@unibo.it
Marc Humbert, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Sud, Assistance Publique Hôpitaux de Paris, 78 rue du Général Leclerc, 94270 Le Kremlin-Bicetre, France,
Tel: +33 145217972, Fax: +33 145217971, Email: marc.humbert@aphp.fr
ESC Committee for Practice Guidelines (CPG) and National Cardiac Societies document reviewers: listed in Appendix
a
Representing the European Respiratory Society; bRepresenting the Association for European Paediatric and Congenital Cardiology; cRepresenting the Inter-
national Society for Heart and Lung Transplantation; dRepresenting the European League Against Rheumatism; and eRepresenting the European Society of
Radiology.
ESC entities having participated in the development of this document:
ESC Associations: Acute Cardiovascular Care Association (ACCA), European Association for Cardiovascular Prevention & Rehabilitation (EACPR), European Association of Cardio-
vascular Imaging (EACVI), European Association of Percutaneous Cardiovascular Interventions (EAPCI), European Heart Rhythm Association (EHRA), Heart Failure Association (HFA).
ESC Councils: Council for Cardiology Practice (CCP), Council on Cardiovascular Nursing and Allied Professions (CCNAP), Council on Cardiovascular Primary Care (CCPC).
ESC Working Groups: Cardiovascular Pharmacotherapy, Cardiovascular Surgery, Grown-up Congenital Heart Disease, Pulmonary Circulation and Right Ventricular Function,
Valvular Heart Disease.
The content of these European Society of Cardiology (ESC) and European Respiratory Society (ERS) Guidelines has been published for personal and educational use only. No com-
mercial use is authorized. No part of the ESC/ERS Guidelines may be translated or reproduced in any form without written permission from the ESC and/or ERS. Permission can be
obtained upon submission of a written request to Oxford University Press, the publisher of the European Heart Journal or from the European Respiratory Journal and the party author-
ized to handle such permissions on behalf of the ESC and ERS.
Disclaimer: The ESC/ERS Guidelines represent the views of the ESC and ERS and were produced after careful consideration of the scientific and medical knowledge and the evidence
available at the time of their publication. The ESC and ERS are not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC/ERS Guidelines and any
other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies. Health profes-
sionals are encouraged to take the ESC/ERS Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive,
diagnostic or therapeutic medical strategies; however, the ESC/ERS Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make
appropriate and accurate decisions in consideration of each patient’s health condition and in consultation with that patient and, where appropriate and/or necessary, the patient’s
caregiver. Nor do the ESC/ERS Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines
issued by the competent public health authorities, in order to manage each patient’s case in light of the scientifically accepted data pursuant to their respective ethical and professional
obligations. It is also the health professional’s responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.
Published on behalf of the European Society of Cardiology. All rights reserved. & 2015 European Society of Cardiology & European Respiratory Society.
This article is being published concurrently in the European Heart Journal (10.1093/eurheartj/ehv317) and the European Respiratory Journal (10.1183/13993003.01032-2015). The articles
are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article.
Page 2 of 58 ESC/ERS Guidelines
Document Reviewers: Victor Aboyans (CPG Review Coordinator) (France), Antonio Vaz Carneiro (CPG Review
Coordinator) (Portugal), Stephan Achenbach (Germany), Stefan Agewall (Norway), Yannick Allanored (France),
Riccardo Asteggiano (Italy), Luigi Paolo Badano (Italy), Joan Albert Barberàa (Spain), Hélène Bouvaist (France),
Héctor Bueno (Spain), Robert A. Byrne (Germany), Scipione Carerj (Italy), Graça Castro (Portugal), Çetin Erol
(Turkey), Volkmar Falk (Germany), Christian Funck-Brentano (France), Matthias Gorenflob (Germany),
John Granton c (Canada), Bernard Iung (France), David G. Kiely (UK), Paulus Kirchhof (Germany/UK),
Barbro Kjellstrom (Sweden), Ulf Landmesser (Switzerland), John Lekakis (Greece), Christos Lionis (Greece),
Gregory Y. H. Lip (UK), Stylianos E. Orfanos a (Greece), Myung H. Parkc (USA), Massimo F. Piepoli (Italy),
Piotr Ponikowski (Poland), Marie-Pierre Revel e (France), David Rigau a (ERS methodologist) (Switzerland),
Stephan Rosenkranz (Germany), Heinz Völler (Germany), and Jose Luis Zamorano (Spain)
The disclosure forms of all experts involved in the development of these guidelines are available on the ESC website
http://www.escardio.org/guidelines
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Keywords Guidelines † Pulmonary hypertension † Pulmonary arterial hypertension † Chronic thromboembolic

pulmonary hypertension † Congenital heart disease † Connective tissue disease † Heart failure † Respiratory
failure † Endothelin receptor antagonists † Phosphodiesterase type 5 inhibitors † Prostacyclin analogues †
Lung disease † Left heart disease
Table of Contents
Abbreviations and acronyms . . . . . . . . . . . . . . . . . . . . . . . 3 6.2.4 Comprehensive prognostic evaluation and risk
1. Preamble . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 assessment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 6.2.5 Definition of patient status . . . . . . . . . . . . . . . . . 19
3. Definitions and classifications . . . . . . . . . . . . . . . . . . . . . . 6 6.2.6 Treatment goals and follow-up strategy . . . . . . . . . 19
3.1 Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6.3 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20
3.2. Classifications . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 6.3.1 General measures . . . . . . . . . . . . . . . . . . . . . . . 20
4. Epidemiology and genetics of pulmonary hypertension . . . . . 8 6.3.1.1 Physical activity and supervised rehabilitation . . . 20
4.1 Epidemiology and risk factors . . . . . . . . . . . . . . . . . . 8 6.3.1.2 Pregnancy, birth control, and post-menopausal
4.2 Genetics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 hormonal therapy . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5. Pulmonary hypertension diagnosis . . . . . . . . . . . . . . . . . . 9 6.3.1.3 Elective surgery . . . . . . . . . . . . . . . . . . . . . . 21
5.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 6.3.1.4 Infection prevention . . . . . . . . . . . . . . . . . . . 21
5.1.1 Clinical presentation . . . . . . . . . . . . . . . . . . . . . 9 6.3.1.5 Psychosocial support . . . . . . . . . . . . . . . . . . 21
5.1.2 Electrocardiogram . . . . . . . . . . . . . . . . . . . . . . 9 6.3.1.6 Adherence to treatments . . . . . . . . . . . . . . . . 21
5.1.3 Chest radiograph . . . . . . . . . . . . . . . . . . . . . . . 10 6.3.1.7 Travel . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
5.1.4 Pulmonary function tests and arterial blood gases . . 10 6.3.1.8 Genetic counselling . . . . . . . . . . . . . . . . . . . 21
5.1.5 Echocardiography . . . . . . . . . . . . . . . . . . . . . . . 10 6.3.2 Supportive therapy . . . . . . . . . . . . . . . . . . . . . . 21
5.1.6 Ventilation/perfusion lung scan . . . . . . . . . . . . . . 12 6.3.2.1 Oral anticoagulants . . . . . . . . . . . . . . . . . . . . 21
5.1.7 High-resolution computed tomography, contrast 6.3.2.2 Diuretics . . . . . . . . . . . . . . . . . . . . . . . . . . 22
enhanced computed tomography, and pulmonary 6.3.2.3 Oxygen . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
angiography . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12 6.3.2.4 Digoxin and other cardiovascular drugs . . . . . . 22
5.1.8 Cardiac magnetic resonance imaging . . . . . . . . . . . 12 6.3.2.5 Anaemia and iron status . . . . . . . . . . . . . . . . 22
5.1.9 Blood tests and immunology . . . . . . . . . . . . . . . . 12 6.3.3 Specific drug therapy . . . . . . . . . . . . . . . . . . . . . 22
5.1.10 Abdominal ultrasound scan . . . . . . . . . . . . . . . . 13 6.3.3.1 Calcium channel blockers . . . . . . . . . . . . . . . 22
5.1.11 Right heart catheterization and vasoreactivity . . . . 13 6.3.3.2 Endothelin receptor antagonists . . . . . . . . . . . 23
5.1.12 Genetic testing . . . . . . . . . . . . . . . . . . . . . . . . 14 6.3.3.3 Phosphodiesterase type 5 inhibitors and guanylate
5.2 Diagnostic algorithm . . . . . . . . . . . . . . . . . . . . . . . . 15 cyclase stimulators . . . . . . . . . . . . . . . . . . . . . . . . . 23
6. Pulmonary arterial hypertension (group 1) . . . . . . . . . . . . . 16 6.3.3.4 Prostacyclin analogues and prostacyclin receptor
6.1 Clinical characteristics . . . . . . . . . . . . . . . . . . . . . . . 16 agonists . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 24
6.2 Evaluation of severity . . . . . . . . . . . . . . . . . . . . . . . 16 6.3.3.5 Experimental compounds and strategies . . . . . . 26
6.2.1 Clinical parameters, imaging and haemodynamics . . 16 6.3.4 Combination therapy . . . . . . . . . . . . . . . . . . . . . 26
6.2.2 Exercise capacity . . . . . . . . . . . . . . . . . . . . . . . 17 6.3.5 Drug interactions . . . . . . . . . . . . . . . . . . . . . . . 27
6.2.3 Biochemical markers . . . . . . . . . . . . . . . . . . . . . 17 6.3.6 Balloon atrial septostomy . . . . . . . . . . . . . . . . . . 28
ESC/ERS Guidelines Page 3 of 58
6.3.7 Advanced right ventricular failure . . . . . . . . . . . . . 28

Abbreviations and acronyms
6.3.7.1 Intensive care unit management . . . . . . . . . . . 28
6.3.7.2 Right ventricle assistance . . . . . . . . . . . . . . . . 28
6.3.8 Transplantation . . . . . . . . . . . . . . . . . . . . . . . . 28 ALAT alanine aminotransferase
6.3.9 Treatment algorithm . . . . . . . . . . . . . . . . . . . . . 29 ASAT aspartate aminotransferase
6.3.10 Diagnosis and treatment of pulmonary arterial APAH associated pulmonary arterial hypertension
hypertension complications . . . . . . . . . . . . . . . . . . . . 31 BAS balloon atrial septostomy
6.3.10.1 Arrhythmias . . . . . . . . . . . . . . . . . . . . . . . 31 BMPR2 bone morphogenetic protein receptor 2
6.3.10.2 Haemoptysis . . . . . . . . . . . . . . . . . . . . . . . 31 BNP brain natriuretic peptide
6.3.10.3 Mechanical complications . . . . . . . . . . . . . . . 31 BPA balloon pulmonary angioplasty
6.3.11 End of life care and ethical issues . . . . . . . . . . . . 31 BREATHE Bosentan Randomised trial of Endothelin
7. Specific pulmonary (arterial) hypertension subsets . . . . . . . . 31 Antagonist THErapy
7.1 Paediatric pulmonary arterial hypertension . . . . . . . . . 31 CAV1 caveolin-1
7.1.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 CCB calcium channel blocker
7.1.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32 cGMP cyclic guanosine monophosphate
7.2 Pulmonary arterial hypertension associated with adult CHD congenital heart disease
congenital heart disease . . . . . . . . . . . . . . . . . . . . . . . . . 33 CI cardiac index
CMR cardiac magnetic resonance

7.2.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
7.2.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33 CO cardiac output
7.3 Pulmonary arterial hypertension associated with COPD chronic obstructive pulmonary disease
connective tissue disease . . . . . . . . . . . . . . . . . . . . . . . . 34 Cpc-PH combined post-capillary and pre-capillary
7.3.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 pulmonary hypertension
7.3.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 CPET cardiopulmonary exercise testing
7.4 Pulmonary arterial hypertension associated with portal CPFE combined pulmonary fibrosis and emphysema
hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35 CT computed tomography
7.4.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 CTD connective tissue disease
7.4.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 36 CTPA computed tomography pulmonary angiogram
7.5 Pulmonary arterial hypertension associated with human CTEPH chronic thromboembolic pulmonary
immunodeficiency virus infection . . . . . . . . . . . . . . . . . . . 36 hypertension
7.5.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 DLCO diffusing capacity of the lung for carbon monoxide
7.5.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37 DPAH drug-induced pulmonary arterial hypertension
7.6 Pulmonary veno-occlusive disease and pulmonary DPG diastolic pressure gradient (diastolic PAP 2 mean
capillary haemangiomatosis . . . . . . . . . . . . . . . . . . . . . . 37 PAWP)
7.6.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 EACVI European association of cardiovascular imaging
7.6.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38 ECG electrocardiogram
8. Pulmonary hypertension due to left heart disease (group 2) . . 38 ECMO extracorporeal membrane oxygenation
8.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39 EIF2AK4 eukaryotic translation initiation factor 2 alpha
8.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 kinase 4
9. Pulmonary hypertension due to lung diseases and/or hypoxia EMA European Medicines Agency
(group 3) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40 ERA endothelin receptor antagonist
9.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 FC functional class
9.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 41 FDA US Food and Drug Administration
10. Chronic thromboembolic pulmonary hypertension (group 4) 42 HAART highly active antiretroviral therapy
10.1 Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 42 HIV human immunodeficiency virus
10.2 Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 HF-pEF heart failure with preserved left ventricular ejec-
10.2.1 Surgical . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43 tion fraction
10.2.2 Medical . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44 HPAH heritable pulmonary arterial hypertension
10.2.3 Interventional . . . . . . . . . . . . . . . . . . . . . . . . . 44 HRCT high resolution computed tomography
11. Pulmonary hypertension with unclear and/or multifactorial ICU intensive care unit
mechanisms (group 5) . . . . . . . . . . . . . . . . . . . . . . . . . . . . 45 INR international normalized ratio
12. Definition of a pulmonary hypertension expert referral centre 45 IPAH idiopathic pulmonary arterial hypertension
12.1 Facilities and skills required for a expert referral centre 45 Ipc-PH isolated post-capillary pulmonary hypertension
13. To do and not to do messages from the guidelines . . . . . . . 46 IPF idiopathic pulmonary fibrosis
14. Web addenda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 i.v. intravenous
15. Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 IVC inferior vena cava
16. References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47 LA left atrium/atrial
LHD left heart disease ratio of particular diagnostic or therapeutic means. Guidelines
LV left ventricle/ventricular and recommendations should help health professionals to make
MR magnetic resonance decisions in their daily practice. However, the final decisions con-
NYHA New York Heart Association cerning an individual patient must be made by the responsible
NO nitric oxide health professional(s) in consultation with the patient and care-
NT-proBNP N-terminal pro-brain natriuretic peptide giver as appropriate.
PA pulmonary artery A great number of Guidelines have been issued in recent years by
PaCO2 arterial carbon dioxide pressure the European Society of Cardiology (ESC) and by the European
PaO2 arterial oxygen pressure Respiratory Society (ERS), as well as by other societies and organi-
PAH pulmonary arterial hypertension sations. Because of the impact on clinical practice, quality criteria for
PAP pulmonary arterial pressure the development of guidelines have been established in order to
PAPm mean pulmonary arterial pressure make all decisions transparent to the user. The recommendations
PAPs systolic pulmonary arterial pressure for formulating and issuing ESC Guidelines can be found on the
PAWP pulmonary artery wedge pressure ESC website (http://www.escardio.org/Guidelines-&-Education/
PASP pulmonary artery systolic pressure Clinical-Practice-Guidelines/Guidelines-development/Writing-
PCH pulmonary capillary haemangiomatosis ESC-Guidelines). ESC Guidelines represent the official position of
PDE-5i phosphodiesterase type 5 inhibitor the ESC on a given topic and are regularly updated.

PE pulmonary embolism Members of this Task Force were selected by the ESC and ERS
PEA pulmonary endarterectomy to represent professionals involved with the medical care
PFTs pulmonary function tests of patients with this pathology. Selected experts in the field
PH pulmonary hypertension undertook a comprehensive review of the published evidence
PoPH porto-pulmonary hypertension for management (including diagnosis, treatment, prevention and
PPHN persistent pulmonary hypertension of the rehabilitation) of a given condition according to ESC Committee
newborn for Practice Guidelines (CPG) policy and approved by the ERS.
PVOD pulmonary veno-occlusive disease A critical evaluation of diagnostic and therapeutic procedures
PVR pulmonary vascular resistance was performed, including assessment of the risk – benefit ratio.
RA right atrium Estimates of expected health outcomes for larger populations
RAP right atrial pressure were included, where data exist. The level of evidence and
RCT randomized controlled trial the strength of the recommendation of particular management
RHC right heart catheterization options were weighed and graded according to predefined scales,
RV right ventricle/ventricular as outlined in Tables 1 and 2.
6MWD/6MWT 6-minute walking distance/6-minute walking test The experts of the writing and reviewing panels provided declar-
SCD sickle cell disease ation of interest forms for all relationships that might be perceived as
sGC soluble guanylate cyclase real or potential sources of conflicts of interest. These forms were
SSc systemic sclerosis compiled into one file and can be found on the ESC website (http://
SvO2 mixed venous oxygen saturation www.escardio.org/guidelines). Any changes in declarations of inter-
SVR systemic vascular resistance est that arise during the writing period must be notified to the ESC
TAPSE tricuspid annular plane systolic excursion and ERS and updated. The Task Force received its entire financial
t.i.d. three times a day support from the ESC and ERS without any involvement from the
TGF-b transforming growth factor b healthcare industry.
TPG transpulmonary pressure gradient (mean PAP 2 The ESC CPG supervises and coordinates the preparation of new
mean PAWP) Guidelines produced by task forces, expert groups or consensus pa-
TRV tricuspid regurgitant velocity nels. The Committee is also responsible for the endorsement pro-
VE/VCO2 minute ventilation – carbon dioxide production cess of these Guidelines. The ESC Guidelines undergo extensive
relationship review by the CPG and external experts, and in this case by
V/Q ventilation/perfusion ERS-appointed experts. After appropriate revisions the Guidelines
WHO-FC World Health Organization functional class are approved by all the experts involved in the Task Force. The fina-
WU Wood units lized document is approved by the CPG and by ERS for publication
in the European Heart Journal and in the European Respiratory Jour-
nal. The Guidelines were developed after careful consideration of
the scientific and medical knowledge and the evidence available at
1. Preamble the time of their dating.
Guidelines summarize and evaluate all available evidence on a par- The task of developing ESC/ERS Guidelines covers not only
ticular issue at the time of the writing process, with the aim of as- integration of the most recent research, but also the creation of
sisting health professionals in selecting the best management educational tools and implementation programmes for the recom-
strategies for an individual patient with a given condition, taking mendations. To implement the guidelines, condensed pocket guide-
into account the impact on outcome, as well as the risk – benefit line versions, summary slides, booklets with essential messages,
Table 1 Classes of recommendations
Classes of Suggested wording to use

recommendations
Class I Evidence and/or general Is recommended/is

agreement that a given treatment indicated
or procedure is beneficial, useful,
effective.
Class II Conflicting evidence and/or a

divergence of opinion about the
usefulness/efficacy of the given
treatment or procedure.
Class IIa Weight of evidence/opinion is in Should be considered

favour of usefulness/efficacy.
Class IIb Usefulness/efficacy is less well May be considered

established by evidence/opinion.
Class III Evidence or general agreement Is not recommended

that the given treatment or
procedure is not useful/effective,
and in some cases may be harmful.
appropriate and/or necessary. It is also the health professional’s re-

Table 2 Level of evidence sponsibility to verify the rules and regulations applicable to drugs
and devices at the time of prescription.
Level of Data derived from multiple randomized
evidence A clinical trials or meta-analyses.
Level of
Data derived from a single randomized
clinical trial or large non-randomized
2. Introduction
evidence B
studies. Pulmonary hypertension (PH) is a pathophysiological disorder that
Consensus of opinion of the experts and/ may involve multiple clinical conditions and can complicate the major-
Level of
or small studies, retrospective studies, ity of cardiovascular and respiratory diseases. The composition of the
evidence C
registries.
guidelines task force reflects the multidisciplinary nature of PH, includ-
ing members of different medical societies, associations and working
groups. The current document follows the two previous ESC and ERS
Guidelines, published in 2004 and 2009, focusing on clinical manage-
summary cards for non-specialists and an electronic version for
ment of PH. A systematic literature review was performed from
digital applications (smartphones, etc.) are produced. These ver-
MEDLINEw to identify new studies published since 2009 concerning
sions are abridged and thus, if needed, one should always refer to
the topic of PH. Task force members selected studies based on rele-
the full text version, which is freely available on the ESC website.
vance and appropriateness. The main changes and adaptations as
The National Societies of the ESC are encouraged to endorse,
compared with the 2009 ESC and ERS PH guidelines are as follows:
translate and implement all ESC Guidelines. Implementation pro-
grammes are needed because it has been shown that the outcome † The table of contents structure has been simplified, with three
of disease may be favourably influenced by the thorough application initial general chapters including classifications, basic aspects
of clinical recommendations. and differential diagnosis, two chapters for pulmonary arterial
Surveys and registries are needed to verify that real-life daily prac- hypertension (PAH) and one chapter each for PH due to left
tice is in keeping with what is recommended in the guidelines, thus heart disease (LHD), lung disease and/or hypoxia, chronic
completing the loop between clinical research, writing of guidelines, thromboembolic pulmonary hypertension (CTEPH) and unclear
disseminating them and implementing them into clinical practice. and/or multifactorial mechanisms.
Health professionals are encouraged to take the ESC/ERS Guide- † New wordings and parameters for the haemodynamic definition
lines fully into account when exercising their clinical judgment, as of post-capillary PH subgroups have been adopted. Pulmonary
well as in the determination and the implementation of preventive, vascular resistance (PVR) has been included in the haemodynamic
diagnostic or therapeutic medical strategies. However, the ESC/ERS definition of PAH.
Guidelines do not override in any way whatsoever the individual re- † An updated common clinical classification for adult and paediatric
sponsibility of health professionals to make appropriate and accur- patients is reported.
ate decisions in consideration of each patient’s health condition and † New advances in pathology, pathobiology, genetics, epidemi-
in consultation with that patient and the patient’s caregiver where ology and risk factors are reported.
† An updated diagnostic algorithm has been provided in an inde- not be used.1 A recent retrospective study has proposed a definition
pendent chapter and novel screening strategies are proposed in of PH on exercise with the combination of PAPm and total PVR
the web addenda. data, but no outcome prospective validation has been provided.3
† The importance of expert referral centres in the management of The term PAH describes a group of PH patients characterized
PH patients has been highlighted in both the diagnostic and treat- haemodynamically by the presence of pre-capillary PH, defined by
ment algorithms. a pulmonary artery wedge pressure (PAWP) ≤15 mmHg and a
† New developments on PAH severity evaluation and on treat- PVR .3 Wood units (WU) in the absence of other causes of pre-
ments and treatment goals are reported, including combination capillary PH such as PH due to lung diseases, CTEPH or other rare
therapy and two new recently approved drugs. The treatment al- diseases.1
gorithm has been updated accordingly. According to various combinations of PAP, PAWP, cardiac output
† The chapters on PH due to LHD and lung diseases have been up- (CO), diastolic pressure gradient (DPG) and PVR, assessed in stable
dated. The term ‘out of proportion PH’ has been abandoned in clinical conditions, different haemodynamic definitions of PH are
both conditions. shown in Table 3 together with their corresponding clinical
† New diagnostic and treatment algorithms are reported in the classification (Table 4).1,4 The reasons for the updated definitions
CTEPH chapter, including general criteria for operability and bal- of post-capillary PH are reported in the specific section (8.0).
loon pulmonary angioplasty (BPA) and a newly approved drug.
† A short chapter on PH due to unclear and/or multifactorial 3.2 Classifications

mechanisms has been added. The clinical classification of PH is intended to categorize multiple
clinical conditions into five groups according to their similar clinical
3. Definitions and classifications presentation, pathological findings, haemodynamic characteristics
and treatment strategy.5 The clinical classification may be updated
3.1 Definitions when new data are available on the above features or when add-
itional clinical entities are considered. A comprehensive version of
PH is defined as an increase in mean pulmonary arterial pressure
the clinical classification is presented in Table 4.6 A condensed ver-
(PAPm) ≥25 mmHg at rest as assessed by right heart catheteriza-
sion is provided in a web addenda (Web Table I).
tion (RHC).1 Available data have shown that the normal PAPm at
The new findings are as follows:
rest is 14 + 3 mmHg with an upper limit of normal of approximately
20 mmHg.1,2 The clinical significance of a PAPm between 21 and 24 † New conditions that are frequently found in children have been in-
mmHg is unclear. Patients presenting with a pulmonary artery cluded in different clinical groups in order to provide a comprehen-
pressure (PAP) in this range should be carefully followed when sive classification appropriate to both adult and paediatric patients.
they are at risk for developing PAH [e.g. patients with connective † Recently identified gene mutations have been included in the
tissue disease (CTD) or family members of patients with heritable HPAH subgroup of clinical group 1 (PAH). The new mutations
PAH (HPAH)].1 are more rare as compared with the traditional bone morpho-
Due to the lack of reliable data that define which levels of genetic protein receptor 2 (BMPR2) mutations (Table 4).
exercise-induced changes in PAPm or PVR have prognostic implica- † Pre-capillary PH associated with chronic haemolytic anaemia
tions, a disease entity ‘PH on exercise’ cannot be defined and should appears to be significantly different from other forms of PAH in
Table 3 Haemodynamic definitions of pulmonary hypertensiona
Characteristicsa Clinical group(s)b
PH PAPm ≥25 mmHg All
Pre-capillary PH PAPm ≥25 mmHg 1. Pulmonary arterial hypertension

PAWP ≤15 mmHg 3. PH due to lung diseases
4. Chronic thromboembolic PH
5. PH with unclear and/or multifactorial mechanisms
Post-capillary PH PAPm ≥25 mmHg 2. PH due to left heart disease

PAWP >15 mmHg 5. PH with unclear and/or multifactorial mechanisms
Isolated post-capillary PH DPG <7 mmHg and/or

(Ipc-PH) PVR ≤3 WUc
Combined post-capillary and pre-capillary PH DPG ≥7 mmHg and/or

(Cpc-PH) PVR >3 WUc
CO ¼ cardiac output; DPG ¼ diastolic pressure gradient (diastolic PAP – mean PAWP); mPAP ¼ mean pulmonary arterial pressure; PAWP ¼ pulmonary arterial wedge pressure;
PH ¼ pulmonary hypertension; PVR ¼ pulmonary vascular resistance; WU ¼ Wood units.
a
All values measured at rest; see also section 8.0.
b
According to Table 4.
c
Wood Units are preferred to dynes.s.cm25.
regard to pathological findings (absence of plexiform lesions),

Table 4 Comprehensive clinical classification of haemodynamic characteristics (low PVR and high CO) and re-
pulmonary hypertension (updated from Simonneau et al.5) sponse to PAH-specific therapies (no demonstration of efficacy).
Therefore these clinical conditions have been moved from group
1. Pulmonary arterial hypertension
1 (PAH) to group 5 (unclear and/or multifactorial mechanisms).
1.1 Idiopathic † Group 1’ [pulmonary veno-occlusive disease (PVOD) and/or
1.2 Heritable
1.2.1 BMPR2 mutation pulmonary capillary haemangiomatosis (PCH)] has been
1.2.2 Other mutations expanded and includes idiopathic, heritable, drug-, toxin- and
1.3 Drugs and toxins induced radiation-induced and associated forms.
1.4 Associated with:
1.4.1 Connective tissue disease
Table 5 Important pathophysiological and clinical
1.4.3 Portal hypertension definitions
1.4.4 Congenital heart disease (Table 6)
1.4.5 Schistosomiasis
1. Pulmonary hypertension (PH) is a haemodynamic and
1’. Pulmonary veno-occlusive disease and/or pulmonary
capillary haemangiomatosis pulmonary arterial pressure ≥25 mmHg at rest as assessed by right
1’.1 Idiopathic heart catheterization (Table 3). PH can be found in multiple clinical
1’.2 Heritable conditions (Table 4).

1’.2.1 EIF2AK4 mutation 2. Pulmonary arterial hypertension (PAH, group 1) is a clinical
1’.2.2 Other mutations condition characterized by the presence of pre-capillary PH (Table 3)
1’.3 Drugs, toxins and radiation induced and pulmonary vascular resistance >3 Wood units, in the absence
1’.4 Associated with: of other causes of pre-capillary PH such as PH due to lung diseases,
1’.4.1 Connective tissue disease chronic thromboembolic PH, or other rare diseases (Table 4). PAH
1’.4.2 HIV infection includes different forms that share a similar clinical picture and
1”. Persistent pulmonary hypertension of the newborn virtually identical pathological changes of the lung microcirculation
(Table 4).
2. Pulmonary hypertension due to left heart disease
3.
2.1 Left ventricular systolic dysfunction exercise’.
2.2 Left ventricular diastolic dysfunction
2.3 Valvular disease
obstruction and congenital cardiomyopathies

2.5 Congenital /acquired pulmonary veins stenosis Table 6 Clinical classification of pulmonary arterial
3. Pulmonary hypertension due to lung diseases and/or hypertension associated with congenital heart disease
hypoxia (updated from Simonneau et al. 5)
3.1 Chronic obstructive pulmonary disease
3.2 Interstitial lung disease
1. Eisenmenger’s syndrome
3.3 Other pulmonary diseases with mixed restrictive and
Includes all large intra- and extra-cardiac defects which begin as
obstructive pattern
systemic-to-pulmonary shunts and progress with time to severe
3.4 Sleep-disordered breathing
elevation of PVR and to reversal (pulmonary-to-systemic) or
3.5 Alveolar hypoventilation disorders
bidirectional shunting; cyanosis, secondary erythrocytosis, and
3.6 Chronic exposure to high altitude
multiple organ involvement are usually present.
3.7 Developmental lung diseases (Web Table III)
2. PAH associated with prevalent systemic-to-pulmonary shunts
4. Chronic thromboembolic pulmonary hypertension
• Correctablea
and other pulmonary artery obstructions
• Non-correctable
4.1 Chronic thromboembolic pulmonary hypertension Includes moderate to large defects; PVR is mildly to moderately
4.2 Other pulmonary artery obstructions increased, systemic-to-pulmonary shunting is still prevalent, whereas
4.2.1 Angiosarcoma cyanosis at rest is not a feature.
4.2.2 Other intravascular tumors
3. PAH with small/coincidental defects b
4.2.3 Arteritis
Marked elevation in PVR in the presence of small cardiac defects
4.2.4 Congenital pulmonary arteries stenoses
(usually ventricular septal defects <1 cm and atrial septal defects <2 cm
4.2.5 Parasites (hydatidosis)
of effective diameter assessed by echo), which themselves do not
5. Pulmonary hypertension with unclear and/or account for the development of elevated PVR; the clinical picture is
multifactorial mechanisms very similar to idiopathic PAH. Closing the defects is contra-indicated.
5.1 Haematological disorders: chronic haemolytic anaemia, 4. PAH after defect correction
myeloproliferative disorders, splenectomy Congenital heart disease is repaired, but PAH either persists
5.2 Systemic disorders: sarcoidosis, pulmonary histiocytosis, immediately after correction or recurs/develops months or years
lymphangioleiomyomatosis, neurofibromatosis
5.3 Metabolic disorders: glycogen storage disease, Gaucher haemodynamic lesions.
disease, thyroid disorders
5.4 Others: pulmonary tumoral thrombothic microangiopathy,
osing mediastinitis, chronic renal failure (with/without PAH ¼ pulmonary arterial hypertension; PVR ¼ pulmonary vascular resistance.
a
dialysis), segmental pulmonary hypertension With surgery or intravascular percutaneous procedure.
b
The size applies to adult patients. However, also in adults the simple diameter may
be not sufficient for defining the haemodynamic relevance of the defect and also
BMPR2 ¼ bone morphogenetic protein receptor, type 2; EIF2AK4 ¼ eukaryotic. the pressure gradient, the shunt size and direction, and the pulmonary to systemic
translation initiation factor 2 alpha kinase 4; HIV ¼ human immunodeficiency virus. flows ratio should be considered (Web Table II).
† Persistent PH of the newborn (PPHN) includes a heterogeneous clinical conditions.13 IPAH corresponds to sporadic disease, without
group of conditions that may differ from classical PAH. As a con- any familial history of PAH or known triggering factor. While the
sequence, PPHN has been subcategorised as group I′′ .7 – 9 mean age of patients with IPAH in the first US National Institutes
† Paediatric heart diseases such as congenital or acquired left heart of Health registry created in 1981 was 36 years, PAH is now
inflow or outflow tract obstruction and congenital cardiomyop- more frequently diagnosed in elderly patients, resulting in a mean
athies have been included in group 2 (PH due to LHD). age at diagnosis between 50 and 65 years in current registries.
† No changes are proposed for group 3 (PH due to lung diseases Furthermore, the female predominance is quite variable among
and/or hypoxia). registries and may not be present in elderly patients, and survival ap-
† Group 4 has been renamed as ‘CTEPH and other pulmonary pears to have improved over time.
artery (PA) obstructions’, which includes CTEPH, pulmonary A number of risk factors for the development of PAH has been
angiosarcoma, other intravascular tumours, arteritis, congenital identified and are defined as any factor or condition that is suspected
pulmonary arteries stenoses and parasites (Table 4). to play a predisposing or facilitating role in disease development. Risk
† Segmental PH is observed in discrete lung areas perfused by aorto- factors were classified as definite, likely or possible, based on the
pulmonary collaterals in congenital heart diseases such as pulmon- strength of their association with PH and their probable causal
ary or tricuspid atresia. This very unusual haemodynamic condition role.13 A definite association is acknowledged in the case of either an
has been included in group 5 (unclear and/or multifactorial epidemic, such as occurred with appetite suppressants, or if large,
mechanisms). multicentre epidemiological studies demonstrate an association

† Some pathological and pathophysiological information on the between the clinical condition or drug and PAH. A likely association
clinical groups are reported in the web addenda. is acknowledged if a single-centre case–control study or multiple
case series demonstrate an association or if clinical and haemo-
Important pathophysiological and clinical definitions are reported in
dynamic recovery occurs after stopping exposure, such as oc-
Table 5. A clinical classification of PAH associated with congenital
curred in dasatinib-induced PAH. A possible association can be
heart disease (CHD) is reported in Table 6.
suspected, for example, for drugs with similar mechanisms of action
An anatomical – pathophysiological classification of congenital
as those in the definite or likely category but which have not yet
systemic-to-pulmonary shunts associated with PAH is presented
been studied, such as drugs used to treat attention deficit disorder.
in Web Table II. A list of developmental lung diseases associated
Definite clinical associations are listed among APAH in Table 4 and
with PH is presented in Web Table III.
the risk level of different drugs and toxins are listed in Table 7.6,14 – 16
† Group 2 (PH due to LHD): The prevalence of PH in patients with
4. Epidemiology and genetics chronic heart failure increases with the progression of functional
class (FC) impairment. Up to 60% of patients with severe left ven-
of pulmonary hypertension tricular (LV) systolic dysfunction and up to 70% of patients with heart
4.1 Epidemiology and risk factors failure with preserved ejection fraction may present with PH. In left-
sided valvular diseases, the prevalence of PH increases with the se-
Reporting in the literature of PH incidence data at the global level is
verity of the defect and of the symptoms. PH can be found in virtually
poor. In the UK, a prevalence of 97 cases per million with a female:-
all patients with severe symptomatic mitral valve disease and in up to
male ratio of 1.8 has been reported. The age-standardized death rate
65% of those with symptomatic aortic stenosis.17 – 19
in the USA ranges between 4.5 and 12.3 per 100,000 population.
† Group 3 (PH due to lung diseases and/or hypoxaemia): Mild PH is
Comparative epidemiological data on the prevalence of the different
common in both severe interstitial lung disease and severe chronic
groups of PH are not widely available, but it is clear that LHD (group
2) is believed to be the most common cause of PH, although severe
PH is relatively uncommon in this setting. Although patients belonging
Table 7 Updated risk level of drugs and toxins known
to groups 2 and 3 represent an important part of the clinical practice,
to induce pulmonary arterial hypertension
there is disproportionately little information about the demographics
and clinical course of this segment of the PH population, suggesting
Likely Possible
that registry database methodology may be useful for these groups.
• Aminorex • Amphetamines • Cocaine
Globally, schistosomiasis-associated PAH and high altitude–related •F • Dasatinib • Phenylpropanolamine
PH represent an important burden to mankind. • Dexf • L-tryptophan • St John’s Wort
• Toxic rapeseed oil • Methamphetamines • Amphetamine-like
† Group 1 (PAH): Several registries have described the epidemiology • ex drugs
of PAH.10 – 12 The lowest estimate of the prevalence of PAH and • Selective serotonin • Interferon α and β
idiopathic PAH (IPAH) are 15 cases and 5.9 cases per million adult reuptake inhibitorsa • Some
chemotherapeutic
population, respectively. The lowest estimate of PAH incidence is agents such as
2.4 cases per million adult population per year. In Europe, PAH alkylating agents
prevalence and incidence are in the range of 15–60 subjects per mil- (mytomycine C,
cyclophosphamide)b
lion population and 5–10 cases per million per year, respectively.11
In registries, around half of PAH patients have idiopathic, heritable or
a
drug-induced PAH. In the subgroup of associated PAH conditions Increased risk of persistent pulmonary hypertension in the newborns of mothers
with intake of selective serotonin reuptake inhibitors.
(APAH), the leading cause is CTD, mainly systemic sclerosis (SSc).10 b
Alkylating agents are possible causes of pulmonary veno-occlusive disease.
PAH may occur in different settings depending on associated
obstructive pulmonary disease (COPD),20 while severe PH is un- investigations to confirm that haemodynamic criteria are met and
common.21 Severe PH can be seen in the combined emphysema/ to describe the aetiology and the functional and haemodynamic
fibrosis syndrome, where the prevalence of PH is high.22 severity of the condition. The interpretation of these investigations
† Group 4 [CTEPH and other PA obstructions]: In the Spanish PH requires, at the very least, expertise in cardiology, imaging and
Registry, CTEPH prevalence and incidence were 3.2 cases per respiratory medicine and may best be discussed at a multidisciplin-
million and 0.9 cases per million per year, respectively.23 Even ary team meeting. This is particularly important for identifying
though a prevalence of CTEPH of 3.8% has been reported in sur- patients who may have more than one cause of PH. The main
vivors of acute pulmonary embolism (PE), the true incidence of cause of PH should be identified according to the clinical classifica-
CTEPH after acute PE is lower, in the range of 0.5 –2%.24 A his- tion in Table 4. An algorithm for reaching a diagnosis is shown in
tory of acute PE was reported for 74.8% of patients from the Figure 1.
International CTEPH Registry.25 Associated conditions included
thrombophilic disorders (lupus anticoagulant/antiphospholipid 5.1.1 Clinical presentation
antibodies, protein S and C deficiency, activated protein C resist- The symptoms of PH are non-specific and mainly related to progres-
ance including factor V Leiden mutation, prothrombin gene mu- sive right ventricular (RV) dysfunction. Initial symptoms are typically
tation, antithrombin III deficiency and elevated factor VIII) in induced by exertion. They include shortness of breath, fatigue,
31.9% of patients and splenectomy in 3.4%. weakness, angina and syncope. Less commonly patients may also de-
scribe dry cough and exercise-induced nausea and vomiting. Symp-

4.2 Genetics toms at rest occur only in advanced cases. Abdominal distension and
ankle oedema will develop with progressing RV failure. The presen-
† Group 1 (PAH): Heterozygous BMPR2 mutations account for
tation of PH may be modified by diseases that cause or are asso-
approximately 75% of familial PAH and up to 25% of apparently
ciated with PH as well as other concurrent diseases.
sporadic PAH cases.26 BMPR2 encodes a type 2 receptor for
In some patients the clinical presentation may be related to mech-
bone morphogenetic proteins involved in the control of vascular
anical complications of PH and the abnormal distribution of blood
cell proliferation. Mutations of genes coding for activin receptor-like
flow in the pulmonary vascular bed. These include haemoptysis re-
kinase 1 and endoglin have been identified in PAH patients with a
lated to rupture of hypertrophied bronchial arteries, as well as
personal or family history of hereditary haemorrhagic telangiectasia,
symptoms attributable to pulmonary arterial dilatation such as
as well as in BMPR1B and SMAD9, supporting a prominent role for
hoarseness caused by compression of the left recurrent laryngeal
transforming growth factor b (TGF-b) family members in PAH.26
nerve, wheeze caused by large airway compression and angina
Whole exome sequencing has identified rare heterozygous muta-
due to myocardial ischaemia caused by compression of the left
tions in genes coding for proteins such as caveolin 1 (CAV1) and the
main coronary artery. Significant dilation of the PA may result in
potassium channel subfamily K member 3 (KCNK3).26,27
its rupture or dissection, leading to signs and symptoms of cardiac
† Group 1: Heritable PVOD/PCH has been recognized in consan-
tamponade.
guineous families, suggesting recessive transmission. Whole gen-
The physical signs of PH include left parasternal lift, an accentu-
ome sequencing demonstrated that bi-allelic mutations in
ated pulmonary component of the second heart sound, an RV third
eukaryotic translation initiation factor 2 alpha kinase 4 (EIF2AK4)
heart sound, a pansystolic murmur of tricuspid regurgitation and a
were present in all familial PVOD/PCH and in 25% of histologically
diastolic murmur of pulmonary regurgitation. Elevated jugular ven-
confirmed sporadic PVOD/PCH.28 EIF2AK4 encodes a serine-
ous pressure, hepatomegaly, ascites, peripheral oedema and cool
threonine kinase present in all eukaryotes that can induce changes
extremities characterize patients with advanced disease. Wheeze
in gene expression in response to amino acid deprivation.
and crackles are usually absent.
† Group 2 (PH due to LHD): No specific genetic linkage has been
Clinical examination may suggest an underlying cause of PH.
identified.18
Telangiectasia, digital ulceration and sclerodactyly are seen in sclero-
† Group 3 (PH due to lung diseases and/or hypoxaemia): Gene
derma, inspiratory crackles may point towards interstitial lung dis-
polymorphism might contribute towards determining the sever-
ease and spider naevi, testicular atrophy, and palmar erythema
ity of PH in hypoxaemic patients with COPD.29
suggest liver disease. When digital clubbing is encountered,
† Group 4 (CTEPH and other PA obstructions): No specific genet-
PVOD, cyanotic CHD, interstitial lung disease or liver disease
ic mutations have been linked to the development of CTEPH.
should be considered.
† Group 5 (PH with unclear and/or multifactorial mechanisms):
The heterogeneity of this group prevents an appropriate descrip-
5.1.2 Electrocardiogram
tion of genetics, epidemiology and risk factors in these guidelines.
An electrocardiogram (ECG) may provide supportive evidence of
PH, but a normal ECG does not exclude the diagnosis. An abnormal
ECG is more likely in severe rather than mild PH. ECG abnormalities
5. Pulmonary hypertension may include P pulmonale, right axis deviation, RV hypertrophy, RV
diagnosis strain, right bundle branch block, and QTc prolongation. While RV
hypertrophy has insufficient sensitivity (55%) and specificity (70%)
5.1 Diagnosis to be a screening tool, RV strain is more sensitive.30 Prolongation
The diagnosis of PH requires a clinical suspicion based on symptoms of the QRS complex and QTc suggest severe disease.31,32 The
and physical examination and review of a comprehensive set of ECG differential diagnosis includes anterolateral myocardial
ischaemia. In contrast to PH, ECG changes in ischaemia more com- 5.1.5 Echocardiography
monly affect the lateral and inferior leads, and when present in the Transthoracic echocardiography is used to image the effects of PH
anterior chest leads are usually accompanied by a Q wave in V1 to on the heart and estimate PAP from continuous wave Doppler mea-
V3, and rarely cause right axis deviation. surements. Echocardiography should always be performed when
Supraventricular arrhythmias may occur in advanced disease, in PH is suspected and may be used to infer a diagnosis of PH in pa-
particular atrial flutter, but also atrial fibrillation, with a cumulative tients in whom multiple different echocardiographic measurements
incidence in 25% of patients after 5 years.33 Atrial arrhythmias com- are consistent with this diagnosis. When treatment of PH itself is
promise CO and almost invariably lead to further clinical deterior- being considered, echocardiography alone is not sufficient to sup-
ation. Ventricular arrhythmias are rare. port a treatment decision and cardiac catheterization is required.
Detailed guidelines describing the echocardiographic assessment
of the right heart can be found in documents created and/or en-
5.1.3 Chest radiograph dorsed by the European Association of Cardiovascular Imaging
In 90% of patients with IPAH the chest radiograph is abnormal at the
time of diagnosis.34 Findings in patients with PAH include central
Table 8A Echocardiographic probability of
pulmonary arterial dilatation, which contrasts with ‘pruning’ (loss)
pulmonary hypertension in symptomatic patients with
of the peripheral blood vessels. Right atrium (RA) and RV enlarge-
a suspicion of pulmonary hypertension
ment may be seen in more advanced cases. A chest radiograph may

assist in differential diagnosis of PH by showing signs suggesting lung
Peak tricuspid Presence of Echocardiographic
disease (group 3, Table 4) or pulmonary venous congestion due to regurgitation other echo probability of pulmonary
LHD (group 2, Table 4). Chest radiography may help in distinguishing velocity (m/s) ‘PH signs’ a hypertension
between arterial and venous PH by respectively demonstrating in- ≤2.8 or not
No Low
creased and decreased artery:vein ratios.35 measurable
Overall, the degree of PH in any given patient does not correlate ≤2.8 or not
Yes
with the extent of radiographic abnormalities. As for ECG, a normal measurable Intermediate
chest radiograph does not exclude PH. 2.9–3.4 No
2.9–3.4 Yes
High
>3.4 Not required
5.1.4 Pulmonary function tests and arterial blood gases
Pulmonary function tests and arterial blood gases identify the con-
PH ¼ pulmonary hypertension.
tribution of underlying airway or parenchymal lung disease. Patients a
See Table 8B.
with PAH have usually mild to moderate reduction of lung volumes
related to disease severity.36,37 Although diffusion capacity can be
normal in PAH, most patients have decreased lung diffusion capacity
for carbon monoxide (DLCO). An abnormal low DLCO, defined as Table 8B Echocardiographic signs suggesting
,45% of predicted, is associated with a poor outcome.36,37 The pulmonary hypertension used to assess the probability
differential diagnosis of a low DLCO in PAH includes PVOD, PAH of pulmonary hypertension in addition to tricuspid
associated with scleroderma and parenchymal lung disease. regurgitation velocity measurement in Table 8A
Although airflow obstruction is unusual, peripheral airway obstruc-
tion can be detected. Due to alveolar hyperventilation at rest, arter- A: The ventricles a B: Pulmonary C: Inferior vena
ial oxygen pressure (PaO2) remains normal or is only slightly lower artery a cava and right
atriuma
than normal and arterial carbon dioxide pressure (PaCO2) is
Right ventricle/ Right ventricular Inferior cava diameter
decreased.38
left ventricle basal >21 mm with
COPD as a cause of hypoxic PH is diagnosed on the evidence of diameter ratio >1.0 acceleration time decreased inspiratory
irreversible airflow obstruction together with increased residual vo- <105 msec and/or collapse (<50 % with
lumes and reduced DLCO.39 Arterial blood gases of COPD patients midsystolic notching a sniff or <20 % with
quiet inspiration)
show a decreased PaO2 with normal or increased PaCO2.40 A de-
Flattening of the Early diastolic Right atrial area
crease in lung volume combined with decreased diffusion capacity interventricular pulmonary (end-systole) >18 cm2
for carbon monoxide may indicate interstitial lung disease.39 The se- septum (left ventricular regurgitation velocity
verity of emphysema and of interstitial lung disease can be diagnosed eccentricity index >2.2 m/sec
>1.1 in systole and/or
using high-resolution computed tomography (CT). Combined em-
diastole)
physema and pulmonary fibrosis may pseudonormalize spirometry,
PA diameter >25 mm.
although the DLCO is almost always reduced, emphasizing the need
to interpret pulmonary function alongside lung imaging.
The prevalence of nocturnal hypoxaemia and central sleep ap- PA ¼ pulmonary artery.
a
Echocardiographic signs from at least two different categories (A/B/C) from the
noeas are high in PAH (70– 80%).41,42 Overnight oximetry or poly-
list should be present to alter the level of echocardiographic probability of
somnography should be performed where obstructive sleep apnoea pulmonary hypertension.
syndrome or hypoventilation are considered.
(EACVI), a registered branch of the ESC, and the reader is referred solely on Doppler transthoracic echocardiography measurements
to these for further instruction.43,44 is not suitable for screening for mild, asymptomatic PH. Other echo-
The estimation of systolic PAP is based on the peak tricuspid re- cardiographic variables that might raise or reinforce suspicion of PH
gurgitation velocity (TRV) taking into account right atrial pressure independent of TRV should always be sought.
(RAP) as described by the simplified Bernoulli equation. RAP can Conclusions derived from an echocardiographic examination
be estimated by echocardiography based on the diameter and re- should aim to assign a level of probability of PH. This ESC Guideline
spiratory variation in diameter of the inferior vena cava (IVC): an suggests grading the probability of PH based on TRV at rest and on
IVC diameter ,2.1 cm that collapses .50% with a sniff suggests the presence of additional pre-specified echocardiographic variables
a normal RA pressure of 3 mmHg (range 0 – 5 mmHg), whereas suggestive of PH (Table 8A). The probability of PH may then be
an IVC diameter .2.1 cm that collapses ,50% with a sniff judged as high, intermediate or low. When interpreted in a clinical
or ,20% on quiet inspiration suggests a high RA pressure of context, the echocardiographic result is required to decide the need
15 mmHg (range 10 – 20 mmHg). In scenarios in which the IVC for cardiac catheterization in individual patients. In order to facilitate
diameter and collapse do not fit this paradigm, an intermediate value and standardize assignment to the level of probability of PH, several
of 8 mmHg (range 5 –10 mmHg) may be used. The EACVI recom- additional echocardiographic signs are proposed in addition to cri-
mends such an approach rather than using a fixed value of 5 or 10 teria based on TRV (Table 8B). These signs provide assessment of
mmHg for PA systolic pressure (PASP) estimations. However, given the RV size and pressure overload, the pattern of blood flow vel-
the inaccuracies of RAP estimation and the amplification of meas- ocity out of the RV, the diameter of the PA and an estimate of

urement errors by using derived variables, we recommend using RAP.43 – 45 Their measurement has been defined in recommenda-
the continuous wave Doppler measurement of peak TRV (and tions endorsed by the EACVI.43,44
not the estimated PASP) as the main variable for assigning the echo- The recommended plan for further patient investigation based on
cardiographic probability of PH. echocardiographic probability of PH is shown in Table 9 for symp-
When peak TRV is technically difficult to measure (trivial or mild tomatic patients. In the Web addendum, a similar table (Web
tricuspid regurgitation) some laboratories use contrast echocardi- Table IX) for screening for asymptomatic patients with risk factors
ography [e.g. agitated saline administered by intravenous (i.v.) injec- for PAH or with incidental findings suggesting the possibility of PH
tion], which may improve the Doppler signal, allowing measurement on ECG or lung imaging is provided.
of peak TRV velocity. Unfortunately, despite the strong correlation Echocardiography can be helpful in detecting the cause of sus-
of TRV with a tricuspid regurgitation pressure gradient, Doppler- pected or confirmed PH. Two-dimensional, Doppler and contrast
derived pressure estimation may be inaccurate in the individual pa- examinations can be used to identify CHD. High pulmonary blood
tient. In patients with severe tricuspid regurgitation, TRV may be sig- flow found on pulsed wave Doppler in the absence of a detectable
nificantly underestimated and cannot be used to exclude PH. shunt or significant dilatation of proximal PA despite only moderate
Overestimation may also occur.44 PH cannot be reliably defined PH may warrant transoesophageal examination with contrast or
by a cut-off value of TRV. Consequently, estimation of PAP based cardiac magnetic resonance (CMR) imaging to exclude sinus
Table 9 Diagnostic management suggested according to echocardiographic probability of pulmonary hypertension in

patients with symptoms compatible with pulmonary hypertension, with or without risk factors for pulmonary arterial
hypertension or chronic thromboembolic pulmonary hypertension
Without risk factors or With risk factors or

Echocardiographic
associated condition for PAH Classa Level b associated conditions for Classa Level b Ref c
probability of PH
or CTEPH d PAH or CTEPHc
Alternative diagnosis should be Echo follow-up should be
Low IIa C IIa C
considered considered
Alternative diagnosis, echo follow-up,
IIa
should be considered Further assessment of PH including
Intermediate C IIa B 45, 46
Further investigation of PH may be RHC should be considerede
IIb
considerede
Further investigation of PH Further investigation of PHe
High I C I C
(including RHCe) is recommended including RHC is recommended
CTEPH ¼ chronic thromboembolic pulmonary hypertension; Echo ¼ echocardiographic; PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary hypertension; RHC ¼ right
heart catheterization.
a
Class of recommendation.
b
Level of evidence.
c
Reference(s) supporting recommendations.
d
These recommendations do not apply to patients with diffuse parenchymal lung disease or left heart disease.
e
Depending on the presence of risk factors for PH group 2, 3 or 5.
Further investigation strategy may differ depending on whether risk factors/associated conditions suggest higher probability of PAH or CTEPH – see diagnostic algorithm.
venosus atrial septal defect and/or anomalous pulmonary venous re- effusions.53 Pulmonary capillary haemangiomatosis is suggested by
turn. In cases of suspicion of LV diastolic dysfunction, Doppler echo- diffuse bilateral thickening of the interlobular septa and the presence
cardiographic signs should be assessed even if their reliability is of small, centrilobular, poorly circumscribed nodular opacities.
considered low. RHC should be considered when the diagnosis re- However, ground-glass abnormalities are also present in PAH, oc-
mains uncertain after non-invasive investigations (see section 8.1). curring in more than one-third of patients.50
The practical clinical value of exercise Doppler echocardiography Contrast CT angiography of the PA is helpful in determining
in the identification of cases with PH limited to exercise is whether there is evidence of surgically accessible CTEPH. It can de-
uncertain because of the lack of validated criteria and prospective lineate the typical angiographic findings in CTEPH, such as complete
confirmatory data. obstruction, bands and webs and intimal irregularities, as accurately
and reliably as digital subtraction angiography.54,55 With this tech-
5.1.6 Ventilation/perfusion lung scan nique, collaterals from bronchial arteries can be identified.
A ventilation/perfusion (V/Q) lung scan should be performed in pa- Traditional pulmonary angiography is required in most patients
tients with PH to look for CTEPH. The V/Q scan has been the for the workup of CTEPH to identify those who may benefit from
screening method of choice for CTEPH because of its higher sensi- pulmonary endarterectomy (PEA) or BPA.56,57 Angiography can be
tivity compared with CT pulmonary angiogram (CTPA), especially in performed safely by experienced staff in patients with severe PH
inexperienced centres.47 A normal- or low-probability V/Q scan ef- using modern contrast media and selective injections. Angiography
fectively excludes CTEPH with a sensitivity of 90 –100% and a spe- may also be useful in the evaluation of possible vasculitis or pulmon-

cificity of 94 – 100%; however, many V/Q scans are not diagnostic. ary arteriovenous malformations, but CT angiography has similar or
While in PAH the V/Q lung scan may be normal, it may also show even higher accuracy for both diagnoses, and is less invasive.58,59
small peripheral unmatched and non-segmental defects in perfusion.
A caveat is that unmatched perfusion defects may also be seen in 5.1.8 Cardiac magnetic resonance imaging
other pulmonary vascular disease such as PVOD. While a V/Q CMR imaging is accurate and reproducible in the assessment of RV
scan is still recommended as the screening test of choice, ventilation size, morphology and function and allows non-invasive assessment
scans are often replaced with either a recent chest radiograph or a of blood flow, including stroke volume, CO, pulmonary arterial dis-
recent high-resolution CT of the lungs, but such practices are not tensibility and RV mass.
really evidence-based. Also, CT is preferred in many centres since In patients with suspected PH, the presence of late gadolinium en-
it is more readily available. A few studies suggest that single photon hancement, reduced pulmonary arterial distensibility and retrograde
emission CT, also a nuclear medicine technique, could be superior flow have high predictive value for the identification of PH; however,
to V/Q planar scan and CTPA, but these results need more exten- no single CMR measurement can exclude PH.60 – 62 In patients with
sive evaluation.48 More recently, newer techniques such as three- PH, CMR may also be useful in cases of suspected CHD if echocar-
dimensional magnetic resonance (MR) perfusion mapping, have diography is not conclusive.
been demonstrated to be as sensitive as traditional perfusion scintig- Contrast-enhanced and unenhanced MR angiography have a po-
raphy in screening for CTEPH; MR can also be used as a radiation- tential in the study of the pulmonary vasculature in patients with sus-
free modality to assess both ventilation and perfusion in CTEPH.49 pected CTEPH, particularly in clinical scenarios such as suspected
chronic embolism in pregnant women, young patients or when
5.1.7 High-resolution computed tomography, iodine-based contrast media injection is contraindicated.63
contrast-enhanced computed tomography, and CMR provides useful prognostic information in patients with PAH
pulmonary angiography both at baseline and at follow-up.64 – 66
CT imaging is a widely available tool that can provide important in-
formation on vascular, cardiac, parenchymal and mediastinal abnor- 5.1.9 Blood tests and immunology
malities. It may suggest the diagnosis of PH (PA or RV enlargement), Blood tests are not useful in diagnosing PH, but are required to iden-
identify a cause of PH such as CTEPH or lung disease, provide clues tify the aetiology of some forms of PH as well as end organ damage.
as to the form of PAH (e.g. oesophageal dilation in SSc or congenital Routine biochemistry, haematology and thyroid function tests are
cardiac defects such as anomalous pulmonary venous drainage) and required in all patients, as well as a number of other specific blood
also provide prognostic information.50 tests. Liver function tests may be abnormal because of high hepatic
CT may raise a suspicion of PH in symptomatic patients or those venous pressure, liver disease and/or endothelin receptor antagon-
examined for unrelated indications by showing an increased PA ist (ERA) therapy. Hepatitis serology should be performed if clinical
diameter (≥29 mm) and pulmonary:ascending aorta diameter ratio abnormalities are noted. Thyroid disease is common in PAH and
(≥1.0). A segmental artery:bronchus ratio .1 : 1 in three or four may develop during the course of the disease. This should always
lobes has been reported to have high specificity for PH.51,52 be considered in cases of abrupt deterioration.
High-resolution CT provides detailed views of the lung paren- Serological testing is required to detect underlying CTD, hepatitis
chyma and facilitates the diagnosis of interstitial lung disease and em- and human immunodeficiency virus (HIV). Up to 40% of patients
physema. High-resolution CT may also be very helpful where there with IPAH have elevated antinuclear antibodies usually in a low titre
is a clinical suspicion of PVOD. Characteristic changes of interstitial (1:80). It is important to look for evidence of SSc since this disease
oedema with diffuse central ground-glass opacification and thicken- has a relatively high prevalence of PAH. Limited scleroderma typic-
ing of interlobular septa support the diagnosis of PVOD; additional ally has antinuclear antibodies, including anti-centromere, dsDNA,
findings may include lymphadenopathy, pleural shadows and anti-Ro, U3-RNP, B23, Th/To and U1-RNP. Diffuse scleroderma is
typically associated with a positive U3-RNP. Patients with systemic pulmonary arteries. The PAWP is a surrogate of LA pressure and
lupus erythematosus may have anticardiolipin antibodies. should be recorded as the mean of three measurements. Blood
Patients with CTEPH should undergo thrombophilia screening, sampling should also be considered with the balloon inflated in
including antiphospholipid antibodies, anticardiolipin antibodies the wedge position to confirm that a true PAWP measurement
and lupus anticoagulant. HIV testing is required in PAH. N-terminal has been taken, as this should have the same saturation as system-
pro-brain natriuretic peptide (NT-proBNP) may be elevated in pa- ic blood. All pressure measurements should be determined at the
tients with PH and is an independent risk predictor in these patients. end of normal expiration (breath holding is not required). Alter-
natively, assuming that negative inspiratory and positive expira-
5.1.10 Abdominal ultrasound scan tory intrathoracic pressures cancel each other out, averaging
Similar to blood tests, abdominal ultrasound may be useful for pulmonary vascular pressures over several respiratory cycles is
identification of some of the clinical entities associated with PAH. also acceptable, except in dynamic hyperinflation states.70 Ideally,
Abdominal ultrasound may confirm but not formally exclude portal high-fidelity tracings that can be printed on paper should be used
hypertension. The use of contrast agents and the addition of a rather than small moving traces on a cardiac monitor. Non-
colour Doppler examination may improve the accuracy of the invasive blood pressure should be recorded at the time of the
diagnosis.67 Portal hypertension can be reliably confirmed or procedure if left heart catheterization is not undertaken.
excluded by measurement of the gradient between free and † Blood samples for oximetry should be taken from the high super-
occluded (wedge) hepatic vein pressure at the time of RHC.68 ior vena cava, IVC and PA at a minimum. Systemic arterial blood

oxygen (O2) saturation should also be determined. A stepwise
assessment of O2 saturation should be performed in every pa-
5.1.11 Right heart catheterization and vasoreactivity
tient with a pulmonary arterial O2 saturation .75% and when-
RHC is required to confirm the diagnosis of PAH and CTEPH, to
ever a left-to-right shunt is suspected.
assess the severity of haemodynamic impairment and to undertake
† CO should be measured using thermodilution or the direct Fick
vasoreactivity testing of the pulmonary circulation in selected pa-
method. Thermodilution measured in triplicate is the preferred
tients (Table 10). When performed at expert centres, these proce-
method because it can provide reliable measurements even in pa-
dures have low morbidity (1.1%) and mortality (0.055%) rates.69
tients with low CO and/or severe tricuspid regurgitation.71 In pa-
The threshold to perform left heart catheterization in addition to
tients with intracardiac shunts, thermodilution may be inaccurate
RHC should be low in patients with clinical risk factors for coronary
because of early recirculation of the injectate. The direct Fick
artery disease or heart failure with preserved ejection fraction, as
method requires direct measurement of O2 uptake, a technique
well as in patients with echocardiographic signs of systolic and/or
that is not widely available. The indirect Fick method, which uses
diastolic LV dysfunction. Specific recommendations for catheteriza-
estimated values of O2 uptake, is acceptable but lacks reliability.
tion of patients with LHD or lung disease in addition to Table 10 are
† Pulmonary vasoreactivity testing for identification of patients suit-
described in Tables 31 and 33, respectively. Measurement of LV end-
able for high-dose calcium channel blocker (CCB) treatment is re-
diastolic pressure is also important to avoid misclassification of
commended only for patients with IPAH, HPAH or drug-induced
patients with an elevated PAWP when this is unexpected and may
PAH. It should be performed at the time of RHC. In all other forms
be inaccurate [absence of risk factors for heart failure with pre-
of PAH and PH the results can be misleading and responders are
served ejection fraction, normal left atrial (LA) size and absence
rare. Inhaled nitric oxide (NO) at 10–20 parts per million (ppm)
of echocardiographic markers of elevated LV filling pressures].
is the standard of care for vasoreactivity testing, but i.v. epoproste-
The interpretation of invasive haemodynamics should be made in
nol, i.v. adenosine or inhaled iloprost can be used as alternatives
the context of the clinical picture and imaging, in particular echocar-
(Web Table IV). A positive acute response is defined as a reduction
diography. Cardiac catheterization should be performed after the
of the mean PAP ≥10 mmHg to reach an absolute value of mean
completion of other investigations so that it can answer specific
PAP ≤40 mmHg with an increased or unchanged CO. Only about
questions that may arise from these investigations and avoid an un-
10% of patients with IPAH will meet these criteria. The use of
necessary procedure where an alternative diagnosis is revealed.
CCBs, O2, phosphodiesterase type 5 inhibitors or other vasodila-
RHC is a technically demanding procedure that requires meticu-
tors for acute vasoreactivity testing is discouraged.
lous attention to detail to obtain clinically useful information. To ob-
† Interpretation of the PAWP at a single point in time needs to be
tain high-quality results and to be of low risk to patients, the
performed in a clinical context. In many patients with LHD,
procedure should be limited to expert centres. Particular attention
PAWP may be reduced to ,15 mmHg with diuretics.72 – 74 For
should be paid to the following issues:
this reason, the effect of an acute volume challenge on left heart
† The external pressure transducer should be zeroed at the mid- filling pressures has been considered.75 Limited data suggest that
thoracic line in a supine patient, halfway between the anterior ster- a fluid bolus of 500 ml appears to be safe and may discriminate
num and the bed surface.70 This represents the level of the LA. patients with PAH from those with LV diastolic dysfunction.76,77
† Pressure measurements should be made in the PA, PA wedge Further evaluation of administering a fluid challenge is required
position, RV and RA. Where a balloon catheter is used, it should before this can be considered for routine clinical practice. Similar-
be inflated in the RA, from where the catheter should be ad- ly, exercise haemodynamics to identify patients with LV diastolic
vanced until it reaches the PAWP position. Repeated deflations dysfunction is likely to be useful,2,78,79 but lacks standardisation
and inflations of the balloon in the end pulmonary arteries should and requires further evaluation.17 Furthermore, PAWP may
be avoided because this has been associated with rupture of the underestimate LV end-diastolic pressure.80
† Derived variables calculated from the RHC measurements

should include transpulmonary pressure gradient (TPG) and Table 11 Recommendations for vasoreactivity
PVR. A PVR .3 WU is required for the diagnosis of PAH.1 testing
PVR is commonly used but has the disadvantage of being a com-
posite variable that is highly sensitive to changes in both flow and Recommendations Classa Levelb Ref.c
filling pressure and may not reflect changes in the pulmonary cir-
Vasoreactivity testing is indicated only in
culation at rest.81,82 The DPG between the mean PAWP and dia- expert centres
I C 69
stolic PAP is less affected by flow and filling pressures81 but may
Vasoreactivity testing is recommended in
not be of prognostic value.83 DPG may have a role in patients sus- patients with IPAH, HPAH and PAH
pected of having PH related to LHD, as discussed in section 8.4 associated with drugs use to detect I C 84,85
† Coronary angiography may be required in the presence of angina, patients who can be treated with high
risk factors for coronary artery disease and listing for PEA or lung doses of a CCB
transplantation. It may identify left main stem coronary artery com- A positive response to vasoreactivity
pression by an enlarged PA as well as coronary artery disease. testing is defined as a reduction of mean
PAP ≥10 mmHg to reach an absolute I C 85,86
Recommendations for right and left heart catheterization and vasor- value of mean PAP ≤40 mmHg with an
increased or unchanged cardiac output
eactivity testing are summarised in the Tables 10 and 11.
Nitric oxide is recommended for

I C 85,86
performing vasoreactivity testing
Table 10 Recommendations for right heart Intravenous epoprostenol is
catheterization in pulmonary hypertension recommended for performing I C 85,86
vasoreactivity testing as an alternative
Adenosine should be considered for
Recommendations Classa Levelb Ref.c performing vasoreactivity testing as an IIa C 87,88
RHC is recommended to confirm the alternative
diagnosis of pulmonary arterial Inhaled iloprost may be considered for
I C
hypertension (group 1) and to support performing vasoreactivity testing as an IIb C 89,90
treatment decisions alternative
In patients with PH, it is recommended The use of oral or intravenous CCBs in
to perform RHC in expert centres acute vasoreactivity testing is not III C
(see section 12) as it is technically I B 69 recommended
demanding and may be associated with
Vasoreactivity testing to detect patients
serious complications
who can be safely treated with high doses
RHC should be considered in pulmonary of a CCB is not recommended in patients
arterial hypertension (group 1) to assess IIa C III C
with PAH other than IPAH, HPAH and
the treatment effect of drugs (Table 16) PAH associated with drugs use and is not
RHC is recommended in patients with recommended in PH groups 2, 3, 4 and 5
congenital cardiac shunts to support I C
decisions on correction (Table 24) CCB ¼ calcium channel blocker; HPAH ¼ heritable pulmonary arterial
hypertension; IPAH ¼ idiopathic pulmonary arterial hypertension; PAP ¼
RHC is recommended in patients with
pulmonary arterial pressure; PAH ¼ pulmonary arterial hypertension.
PH due to left heart disease (group 2) or a
I C Class of recommendation.
lung disease (group 3) if organ b
Level of evidence.
transplantation is considered c
When measurement of PAWP is
unreliable, left heart catheterization IIa C
should be considered to measure LVEDP
RHC may be considered in patients with 5.1.12 Genetic testing
suspected PH and left heart disease or The availability of molecular genetic diagnosis has opened up a new field
IIb C
lung disease to assist in the differential for patient care, including genetic counselling for PAH (developed in
diagnosis and support treatment decisions
section 6.3.1.8).26 Genetic testing and counselling follows strict local reg-
RHC is indicated in patients with CTEPH ulations that set the conditions for prescribing and conducting reviews
(group 4) to confirm the diagnosis and I C
of the genetic characteristics of a patient. The ethical principles are to
support treatment decisions
inform patients properly to avoid harm, to allow patients to preserve
their autonomy (disclosure about the process, risks and benefits of
CTEPH ¼ chronic thromboembolic pulmonary hypertension; LVEDP ¼ left
ventricular end-diastolic pressure; PAWP ¼ pulmonary artery wedge pressure; the genetic test without external pressures) and to allow equal access
PH ¼ pulmonary hypertension; RHC ¼ right heart catheterization. to genetic counselling and testing. Patients with sporadic or familial PAH
a
Class of recommendation. or PVOD/PCH should be advised about the availability of genetic testing
b
Level of evidence.
c
Reference(s) supporting recommendations. and counselling because of the strong possibility that they carry a
disease-causing mutation. Trained professionals should offer counselling
and testing to the patient. Genetic counselling and BMPR2 mutation Patients with sporadic or familial PVOD/PCH should be tested
screening (point mutations and large rearrangements) should be offered for EIF2AK4 mutations.28 The presence of a bi-allelic EIF2AK4 muta-
by expert referral centres to patients with IPAH considered to be spor- tion is sufficient to confirm a diagnosis of PVOD/PCH without per-
adic or induced by anorexigens and to patients with a family history of forming a hazardous lung biopsy for histological confirmation.
PAH. When no BMPR2 mutations are identified in familial PAH patients
or in IPAH patients ,40 years old, or when PAH occurs in patients with 5.2 Diagnostic algorithm
a personal or familial history of hereditary haemorrhagic telangiectasia, The diagnostic algorithm is shown in Figure 1: the diagnostic process
screening of the ACVRL1 and ENG genes may be performed. If no muta- starts after the suspicion of PH and echocardiography compatible
tions in the BMPR2, ACVRL1 and ENG genes are identified, screening of with PH (according to the different levels of PH probability reported
rare mutations may be considered (KCNK3, CAV1, etc.). in Tables 8 and 9) and continues with the identification of the more
Symptoms, signs, history suggestive of PH
Echocardiographic probability of PH (Table 8)

High or intermediate Low
Consider left heart disease and lung diseases Consider other causes
by symptoms, signs, risk factors, ECG, and/or follow-up (Table 9)
PFT+DLCO, chest radiograph and HRCT,
arterial blood gases (Table 9)
Yes Diagnosis of left heart diseases or Yes

lung diseases confirmed?
No signs of severe Signs of severe PH/RV
PH/RV dysfunction No dysfunction
Treat underlying V/Q scana Refer to PH

disease Mismatched perfusion defects? expert centre
Yes Refer to PH No
expert centre
CTEPH possible: RHC (Table 10)
No
CT pulmonary angiography, mPAP 25 mmHg, PAWP
RHC +/- Pulmonary Angiography Yes 15 mmHg, PVR >3 Wood units
PAH likely Consider other

Specific diagnostic tests causes
CTD CHD
Group 5
Porto-
Drugs - Toxin ppulmonaryy
HIV Schistosomiasis
Heritable Idiopathic Idiopathic Heritable

PVOD/PCH PVOD/PCH PAH PAH
CHD = congenital heart diseases; CT = computed tomography; CTD = connective tissue disease; CTEPH = chronic thromboembolic pulmonary hypertension;
pressure; PA = pulmonary angiography; PAH = pulmonary arterial hypertension; PAWP = pulmonary artery wedge pressure; PFT = pulmonary function tests;
PH = pulmonary hypertension; PVOD/PCH = pulmonary veno-occlusive disease or pulmonary capillary hemangiomathosis; PVR = pulmonary vascular resistance;
RHC = right heart catheterisation; RV = right ventricular; V/Q = ventilation/perfusion.
a
CT pulmonary angiography alone may miss diagnosis of chronic thromboembolic pulmonary hypertension.
Figure 1 Diagnostic algorithm.

common clinical groups of PH [group 2 (LHD) and group 3 (lung

diseases)], then distinguishes group 4 (CTEPH) and finally makes Table 12 Recommendations for diagnostic strategy
the diagnosis and recognizes the different types in group 1 (PAH)
and the rarer conditions in group 5. Recommendations Classa Levelb Ref.c
PAH should be considered in the differential diagnosis of exer-
Echocardiography is recommended as a
tional dyspnoea, syncope, angina and/or progressive limitation of first-line non-invasive diagnostic I C
exercise capacity, particularly in patients without apparent investigation in case of suspicion of PH
risk factors, symptoms or signs of common cardiovascular and Ventilation/perfusion or perfusion lung
respiratory disorders. Special awareness should be directed scan is recommended in patients with I C 47
towards patients with associated conditions and/or risk factors unexplained PH to exclude CTEPH
for the development of PAH, such as family history, CTD, Contrast CT angiography of the PA is
CHD, HIV infection, portal hypertension or a history of drug recommended in the workup of patients I C 93
or toxin intake known to induce PAH (Table 7). In everyday clin- with CTEPH
ical practice such awareness may be low. More often PH is found Routine biochemistry, haematology,
unexpectedly on transthoracic echocardiography requested for immunology, HIV testing and thyroid
another indication. function tests are recommended in all I C
patients with PAH to identify the specific
If transthoracic echocardiography is compatible with a high or
associated condition

intermediate probability of PH (Table 9), a clinical history, symp-
Abdominal ultrasound is recommended
toms, signs, ECG, chest radiograph, pulmonary function tests I C 67
for the screening of portal hypertension
(PFTs, including DLCO, arterial blood gases analysis and nocturnal
oximetry, if required) and high-resolution CT of the chest are re- Lung function test with DLCO is
recommended in the initial evaluation of I C 36
quested to identify the presence of group 2 (LHD) or group 3 patients with PH
(lung diseases) PH. In case of an echocardiographic low probability
High-resolution CT should be
of PH (Table 9), no additional investigations are required and other IIa C 94
considered in all patients with PH
causes for the symptoms should be considered together with
Pulmonary angiography should be
follow-up. If the diagnosis of left heart or lung diseases is con-
considered in the workup of patients with IIa C
firmed, the appropriate treatment for these conditions should CTEPH
be considered. In the presence of severe PH and/or RV dysfunc-
Open or thoracoscopic lung biopsy is not
tion, the patient should be referred to a PH expert centre where III C
recommended in patients with PAH
additional causes of PH can be explored. If the diagnosis of left
heart or lung diseases is not confirmed, a V/Q lung scan should
CT ¼ computed tomography; CTEPH ¼ chronic thromboembolic pulmonary
be performed for the differential diagnosis between CTEPH and hypertension; DLCO ¼ diffusing capacity of the lung for carbon monoxide;
PAH. Concurrently the patient should be referred to a PH expert PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary hypertension.
a
centre. b
Level of evidence.
If the V/Q scan shows multiple segmental perfusion defects, a c
diagnosis of group 4 (CTEPH) PH should be suspected.91 The final
diagnosis of CTEPH (and the assessment of suitability for PEA) will
require CT pulmonary angiography, RHC and selective pulmonary
angiography. The CT scan may also show signs suggestive of group 6. Pulmonary arterial
1′ (PVOD). If a V/Q scan is normal or shows only subsegmental hypertension (group 1)
‘patchy’ perfusion defects, a diagnosis of group 1 (PAH) or the
rarer conditions of group 5 should be considered. In Table 9, 6.1 Clinical characteristics
further management according to the probability of PH is given, The clinical characteristics of PAH are not specific and can be de-
including indications for RHC. Additional specific diagnostic tests, rived from the general description reported in section 5.1.1. More
including haematology, biochemistry, immunology, serology, ultra- detailed descriptions of the individual PAH subsets are reported
sonography and genetics, will allow the final diagnosis to be in the section 7.
refined.
Open or thoracoscopic lung biopsy entails a substantial risk of
morbidity and mortality.92 Because of the low likelihood of altering 6.2 Evaluation of severity
the diagnosis and treatment, biopsy is not recommended in PAH 6.2.1 Clinical parameters, imaging and haemodynamics
patients. Clinical assessment remains a key part of the evaluation of patients
The recommendations for a diagnostic strategy are reported in with PH, as it provides valuable information for determining disease
the Table 12. severity, improvement, deterioration or stability. Elementary parts
The pulmonary arterial hypertension screening programme is of history taking between follow-up visits include changes in exer-
reported in the Web Addenda. cise capacity, episodes of chest pain, arrhythmia, haemoptysis or
syncope and changes in medications, as well as adherence to the follow-up strategy. There is no evidence that an approach involving
prescribed drugs. Physical examination provides information on regular RHC is associated with better outcomes than a predomin-
the presence or absence of peripheral or central cyanosis, enlarged antly non-invasive follow-up strategy. However, there is consensus
jugular veins, oedema, ascites and pleural effusions and on heart among experts that RHC should be performed whenever thera-
rate, rhythm and blood pressure. peutic decisions can be expected from the results, which may in-
The World Health Organization functional class (WHO-FC) clude changes in medications and/or decisions regarding listing for
(Web Table V), despite its interobserver variability,95 remains one transplantation.
of the most powerful predictors of survival, not only at diagnosis,
but also during follow-up.96 – 98 A worsening FC is one of the most 6.2.2 Exercise capacity
alarming indicators of disease progression, which should trigger further The 6-minute walking test (6MWT), a submaximal exercise test, re-
diagnostic studies to identify the causes of clinical deterioration.97,99 mains the most widely used exercise test in PH centres. The test is
As RV function is a key determinant of exercise capacity and out- easy to perform, inexpensive and familiar to patients and centres. As
come in patients with PH, echocardiography remains an important with all PH assessments, 6MWT results must always be interpreted
follow-up tool. In contrast to common belief, the estimated systolic in the clinical context. The 6-minute walking distance (6MWD) is in-
PAP (PAPs) at rest is usually not prognostic and not relevant for fluenced by several factors, including sex, age, height, weight, co-
therapeutic decision making.96,97,100 An increase in PAPs does not morbidities, need for O2, learning curve and motivation. Neverthe-
necessarily reflect disease progression and a decrease in PAPs less, test results are usually given in absolute numbers rather than

does not necessarily signal improvement. A comprehensive echo- percent predicted. Absolute values, but not changes in 6MWD, pro-
cardiographic assessment includes a description of chamber sizes, vide prognostic information, but there is no single threshold that is
particularly of the RA and RV area, the magnitude of tricuspid regur- applicable for all patients (see below).96,99,116 – 118 It is recom-
gitation, the LV eccentricity index and RV contractility, which can be mended to use the Borg score at the end of the 6MWT to deter-
determined by several variables, including RV longitudinal systolic mine the level of effort. In addition, some studies suggest that
strain/strain rate and RV fractional area change, Tei index and tricus- adding peripheral O2 measurements and heart rate response may
pid annular plane systolic excursion (TAPSE).101 – 108 improve the prognostic relevance, but these findings await inde-
Three-dimensional echocardiography may achieve a better esti- pendent confirmation.119,120
mation than standard two-dimensional assessment, but underesti- Cardiopulmonary exercise testing (CPET) is usually performed as
mations of volumes and ejection fractions have been reported.109 a maximal exercise test and provides important information on ex-
Speckle tracking improves the quantification of RV function.110 ercise capacity as well as on gas exchange, ventilator efficacy and
Given the complex geometry of the RV, none of these variables cardiac function during exercise. Most PH centres use an incremen-
alone is sufficient to describe RV function, and the overall impres- tal ramp protocol, although the test has not yet been standardized
sion of an experienced physician is often more important than single for this patient population. Patients with PAH show a typical pattern
variables. Echocardiography during exercise provides additional in- with a low end-tidal partial pressure of carbon dioxide (pCO2), high
formation on RV function. Of note, a marked increase (.30 mmHg) ventilator equivalents for carbon dioxide (VE/VCO2), low oxygen
of PAPs during exercise reflects better RV function and is associated pulse (VO2/HR) and low peak oxygen uptake (peak VO2).121 Sev-
with a better long-term outcome than a modest or no increase.111 eral variables determined by CPET provide prognostic information,
This so-called contractile reserve has recently been shown to be an although peak VO2 is most widely used for therapeutic decision
independent prognostic marker in patients with severe PH.111 making.106,122 – 125 The diagnostic and prognostic information pro-
CMR imaging is more accurate for the assessment of RV morph- vided by CPET add to that provided by the 6MWT.122
ology and function than echocardiography and also allows measure-
ment of stroke volume and CO. A number of CMR prognostic 6.2.3 Biochemical markers
markers have been identified, including increased RV volume, re- There is still no specific marker for PAH or pulmonary vascular remod-
duced LV volume, reduced RV ejection fraction and reduced stroke elling, although a wide variety of biomarkers have been explored in the
volume. There is some evidence that follow-up CMR studies may field. These can be grouped into markers of vascular dysfunction
have utility in the long-term management of PAH by identifying [asymmetric dimethylarginine (ADMA), endothelin-1, angiopoeitins,
RV failure prior to the development of clinical features.64,66,112,113 von Willebrand factor],126 – 131 markers of inflammation (C-reactive
Haemodynamics assessed by RHC provide important prognostic protein, interleukin 6, chemokines),132 – 135 markers of myocardial
information, both at the time of diagnosis and during follow-up. RA stress (atrial natriuretic peptide, brain natriuretic peptide (BNP)/
pressure, cardiac index (CI) and mixed venous oxygen saturation NT-proBNP, troponins),97,118,136 – 139 markers of low CO and/or tissue
(SvO2) are the most robust indicators of RV function and prognosis, hypoxia [pCO2, uric acid, growth differentiation factor 15 (GDF15),
whereas PAPm provides little prognostic information (except for osteopontin]38,140 – 142 and markers of secondary organ damage (cre-
CCB responders).96,97,99,100,114 Non-invasive assessment of CO atinine, bilirubin).97,137 This list is constantly growing, but so far BNP
by rebreathing techniques71 or bioreactance115 has not yet been and NT-proBNP remain the only biomarkers that are widely used in
sufficiently validated to allow routine clinical use and therapeutic de- the routine practice of PH centres as well as in clinical trials. BNP/
cision making. NT-proBNP levels correlate with myocardial dysfunction and provide
There are still uncertainties around the optimal timing of follow- prognostic information at the time of diagnosis and during follow-up
up RHC. Strategies vary between centres, from regular invasive assessments.143 They are not specific for PH, but can be elevated in al-
haemodynamic assessments to a predominantly non-invasive most any heart disease. BNP/NT-proBNP levels tend to have a high
variability and should be interpreted in the clinical context. There are The indicated mortality rates are crude estimates and the depicted
no clear advantages of using BNP versus NT-proBNP. BNP appears to variables have been studied mostly in patients with IPAH. Not all
have a slightly tighter correlation with pulmonary haemodynamics and variables may be in the same risk group, and it is the comprehensive
is less affected by kidney function, whereas NT-proBNP seems to be a assessment of individual patients that should guide treatment
stronger predictor of prognosis.137 decisions. The individual risk is further modified by other factors,
such as the rate of disease progression and the presence or absence
6.2.4 Comprehensive prognostic evaluation and risk of signs of right heart failure, or syncope, and also by co-morbidities,
assessment age, sex, background therapy, and PAH subtype, among others.
Regular assessment of patients with PAH in expert PH centres is Finally, the assessment of PAH patients should provide information
strongly recommended. A comprehensive assessment is required on co-morbidities and disease complications. ECGs should be ob-
since there is no single variable that provides sufficient diagnostic tained on a regular basis to detect clinically relevant arrhythmias,
and prognostic information. The most important questions to be ad- which occur frequently in this patient population.33 Patients with
dressed at each visit are (i) is there any evidence of clinical deterior- PAH occasionally present with progressive hypoxaemia and may be
ation since the last assessment?; (ii) if so, is clinical deterioration candidates for long-term O2 therapy. In addition, a low PaCO2 is asso-
caused by progression of PH or by a concomitant illness?; (iii) is ciated with reduced pulmonary blood flow and has prognostic impli-
RV function stable and sufficient?; and (iv) is the current status com- cations.38 Thus arterial or capillary blood gases provide important
patible with a good long-term prognosis, i.e. does the patient meet information and should be part of the regular clinical assessment, at

the low-risk criteria (see below)? least in cases of clinical deterioration. Alternatively the peripheral
In order to answer these questions, a multidimensional approach O2 saturation may be used, but it is less reliable and does not provide
is needed. Table 13 lists the variables that are most frequently used information on PaCO2. The recommended basic laboratory workup
in PH centres. Not all of them need to be assessed at each visit. (in addition to BNP/NT-proBNP) includes blood counts and inter-
However, the basic programme should include determination of national normalized ratio (INR) (in patients receiving vitamin K antago-
the FC and at least one measurement of exercise capacity, e.g. nists), as well as serum sodium, potassium, creatinine, uric acid,
6MWD or CPET. It is also recommended to obtain some informa- aspartate aminotransferase (ASAT), alanine aminotransferase
tion on RV function, either by measuring BNP/NT-proBNP or by (ALAT) (in patients receiving ERAs) and bilirubin. In addition, troponin,
performing echocardiography. Most of the proposed variables and uric acid, iron status and thyroid function should be checked at least
cut-off values are based on expert opinion. They may provide prog- once a year or whenever the patient presents with clinical worsening.
nostic information and may be used to guide therapeutic decisions, Tables 14 and 15 provide detailed recommendations on the follow-up
but application to individual patients must be done carefully. assessment of patients with PAH.
Table 13 Risk assessment in pulmonary arterial hypertension
Determinants of prognosis a
Low risk <5% Intermediate risk 5–10% High risk >10%
(estimated 1-year mortality)
Clinical signs of right heart failure Absent Absent Present
Progression of symptoms No Slow Rapid
Syncope No Occasional syncopeb Repeated syncopec
WHO functional class I, II III IV
6MWD >440 m 165–440 m <165 m
Peak VO2 >15 ml/min/kg Peak VO2 Peak VO2 <11 ml/min/kg
Cardiopulmonary exercise testing (>65% pred.) 11–15 ml/min/kg (35–65% pred.) (<35% pred.)
VE/VCO2 slope <36 VE/VCO2 slope 36–44.9 VE/VCO2 slope ≥45
BNP <50 ng/l BNP 50–300 ng/l BNP >300 ng/l
NT-proBNP plasma levels
NT-proBNP <300 ng/l NT-proBNP 300–1400 ng/l NT-proBNP >1400 ng/l
RA area 18–26 cm2
RA area <18 cm2 RA area >26 cm2
Imaging (echocardiography, CMR imaging) No or minimal, pericardial
No pericardial effusion Pericardial effusion
effusion
RAP <8 mmHg RAP 8–14 mmHg RAP >14 mmHg

Haemodynamics CI ≥2.5 l/min/m2 CI 2.0–2.4 l/min/m2 CI <2.0 l/min/m2
SvO2 >65% SvO2 60–65% SvO2 <60%
6MWD ¼ 6-minute walking distance; BNP ¼ brain natriuretic peptide; CI ¼ cardiac index; CMR ¼ cardiac magnetic resonance; NT-proBNP ¼ N-terminal pro-brain natriuretic
peptide; pred. ¼ predicted; RA ¼ right atrium; RAP ¼ right atrial pressure; SvO2 ¼ mixed venous oxygen saturation; VE/VCO2 ¼ ventilatory equivalents for carbon dioxide;
VO2 ¼ oxygen consumption; WHO ¼ World Health Organization.
a
Most of the proposed variables and cut-off values are based on expert opinion. They may provide prognostic information and may be used to guide therapeutic decisions, but
application to individual patients must be done carefully. One must also note that most of these variables have been validated mostly for IPAH and the cut-off levels used above may
not necessarily apply to other forms of PAH. Furthermore, the use of approved therapies and their influence on the variables should be considered in the evaluation of the risk.
b
Occasional syncope during brisk or heavy exercise, or occasional orthostatic syncope in an otherwise stable patient.
c
Repeated episodes of syncope, even with little or regular physical activity.
Table 14 Suggested assessment and timing for the follow-up of patients with pulmonary arterial hypertension
At baseline Every 3–6 Every 6–12 3–6 months after In case of clinical
monthsa monthsa changes in therapy a worsening
Medical assessment and

+ + + + +
determination of functional class
ECG + + + + +
6MWT/Borg dyspnoea score + + + + +
CPET + + +e
Echo + + + +
Basic labb + + + + +
Extended labc + + +
Blood gas analysisd + + + +
Right heart catheterization + +f +e +e

ALAT ¼ alanine aminotransferase; ASAT ¼ aspartate aminotransferase; BGA ¼ blood gas analysis; BNP ¼ brain natriuretic peptide; CPET ¼ cardiopulmonary exercise testing;
Echo ¼ echocardiography; ECG ¼ electrocardiogram; ERAs ¼ endothelin receptor antagonists; FC ¼ functional class; INR ¼ international normalized ratio; lab ¼ laboratory
assessment; NT-proBNP ¼ N-terminal pro-brain natriuretic peptide; RHC ¼ right heart catheterization; TSH ¼ thyroid stimulating hormone; 6MWT ¼ 6-minute walking test.
a
Intervals to be adjusted according to patient needs.
b
Basic lab includes blood count, INR (in patients receiving vitamin K antagonists), serum creatinine, sodium, potassium, ASAT/ALAT (in patients receiving ERAs), bilirubin and BNP/
NT-proBNP.
c
Extended lab includes TSH, troponin, uric acid, iron status (iron, ferritin, soluble transferrin receptor) and other variables according to individual patient needs.
d
From arterial or arterialized capillary blood; may be replaced by peripheral oxygen saturation in stable patients or if BGA is not available.
e
Should be considered.
f
Some centres perform RHCs at regular intervals during follow-up.
6.2.5 Definition of patient status

Table 15 Recommendations for evaluation of the
Based on the comprehensive assessment described in the last sec-
severity of pulmonary arterial hypertension and
tion, the patient can be classified as low risk, intermediate risk or
clinical response to therapy
high risk for clinical worsening or death (Table 13). Of course, there
are several other factors that have an impact on disease manifest-
Recommendations Classa Levelb Ref.c ation and prognosis that cannot be affected by PAH therapy, includ-
It is recommended to evaluate the ing age, sex, underlying disease and co-morbidities. Although
severity of PAH patients with a panel of reliable individual predictions are always difficult, patients categor-
data derived from clinical assessment, 96,97, ized as low risk have an estimated 1-year mortality ,5%. Basically
I C
exercise tests, biochemical markers and 99 these patients present with non-progressive disease in WHO-FC I
echocardiographic and haemodynamic
or II with a 6MWD .440 m and no signs of clinically relevant RV
evaluations (Tables 13 and 14)
dysfunction. The estimated 1-year mortality in the intermediate-risk
It is recommended to perform regular
group is 5 – 10%. These patients typically present in WHO-FC III,
follow-up assessments every 3 –6 I C 98
months in stable patients (Table 14) with moderately impaired exercise capacity and signs of RV dysfunc-
tion, but not with RV failure. Patients in the high-risk group have an
Achievement/maintenance of a low-risk
profile (Table 13) is recommended as an estimated 1-year mortality .10%. These patients present in
I C 96–99 WHO-FC III or IV with progressive disease and signs of severe RV
adequate treatment response for
patients with PAH dysfunction, or with RV failure and secondary organ dysfunction.
Achievement/maintenance of an The variables shown in Table 13 may not behave consistently,
intermediate-risk profile (Table 13) i.e. they may fall into different risk categories. Again, it is the overall
should be considered an inadequate IIa C 96–99 assessment that should drive therapeutic decisions.
treatment response for most patients
with PAH
6.2.6 Treatment goals and follow-up strategy
PAH ¼ pulmonary arterial hypertension. The overall treatment goal in patients with PAH is achieving a low-
a
Class of recommendation. risk status (Table 13), which is usually associated with good exer-
b
Level of evidence.
c
Reference(s) supporting recommendations. cise capacity, good quality of life, good RV function and a low mor-
tality risk. Specifically, this means bringing and/or keeping the
patient in WHO-FC II whenever possible. In most patients, this

will be accompanied by a near-normal or normal 6MWD. Several Table 16 Recommendations for general measures
treatment goals for the 6MWD have been proposed including
.380 m, .440 m and .500 m.96,99,116 – 118,144 All of these num- Recommendations Classa Levelb Ref.c
bers are based on survival analyses from selected cohorts or on
It is recommended that PAH patients 160,
expert opinion. The present guidelines adopt a threshold of I C
avoid pregnancy 161
.440 m as suggested during the 5th World Symposium on Pul-
Immunization of PAH patients against
monary Hypertension,145 because this number was derived from influenza and pneumococcal infection is I C
the largest cohort investigated so far.99 Nevertheless, individual recommended
factors must be considered and lower values may be acceptable
Psychosocial support is recommended in
in elderly patients or patients with co-morbidities, whereas even I C 168
PAH patients
values .440 m may not be sufficient in younger, otherwise
Supervised exercise training should be
healthy patients. Especially in those patients, CPET should be regu- 153–
considered in physically deconditioned IIa B
larly used, as it provides more objective information on exercise 157
PAH patients under medical therapy
capacity and RV performance. In-flight O2 administration should
It should be noted that these treatment goals are not always real- be considered for patients in WHO-FC III
IIa C
istic and may not be achievable in patients with advanced disease, and IV and those with arterial blood O2

patients with severe co-morbidities or very old patients. pressure consistently ,8 kPa (60 mmHg)
In elective surgery, epidural rather than
general anaesthesia should be preferred IIa C
whenever possible
6.3 Therapy Excessive physical activity that leads to
The therapy for PAH patients has evolved progressively in the past distressing symptoms is not III C
decade, increasing in complexity and in evidence for efficacy.146 – 148 recommended in PAH patients
The treatment process of PAH patients cannot be considered as a
mere prescription of drugs, but is characterised by a complex strat- O2 ¼ oxygen; PAH ¼ pulmonary arterial hypertension; WHO-FC ¼ World
Health Organization functional class.
egy that includes the initial evaluation of severity and the subsequent a
response to treatment. b
Level of evidence.
c
The current treatment strategy for PAH patients can be divided Reference(s) supporting recommendations.
into three main steps:149
(1) The initial approach includes general measures (physical activity
and supervised rehabilitation, pregnancy, birth control and
post-menopausal hormonal therapy, elective surgery, infection 6.3.1.1 Physical activity and supervised rehabilitation
prevention, psychosocial support, adherence to treatments, The 2009 PH guidelines suggested that PAH patients should be en-
genetic counselling and travel), supportive therapy (oral antic- couraged to be active within symptom limits.151 It was recom-
oagulants, diuretics, O2, digoxin), referral to expert centres mended that patients should avoid excessive physical activity that
and acute vasoreactivity testing for the indication of chronic leads to distressing symptoms, but when physically deconditioned,
CCB therapy. patients may undertake supervised exercise rehabilitation. This
(2) The second step includes initial therapy with high-dose CCB was based on a randomized controlled trial (RCT) that demon-
in vasoreactive patients or drugs approved for PAH in strated an improvement in exercise and functional capacity and in
non-vasoreactive patients according to the prognostic risk quality of life in patients with PH who took part in a training pro-
(Table 13) of the patient and the grade of recommendation gramme as compared with an untrained control group.152 Since
and level of evidence for each individual compound or com- then, additional uncontrolled experiences have supported these
bination of compounds. data utilising different models of exercise training.153 – 157 Two add-
(3) The third part is related to the response to the initial treatment itional RCTs have been published reporting that trained PAH pa-
strategy; in the case of an inadequate response, the role of com- tients reached higher levels of physical activity, had decreased
binations of approved drugs and lung transplantation are fatigue severity and showed improved 6MWD, cardiorespiratory
proposed. function and patient-reported quality of life as compared with un-
trained controls.158,159 The sample sizes of all these studies are quite
6.3.1 General measures small (ranging from 19 to 183 patients) and all or the initial training
Patients with PAH require sensible advice about general activities of was highly supervised and in some instances conducted in an in-
daily living and need to adapt to the uncertainty associated with a patient setting.
serious chronic life-threatening disease. The diagnosis usually con- This recommendation is limited by gaps in the knowledge about
fers a degree of social isolation.150 Encouraging patients and their the optimal method of exercise rehabilitation and the intensity and
family members to join patient support groups can have positive ef- duration of the training. In addition, the characteristics of the super-
fects on coping, confidence and outlook. The recommendations for vision and the mechanisms for the improvement of symptoms, ex-
general measures are reported in the Table 16. ercise and functional capacity are unclear, as are the possible effects
on prognosis. Exercise training programmes should be implemented 6.3.1.5 Psychosocial support

by centres experienced in both PAH patient care and rehabilitation PH is a disease with a significant impact on the psychological, social
of compromised patients. In addition, patients should be treated (including financial), emotional and spiritual functioning of patients
with the best standard of pharmacological treatment and in stable and their families.168 Teams managing these patients should have
clinical condition before embarking on a supervised rehabilitation the skills and expertise to assess and manage issues in all of these
programme. domains, with close links to colleagues in relevant disciplines for
those with severe problems, e.g. psychiatry, clinical psychology, wel-
6.3.1.2 Pregnancy, birth control and post-menopausal hormonal therapy fare and social work. Patient support groups may also play an im-
Pregnancy remains associated with a substantial mortality rate in portant role and patients should be advised to join such groups.
PAH. However, a recent report indicates that the outcome of preg- PH is a disease that may be severely life-limiting. In addition to
nancies in PAH has improved, at least when PAH is well controlled, psychological and social support there should be proactive ad-
and particularly in long-term responders to CCBs.160 During a vanced care planning with referral to specialist palliative care ser-
3-year period, the 13 participating centres reported 26 pregnancies. vices when appropriate.
Three women (12%) died and one (4%) developed right heart failure 6.3.1.6 Adherence to treatments
requiring urgent heart– lung transplantation. There were eight abor- Adherence to medical treatments needs to be checked periodically
tions; two spontaneous and six induced. Sixteen pregnancies (62%) due to the complexity of the PAH therapy and possible reductions
were successful, i.e. the women delivered healthy babies without or changes to the treatment regimen induced spontaneously by pa-

complications. A study from the USA from five centres between tients or non-expert physicians.
1999 and 2009 managed 18 pregnancies with three deaths
(17%).161 These data must be confirmed by larger series before 6.3.1.7 Travel
the general recommendation to avoid pregnancy in all patients There are no studies using flight simulation to determine the need
with PAH is reconsidered. There is less consensus relating to the for supplemental O2 during prolonged flights in patients with PAH.
most appropriate methods of birth control. Barrier contraceptive The known physiological effects of hypoxia suggest that in-flight O2
methods are safe for the patient, but with an unpredictable effect. administration should be considered for patients in WHO-FC III and
Progesterone-only preparations such as medroxyprogesterone IV and those with arterial blood O2 pressure consistently ,8 kPa
acetate and etonogestrel are effective approaches to contraception (60 mmHg).169 A flow rate of 2 l/min will raise inspired O2 pressure
and avoid the potential issues of oestrogens such as those associated to values seen at sea level. Similarly, such patients should avoid going
with the old-generation mini-pill.162 It should be remembered that to altitudes .1500 – 2000 m without supplemental O2. Patients
the ERA bosentan may reduce the efficacy of oral contraceptive should be advised to travel with written information about their
agents. The levonorgestrel-releasing intrauterine coil is also effect- PAH and be advised on how to contact local PH clinics in close
ive but may rarely lead to a vasovagal reaction when inserted, which proximity to where they are travelling.
may be poorly tolerated in severe PAH.162 A combination of two
6.3.1.8 Genetic counselling
methods may also be utilised. The patient who becomes pregnant
Genetic counselling should be offered to selected PAH patients
should be informed of the high risk of pregnancy and termination
(detailed in section 5.1.12).26 Because of the psychological impact
of the pregnancy should be discussed. Those patients who choose
of the positive or negative results, genetic testing and counselling
to continue pregnancy should be treated with disease-targeted
should be provided according to local regulations in the setting of
therapies, planned elective delivery and effective close collaboration
a multidisciplinary team with availability of PH specialists, genetic
between obstetricians and the PAH team.163,164
counsellors, geneticists, psychologists and nurses. Affected indivi-
It is unclear whether the use of hormonal therapy in post-
duals and at-risk family members may want to know their mutation
menopausal women with PAH is advisable. It may be considered
status for family planning purposes. Current reproductive options
in cases of intolerable menopausal symptoms in conjunction with
for couples with a BMPR2 mutation carrier are to remain childless,
oral anticoagulation.
to have no genetic prenatal testing (reproductive chance), to under-
go prenatal or pre-implantation genetic diagnosis,170 to use gamete
6.3.1.3 Elective surgery donation or to adopt.
Elective surgery is expected to have an increased risk in patients
with PAH. It is unclear as to which form of anaesthesia is preferable, 6.3.2 Supportive therapy
but epidural is probably better tolerated than general anaesthe- The recommendations for supportive therapy are reported in
sia.165 – 167 Patients usually maintained on oral therapy may require Table 17.
temporary conversion to i.v. or nebulized treatment until they are 6.3.2.1 Oral anticoagulants
able to both swallow and absorb drugs taken orally. There is a high prevalence of vascular thrombotic lesions at post-
mortem examination in patients with IPAH.171 Abnormalities in co-
6.3.1.4 Infection prevention agulation and fibrinolytic pathways have also been reported.172 – 174
Patients with PAH are susceptible to developing pneumonia, which This, together with the non-specific increased risk factors for ven-
is the cause of death in 7% of cases.34 While there are no controlled ous thromboembolism, including heart failure and immobility, re-
trials, it is recommended to vaccinate against influenza and pneumo- presents the rationale for oral anticoagulation in PAH. Evidence in
coccal pneumonia. favour of oral anticoagulation is confined to patients with IPAH,
6.3.2.3 Oxygen
Table 17 Recommendations for supportive therapy Although O2 administration has been demonstrated to reduce the
PVR in patients with PAH, there are no randomised data to suggest
Recommendations Classa Levelb Ref.c that long-term O2 therapy is beneficial. Most patients with PAH, ex-
cept those with CHD and pulmonary-to-systemic shunts, have min-
Diuretic treatment is
recommended in PAH patients with or degrees of arterial hypoxaemia at rest unless they have a patent
I C 178 foramen ovale. There are data showing that nocturnal O2 therapy
signs of RV failure and fluid
retention does not modify the natural history of advanced Eisenmenger syn-
Continuous long-term O2 therapy is drome.179 Guidance may be based on evidence in patients with
recommended in PAH patients COPD; when arterial blood O2 pressure is consistently ,8 kPa
I C 179
when arterial blood O2 pressure is (60 mmHg; alternatively, ,91% of arterial O2 saturation) patients
consistently ,8 kPa (60 mmHg)d are advised to take O2 to achieve an arterial blood O2 pressure
Oral anticoagulant treatment may
84,171, .8 kPa.169 Ambulatory O2 may be considered when there is evi-
be considered in patients with dence of symptomatic benefit and correctable desaturation on
IIb C 175–
IPAH, HPAH and PAH due to use of
177 exercise.
anorexigens
Correction of anaemia and/or iron
6.3.2.4 Digoxin and other cardiovascular drugs
status may be considered in PAH IIb C 184

patients Digoxin has been shown to improve CO acutely in IPAH, although
its efficacy is unknown when administered chronically.180 It may be
The use of angiotensin-converting
enzyme inhibitors, angiotensin-2 given to slow ventricular rate in patients with PAH who develop at-
receptor antagonists, beta-blockers rial tachyarrhythmias.
and ivabradine is not recommended No convincing data are available on the usefulness and safety of
III C
in patients with PAH unless angiotensin-converting enzyme inhibitors, angiotensin II receptor
required by co-morbidities (i.e. high
antagonists, beta-blockers or ivabradine in patients with PAH.
blood pressure, coronary artery
disease or left heart failure)
6.3.2.5 Anaemia and iron status
HPAH ¼ heritable pulmonary arterial hypertension; IPAH ¼ idiopathic
Iron deficiency is common in patients with PAH and has been re-
pulmonary arterial hypertension; O2 ¼ oxygen; PAH ¼ pulmonary arterial ported in 43% of patients with IPAH, 46% of patients with SSc-PAH
hypertension; RV ¼ right ventricular.
a
and 56% of patients with Eisenmenger syndrome.181 – 183 In all of
b
Level of evidence.
these entities, preliminary data indicate that iron deficiency may
c
Reference(s) supporting recommendations. be associated with reduced exercise capacity, and perhaps also
d
See also recommendations for PAH associated with congenital cardiac shunts. with a higher mortality, independent of the presence or severity
of anaemia.181,182,184,185 Based on these data, regular monitoring
of the iron status should be considered in patients with PAH and de-
HPAH and PAH due to anorexigens and is generally retrospective tection of an iron deficiency should trigger a search for potential
and based on single-centre experience. 84,171 Registry and RCT reasons. Iron substitution should be considered in patients with
data appear to be heterogeneous and inconclusive.175 – 177 The po- iron deficiency. Some studies suggest that oral iron absorption is im-
tential benefits of oral anticoagulation in APAH is even less clear. paired in patients with PAH, so i.v. iron administration may be pref-
Generally patients with PAH receiving therapy with long-term erable.181,184,186 However, controlled trials are lacking.
i.v. prostaglandins are anticoagulated in the absence of contraindica-
tions due in part to the additional risk of catheter-associated 6.3.3 Specific drug therapy
thrombosis. The role of the new oral anticoagulants in PAH is 6.3.3.1 Calcium channel blockers
unknown. Additional information on APAH is provided in the It has been increasingly recognised that only a small number of pa-
individual chapters. tients with IPAH who demonstrate a favourable response to acute
vasodilator testing (Table 11) at the time of RHC do well with
6.3.2.2 Diuretics CCBs.84,85 The CCBs that have been predominantly used in re-
Decompensated right heart failure leads to fluid retention, raised ported studies are nifedipine, diltiazem and amlodipine, with par-
central venous pressure, hepatic congestion, ascites and peripheral ticular emphasis on nifedipine and diltiazem.84,85 The choice of
oedema. Although there are no RCTs on the use of diuretics in CCB is based on the patient’s heart rate at baseline, with a relative
PAH, clinical experience shows clear symptomatic benefit in fluid bradycardia favouring nifedipine and amlodipine and a relative tachy-
overloaded patients treated with this therapy. The choice and cardia favouring diltiazem. The daily doses of these drugs that have
dose of diuretic therapy may be left to the PAH physician.178 The shown efficacy in IPAH are relatively high: 120– 240 mg for nifedi-
addition of aldosterone antagonists should also be considered to- pine, 240–720 mg for diltiazem and up to 20 mg for amlodipine. It
gether with systematic assessments of electrolyte plasma levels. It is advisable to start with an initial lower dose, e.g. 30 mg of slow re-
is important with diuretic use to monitor renal function and blood lease nifedipine twice a day or 60 mg of diltiazem three times a day
biochemistry in patients to avoid hypokalaemia and the effects of (t.i.d.) or 2.5 mg of amlodipine once a day, and increase cautiously
decreased intravascular volume leading to pre-renal failure. and progressively to the maximum tolerated dose. Limiting factors
for dose increase are usually systemic hypotension and lower limb 6.3.3.2 Endothelin receptor antagonists
peripheral oedema. Patients with IPAH who meet the criteria for a Activation of the endothelin system has been demonstrated in both
positive vasodilator response and are treated with CCBs should be plasma and lung tissue of PAH patients.190 Although it is unclear if
followed closely for reasons of both safety and efficacy, with a com- the increases in endothelin-1 plasma levels are a cause or a conse-
plete reassessment after 3–4 months of therapy including RHC. quence of PH,191 these data support a prominent role for the en-
If the patient does not show an adequate response, defined as dothelin system in the pathogenesis of PAH.192 Endothelin-1
being in WHO-FC I or II and with a marked haemodynamic im- exerts vasoconstrictor and mitogenic effects by binding to two dis-
provement (near normalization), additional PAH therapy should tinct receptor isoforms in the pulmonary vascular smooth muscle
be instituted. In some cases the combination of CCB with the ap- cells, endothelin receptors type A and B. The characteristics of
proved PAH drugs is required because of further clinical deterior- RCTs with PAH drugs interfering with the endothelin pathway are
ation in case of CCB withdrawal attempts. Patients who have not reported in Web Table VIA.
undergone a vasoreactivity study or those with a negative study
should not be started on CCBs because of potential severe side ef- Ambrisentan
fects (e.g. hypotension, syncope and RV failure).187 Ambrisentan is an ERA that preferentially binds with endothelin re-
Vasodilator responsiveness does not appear to predict a favour- ceptor type A. Ambrisentan has been evaluated in a pilot study193
able long-term response to CCB therapy in patients with PAH in the and in two large RCTs that have demonstrated efficacy on symp-
setting of CTD, HIV, porto-pulmonary hypertension (PoPH) and toms, exercise capacity, haemodynamics and time to clinical wor-

PVOD.188,189 sening of patients with IPAH and PAH associated with CTD and
The recommendations for CCB therapy are reported in Table 18. HIV infection.194 The incidence of abnormal liver function tests
For specific approved doses of the drugs, please refer to the ranges from 0.8 to 3%. Monthly liver function assessment is not
updated official prescription information. mandated in the USA.195 An increased incidence of peripheral
oedema has been reported with ambrisentan use.
Bosentan
Table 18 Recommendations for calcium channel
Bosentan is an oral active dual endothelin receptor type A and B antag-
blocker therapy in patients who respond to the acute
onist and the first molecule of its class to be synthesized. Bosentan has
vasoreactivity test
been evaluated in PAH (idiopathic, associated with CTD and Eisen-
menger syndrome) in six RCTs (Study-351, BREATHE-1, BREATHE-2,
Recommendations Classa Levelb Ref.c BREATHE-5, EARLY and COMPASS 2), which showed improvement
High doses of CCBs are recommended in
in exercise capacity, FC, haemodynamics, echocardiographic and Dop-
patients with IPAH, HPAH and DPAH pler variables and time to clinical worsening.196 – 200 Increases in hepatic
I C 84,85
who are responders to acute aminotransferases occurred in approximately 10% of the patients and
vasoreactivity testing were found to be dose dependent and reversible after dose reduction
Close follow-up with complete or discontinuation. For these reasons, liver function testing should be
reassessment after 3–4 months of performed monthly in patients receiving bosentan.
therapy (including RHC) is
I C 84,85
recommended in patients with IPAH,
Macitentan
HPAH and DPAH treated by high doses
of CCBs The dual ERA macitentan has been evaluated in an event-driven
RCT:201 742 PAH patients were treated with 3 mg or 10 mg maciten-
Continuation of high doses of CCBs is
recommended in patients with IPAH, tan as compared with placebo for an average of 100 weeks. The pri-
HPAH and DPAH in WHO-FC I or II I C 84,85 mary endpoint was the time from the initiation of treatment to the
with marked haemodynamic first occurrence of a composite endpoint of death, atrial septostomy,
improvement (near normalization) lung transplantation, initiation of treatment with i.v. or subcutaneous
Initiation of specific PAH therapy is prostanoids or worsening of PAH. Macitentan significantly reduced
recommended in patients in WHO-FC III this composite endpoint of morbidity and mortality among patients
or IV or those without marked I C 84,85
with PAH and also increased exercise capacity. Benefits were shown
haemodynamic improvement (near
normalization) after high doses of CCBs both for patients who had not received treatment previously and for
those receiving additional therapy for PAH. While no liver toxicity
High doses of CCBs are not indicated in
patients without a vasoreactivity study or
was shown, reduction in blood haemoglobin ≤8 g/dl was observed
non-responders unless standard doses III C in 4.3% of patients receiving 10 mg of macitentan.
are prescribed for other indications (e.g.
Raynaud’s phenomenon) 6.3.3.3 Phosphodiesterase type 5 inhibitors and guanylate cyclase
stimulators
CCB ¼ calcium channel blocker; DPAH ¼ drug-induced PAH; HPAH = Inhibition of the cyclic guanosine monophosphate (cGMP) degrading
heritable PAH; IPAH ¼ idiopathic PAH; PAH ¼ pulmonary arterial enzyme phosphodiesterase type 5 results in vasodilation through the
hypertension; RHC ¼ right heart catheterization; RV ¼ right ventricular;
WHO-FC ¼ World Health Organization functional class. NO/cGMP pathway at sites expressing this enzyme. Since the pulmon-
ary vasculature contains substantial amounts of phosphodiesterase
type 5, the potential clinical benefit of phosphodiesterase type 5 inhi- activities.216 Dysregulation of the prostacyclin metabolic pathways
bitors (PDE-5is) has been investigated in PAH. In addition, PDE-5is ex- has been shown in patients with PAH as assessed by a reduction
ert antiproliferative effects.202,203 All three PDE-5is approved for the of prostacyclin synthase expression in the pulmonary arteries and
treatment of erectile dysfunction—sildenafil, tadalafil and vardena- of prostacyclin urinary metabolites.217 The clinical use of prostacyc-
fil—cause significant pulmonary vasodilation, with maximum effects lin in patients with PAH has been extended by the synthesis of stable
observed after 60, 75–90 and 40–45 minutes, respectively.204 The analogues that possess different pharmacokinetic properties but
characteristics of RCTs with PAH drugs interfering with the NO path- share qualitatively similar pharmacodynamic effects.
way [soluble guanylate cyclase (sGC) stimulators, PDE-5is] are re- The characteristics of RCTs with PAH drugs interfering with the
ported in Web Table VIB. prostacyclin pathway (prostanoids and prostacyclin IP receptor
agonists) are reported in Web Table VIC.
Sildenafil
Sildenafil is an orally active, potent and selective inhibitor of phospho- Beraprost
diesterase type 5. Four RCTs in PAH patients treated with sildenafil Beraprost is the first chemically stable and orally active prostacyclin
have confirmed favourable results on exercise capacity, symptoms analogue. An RCT218 in Europe and a second in the USA219
and/or haemodynamics.205 – 208 An RCT addressing the effects of add- have shown an improvement in exercise capacity that persists up
ing sildenafil to epoprostenol showed improvements after 12 weeks to 3 – 6 months. There were no haemodynamic improvements or
in 6MWD and time to clinical worsening. Of note, seven deaths oc- long-term outcome benefits. The most frequent adverse events
curred in this trial, all in the placebo group.209 The approved dose of were headache, flushing, jaw pain and diarrhoea.

sildenafil is 20 mg t.i.d. Most side effects of sildenafil are mild to mod-
erate and mainly related to vasodilation (headache, flushing, epistaxis). Epoprostenol
Based on pharmacokinetic data, an i.v. formulation of sildenafil210 has Epoprostenol (synthetic prostacyclin) has a short half-life (3–5 min-
been proposed as a bridge for PAH patients on long-term oral treat- utes) and is stable at room temperature for only 8 hours; it requires
ment who are temporarily unable to ingest tablets. cooling and continuous administration by means of an infusion pump
and a permanent tunnelled catheter. The efficacy of continuous i.v. ad-
Tadalafil ministration of epoprostenol has been tested in three unblinded RCTs
Tadalafil is a once-daily dispensed selective PDE-5i. An RCT in 406 in patients with WHO-FC III and IV IPAH220,221 and in those with PAH
PAH patients (53% on background bosentan therapy) treated with associated with the scleroderma spectrum of diseases.222 Epoproste-
tadalafil 2.5, 10, 20 or 40 mg once daily has shown favourable results nol improves symptoms, exercise capacity and haemodynamics in
on exercise capacity, symptoms, haemodynamics and time to clinical both clinical conditions and is the only treatment shown to reduce
worsening at the highest dose.211 The side-effect profile was similar mortality in IPAH in a single RCT study.221 The meta-analysis for total
to that of sildenafil. mortality of the three epoprostenol RCTs220 – 222 has shown a risk re-
duction for mortality of about 70%. Long-term persistence of efficacy
Vardenafil
has also been shown96,107 in IPAH as well as in other APAH condi-
Vardenafil is a twice-daily dispensed PDE-5i. An RCT in 66
tions223 – 225 and in non-operable CTEPH.226
treatment-naive PAH patients treated with vardenafil 5 mg twice
Treatment with epoprostenol is initiated at a dose of 2–4 ng/kg/min,
daily has shown favourable results on exercise capacity, haemo-
with doses increasing at a rate limited by side effects (flushing, head-
dynamics and time to clinical worsening.212 The side-effect profile
ache, diarrhoea, leg pain). The optimal dose varies between individual
was similar to that of sildenafil.
patients, ranging in the majority between 20 and 40 ng/kg/min.96,107
Riociguat Serious adverse events related to the delivery system include pump
While PDE-5is such as sildenafil, tadalafil and vardenafil enhance the malfunction, local site infection, catheter obstruction and sepsis. Guide-
NO –cGMP pathway, slowing cGMP degradation, sGC stimulators lines for the prevention of central venous catheter bloodstream infec-
enhance cGMP production.213 Moreover, pre-clinical studies with tions have been proposed.227 Abrupt interruption of the epoprostenol
sGC stimulators have antiproliferative and antiremodelling proper- infusion should be avoided, because in some patients this may lead to a
ties in various animal models. PH rebound with symptomatic deterioration and even death. A thermo-
An RCT214 in 443 PAH patients (44% and 6% on background stable formulation of epoprostenol is also available and does not usually
therapy with ERAs or prostanoids, respectively) treated with rioci- require cooling packs to maintain stability beyond 8–12 hours.228
guat up to 2.5 mg t.i.d. has shown favourable results on exercise cap-
Iloprost
acity, haemodynamics, WHO-FC and time to clinical worsening.
Iloprost is a chemically stable prostacyclin analogue available for i.v.,
The increase in exercise capacity was also demonstrated in patients
oral or aerosol administration. Inhaled iloprost has been evaluated in
on background therapy. The most common serious adverse event in
one RCT in which daily repetitive iloprost inhalations (six to nine
the placebo group and in the 2.5-mg group was syncope (4% and 1%,
times, 2.5 – 5 mg/inhalation, median 30 mg daily) were compared
respectively). The combination of riociguat and PDE-5i is contrain-
with placebo inhalation in patients with PAH and CTEPH.229 The
dicated due to hypotension and other relevant side effects detected
study showed an increase in exercise capacity and improvement in
in the open-label phase of an RCT study.215
symptoms, PVR and clinical events in enrolled patients. A second
6.3.3.4 Prostacyclin analogues and prostacyclin receptor agonists RCT involving 60 patients already treated with bosentan showed
Prostacyclin is produced predominantly by endothelial cells and in- an increase in exercise capacity (P , 0.051) in the subjects rando-
duces potent vasodilation of all vascular beds. This compound is the mized to the addition of inhaled iloprost compared with placebo.230
most potent endogenous inhibitor of platelet aggregation and also Another similar study was terminated prematurely for futility.231
appears to have both cytoprotective and antiproliferative Overall, inhaled iloprost was well tolerated, with flushing and jaw
pain being the most frequent side effects. Continuous i.v. administra- increases in an additional proportion of patients.233 Treatment
tion of iloprost appeared to be as effective as epoprostenol in a with subcutaneous treprostinil is initiated at a dose of 1 – 2 ng/kg/
small series of patients with PAH and CTEPH.232 The effects of min, with doses increasing at a rate limited by side effects (local
oral iloprost have not been assessed in PAH. site pain, flushing, headache). The optimal dose varies between indi-
vidual patients, ranging in the majority between 20 and 80 ng/kg/min.
Treprostinil An RCT was performed with i.v. treprostinil in PAH patients, but
Treprostinil is a tricyclic benzidine analogue of epoprostenol, with the enrolment of this trial was closed because of safety considera-
sufficient chemical stability to be administered at ambient tempera- tions after 45 (36%) of the planned 126 patients had been rando-
ture. These characteristics allow administration of the compound by mized.234 The data generated from 31 (25%) survivors after the
i.v. and subcutaneous routes. The subcutaneous administration of randomized phase (23 active and 8 placebo) are not considered re-
treprostinil can be accomplished by a micro-infusion pump and a liable. The dose of i.v. treprostinil is two to three times higher than
small subcutaneous catheter. The effects of treprostinil in PAH the dose of i.v. epoprostenol.235,236
were assessed in an RCT and showed improvements in exercise An RCT with inhaled treprostinil in PAH patients on background
capacity, haemodynamics and symptoms.233 The greatest exercise therapy with either bosentan or sildenafil showed improvements in
improvement was observed in patients who were more compro- the 6MWD by 20 m at peak dose and 12 m at trough dose,
mised at baseline and in subjects who could tolerate the upper quar- NT-proBNP and quality of life measures.237
tile dose (.13.8 ng/kg/min). Infusion site pain was the most Oral treprostinil has been evaluated in two RCTs in PAH patients on

common adverse effect of treprostinil, leading to discontinuation background therapy with bosentan and/or sildenafil and in both trials
of the treatment in 8% of cases on active drug and limiting dose the primary endpoint 6MWD did not reach statistical significance.238,239
Table 19 Recommendations for efficacy of drug monotherapy for pulmonary arterial hypertension (group 1) according to
World Health Organization functional class. The sequence is by pharmacological group, by rating and by alphabetical order
Measure/treatment Classa-Levelb Ref.c

WHO-FC II WHO-FC III WHO-FC IV
d d
Calcium channel blockers I C I C - - 84,85
Endothelin receptor antagonists Ambrisentan I A I A IIb C 194
Bosentan 196–
I A I A IIb C
200
Macitentane I B I B IIb C 201
Phosphodiesterase type 5 inhibitors Sildenafil 205–
I A I A IIb C
208
Tadalafil I B I B IIb C 211
g
Vardenafil IIb B IIb B IIb C 212
Guanylate cyclase stimulators Riociguat I B I B IIb C 214
e
Prostacyclin analogues Epoprostenol Intravenous - - 220–
I A I A
222
Iloprost Inhaled - - 229–
I B IIb C
231
Intravenousg - - IIa C IIb C 232
Treprostinil Subcutaneous - - I B IIb C 233
g
Inhaled - - I B IIb C 237
Intravenousf - - IIa C IIb C 234
g
Oral - - - - 238–
IIb B
240
Beraprostg - - IIb B - - 218
g
IP receptor agonists Selexipag (oral) I B I B - - 241,248
EMA ¼ European Medicines Agency; PAH ¼ pulmonary arterial hypertension; RCT ¼ randomized controlled trial; WHO-FC ¼ World Health Organization functional class.
a
b
Level of evidence.
c
d
Only in responders to acute vasoreactivity tests ¼ class I, for idiopathic PAH, heritable PAH and PAH due to drugs; class IIa, for conditions associated with PAH.
e
Time to clinical worsening as primary endpoint in RCTs or drugs with demonstrated reduction in all-cause mortality.
f
In patients not tolerating the subcutaneous form.
g
This drug is not approved by the EMA at the time of publication of these guidelines.
An additional RCT in treatment-naive PAH patients showed improve- significant. However, the incidence of mortality in RCTs with PAH
ment in the 6MWD by 26 m at peak dose and 17 m at trough dose.240 medications is relatively low and to achieve statistical significance a
sample size of several thousand patients may be required.244
Selexipag
Combination therapy may be applied sequentially or initially
Selexipag is an orally available, selective prostacyclin IP receptor
(upfront).
agonist. Although selexipag and its metabolite have modes of action
Sequential combination therapy is the most widely utilised strategy
similar to that of endogenous prostacyclin (IP receptor agonism),
both in RCTs and in clinical practice: from monotherapy there is an
they are chemically distinct from prostacyclin with a different
addition of a second and then a third drug in cases of inadequate clin-
pharmacology. In a pilot RCT in PAH patients (receiving stable
ical results or in cases of deterioration. A structured prospective pro-
ERA and/or PDE-5i therapy), selexipag reduced PVR after 17
gramme to evaluate the adequacy of clinical results is the so-called
weeks.241 An event-driven phase 3 RCT that enrolled 1156 patients248
goal-oriented therapy, a treatment strategy that uses known prognos-
has shown that selexipag alone or on top of mono- or double therapy
tic indicators as treatment targets. The therapy is considered adequate
with ERAs and/or PDE-5i was able to reduce by 40% (hazard ratio
only if the targets are met. The key difference between goal-oriented
0.60, P , 0.001) a composite morbidity and mortality endpoint
therapy and non-structured approaches is that patients who are stabi-
(including death from all causes, hospitalization for worsening of
lised, or even those who improve slightly, can still receive additional
PAH, worsening of PAH resulting in the need for lung transplantation
therapy if treatment goals are not met. The goal-oriented treatment
or atrial septostomy, initiation of parenteral prostanoids or chronic
strategy utilises different targets, including WHO-FC I or II, and the
O2 for worsening of PAH and disease progression).

near-normalization of resting CI and/or of NT-proBNP plasma levels.
Recommendations for efficacy of specific drug monotherapies
A recent study has confirmed a better prognosis in patients achieving
are reported in the Table 19.
these goals as compared with patients who did not.97
6.3.3.5 Experimental compounds and strategies Recommendations and evidence on the use of specific drugs for
Despite progress in the treatment of PAH, the functional limitation and initial combination therapy and for sequential combination therapy
survival of these patients remain unsatisfactory. There are three well- for PAH according to WHO-FC are provided in Table 20 and
known pathways that contribute to the pathogenesis of PAH: the en- Table 21, respectively.
dothelin, NO and prostacyclin pathways. Treatments targeting these
pathways are well established in clinical practice, such as ERAs, PDE-5is
Table 20 Recommendations for efficacy of initial
and prostanoids. Additional therapeutic strategies targeted at diverse
drug combination therapy for pulmonary arterial
pathobiological changes are being explored in order to further improve
hypertension (group 1) according to World Health
symptoms and prognosis. Three pathways have been explored with
Organization functional class. Sequence is by rating
unsatisfactory results using the following compounds: inhaled vaso-
active intestinal peptide, tyrosine kinase inhibitors (platelet-derived
growth factor inhibitors) and serotonin antagonists. The following Measure/ Classa-Levelb Ref.c
additional compounds are in an earlier stage of development: rho treatment
WHO-FC WHO-FC WHO-FC
kinase inhibitors, vascular endothelial growth factor receptor inhibi- II III IV
tors, angiopoietin-1 inhibitors and elastase inhibitors. Gene therapy
Ambrisentan +
strategies have been tested in animal models. Stem cell therapy has I B I B IIb C 247
tadalafild
proven to be effective in the monocrotaline rat model and is currently
Other ERA + -
being tested in a proof-of-concept and dose-finding study in PAH pa- IIa C IIa C IIb C
PDE-5i
tients. A controversial study has shown a preliminary favourable effect
Bosentan + - -
of PA denervation by a radiofrequency ablation catheter.242,243 sildenafil + IIa C IIa C 246
i.v. epoprostenol
6.3.4 Combination therapy
Bosentan + i.v. - - 198,
Combination therapy—using two or more classes of drugs simul- IIa C IIa C
epoprostenol 245
taneously—has been used successfully in the treatment of systemic
Other ERA or -
hypertension and heart failure. It is also an attractive option for the PDE-5i + IIb C IIb C
management of PAH, because three separate signalling pathways s.c. treprostinil
known to be involved in the disease can be addressed by specific Other ERA or -
drugs: the prostacyclin pathway (prostanoids), the endothelin path- PDE-5i + other
IIb C IIb C
way (ERAs) and the NO pathway (PDE-5is and sGCs). i.v. prostacyclin
The experience with combination therapy is increasing and a re- analogues
cent meta-analysis on six RCTs with combination therapy including
858 patients has been published;244 compared with the control ERA ¼ endothelin receptor antagonist; i.v. ¼ intravenous;
group, combination therapy reduced the risk of clinical worsening PDE-5i ¼ phosphodiesterase type 5 inhibitor; RCT ¼ randomized controlled trial;
s.c. ¼ subcutaneous; WHO-FC ¼ World Health Organization functional class.
{relative risk [RR] 0.48 [95% confidence interval (CI) 0.26, 0.91], a
P ¼ 0.023}, increased the 6MWD significantly by 22 m and reduced b
Level of evidence.
c
mean PAP, RAP and PVR. The incidence of serious adverse Reference(s) supporting recommendations.
d
Time to clinical failure as primary endpoint in RCTs or drugs with demonstrated
events was similar in the two groups [RR 1.17 (95% CI 0.40, 3.42), reduction in all-cause mortality (prospectively defined).
P ¼ 0.77]. The reduction in all-cause mortality was not statistically
medical illnesses (heart failure, malignant hypertension) are not

Table 21 Recommendations for efficacy of treated with a stepwise approach to therapy, but rather with
sequential drug combination therapy for pulmonary pre-emptive combination therapy. The experience in RCTs with
arterial hypertension (group 1) according to World initial combination therapy started with the small BREATHE-2
Health Organization functional class. Sequence is by (Web Table VID) study, which failed to demonstrate any signifi-
rating and by alphabetical order cant difference between patients treated initially with the combin-
ation epoprostenol and bosentan as compared with epoprostenol
Measure/ Classa-Levelb Ref.c alone.198 In a more recent experience, 23 treatment-naive PAH
treatment
WHO-FC WHO-FC WHO-FC
patients were treated with the initial combination of epoprostenol
II III IV and bosentan and compared with a matched historical control
Macitentan group treated with epoprostenol.245 The study showed a statis-
added to I B I B IIa C 201 tically significant greater decrease in PVR in the initial combina-
sildenafild tion therapy group, but this haemodynamic benefit did not
Riociguat added
I B I B IIa C 214
translate into a statistically significant difference in survival or in
to bosentan transplant-free survival. A pilot study on an initial triple com-
Selexipage bination in 19 WHO-FC class III and IV patients has provided
241,
added to ERA I B I B IIa C preliminary evidence of the long-term benefits of upfront triple
248
and/or PDE-5id

combination therapy in patients with severe PAH. 246 A recent
Sildenafil added – –
I B IIa B 209 multicentre, multinational, blinded, placebo-controlled trial
to epoprostenol
(Web Table VID) compared first-line monotherapy with tadalafil
Treprostinil
inhaled added or monotherapy with ambrisentan with upfront combination
IIa B IIa B IIa C 237 therapy with tadalafil and ambrisentan in de novo WHO-FC II
to sildenafil or
bosentan and III PAH patients.247 The primary endpoint was a composite
Iloprost inhaled of clinical failure events (including death, hospitalization, PAH pro-
230,
added to IIb B IIb B IIb C gression and unsatisfactory clinical status). The study was positive,
231
bosentan
with a 50% reduction in events in the combination group. In add-
Tadalafil added ition, improvements were observed in exercise capacity, rate of
IIa C IIa C IIa C 211
to bosentan
satisfactory clinical response and NT-proBNP plasma levels.247
Ambrisentan
added to IIb C IIb C IIb C 249
sildenafil 6.3.5 Drug interactions
Bosentan added – – Significant drug interactions involving the disease-targeted
IIb C IIb C 250 therapies for PAH are shown in Web Table VII. This table high-
to epoprostenol
Bosentan lights known important interactions but does not include
251,
added to IIb C IIb C IIb C theoretical untested interactions, which may still be clinically im-
252
sildenafil portant. In addition, updated official prescribing information for
Sildenafil added each compound should be read.
IIb C IIb C IIb C 252
to bosentan Bosentan is an inducer of cytochrome P450 isoenzymes CYP3A4
Other double – and CYP2C9. Plasma concentrations of drugs metabolised by these
IIb C IIb C IIb C
combinations
isoenzymes will be reduced when co-administered with bosentan.
Other triple – Bosentan is also metabolised by these enzymes so that their inhib-
IIb C IIb C IIb C
combinations
ition may increase the plasma concentration of bosentan. In addition
Riociguat added to interactions shown in Web Table VII, a combination of a potent
to sildenafil or III B III B III B 215
other PDE-5i CYP3A4 inhibitor (ketoconazole, ritonavir) and/or a CYP2C9 in-
hibitor (e.g. amiodarone, fluconazole) with bosentan may cause a
EMA ¼ European Medicines Agency; ERA ¼ endothelin receptor antagonist;
significant increase in plasma bosentan levels and thus is contraindi-
PAH ¼ pulmonary arterial hypertension; PDE-5i ¼ phosphodiesterase type 5 cated. Interactions may theoretically occur with itraconazole,
inhibitor; RCT ¼ randomized controlled trial; WHO-FC ¼ World Health tacrolimus, sirolimus, carbamazepine, phenytoin, phenobarbitone,
Organization functional class.
a
dapsone and St John’s wort.
b
Level of evidence. Sildenafil is metabolised by cytochrome P450 isoenzymes
c
Reference(s) supporting recommendations. CYP3A4 (major route) and CYP2C9 (minor route). There is an in-
d
Time to clinical worsening as primary endpoint in RCTs or drugs with
demonstrated reduction in all-cause mortality (prospectively defined).
crease in sildenafil bioavailability and reduced clearance with
e
This drug was not approved by the EMA at the time of publication of these CYP3A4 substrates and inhibitors and CYP3A4 substrates plus
guidelines. beta-adrenoceptor blockers. CYP3A4 inducers such as carba-
mazepine, phenytoin, phenobarbital, rifampicin and St John’s
The rationale for initial or upfront combination therapy is wort may significantly lower sildenafil levels. Sildenafil levels are
based on the known mortality of PAH, which is reminiscent of modestly increased by fresh grapefruit juice, a weak inhibitor of
many malignancies, and the fact that malignancies and critical CYP3A4.
Finally, care is needed when PAH-targeted medications Intubation should be avoided in patients with RV failure, as it frequent-
are co-administered with antihypertensive drugs such as beta- ly results in haemodynamic collapse.
adrenoceptor blockers, angiotensin-converting enzyme inhibitors,
etc., to avoid excessive systemic hypotension. 6.3.7.2 Right ventricle assistance
The use of veno-arterial extracorporeal membrane oxygenation
6.3.6 Balloon atrial septostomy (ECMO) should be considered for selected patients with PH and
The creation of an inter-atrial right-to-left shunt can decompress RV failure. A veno-venous approach may improve oxygenation
the right heart chambers and increase LV preload and CO.253,254 but does not unload the RV, which makes it unsuitable for this pa-
In addition, this improves systemic O2 transport despite arterial tient population. There are two basic concepts for the use of ECMO
O 2 desaturation 253 and decreases sympathetic hyperactivity. in these patients: bridge to recovery and bridge to transplantation.
The recommended technique is graded balloon dilation atrial Few reports have been published on the bridge to recovery con-
septostomy, which produces equivalent improvements in hae- cept,261 which is only reasonable in patients for whom a clear thera-
modynamics and symptoms but reduced risk compared with the peutic concept with a realistic chance of recovery exists. There are,
original blade technique. Other techniques are considered however, several reports on the successful use of ECMO as a bridge
experimental.255 to transplantation, especially when used in awake patients.261 – 263
A careful pre-procedure risk assessment ensures reduced mor- An alternative approach involves connecting a pumpless device to
tality. Balloon atrial septostomy (BAS) should be avoided in end- the pulmonary circulation.264,265 All of these procedures are avail-

stage patients presenting with a baseline mean RAP .20 mmHg able only in highly specialized centres.
and O2 saturation at rest ,85% on room air. Patients should be
on optimal medical therapy, which may include preconditioning 6.3.8 Transplantation
with i.v. inotropic drugs, prior to considering BAS. Published re- The advent of disease-targeted therapy for severe PAH has reduced
ports suggest a benefit in patients who are in WHO-FC IV with and delayed patient referral for lung transplant programmes.256 The
right heart failure refractory to medical therapy or with severe syn- long-term outcomes of medically treated patients remain uncertain
copal symptoms.253,254 It may also be considered in patients await- and transplantation should continue to be an important option for
ing lung transplantation with unsatisfactory clinical response on those who fail on such therapy and remain in WHO-FC III or
maximal medical therapy or when medical therapy is not available. IV.96,107 Delayed referral in combination with the length of the wait-
Studies show improvements in CI and decreases in RAP with im- ing time, due to the shortage of organ donors, may increase the
provement in 6MWD.253,254 The impact of BAS on long-term sur- mortality of patients on the waiting list and their clinical severity
vival has not been established in RCTs. 253,254 BAS should be at the time of transplantation.
regarded as a palliative or bridging procedure to be performed The overall 5-year survival following transplantation for PAH was
only in centres with experience in the method.256 Since BAS is per- considered to be 45– 50%, with evidence of continued good quality
formed very rarely, it has not been included in the treatment algo- of life.266 More recent data show that survival is increased to 52 –
rithm (Figure 2). 75% at 5 years and to 45– 66% at 10 years.267 – 269
Considering the above information, it seems reasonable to consider
6.3.7 Advanced right ventricular failure eligibility for lung transplantation after an inadequate clinical response
6.3.7.1 Intensive care unit management to the initial monotherapy and to refer the patient soon after an inad-
Patients with PH may require intensive care unit (ICU) treatment for equate clinical response is confirmed on maximal combination therapy
a co-morbid condition (including major surgery), right heart failure (Figure 2). Also the aetiology of PAH may help the decision making since
or both. In a series from France, the mortality among PAH patients the prognosis varies according to the underlying condition. In fact, PAH
admitted to the ICU was 41%,257 underscoring the poor prognosis. associated with CTD has a worse prognosis than IPAH, even when trea-
Hence PAH patients requiring ICU treatment should be managed at ted with prostanoids, while patients with PAH associated with CHD
specialized centres whenever possible. Basic monitoring includes have a better survival. The poorest prognosis is seen in patients with
vital signs (heart rate, blood pressure, body temperature and O2 PVOD and PCH because of the lack of effective medical treatments;
saturation), urine production, central venous pressure, central these patients should be listed for transplantation at diagnosis.
venous O2 saturation and blood lactate levels. The combination of Both heart–lung and double-lung transplantation have been per-
a low central venous O2 saturation (,60%) with rising lactate levels formed for PAH, although the threshold for unrecoverable RV systol-
and low or absent urine production signals imminent right heart fail- ic dysfunction and/or LV diastolic dysfunction is unknown. Currently
ure. In certain situations, placement of a right heart catheter might be the vast majority of patients worldwide receive bilateral lungs, as in-
required to allow comprehensive haemodynamic monitoring. The ba- dicated by the International Society for Heart and Lung Transplant-
sic principles of ICU management of patients with PH and RV failure ation Registry figures.270 Patients with Eisenmenger syndrome due
include the treatment of triggering factors (such as anaemia, arrhyth- to simple shunts have been treated with isolated lung transplantation
mias, infections or other co-morbidities), optimization of fluid balance and repair of the cardiac defect or by heart–lung transplantation.266
(usually with i.v. diuretics), reduction of RV afterload (usually with While registry data initially supported a survival benefit of heart–
parenteral prostacyclin analogues, but sometimes also with other lung transplantation for patients with PH associated with a ventricu-
PAH drugs), improvement of CO with inotropes (with dobutamine lar septal defect,271 experience with isolated bilateral lung trans-
being the preferred inotrope to treat RV failure) and maintenance plantation has increased and more recent data support a role for
of systemic blood pressure with vasopressors, if necessary.258 – 260 this approach combined with repair of the defect.272
Recent reports indicate that veno-arterial ECMO may be and interventions). Definitions of clinical response to treatments are
employed in awake end-stage PH patients for bridging to lung reported in Table 15. It is recognized that the therapeutic approach
transplantation.263 to PAH may vary depending on the local availability (and expertise)
of therapeutic options in various hospitals and clinical settings.
Accordingly, Tables 19, 20, 21 and 22 provide the necessary
Table 22 Recommendations for efficacy of intensive evidence for alternative evidence-based therapeutic strategies. In
care unit management, balloon atrial septostomy and these tables only the compounds officially approved for PAH or
lung transplantation for pulmonary arterial undergoing regulatory approval in at least one country are included.
hypertension (group 1) according to World Health A four-level hierarchy for endpoints in RCTs has been proposed by
Organization functional class experts according to the level of evidence regarding efficacy.273,274
According to this hierarchy, drugs or combinations of drugs
with time to clinical failure or to clinical worsening as the primary
Measure/ Classa-Levelb Ref.c
endpoint in RCTs or drugs with a demonstrated reduction in all-
treatment
WHO-FC WHO-FC WHO-FC cause mortality (prospectively defined) have been highlighted
II III IV with a footnote in Tables 19, 20 and 21. The PAH treatment algo-
Hospitalization – – – – rithm does not apply to patients in other clinical groups, and in par-
in ICU is ticular it does not apply to patients with PH associated with group 2
recommended in

(LHD) or group 3 (lung diseases). In addition, the different treat-
PH patients with
high heart rate ments have been evaluated by RCTs mainly in IPAH, HPAH, PAH
(.110 beats/ due to drugs and in PAH associated with CTD or with CHD (surgi-
min), low blood cally corrected or not).
pressure
I C 257
(systolic blood Treatment algorithm description (Figure 2)
pressure ,90
mmHg), low † After confirmation of the diagnosis of the treatment-naive PAH
urine output and patient in an expert centre, the suggested initial approach is the
rising lactate adoption of general measures and the initiation of supportive
levels due or therapy if needed (Tables 16 and 17).
not due to
† Acute vasoreactivity testing should be performed only in patients
co-morbidities
with IPAH, HPAH and PAH associated with drugs or toxins use.
Inotropic
Vasoreactive patients should be treated with high doses (pro-
support is
recommended in I C I C gressively titrated) of CCB; adequate response should be con-
hypotensive firmed after 3 – 4 months of treatment (Table 18). Patient
patients responders without an adequate clinical response to CCB treat-
Lung – – ment should be treated with approved PAH medications accord-
transplantation is ing to the non-vasoreactive patient’s treatment strategy.
recommended † Non-responders to acute vasoreactivity testing who are at low or
soon after
I C I C 270 intermediate risk (Table 13) can be treated with either initial mono-
inadequate
clinical response therapy (Table 19) or initial oral combination therapy (Table 20).
on maximal † If initial monotherapy is chosen, since head-to-head comparisons
medical therapy among different compounds are not available, no evidence-based
BAS may be – – first-line monotherapy can be proposed. In this case the choice of
considered the drug may depend on a variety of factors, including the approv-
where available 253, al status, labelling, route of administration, side-effect profile,
IIb C IIb C
after failure of 254 potential interaction with background therapies, patient prefer-
maximal medical
therapy
ences, co-morbidities, physician experience and cost.
† Since head-to-head comparison between initial combination
therapy with ambrisentan plus tadalafil has proven to be superior
BAS ¼ Balloon atrial septostomy; ICU ¼ intensive care unit; PH ¼ pulmonary
hypertension; WHO-FC ¼ World Health Organization functional class. to initial monotherapy with ambrisentan or tadalafil in delaying
a
Class of recommendation. clinical failure, a higher grade of recommendation has been given
b
Level of evidence. to this initial combination (Table 20).247
c
† In non-vasoreactive and treatment-naive patients at high risk
(Table 13), initial combination therapy including i.v. prostacyclin
6.3.9 Treatment algorithm analogues should be considered (Table 20). I.V. epoprostenol
A treatment algorithm for PAH patients is shown in Figure 2. The should be prioritised since it has reduced the 3-month rate of
classes of recommendation and levels of evidence for the PAH mortality in high-risk PAH patients also as monotherapy
treatments are shown in Tables 19 (monotherapy), 20 (initial com- (Table 19).149 Alternative types of initial combination therapy
bination therapy), 21 (sequential combination therapy) and 22 (ICU may be considered (Table 20).
† In case of inadequate clinical response to initial combination ther- † It seems reasonable to consider eligibility for lung transplantation
apy or initial monotherapy (Table 15), sequential double or triple after an inadequate clinical response to the initial monotherapy
combination therapy is recommended according to Table 21. The or initial combination therapy and to refer the patient for lung
combination of riociguat and PDE-5i is contraindicated. transplantation soon after the inadequate clinical response is con-
† In case of inadequate clinical response with sequential double firmed on maximal combination therapy. BAS should be regarded
combination therapy, triple combination therapy should be as a palliative or bridging procedure in patients deteriorating des-
attempted (Tables 20 and 21). pite maximal medical therapy.
General measures
Treatment naïve PAH confirmed by (Table 16)
patient expert center Supportive therapy
(Table 17)

CCB Therapy Acute vasoreactivity test
(Table 18) (IPAH/HPAH/DPAH only)
Vasoreactive
Non-vasoreactive
Low or intermediate risk High risk

(WHO FC II–III) a (WHO FC IV)a
Initial Initial oral Initial combination

monotherapy b combination b including i.v. PCA c
(Table 19) (Table 20) (Table 20)
Patient already Inadequate clinical response Consider referral for

on treatment (Table 15) lung transplantation
Double or triple sequential combination

(Table 21)
Inadequate clinical response

(Table 15)
Consider listing for lung transplantationd

(Table 22)
CCB = calcium channel blockers; DPAH = drug-induced PAH; HPAH = heritable PAH; IPAH = idiopathic PAH; i.v. = intravenous; PAH = pulmonary arterial hypertension;
PCA = prostacyclin analogues; WHO-FC = World Health Organization functional class.
a
Some WHO-FC III patients may be considered high risk (see Table 13).
b
c
Intravenous epoprostenol should be prioritised as it has reduced the 3 months rate for mortality in high risk PAH patients also as monotherapy.
d
Consider also balloon atrial septostomy.
Figure 2 Evidence based treatment algorithm for pulmonary arterial hypertension patients (for group 1 patients only; see description in the
text).
6.3.10 Diagnosis and treatment of pulmonary arterial The indications and results of a traditional surgical approach in the
hypertension complications presence of PH are unknown and the predictable risks may be very
6.3.10.1 Arrhythmias high. The percutaneous approach (stenting) faces relevant technical
Arrhythmias are an increasing clinical problem in PAH patients. In issues mainly due to early branching of the main and lobar PA.
particular, the presence of symptomatic atrial arrhythmia might por- A possible approach is double-lung or heart – lung transplantation,
tend a poor prognosis.275 In contrast to patients with LHD, malig- but this solution can be applied only in chronic stabilised cases,
nant ventricular arrhythmias such as ventricular tachycardia, and clear indications are lacking. In patients with left main coronary
ventricular flutter and ventricular fibrillation are rare in PAH pa- artery compression, a percutaneous stenting procedure should be
tients. In a series of 132 witnessed cardiac arrests in patients with performed.282
PAH, ventricular fibrillation was observed in only 8% of the cases.276
Another series of 231 patients with PAH or CTEPH followed over a 6.3.11 End of life care and ethical issues
6-year period did not report any case of malignant ventricular ar- The clinical course of PH is one of progressive deterioration inter-
rhythmia.275 In that series, supraventricular tachyarrhythmias oc- spersed with episodes of acute decompensation. It is difficult to pre-
curred with an annual incidence of 2.8%. Atrial flutter and atrial dict when patients will die since death may come either suddenly or
fibrillation were equally common and both arrhythmias invariably slowly because of progressive heart failure. It has been shown that
led to clinical deterioration with signs of right heart failure. Treat- physicians caring for patients tend to be overoptimistic in their prog-
ment of atrial flutter proved to be more successful than treatment nostication and frequently misunderstand their patients’ wishes.

of atrial fibrillation. Restoration of a stable sinus rhythm was asso- Open and sensitive communication with patients allows advanced
ciated with a favourable long-term survival, while persistent atrial planning and discussion of their fears, concerns and wishes, which is
fibrillation was associated with a 2-year mortality .80%.275 Supra- essential to good care. Opportunities to discuss prognosis should be
ventricular arrhythmias represent an indication for oral anticoagula- created at the time of initial diagnosis. Recognition that cardiopul-
tion with vitamin K antagonists or new oral anticoagulants. Both monary resuscitation in severe PH has a poor outcome may enable
electric cardioversion and radiofrequency ablation in refractory a do-not-resuscitate order. This may increase the chance of patients
cases have proven to be effective.277 being in their preferred place of care at the end of life.
Although prospective and controlled data are lacking, these find- Patients approaching the end of life require frequent assessment
ings suggest that maintenance of a stable sinus rhythm after cardio- of their full needs by a multidisciplinary team. Attention should be
version should be considered an important treatment goal in given to controlling the distressing symptoms and prescribing ap-
patients with PAH. In order to achieve a stable sinus rhythm, propriate drugs while withdrawing unnecessary medication. Well-
prophylaxis with antiarrhythmic drugs without negative inotropic informed psychological, social and spiritual support is also vital. Spe-
effects, such as oral amiodarone (see interactions in Web cialist palliative care should be consulted about patients whose
Table VII), should also be considered, even if specific data regarding needs are beyond the expertise of the PH team.
efficacy are lacking. PH is a disease that may be severely life-limiting. In addition to
psychological and social support, there should be proactive ad-
6.3.10.2 Haemoptysis vanced care planning with referral to specialist palliative care ser-
Haemoptysis is a recognised complication of PH, represents a risk vices when appropriate.
factor for mortality and appears to be more frequent in specific
types, such as HPAH, PAH associated with CHD and CTEPH.
Haemoptysis severity ranges from mild to very severe leading to
7. Specific pulmonary (arterial)
sudden death. Reported prevalence is variable, from 1% to 6%.278 hypertension subsets
Bronchial artery embolization is suggested as an acute emergency
procedure in the case of severe haemoptysis or as elective interven- 7.1 Paediatric pulmonary arterial
tion in cases of frequent mild or moderate episodes. Haemoptysis hypertension
may represent a contraindication to anticoagulant therapy. PH can present at any age from the neonatal period to adulthood.
Paediatric PH has some unique features that are not found in adult
6.3.10.3 Mechanical complications PH, including prenatal aetiological factors, and postnatal parenchy-
Mechanical complications in PAH patients are usually related to pro- mal and vascular abnormalities in lung development.283 Before the
gressive dilatation of the PA and include PA aneurysms, rupture and epoprostenol era, the prognosis had been worse in children, with
dissection and compression of different intrathoracic structures a median survival estimated at 10 months, compared to 2.8 years
such as the left main coronary artery, pulmonary veins, main bronchi in adults; however, with new targeted therapies the outcome has
and the recurrent laryngeal nerves.279 – 281 Symptoms and signs are improved significantly.9,284
not specific and are variable according to the different complica- Recent data from registries have shed light on the prevalence and
tions, including chest pain (angina-like or not), dyspnoea, regional incidence of paediatric PH. In the Netherlands, the incidence and
lung oedema and sudden death. Contrast-enhanced and high- prevalence of IPAH is 0.7 and 4.4 per million children, respective-
resolution CT scan represent the best imaging option to detect ly.285 Similar numbers have been observed in the UK, with annual
mechanical complications. cases of IPAH of 0.48 per million and a prevalence of 2.1 per mil-
Treatment options are not well established in cases of PA aneur- lion.286 National and large-scale registries either including chil-
ysms, pseudo-aneurysms and dissection.279,280 dren284 or exclusively dedicated to paediatrics287,288 have
described the different aetiologies of PH, with IPAH, HPAH and is required.293,294 Use of i.v. iloprost and trepostinil, as well as sub-
CHD-PAH as the most common. However, PH associated with cutaneous trepostinil,295 has been reported. Oral beraprost is used
respiratory disease is also noted to be important and may be in some countries, but lack of proof of efficacy is a problem. Inhaled
underreported.287 iloprost is difficult to deliver, but some reports have shown efficacy,
Although the 2009 Dana Point classification included most of the mostly in combination with other therapies.296
paediatric causes, it was felt that paediatric aetiologies should be Bosentan pharmacokinetics have been assessed in two stud-
better described. The 2011 Panama classification was recently pro- ies.297,298 Several uncontrolled studies have shown positive results
posed, with 10 different subgroups of paediatric PH.289 The 2013 similar to adults, with survival rates around 80 – 90% at 1 year.298
Nice classification includes new groups and aetiologies specific to A paediatric formulation is available in Europe.299 Data with ambri-
children,9 such as congenital and acquired left heart inflow/outflow sentan are scarce and a study is ongoing.
tract obstruction and segmental PH; it has been further adapted for Sildenafil has shown efficacy300 and has been approved in Europe
the current ESC/ERS Guidelines (Table 4 and Web Table I) with for children 1–17 years of age. Increased mortality using high doses
provision of clinical (Table 6) and anatomical – pathophysiological has raised concerns; therefore high doses should not be used in chil-
classification of congenital systemic-to-pulmonary shunts associated dren (high individual doses of sildenafil on a three daily dosing not
with PAH (Web Table II) and of developmental lung disease recommended: .10 mg/dose with a bodyweight of 8 – 20 kg,
(Web Table III). .20 mg/dose in children with a bodyweight .20 kg or .1 mg/
PPHN remains in the PAH group but has been moved to a sub- kg/dose in infants and small children).301

group, as it is considered to be a specific entity with a more transient Data on tadalafil also suggest efficacy;302 a trial is currently under
course (Table 4 and Web Table IV) in most cases. way to define the specific dosage for children.
An increasing number of paediatric patients are on combination
7.1.1 Diagnosis therapies even though evidence is still limited.303
Dyspnoea, fatigue and failure to thrive are common symptoms; syn- RV decompression strategies include atrioseptostomy,304 ductal
cope is more common in children, but overt RV failure is a late event stenting in cases of patent ductus arteriosus305 and a surgical Potts
and the child may die of sudden death before the occurrence of RV shunt.306 Transcatheter Potts shunt creation has also been pro-
failure.284,287 A specific diagnostic workup has been recently recom- posed.307 Lung transplantation remains an important option for
mended, and even if some causes are rare, they should be excluded paediatric PH patients.
before a definite diagnosis of IPAH.284 A thorough family and per- Specific goals for treatment should be applied for children. Some
sonal history, including pregnancy, delivery and postnatal details, is have been extrapolated from defined risk factors in children but still
essential.290 Diagnosis must be confirmed by heart catheterization, require validation in large cohorts.9 Recently FC, TAPSE and
and vasoreactivity testing should be performed. Recent reports sug- NT-proBNP have been recognized as treatment goals.308
gest that cardiac catheterization may be a greater risk in children The recommendations for paediatric PH are reported in the
compared with adults, with younger age (,1 year) and worse FC Table 23.
(WHO-FC IV) as risk factors. Cardiac catheterization performed
in expert centres is recommended.290 The general scheme of the Table 23 Recommendations for paediatric
diagnostic algorithm for adult patients with PH (Figure 1) may also pulmonary hypertension
be adopted in children, with some adaptation related to the different
epidemiology.9
As in adults, clinical evidence of RV failure, progression of symp- Recommendations Classa Levelb Ref.c
toms, WHO-FC III/IV and elevated BNP levels are recognized as A PH diagnostic algorithm workup
being associated with higher risk of death. In children, failure to is recommended for diagnosis and
I C 9,290
thrive, haemodynamic parameters such as the PAPm:systemic artery definition of the specific aetiology
group in paediatric PH patientsd
pressure ratio, RAP .10 mmHg and PVR index .20 WU/m2 have
also been associated with a higher risk of death, while the 6MWD A PAH-specific therapeutic
algorithm is recommended in I C 9
was not a prognostic parameter.
paediatric PH patientsd
7.1.2 Therapy Combination therapy should be 295,298,

IIa C
considered in paediatric PH patients 302
There is a lack of randomized trials in paediatrics, making it difficult
to deliver strong guidelines.291,292 A specific treatment algorithm, Specific paediatric determinants of
IIa C 9,308
similar to that used in adults (Figure 2), has been recommended. risk should be consideredd
Determinants of risk and risk stratification have also been
suggested.9 CCBs are used in responders, but close follow-up is PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary hypertension.
a
mandatory, as some patients may fail long-term therapy. b
Level of evidence.
Indications for epoprostenol are similar to those for adults. The c
d
optimal dose varies between patients and thus individual adaptation See Ivy D et al J Am Coll Cardiol 2013;62(25):D117 –D126.
7.2. Pulmonary arterial hypertension Patients with CHD (in particular those without shunts) may also
associated with adult congenital heart develop PH due to LHD (group 2, Table 4) or concomitant lung dis-
eases (group 3, Table 4). In these cases, a comprehensive diagnostic
disease workup, as reported in the section 7.1.1, is recommended.
PAH associated with adult CHD is included in group 1 of the PH
clinical classification (Table 4) and represents a very heterogeneous
patient population. A specific clinical classification (Table 6) and an 7.2.2. Therapy
anatomical –pathophysiological classification (Web Table II) are pro- Operability may be considered in patients with prevalent
vided to better characterize each individual patient with PAH asso- systemic-to-pulmonary shunting (Table 6). The criteria for shunt
ciated with adult CHD.13,309 Some malformations, such as patent closure based on baseline PVR have been proposed (Table 24)
ductus arteriosus, sinus venosus atrial septal defect or partial anom- based on available literature data.317 – 319 Additional criteria include
alous pulmonary venous return, are often concealed and patients the type of the defect, age, the PVR:SVR ratio and the Qp:Qs
are misclassified as suffering from IPAH. Hence these congenital ratio.320 No prospective data are available on the usefulness of
anomalies should be specifically sought. vasoreactivity testing, closure test or lung biopsy for operability
Epidemiological data remain scarce, as no studies have been de- assessment.320 Surgical or percutaneous intervention is contraindi-
signed to assess the prevalence of PAH in adult CHD, although the cated in patients with Eisenmenger syndrome and likely is useless in
figure of 5 –10% was reported in a European survey.310 Persistent patients with small/coincidental defects.
exposure of the pulmonary vasculature to increased blood flow The medical treatment strategy for patients with PAH associated

due to systemic-to-pulmonary shunts, as well as increased pressure, with CHD, and in particular for subjects with Eisenmenger syn-
may result in a typical pulmonary obstructive arteriopathy (identical drome, is mainly based on the clinical experience of experts rather
to other PAH forms) leading to an increase in PVR. If PVR ap- than being formally evidence-based.311 A specific treatment algo-
proaches or exceeds systemic vascular resistance (SVR), the shunt rithm has been proposed.309
is reversed (Eisenmenger syndrome).311 PAH associated with CHD patients should be managed in specia-
lised centres. Patient education, behavioural modifications and
awareness of potential medical risk factors are important aspects
7.2.1. Diagnosis of management.
As indicated in Table 6, the clinical presentation of adult patients Patients with PAH associated with CHD may present with clinical
with PAH may differ. Eisenmenger syndrome is a multisystem dis- deterioration in different circumstances, such as during non-cardiac
order and the most severe form of PAH in adult CHD. The signs surgery requiring general anaesthesia, dehydration, lung infections
and symptoms of Eisenmenger syndrome result from PH, low arter- and at high altitudes. It is recommended to avoid strenuous exercise,
ial O2 saturation and haematological changes, including secondary but mild activities seem to be beneficial. Pregnancy is associated
erythrocytosis, thrombocytopenia and at times leucopenia. They in- with very high risk to both the mother and foetus and should be dis-
clude dyspnoea, fatigue and syncope. In patients with PAH asso- couraged. Hence effective contraception is mandatory. Dual contra-
ciated with adult CHD without reversal of the shunt, the degree ception is indicated in patients taking ERAs in light of the interaction
of cyanosis and erythrocytosis may be mild to moderate. Eisenmen- with progesterone-based compounds.
ger syndrome patients also present with haemoptysis, cerebrovas- Long-term home O2 therapy may improve symptoms but has not
cular accidents, brain abscesses, coagulation abnormalities and been shown to modify survival, at least when given only at night.179
sudden death. Subjects with Eisenmenger syndrome have reduced The use of supplemental O2 therapy is recommended in cases in
life expectancy, although many survive into their third or fourth dec- which it produces a consistent increase in arterial O2 saturation
ade, with some even surviving up to their seventh decade.312 In pa- and reduces symptoms.
tients listed for lung or heart –lung transplantation when no medical The use of oral anticoagulant treatment in Eisenmenger syn-
treatment was available, Eisenmenger syndrome had better survival drome is controversial: a high incidence of PA thrombosis and
compared with IPAH, with a 3-year survival rate of 77% compared stroke is reported, but there is also an increased risk of haemor-
with 35% for untreated IPAH.313 In a recent study on the different rhage and haemoptysis.321 No data exist on this issue and thus def-
clinical groups of PAH patients associated with CHD (Table 6), the inite recommendations cannot be made. Oral anticoagulant
worst survival was observed in patients with PAH after defect repair treatment may be considered in patients with PA thrombosis, signs
or with small/coincidental defects as compared with patients with of heart failure and absent or only mild haemoptysis.321
Eisenmenger syndrome or those with prevalent systemic-to-pulmonary Secondary erythrocytosis is beneficial for adequate O2 transport
shunts.314 Improved survival may result from preservation of RV func- and delivery and routine phlebotomy should be avoided. If symp-
tion, as the RV does not undergo remodelling at birth and remains toms of hyperviscosity are present, phlebotomy with isovolumic re-
hypertrophied.315 The RV is also relieved by the right-to-left shunt, sus- placement should be performed, usually when the haematocrit is
taining CO at the expense of hypoxaemia and cyanosis. .65%. Iron deficiency should be corrected. No clear data support
Of all patients with CHD, those with Eisenmenger syndrome are the the use of CCBs in patients with Eisenmenger syndrome and the
most severely compromised in terms of exercise intolerance.314,316 empirical use of CCBs is dangerous and should be avoided.
One RCT is available with specific drug therapy in Eisenmenger

syndrome patients: bosentan has been shown to improve 6MWT Table 25 Recommendations for pulmonary arterial
and decrease PVR after 16 weeks of treatment in WHO-FC III hypertension associated with congenital heart disease
patients. Although a beneficial effect of bosentan has been shown
on exercise capacity and quality of life in this group of patients, Recommendations Classa Levelb Ref.c
an effect on mortality remains uncertain.200 Long-term follow-up
Bosentan is recommended in
(40 weeks) showed sustained improvement. 322 Bosentan is WHO-FC III patients with I B 200,322
currently approved in Europe for WHO-FC III Eisenmenger Eisenmenger syndrome
syndrome patients. Other ERAs, PDE-5is and
Experiences with other ERAs323 and the PDE-5is sildenafil314 and prostanoids should be considered 223,314,
IIa C
tadalafil324 show favourable functional and haemodynamic results in patients with Eisenmenger 323,324
in patients with PAH associated with CHD and Eisenmenger syndrome
syndrome. In the absence of significant
The use of i.v. epoprostenol has been reported in Eisenmenger haemoptysis, oral anticoagulant
syndrome patients, with favourable effects on haemodynamics and treatment may be considered in IIb C
patients with PA thrombosis or
exercise capacity, although central lines expose the patients to the
signs of heart failure
risk of paradoxical embolism and sepsis.223 No data are available on
The use of supplemental O2

the use of other prostanoids.
therapy should be considered
There are a few published data on combination therapy, in cases in which it produces
but the rationale is the same as in IPAH. 207,314 The use of IIa C 179
a consistent increase in arterial
PAH therapy to achieve the operability criteria in PAH with O2 saturation and reduces
systemic-to-pulmonary cardiovascular shunts (Table 24), allowing symptoms
defect correction (‘treat-to-close’ concept), is not supported by If symptoms of hyperviscosity are
available data. present, phlebotomy with
isovolumic replacement should be IIa C 183
considered, usually when the
haematocrit is .65%
Table 24 Recommendations for correction of
The use of supplemental iron
congenital heart disease with prevalent
treatment may be considered in
systemic-to-pulmonary shunts IIb C 184
patients with low ferritin plasma
levels
Combination drug therapy may be
Recommendations Classa Levelb Ref.c
considered in patients with IIb C 207,314
d
PVRi PVR Correctable Eisenmenger syndrome
(WU † m2) (WU)
The use of CCBs is not
,4 ,2.3 Yes IIa C 317 recommended in patients with III C 189
.8 .4.6 No IIa C 317 Eisenmenger syndrome
4–8 2.3– Individual

4.6 patient CCBs ¼ calcium channel blockers; ERAs ¼ endothelin receptor antagonists;
IIa C 317 O2 ¼ oxygen; PA ¼ pulmonary artery; PDE-5is ¼ phosphodiesterase type 5
evaluation in
inhibitors; WHO-FC ¼ World Health Organization functional class.
tertiary centres a
b
Level of evidence.
c
PVR ¼ pulmonary vascular resistance; PVRi ¼ pulmonary vascular resistance Reference(s) supporting recommendations.
index; WU ¼ Wood units.
a
b
Level of evidence.
c
d
With surgery or intravascular percutaneous procedure. 7.3 Pulmonary arterial hypertension
associated with connective tissue disease
PAH is a well-known complication of CTDs such as SSc, systemic
Heart – lung or lung transplantation with heart surgery is an lupus erythematosus, mixed CTD and, to a lesser extent, rheuma-
option in special cases not responsive to medical treatment, but is toid arthritis, dermatomyositis and Sjögren’s syndrome.325 – 329 PAH
limited by organ availability. Short- and long-term survival rates associated with CTD is the second most prevalent type of PAH after
following heart – lung transplantation are similar to other forms of IPAH in Western countries.10 SSc, particularly in its limited variant,
PAH. The prolonged estimated survival of patients with Eisenmen- represents the main CTD associated with PAH in Europe and the
ger syndrome makes the decision as to if and when patients should USA (systemic lupus erythematosus is more common in
be listed difficult.309 Asia).325,329 The prevalence of haemodynamically proven pre-
Recommendations for PAH associated with CHD are reported in capillary PH in large cohorts of SSc patients ranges from 5 to
the Table 25. 12%.46,325,330,331 In these patients, PH may occur in association
with interstitial lung disease or as a result of an isolated pulmonary Continuous i.v. epoprostenol therapy was shown to improve ex-
vascular disease, which may affect pre-capillary arterioles (PAH) and ercise capacity, symptoms and haemodynamics in a 3-month RCT in
post-capillary venules (PVOD).326,332 In addition, group 2 pulmon- SSc-PAH.222 However, retrospective analysis shows a better effect
ary venous hypertension from LHD may be present.76,326,333 It is of i.v. epoprostenol on survival in IPAH as compared with SSc-PAH.
thus imperative to determine which mechanism is operative since This may be due, at least in part, to co-morbidities such as cardio-
this dictates treatment in the context of a multifaceted disease. pulmonary involvement.
SSc should not be considered as an a priori contraindication for
7.3.1. Diagnosis lung transplantation.341 A multidisciplinary approach optimizing SSc
Compared with IPAH, patients with CTD and PAH are mainly wo- patient management before, during and after surgery is recom-
men (female:male ratio 4:1), are older (mean age at diagnosis .60 mended.341 Indications and contraindications for transplantation
years), may present concomitant disorders (interstitial lung disease, have to be adapted to the specificities of SSc with a special focus
LHD) and have shorter survival times.326,330,334 – 336 The unadjusted on digestive (gastro-oesophageal reflux disease and intestinal
risk of death for SSc-PAH compared with IPAH is 2.9 and the pre- disease), cardiac, renal and cutaneous involvement.
dictors of outcome are broadly similar as for IPAH.336 Symptoms The recommendations for PAH associated with CTD are
and clinical presentation are very similar to IPAH and occasional pa- reported in the Table 26.
tients thought to have IPAH can be identified as having an associated
CTD by immunological screening tests. High-resolution tomog-
Table 26 Recommendations for pulmonary arterial

raphy of the chest is helpful for evaluating the presence of associated
interstitial lung disease and/or PVOD.326,332,337 An isolated reduc- hypertension associated with connective tissue disease
tion of DLCO is a frequent abnormality in SSc associated with
PAH.327,338 Recommendations Classa Levelb Ref.c
Resting echocardiography is recommended as a screening test in
In patients with PAH associated with
asymptomatic SSc patients, followed by annual screening with echo- CTD, the same treatment algorithm as I C 46
cardiography, DLCO and biomarkers.325 A two-step composite for patients with IPAH is recommended
score has been proposed in the DETECT study to select patients Resting echocardiography is
who should have RHC.327 Specific recommendations for screen- recommended as a screening test in
ing/early detection are provided in Web Table IX. The cost- asymptomatic patients with SSc,
I C 46
effectiveness of these strategies has not been clarified as compared followed by annual screening with
with symptom-based detection. Echocardiography is recommended echocardiography, DLCO and
biomarkers
in the presence of symptoms in other CTDs. As in other forms of
PAH, RHC is recommended in all cases of suspected PAH asso- RHC is recommended in all cases of
I C 46,327
suspected PAH associated with CTD
ciated with CTD to confirm the diagnosis, determine severity and
rule out left-sided heart disease. Oral anticoagulation may be considered
on an individual basis and in the
IIb C 175,339
presence of thrombophilic
7.3.2 Therapy predisposition
Treatment of patients with CTD-associated PAH is more complex
than that of IPAH. Immunosuppressive therapy combining
CTD ¼ connective tissue disease; DLCO ¼ diffusing capacity of the lung for carbon
glucocorticosteroids and cyclophosphamide may result in clinical monoxide; IPAH ¼ idiopathic pulmonary arterial hypertension; PAH ¼ pulmonary
improvement in patients with PAH associated with systemic lupus arterial hypertension; RHC ¼ right heart catheterization; SSc ¼ systemic sclerosis.
a
erythematosus or mixed CTD.339 b
Level of evidence.
Long-term favourable response to CCB treatment is reported in c
,1% of cases.189 In SSc, the long-term risk:benefit ratio of oral an-
ticoagulation is less favourable than in IPAH because of an increased
risk of bleeding.175
Treatment of patients with CTD and PAH should follow the same 7.4 Pulmonary arterial hypertension
treatment algorithm as in IPAH (Figure 2). This recommendation is associated with portal hypertension
based on the fact that patients with CTD have been included in most PAH associated with portal hypertension is commonly referred to
of the major RCTs for regulatory approval of PAH therapy, including as PoPH. This entity should not be confused with hepatopulmonary
those with combination therapy. syndrome, which is characterized by abnormal pulmonary vasodila-
Subgroup analysis of patients with SSc enrolled in the RCTs per- tion and hypoxaemia.342 However, overlaps between both condi-
formed with bosentan, macitentan, sildenafil, riociguat and subcuta- tions may occur.343 As implied by the term, PoPH is associated
neous treprostinil have shown favourable effects. In some of these with the presence of portal hypertension, not necessarily with the
trials the magnitude of the response in the PAH subgroup associated presence of liver disease. However, as cirrhotic liver disease is by
with CTD was lower than in IPAH.340 The choice of PAH therapy in far the most common cause of portal hypertension, PoPH is most
the context of SSc and its generalized microangiopathy must take frequently encountered in patients with cirrhosis. Approximately
into account other vascular damage such as past/current digital 1 – 5% of patients with portal hypertension develop PAH344 and
ulcers. the risk seems to be largely independent from the aetiology of liver
disease and from the impairment of hepatic function.345 Although A few specialized centres offer combined liver – lung or liver –
some genetic risk factors have been described,346 the pathogenetic heart –lung transplantation for carefully selected patients.364
link between portal and PH remains unclear. The recommendations for PAH associated with portal hyperten-
sion are reported in the Table 27.
7.4.1 Diagnosis
In general, the signs and symptoms of PoPH are similar or identical
to most other forms of PAH, with progressive dyspnoea on exertion Table 27 Recommendations for pulmonary arterial
being the chief complaint. The clinical picture may be obscured by hypertension associated with portal hypertension
the presence and severity of the underlying liver disease. The diag-
nostic assessment follows the same recommendations as for other
forms of PH, keeping in mind that the co-existence of portal hyper-
tension and PH does not mean that these patients necessarily suffer Echocardiographic assessment for signs
of PH is recommended in symptomatic
from PoPH.344 A complete diagnostic workup including RHC is re- patients with liver disease or portal I B 344
quired to assess disease severity, haemodynamic profile and other hypertension and in all candidates for
potential causes of PH, including lung disease, LHD or chronic liver transplantation
thromboembolic disease. As a group, patients with PoPH tend to It is recommended that patients affected
have a higher CI and a lower PVR than patients with IPAH,347 but by PAH associated with portal

there is a wide overlap. hypertension should be referred to I C 344
centres with expertise in managing both
conditions
7.4.2 Therapy
The mortality risk of patients with PoPH is at least as high as in It is recommended that the treatment
algorithm for patients with other forms of
IPAH347,348 and these patients should be referred to centres with 214,
PAH should be applied to patients with
expertise in managing both PAH and liver disease. In general, treat- I C 350–
PAH associated with portal hypertension,
ment follows the general rules for other forms of PAH, but there are 356
taking into account the severity of liver
important considerations. Patients with PoPH often have an ele- disease
vated bleeding risk and anticoagulation is usually not recommended Anticoagulation is not recommended in
for these patients. Beta-blockers, which are frequently used to patients with PH associated with portal III C 365
lower the portal pressure, should be avoided in patients with hypertension
PoPH, as they worsen haemodynamics and exercise in this patient Liver transplantation may be considered
361–
population.349 in selected patients responding well to IIb C
363
Patients with PoPH have been excluded from almost all RCTs in PAH therapy
the PAH field (except for the PATENT study, which included 13 pa- Liver transplantation is contraindicated in
361–
tients with PoPH). Anecdotal reports suggest that ERAs, PDE-5is, patients with severe and uncontrolled III C
363
PAH
sGC stimulators and prostacyclin analogues may be used in this pa-
tient population.214,350 – 356 This includes potentially hepatotoxic
PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary hypertension.
drugs such as bosentan, but it should be noted that this compound a
tends to accumulate in patients with severely impaired liver function b
Level of evidence.
(i.e. Child– Pugh class B and C).356 Newer ERAs (ambrisentan, ma- c
citentan) have a theoretical advantage over bosentan, as the risk of
drug-associated liver toxicity is lower,194,201,357 but both drugs have
not been systematically evaluated in patients with PoPH.
The presence of PH is of particular importance in patients under-
going liver transplantation.358 Mild PH with normal or near-normal
7.5 Pulmonary arterial hypertension
PVR in the presence of high CO is usually well tolerated and tends to associated with human immunodeficiency
be reversible after transplantation.359 PAH, in contrast, has been virus infection
identified as a major risk factor in the setting of liver transplantation. The use of highly active antiretroviral therapy (HAART) and
In a series from the Mayo Clinic, the mortality rate was 100% in pa- aggressive management of opportunistic infections has contributed
tients with a PAPm ≥50 mmHg and 50% in patients with a PAPm to increased life expectancy in HIV-infected patients.366,367 Conse-
between 35 and 50 mmHg and a PVR ≥250 dyn.s.cm25.359 There- quently, the spectrum of complications has shifted towards other
fore patients evaluated for liver transplantation should be screened long-term conditions, including PAH. It is likely that modern HIV
for signs of PH, even in the absence of corresponding clinical symp- management with HAART has also resulted in improved survival
toms. In the past, significant PAH was considered a contraindication and decreased incidence of HIV-associated PAH.368 Taken together,
for liver transplantation, but anecdotal reports suggest that pre- these effects on survival and incidence have resulted in a stable
treating these patients with PAH drugs might improve the outcome PAH prevalence in HIV-infected patients over recent decades.
after liver transplantation.360 – 363 There is not yet sufficient evi- A population study indicated that the minimal prevalence of HIV-
dence to allow general recommendations and the transplant deci- related PAH was 0.46%, very similar to the prevalence before the
sion should be made by multidisciplinary teams in expert centres. HAART era.369 The pathogenesis of HIV-related PAH remains
unclear. The absence of viral particles in the complex plexiform le-

sions found from these patients suggests that an indirect action of Table 28 Recommendations for pulmonary arterial
viral infection on inflammation and growth factors may act as a trig- hypertension associated with human
ger in a predisposed patient. immunodeficiency virus infection
7.5.1 Diagnosis Recommendations Classa Levelb Ref.c

HIV-associated PAH shares a similar clinical presentation with Echocardiographic screening in
IPAH. At the time of diagnosis, a majority of patients are in an ad- asymptomatic HIV patients to detect PH III C 369
is not recommended
vanced New York Heart Association (NYHA)-FC III or IV. Patients
may present with other risk factors for PAH, such as liver disease In patients with PAH associated with
(chronic hepatitis B or C), exposure to drugs or toxins or PE due HIV infection, the same treatment
algorithm used for patients with PAH 194,
to i.v. drug abuse. Patients with HIV-associated PAH are more like- IIa C
should be considered, taking into 367
ly to be male and i.v. drug abusers. Animal research supports the consideration co-morbidities and drug–
notion that the additive effect of cocaine on HIV infection might drug interactions
play a role in the development of pulmonary arteriopathy. Because Anticoagulation is not recommended
of its low prevalence, asymptomatic HIV-infected patients should because of a lack of data on the III C 175,367
not be screened for PAH. However, echocardiography must be efficacy:risk ratio

performed in patients with unexplained dyspnoea to detect HIV-
related cardiovascular complications such as myocarditis, cardio- HIV ¼ human immunodeficiency virus; IPAH ¼ idiopathic pulmonary arterial
myopathy or PAH. RHC confirmation is mandatory to establish hypertension; PAH ¼ pulmonary arterial hypertension.
a
the diagnosis of HIV-related PAH and the absence of LHD.369 b
Level of evidence.
c
PAH is an independent risk factor for death in HIV-infected Reference(s) supporting recommendations.
patients.
7.5.2 Therapy
In the absence of specific recommendations, treatment of HIV- 7.6 Pulmonary veno-occlusive disease and
PAH follows guidelines for the treatment of IPAH together with pulmonary capillary haemangiomatosis
HAART. On multivariate analysis, a CI .2.8 l/min/m2 and a Both PVOD and PCH are uncommon conditions but are increasing-
CD4 lymphocyte count .200 cells/ml are independent predictors ly recognized as causes of PH.92,371 Pathologic characteristics of
of survival.225 Anticoagulation is not routinely recommended be- PCH are found in 73% of PVOD patients and, inversely, pathologic
cause of an increased risk of bleeding, anticipated compliance is- characteristics of PVOD are found in 80% of PCH patients.372 Simi-
sues and drug interactions. Patients with HIV-related PAH larities in pathologic features and clinical characteristics and the risk
appear to be non-responders to acute vasodilator challenge and of drug-induced pulmonary oedema with PAH therapy371,373 sug-
thus should not receive CCBs.189 Uncontrolled studies suggest gest that these two conditions overlap, and it has been proposed
that prostacyclins may improve exercise tolerance, haemodynam- that PCH could be a secondary angioproliferative process caused
ics and symptoms in HIV-related PAH.218 An open-label study re- by post-capillary obstruction of PVOD rather than a distinct dis-
ported the effects of bosentan in patients with HIV-related PAH, ease.6,372 Thus PVOD and PCH have been classified together in a
showing an improvement in all efficacy measures, including 6MWT specific subgroup of the clinical classification next to PAH (Table 4,
and invasive haemodynamics.370 Sporadic cases have been in- group 1′ ) because of their pathological, genetic and clinical similar-
cluded in the ambrisentan RCTs.194 Hepatic tolerability was similar ities and differences with PAH.6 The true incidence of PVOD/PCH
to previously reported observations in other forms of PAH. The remains unknown because many cases are still misclassified as
interpretation of these studies is limited by the small sample size PAH.374 The proportion of idiopathic cases of PAH that in reality
and their open-label nature. In the case of sildenafil, the dose fulfil the criteria for PVOD/PCH is likely to be around 10% (lowest
should be reduced if ritonavir and saquinavir are co-administered estimates of PVOD/PCH incidence and prevalence are ,1 case/mil-
due to drug – drug interactions. HIV infection is generally consid- lion).92,374 In contrast to IPAH, there is a male predominance in
ered an exclusion criterion for lung transplantation, even though PVOD and the prognosis appears to be worse.371 Familial occur-
in some centres specific programmes have been implemented. rence of PVOD has been reported, but BMPR2 mutations have rare-
Of note, cases of reversible disease have been described in HIV- ly been found in patients with this disease.28,371,375 While PAH that
PAH patients treated with HAART and specific therapies. This is due to BMPR2 mutations segregates as an autosomal dominant
finding, together with the decreased incidence of HIV-PH in the trait with incomplete penetrance, familial cases of PVOD/PCH typ-
modern management era, may indicate that aggressive manage- ically occur in the young siblings of one generation with unaffected
ment improves outcomes in this patient population. Further stud- parents, indicating that the disease segregates as a recessive trait.28
ies are needed to understand the underlying reasons of improved In these families, PVOD/PCH is caused by bi-allelic mutations in
outcomes in these patients. EIF2AK4.28 Like PAH, PVOD/PCH may complicate the course of
The recommendations for PAH associated with HIV infection are associated conditions (SSc, HIV infection, etc.) and exposure to
reported in the Table 28. drugs or toxins (cyclophosphamide, mitomycin, etc.).
7.6.1 Diagnosis reports of recurrence of disease following transplantation. Eligible

The diagnosis of PVOD/PCH can be established with a high prob- patients with PVOD/PCH should be referred to a transplant centre
ability by the combination of clinical suspicion, physical examination, for evaluation as soon as the diagnosis is established.379
bronchoscopy and radiological findings.371 This non-invasive ap- The recommendations for PVOD/PCH are reported in the
proach may avoid the need to perform a hazardous lung biopsy Table 29.
(the gold standard to confirm a histological diagnosis of PVOD/
PCH), which is no longer recommended in most cases.371 In herit-
able cases, identification of a bi-allelic EIF2AK4 mutation is sufficient Table 29 Recommendations for pulmonary
to confirm a diagnosis of PVOD/PCH without histological confirm- veno-occlusive disease and pulmonary capillary
ation.28,376 Most patients complain of dyspnoea on exertion and fa- haemangiomatosis
tigue, a clinical presentation that is indistinguishable from
PAH.371,374 Physical examination may reveal digital clubbing and bi-
basal crackles on lung auscultation, these being unusual in PAH.371
Case series indicate that patients with PVOD/PCH are more severe- A combination of clinical findings,
physical examination,
ly hypoxaemic and have much lower DLCO levels than in other 92,371,
bronchoscopy and radiological I C
forms of PAH.92,371 This can be explained by the presence of chron- findings is recommended to
378
ic interstitial pulmonary oedema and pulmonary capillary prolifer- diagnose PVOD/PCH

ation typical of PVOD/PCH. Identification of a bi-allelic EIF2AK4
Chest radiography may reveal Kerley B lines, mediastinal lymph mutation is recommended to
node enlargement and peripheral interstitial infiltrate, in addition confirm a diagnosis of heritable I B 28,376
to other signs of PH.92,371 High-resolution CT of the chest is the in- PVOD/PCH without histological
vestigation of choice. Typical findings suggestive of PVOD/PCH are confirmation
the presence of subpleural thickened septal lines, centrilobular Referral of eligible patients with
ground-glass opacities and mediastinal lymphadenopathy.92,371 The PVOD/PCH to a transplant centre
I C 371
for evaluation is indicated as soon as
association of these three findings was found to be 100% specific for
the diagnosis is established
PVOD/PCH in cases of PAH, with 66% sensitivity. In addition, their
Patients with PVOD/PCH should be
presence appears to closely correlate with the risk of pulmonary oe-
managed only in centres with
dema with PAH drugs. V/Q lung scanning is not useful in discrimin- 371,373,
extensive experience in PH due to IIa C
ating PVOD/PCH from IPAH.377 379
the risk of lung oedema after the
Because PVOD/PCH may be associated with occult alveolar initiation of PAH therapy
haemorrhage, bronchoscopy with bronchoalveolar lavage may be
a useful tool in the diagnostic strategy. In a retrospective study, PAH ¼ pulmonary arterial hypertension; PCH ¼ pulmonary capillary
the results of bronchoalveolar lavage performed in 19 patients haemangiomatosis; PH ¼ pulmonary hypertension; PVOD ¼ pulmonary
veno-occlusive disease.
with PAH or PVOD/PCH were analysed. Compared with IPAH, a
the eight cases of PVOD presented with a significantly elevated b
Level of evidence.
c
cell count, a higher percentage of hemosiderin-laden macrophages Reference(s) supporting recommendations.
and a markedly elevated Golde score.378

The haemodynamic presentation of PVOD is similar to
IPAH.92,371 Importantly, PAWP is almost invariably normal, because 8. Pulmonary hypertension due
the pathological changes occur in small venulae and capillaries and
do not affect the larger pulmonary veins.92,371 Vasoreactivity testing
to left heart disease (group 2)
may be complicated by acute pulmonary oedema.92,371 PH is a common complication of LHDs (PH-LHD), frequently occur-
ring as a ‘symptom’ of the underlying condition4,380 and often related
7.6.2 Therapy to disease severity. PH-LHD can complicate any left heart disorder,
There is no established medical therapy for PVOD/PCH.92 Most im- such as valvular heart diseases and congenital defects. However, it
portantly, vasodilators and, in particular, i.v. epoprostenol must be has been most often studied in patients with heart failure and with
used with great caution because of the high risk of severe preserved or reduced ejection fraction.4,380 When present, PH-LHD
drug-induced pulmonary oedema.92,373 However, there are reports results in more severe symptoms and worse exercise tolerance and
of sustained clinical improvement in individual patients treated with exerts a negative impact on outcome.4,380,381 Compared with PAH,
these medications.379 High-dose diuretics, O2 therapy and slow inpatients with PH-LHD [especially in the case of heart failure with pre-
creases in epoprostenol doses are recommended.379 Therefore served LV ejection fraction (HF-pEF)] are often older, female, with a
therapy for PVOD/PCH should be undertaken only at centres higher prevalence of cardiovascular co-morbidities382 and most, if not
with extensive experience in the management of PH and patients all, of the features of metabolic syndrome.383
should be fully informed about the risks. Investigational use of angio- The true prevalence of PH-LHD in heart failure remains un-
genesis inhibitors such as interferon alfa-2a has been considered in known, mostly because the definition of PH in epidemiological stud-
these patients but is not currently recommended.379 The only cura- ies has been based on echocardiography, with a variety of cut-off
tive therapy for PVOD/PCH is lung transplantation, and there are no values.4,384 Invasive haemodynamics were reported in a limited
number of single-centre reports.4 In a retrospective analysis per- PH-LHD. Therefore, for consistency with the general PH definition,
formed in a large PH centre, LHD was identified as the cause of it is recommended to use a combination of DPG and PVR to define
PH in 36% of all patients referred for evaluation, of which 55% the different types of PH-LHD, i.e. isolated post-capillary pulmonary
had ‘passive’ PH, defined as a TPG ,12 mmHg.151,385 hypertension (Ipc-PH) and combined post-capillary and pre-
PH develops in LHD in response to a passive backward transmis- capillary pulmonary hypertension (Cpc-PH) (Table 3).
sion of filling pressures, mainly driven by LV diastolic function, en-
hanced by exercise-induced mitral regurgitation and a loss of LA 8.1 Diagnosis
compliance.4 In some patients, these purely mechanical compo- In LHDs, and more specifically in left heart failure, PH can easily be
nents of venous congestion may trigger a superimposed compo- suspected by a stepwise approach, combining clinical presentation,
nent, combining pulmonary vasoconstriction, decreased NO specific echocardiographic features and other modalities such as
availability, increased endothelin expression, desensitization to ECG and other imaging techniques. Although no single variable
natriuretic peptide – induced vasodilation and vascular remodel- can differentiate PH-LHD from pre-capillary PH, the presence of
ling.4,380,386 This results in a further increase in PAPm in excess of multiple risk factors and findings should raise suspicion for PH-LHD
the elevation of PAWP that may lead to pulmonary vascular disease, (Table 30). PH should be suspected when patients present with
increased RV afterload and RV failure.4 otherwise unexplained symptoms, signs of right heart failure and co-
The definitions of PH and the difference between pre- and post- morbidities associated with PH, such as sleep apnoea syndrome,
capillary PH are based on pressure cut-off. This explains why TPG, COPD, previous PE and risk factors for PAH.

i.e. the difference between PAPm and PAWP, has been used to The respective role of fluid loading and exercise testing to un-
distinguish ‘passive’ PH (TPG ,12 mmHg) from ‘reactive’ PH (TPG cover PH-LHD in patients with HF-pEF is currently not standardized
≥12 mmHg).151 However, this definition and the associated and normal values are lacking to provide a clear recommendation to
terminology have been unsatisfactory, to such an extent that clinicians. In addition, it has been suggested that patients with a diag-
‘out-of-proportion’ PH-LHD has often been used to characterize a nosis of PAH may present an abnormal increase in PAWP in re-
subset of patients with significant changes in pulmonary circula- sponse to fluid loading.77
tion.4,151 Ideally the latter should be defined by a haemodynamic vari-
able that would (i) be a marker of disease, (ii) be least dependent on
changes in PAWP and stroke volume and (iii) take into account the Table 30 Examples of key factors suggestive of group
pulsatile nature of the pulmonary circulation.4,81 The TPG is influenced 2 pulmonary hypertension
by all the determinants of PAPm, including flow, resistance and left
heart filling pressure.4,81,82 In contrast, diastolic PAP when compared Clinical Other
Echocardiography
with PAPs and PAPm is less influenced by PAWP at any level of stroke presentation features
volume.4,81 Therefore the DPG (defined as diastolic PAP 2 mean
Age >65 years Structural left heart ECG
PAWP) appears to best approach the characteristics required to de- abnormality • LVH and/or LAH
termine pulmonary vascular disease.4,81 In normal subjects, DPG lies in • Disease of left heart valves •
the 1–3 mmHg range, and in patients evaluated for cardiac disease • LA enlargement (>4.2 cm) • LBBB
• Bowing of the IAS to the • Presence of Q
(excluding shunts), DPG remains ,5 mmHg in most cases.4,81,387 right waves
The role of DPG and TPG in predicting outcome in heart failure • LV dysfunction
has recently been reported.83,385,388 In a single-centre study of 3107 • Concentric LV hypertrophy
and/or increased LV mass
patients, a DPG .7 mmHg has been reported to be associated with
a worse prognosis in a subgroup of patients with increased TPG Symptoms of left Doppler indices of increased Other imaging
.12 mmHg.385 In another study on 463 patients with LV ejection heart failure • Kerley B lines
• Increased E/e’ • Pleural effusion
fraction ,40%, the risk of death was higher in patients with PH • >T • Pulmonary oedema
when the definition was based on PVR (P , 0.01), with a higher abnormality • LA enlargement
mortality rate in patients with a PVR ≥3 WU.387 However, the out-
Features of Absence of
come was not different whether the TPG was less than or greater metabolic • RV dysfunction
than 12 mmHg,83 suggesting that the latter could be less discrimin- syndrome • Mid systolic notching of
ant than PVR when PH is present. Interestingly, the authors re- the P
• Pericardial effusion
ported that pulmonary arterial compliance was an independent
marker of prognosis. Other investigators have also reported this ob- History of heart
servation, suggesting that PA compliance is altered in heart fail- disease
(past or current)
ure,389 even in the absence of PH.390 In 25 450 patients receiving
a heart transplant in the USA, 22.6% were found to have a TPG Persistent atrial
.12 mmHg.83 In this specific setting, the DPG was not found to pre-
dict a worse outcome at any level studied. Another recent study re-
ported the lack of prognostic value of the DPG even if significant AF ¼ atrial flutter; Afib ¼ atrial fibrillation; ECG ¼ electrocardiogram;
IAS ¼ inter-atrial septum; LA ¼ left atrium; LAH ¼ left atrial hypertrophy/
methodological limitations were raised.391 Although limited by their
dilatation; LBBB ¼ left bundle branch block; LV ¼ left ventricle; LVH ¼ left
retrospective nature, these studies do not provide a clear answer to ventricular hypertrophy; PA ¼ pulmonary artery; RV ¼ right ventricle.
the question of what is the best variable to predict outcome in
The indications for RHC in PH-LHD, preferably electively in

stable condition, are reported in Table 10. Table 31 Management of pulmonary hypertension
in left heart disease
8.2 Therapy
The primary goal of therapy in PH-LHD must be to improve global Recommendations Classa Levelb Ref.c
management of the underlying condition prior to considering specif-
Optimization of the treatment of the
ic measures to treat PH. This includes repair of valvular heart disease underlying condition is recommended
I B 396
when indicated and aggressive therapy for heart failure with reduced before considering assessment of PH-LHD
systolic function.4,392 Some patients may also benefit from non- (i.e. treating structural heart disease)
specific vasodilators such as nitrates and hydralazine, although It is recommended to identify other
evidence supporting this strategy is limited.4,392 In severe heart fail- causes of PH (i.e. COPD, sleep apnoea
ure, optimizing volume status is of critical importance and may re- syndrome, PE, CTEPH) and to treat them I C 396
when appropriate before considering
quire invasive monitoring.4,393 In addition, the implantation of an
assessment of PH-LHD
LV assist device has been shown to lower pulmonary pressures
It is recommended to perform invasive
through LV unloading without increasing the risk of post-
assessment of PH in patients on I C
implantation RV failure.4,394,395 Risk factors for cardiovascular dis- optimized volume status
eases and features of metabolic syndrome should be controlled.4,392
Patients with PH-LHD and a severe

Concomitant disorders leading to PH should be identified and trea- pre-capillary component as indicated by a
ted, including COPD, sleep apnoea syndrome and PE. In contrast, high DPG and/or high PVR should be
IIa C
there is no strong evidence-based recommendation for the treat- referred to an expert PH centre for a
ment for HF-pEF.392 complete diagnostic workup and an
The rationale to use PAH therapies in PH-LHD has been sup- individual treatment decision
ported by acute or short-term studies using prostanoids, ERAs and The importance and role of
PDE-5is. Most of these studies consistently reported improvements vasoreactivity testing is not established in
PH-LHD, except in patients who are III C 396
in haemodynamics, exercise capacity and symptoms.4,396 However,
candidates for heart transplantation and/
these studies carry significant methodological limitations (small sam- or LV assist device implantation
ple size, single centre, unclear or no randomization process) that do
The use of PAH-approved therapies is
not provide enough evidence to support the use of these drugs in the III C 396
not recommended in PH-LHD
clinical management of patients.4 In addition, there is no evidence sug-
gesting that acute changes in pulmonary circulation may have a value COPD ¼ chronic obstructive pulmonary disease; CTEPH ¼ chronic
outside of the setting of major cardiac surgery such as heart trans- thromboembolic pulmonary hypertension; DPG ¼ diastolic pressure gradient;
plantation and/or LV assist device implantation.4,380 LHD ¼ left heart disease; LV ¼ left ventricular; PE ¼ pulmonary embolism;
PH ¼ pulmonary hypertension; PVR ¼ pulmonary vascular resistance.
In a recent multicentre, placebo-controlled trial,397 201 patients a
with PH due to systolic heart failure were randomized in four arms b
Level of evidence.
c
comparing three doses of riociguat (0.5, 1 and 2 mg t.i.d.) with pla- Reference(s) supporting recommendations.
cebo over 16 weeks. No effect on the primary endpoint (a change in
PAPm after 16 weeks) was observed at any dose of riociguat com-
pared with placebo.397
Two multicentre clinical trials in PH-LHD are currently under common lung diseases associated with PH are COPD, interstitial
way with sildenafil [SilHF (NCT01616381)] and macitentan lung disease and combined pulmonary fibrosis and emphysema
[Melody-1 (NCT02070991)], the latter being the only study requir- (CPFE). Rare conditions such as Langerhans cell granulomatosis
ing RHC validation. or sarcoidosis are reported in Web Table VIII. In any lung disease,
Therefore there is no new evidence supporting the use of PAH the development of PH is accompanied by a deterioration of exer-
therapies in PH-LHD, due in part to the absence of studies specific- cise capacity, worsening of hypoxaemia and shorter survival.398 – 400
ally stratifying patients for PH and/or targeting this specific condi- The severity of PH is usually poorly associated with the severity of
tion. Such trials are necessary to address this area of unmet the underlying lung disease.401,402 The most common indicators for
medical need and patients with Cpc-PH should be included in clin- the presence of PH in these patients are a disproportionally low
ical trials. Recommendations for the management of PH-LHD are DLCO and a low pCO2.401,402
listed in Table 31. The haemodynamic classification of PH associated with lung dis-
ease is shown in Table 32.20 In case of severe PH, other potential
causes such as LHD or CTEPH should be excluded. In some patients
9. Pulmonary hypertension due with lung disease and PH, especially in patients with mild lung
to lung diseases and/or hypoxia disease but severe PH, it may be difficult to determine whether
PH is due to lung disease or whether the patient suffers from two
(group 3) diseases, i.e. PAH and chronic lung disease. Those patients should
The pathology, pathophysiology and epidemiology of these condi- be referred to a PH centre where there is also expertise in lung
tions have been discussed previously (see section 4). The most diseases.
Published experience with targeted PAH drug therapy is scarce, and

Table 32 Haemodynamic classification of pulmonary so far there is no evidence from RCTs suggesting that PAH drugs result
hypertension due to lung disease9 in improved symptoms or outcomes in patients with lung disease.411– 416
In summary, patients with lung disease and PH who are hypoxae-
Terminology Haemodynamics (right
heart catheterization)
mic should receive long-term O 2 therapy, adapting the general
recommendations for COPD. Treatment of the underlying lung dis-
COPD/IPF/CPFE without PH PAPm <25 mmHg
ease should be optimized. The use of drugs approved for PAH is not
COPD/IPF/CPFE with PH PAPm ≥25 mmHg
recommended for patients with PH due to lung disease. Patients
COPD/IPF/CPFE with severe PH PAPm >35 mmHg, or with suspected PAH in addition to their lung diseases (characterized
PAPm ≥25 mmHg in the presence
of a low cardiac output
by mild lung parenchymal abnormalities, symptoms insufficiently
(CI <2.5 L/min, not explained by explained by lung mechanical disturbances and a haemodynamic
other causes) ‘PAH phenotype’, i.e. severe PH with high PVR and low CO) may
be treated according to the recommendations for PAH, keeping
CI ¼ cardiac index; COPD ¼ chronic obstructive pulmonary disease; in mind the potential implications of the co-existing lung disease
CPFE ¼ combined pulmonary fibrosis and emphysema; IPF ¼ idiopathic on symptoms and response to therapy.
pulmonary fibrosis; PAP ¼ pulmonary artery pressure; PAPm ¼ mean pulmonary
arterial pressure; PH ¼ pulmonary hypertension. The recommendations for PH due to lung diseases are reported
in the Table 33.

9.1 Diagnosis
Table 33 Recommendations for pulmonary
Clinical symptoms and physical signs of PH may be difficult to identify hypertension due to lung diseases
in patients with respiratory disorders. In addition, in patients with lung
disease, peripheral oedema may not necessarily indicate RV failure, as
it may also result from the effects of hypoxaemia and hypercapnia on Recommendations Classa Levelb Ref.c
the renin-angiotensin-aldosterone system. Furthermore, concomi- Echocardiography is recommended for
tant LHD, which is frequently found in patients with chronic respira- the non-invasive diagnostic assessment 403,
I C
tory diseases, may also contribute to PH. As a general rule, patients of suspected PH in patients with lung 405
presenting with symptoms that are more severe than expected based disease
on their PFT results should be further evaluated, in particular by echo- Referral to an expert centre is
cardiography, to search for concomitant LHD or PH. recommendedd in patients with
echocardiographic signs of severe PH I C
Echocardiography remains the most widely used non-invasive
and/or severe right ventricular
diagnostic tool for the assessment of PH. Indications for echocardi- dysfunction
ography in patients with lung diseases include the clinical suspicion
The optimal treatment of the underlying
of significant PH or the evaluation of concomitant LHD. It should be lung disease, including long-term O2
noted, however, that the accuracy of echocardiography in patients therapy in patients with chronic I C 169
with advanced respiratory diseases is low.403 – 405 Patients with clin- hypoxaemia, is recommended in
ical or echocardiographic signs of severe PH and/or severe RV dys- patients with PH due to lung diseases
function should be referred to a PH centre. Referral to PH expert center should be
A definite diagnosis of PH relies on measurements obtained dur- considered for patients with signs of
IIa C
severe PH/severe RV failure for
ing RHC. Potential indications for RHC in advanced lung disease are
individual-based treatment
(i) proper diagnosis or exclusion of PH in candidates for surgical
treatments (transplantation, lung volume reduction), (ii) suspected RHC is not recommended for suspected
PH in patients with lung disease, unless
PAH or CTEPH, (iii) episodes of RV failure and (iv) inconclusive therapeutic consequences are to be
echocardiographic findings in cases with a high level of suspicion expected (e.g. lung transplantation, III C 169
and potential therapeutic implications. alternative diagnoses such as PAH or
CTEPH, potential enrolment in a clinical
trial)
9.2 Therapy The use of drugs approved for PAH is
411–
Currently there is no specific therapy for PH associated with lung not recommended in patients with PH III C
416
diseases. Long-term O2 administration has been shown to partially due to lung diseases
reduce the progression of PH in COPD. Nevertheless, PAP rarely
returns to normal values and the structural abnormalities of pul- CTEPH ¼ chronic thromboembolic pulmonary hypertension;
monary vessels remain unaltered.169 In interstitial lung diseases, PAH ¼ pulmonary arterial hypertension; PH ¼ pulmonary hypertension;
RHC ¼ right heart catheterization.
the role of long-term O2 therapy on PH progression is less clear. a
b
Treatment with conventional vasodilators such as CCBs is not re- Level of evidence.
c
commended because they may impair gas exchange due to the in- Reference(s) supporting recommendations.
d
This recommendation does not apply to patients with end-stage lung disease
hibition of hypoxic pulmonary vasoconstriction406 – 408 and who are not considered candidates for lung transplantation.
because of their lack of efficacy after long-term use.409,410
10. Chronic thromboembolic symptoms and signs are non-specific or absent in early CTEPH,
with signs of right heart failure only becoming evident in advanced
pulmonary hypertension (group 4) disease. Thus early diagnosis remains a challenge in CTEPH, with a
CTEPH is a disease of obstructive PA remodelling as a consequence median time of 14 months between symptom onset and diagnosis in
of major vessel thromboembolism. CTEPH has been reported with expert centres.421 When present, the clinical symptoms of CTEPH
a cumulative incidence of 0.1 – 9.1% within the first 2 years after a may resemble those of acute PE or IPAH; in the latter context, oe-
symptomatic PE event.417 The large margin of error is probably dema and haemoptysis occur more often in CTEPH, while syncope
due to referral bias, a paucity of early symptoms and difficulty in is more common in IPAH.422
differentiating acute PE from symptoms of pre-existing CTEPH.418 The diagnosis of CTEPH is based on findings obtained after at
Although the exact prevalence and annual incidence of CTEPH least 3 months of effective anticoagulation in order to discriminate
are unknown, some data suggest that this condition may occur in this condition from ‘subacute’ PE. These findings are mean PAP ≥25
approximately 5 individuals per million population per year.419 mmHg with PAWP ≤15 mmHg, mismatched perfusion defects on
In the differential diagnosis of CTEPH the following conditions lung scan and specific diagnostic signs for CTEPH seen by multide-
have to be considered and treated according to current best knowl- tector CT angiography, MR imaging or conventional pulmonary
edge. These conditions include PA sarcoma, tumour cell embolism, cineangiography, such as ring-like stenoses, webs/slits and chronic
parasites (hydatid cyst), foreign body embolism and congenital or total occlusions (pouch lesions or tapered lesions).
acquired PA stenosis (Table 4). Some patients, particularly those with complete unilateral ob-

struction, may present with normal pulmonary haemodynamics at
10.1 Diagnosis rest despite symptomatic disease. These patients are also consid-
ered to have CTEPH and are managed accordingly. A suitable ter-
Routine screening for CTEPH after PE is not supported by current
minology to describe this condition of chronic thromboembolic
evidence; a significant number of CTEPH cases develop in the ab-
pulmonary vascular disease is still lacking.
sence of previous acute PE.
An algorithm for CTEPH diagnosis is shown in Figure 3. While CT
The median age of patients at diagnosis is 63 years and both gen-
pulmonary angiography is the investigation of choice for the
ders are equally affected;25 paediatric cases are rare.287,420 Clinical
Symptoms, signs, history suggestive of CTEPH
Echocardiographic probability of PH (Table 8)
High or intermediate probability of PH
Yes V/Q scan a No

Mismatched perfusion defects?
CTEPH possible CTEPH ruled out
Refer to PH/CTEPH Work-up for PH/¨PAH

expert centre (Figure 1)
CT pulmonary angiography
Right heart catheterization
+/- Pulmonary angiography
CT = computed thomography; CTEPH = chronic thromboembolic pulmonary hypertension; PAH = pulmonary arterial hypertension; PH = pulmonary hypertension;
V/Q = ventilation/perfusion.
a
CT pulmonary angiography alone may miss diagnosis of chronic thromboembolic pulmonary hypertension.
Figure 3 Diagnostic algorithm for chronic thromboembolic pulmonary hypertension.

diagnosis of acute PE, planar V/Q lung scan remains the main first- manifest as a mosaic parenchymal pattern, with dark areas corre-
line imaging modality for CTEPH, as it carries a 96–97% sensitivity sponding to relatively decreased perfusion. Although a mosaic pat-
and a 90 –95% specificity for the diagnosis.47 In contrast, in IPAH and tern is frequent in CTEPH, it can also be observed in up to 12% of
PVOD, perfusion scans typically show non-segmental defects or are patients with PAH.425 MR imaging of the pulmonary vasculature is
normal.377 More recent work suggests that both V/Q scanning and still considered inferior to CT,426 but this modality, as well as
modern CT pulmonary angiography may be accurate methods for cone beam CT,427 angioscopy,428 intravascular ultrasound or optical
the detection of CTEPH, with excellent diagnostic efficacy in expert coherence tomography, may be complimentary and used according
hands (100% sensitivity, 93.7% specificity and 96.5% accuracy for to local experience and practice.
V/Q and 96.1%, 95.2% and 95.6%, respectively, for CT pulmonary RHC is an essential diagnostic tool. Preoperative and immediate
angiography).93,423,424 postoperative PVR is a long-term predictor of prognosis.429 The
Multidetector CT pulmonary angiography has become an estab- final step in the diagnostic pathway is selective pulmonary angiog-
lished imaging modality for confirming CTEPH,93 however, this investi- raphy in the anterior – posterior and lateral projections illustrating
gation alone cannot exclude the disease.47 CT pulmonary angiography ring-like stenosis, webs (‘slits’), pouches, wall irregularities, com-
may help to identify complications of the disease such as PA dilatation plete vascular obstructions as well as bronchial collaterals, and sup-
resulting in left main coronary artery compression and hypertrophied ports the technical assessment of operability.
bronchial arterial collaterals, which may lead to haemoptysis.
A high-resolution CT scan of the chest delivers images of the lung 10.2 Therapy

parenchyma and identifies emphysema, bronchial disease or intersti- 10.2.1 Surgical
tial lung disease, as well as infarcts, vascular and pericardial malfor- PEA is the treatment of choice for CTEPH (Figure 4). In Europe, in-
mations and thoracic wall deformities. Perfusion inequalities hospital mortality is currently as low as 4.7%,430 and even lower in
Diagnosis confirmed by
CTEPH expert center
Lifelong anticoagulation
Operability assessment
by a multidisciplinary CTEPH team
Technically operable Technically non-operable
Acceptable Non-acceptable
risk/benefit ratio risk/benefit ratio a
Targeted medical
therapy
Pulmonary Persistent
endarterectomy symptomatic PH
Consider BPA in
expert center b
Consider lung Persistent severe

transplantation symptomatic PH
BPA = balloon pulmonary angioplasty; CTEPH = chronic thromboembolic pulmonary hypertension; PH = pulmonary hypertension.
a
b
In some centers medical therapy and BPA are initiated concurrently.
Figure 4 Treatment algorithm for chronic thromboembolic pulmonary hypertension.

high-volume single centres.431 The majority of patients experience After PEA, patients should be followed in CTEPH centres, with at
substantial relief from symptoms and near normalization of haemo- least one haemodynamic assessment to be considered at 6 – 12
dynamics.430 – 432 In contrast to surgical embolectomy for acute PE, months after the intervention.
treatment of CTEPH necessitates a true bilateral endarterectomy
through the medial layer of the pulmonary arteries, which is per- 10.2.3 Interventional
formed under deep hypothermia and circulatory arrest,431 without In 2001 Feinstein et al. 443 published a series of 18 patients with
the need for cerebral perfusion.433 non-operable CTEPH who had been subjected to balloon dilata-
Operability of patients with CTEPH is determined by multiple fac- tion of the pulmonary arteries. Despite a significant decrease in
tors that cannot easily be standardized; these are related to the suit- PAPm, 11 patients developed reperfusion pulmonary oedema
ability of the patient, the expertise of the surgical team and available and 3 required mechanical ventilation. Recently, Japanese investiga-
resources. General criteria include preoperative WHO-FC II – IV tors have refined BPA by using smaller balloons, by cautiously lim-
and surgical accessibility of thrombi in the main, lobar or segmental iting the number of balloon inflations per session to one or two
pulmonary arteries. Advanced age per se is not a contraindication for pulmonary vascular segments and by the use of intravascular
surgery. There is no PVR threshold or measure of RV dysfunction imaging.444 – 446 An average number of 4.8 sessions is needed per
that can be considered to preclude PEA. patient to improve parameters of RV function.57 A careful ap-
Postoperative ECMO is recommended as a standard of care proach with targeting only one lobe during each session and
in PEA centres for severe cases.434 – 436 Early postoperative reperfu- very cautious balloon sizing have reduced the incidence of reper-

sion oedema may require veno-arterial ECMO, and severe persist- fusion pulmonary oedema to 2% in individual centres.447 While
ent PH may be bridged to emergency lung transplantation with BPA is still not extensively used,448 it is rapidly gaining attention
veno-venous ECMO. worldwide. BPA should only be performed in experienced and
Patients who do not undergo PEA or suffer from persistent or high-volume CTEPH centres.
recurrent PH after PEA (post-PEA PH) face a poor prognosis. The recommendations for CTEPH are summarised in Table 34.
10.2.2 Medical
Optimal medical treatment for CTEPH consists of anticoagulants
and diuretics, and O2 in cases of heart failure or hypoxaemia. Table 34 Recommendations for chronic
Lifelong anticoagulation is recommended, even after PEA, though thromboembolic pulmonary hypertension
no data exist on the efficacy and safety of new oral anticoagu-
lants. Although there is no consensus, routine cava filter place-
ment is not justified by the available evidence. Pulmonary Recommendations Classa Levelb Ref.c
microvascular disease in CTEPH has provided the rationale for In PE survivors with exercise
off-label use of drugs approved for PAH.25 Some non-randomized dyspnoea, CTEPH should be IIa C 449
studies have provided evidence for improvement in exercise cap- considered
acity and haemodynamics.437 – 439 Medical treatment of CTEPH Life-long anticoagulation is
with targeted therapy may be justified in technically non-operable recommended in all patients with I C 91
patients or in the presence of an unacceptable surgical risk:bene- CTEPH
fit ratio (Figure 2). Patients with persistent or recurrent PH after It is recommended that in all patients with
PEA may also be candidates for targeted medical therapy. The CTEPH the assessment of operability and
decisions regarding other treatment I C 91
use of targeted therapy in operable patients with severe haemo-
strategies should be made by a
dynamic compromise as a bridge to PEA has not yet been sup- multidisciplinary team of experts
ported by scientific evidence.
Surgical PEA in deep hypothermia
The dual endothelin antagonist bosentan was evaluated in 157 pa- circulatory arrest is recommended for I C 91
tients with inoperable CTEPH or persistent/recurrent PH after PEA patients with CTEPH
over 16 weeks; the primary combined endpoint of a decrease in PVR Riociguat is recommended in
and an increase in the 6MWD was not met.440 However, an oral symptomatic patients who have been
sGC stimulator, riociguat, was administered to 261 of 446 screened classified as having persistent/recurrent
patients with non-operable CTEPH or persistent/recurrent PH after CTEPH after surgical treatment or I B 441
inoperable CTEPH by a CTEPH team
PEA for 16 weeks and led to a mean increase of 39 m in the 6MWD
including at least one experienced PEA
(P , 0.001, primary endpoint) and to a least squares mean differ- surgeon
ence of 246 dyn.cm.s25 in PVR (P , 0.001, secondary endpoint);
Off-label use of drugs approved for PAH
the time to clinical worsening remained unchanged.441 may be considered in symptomatic
Preoperative medical treatment is uncertain because the magni- patients who have been classified as 437–
IIb B
tude of effects was small in one RCT.442 One retrospective study in- having inoperable CTEPH by a CTEPH 440
dicated no difference in outcome, but there was a delay in surgery team including at least one experienced
for patients treated medically.442 Prospective RCTs are needed in PEA surgeon
patients with potential treatment benefit; for example, patients
Continued
with a high PVR and technically challenging anatomy.
best outcomes for patients and undertake audits, research and

Table 34 Continued education.
Expert referral centres should have sufficient patients on chronic
therapy as well as new referrals to warrant this status. The ideal
number of patients seen by an adult centre each year is recom-
Interventional BPA may be considered in 57,
mended to be no fewer than 200, of which at least half have a final
patients who are technically 444–
IIb C diagnosis of PAH. In countries with a population .10 million, adult
non-operable or carry an unfavourable 446,
risk:benefit ratio for PEA 448 centres should ideally expand to accommodate .300 patients
Screening for CTEPH in asymptomatic
annually. It is recommended that a expert referral centre, as a
survivors of PE is currently not III C 417 minimum, should follow at least 50 patients with PAH or CTEPH
recommended and receive at least two new referrals per month with documented
PAH or CTEPH. Paediatric centres are recommended to see 30 –50
BPA ¼ balloon pulmonary angioplasty; CTEPH ¼ chronic thromboembolic patients per year. These numbers can be adapted according to spe-
pulmonary hypertension; PAH ¼ pulmonary arterial hypertension; cific country characteristics (population distribution, geographical
PE ¼ pulmonary embolism; PEA ¼ pulmonary endarterectomy.
a
constraints, etc.).
b
Level of evidence.
c

12.1 Facilities and skills required for a
expert referral centre
1. Expert referral centres are recommended to provide care by
An algorithm for the treatment of CTEPH is provided in Figure 4. an interprofessional team that should, as a minimum,
comprise:451 – 456
11. Pulmonary hypertension with (a) two consultant physicians (normally from either or both car-
diology and respiratory medicine) experienced in and with a
unclear and/or multifactorial special interest in PH with dedicated PH clinical sessions for
mechanisms (group 5) outpatients, inpatients and a multidisciplinary team meeting
(b) clinical nurse specialist
PH with unclear and/or multifactorial mechanisms (group 5, Table 4)
(c) radiologist with expertise in pulmonary hypertension imaging
includes several disorders with multiple patho-aetiologies. A com-
(d) cardiologist or PH physician with expertise in echocardiography
mon feature of these diseases is that the mechanisms of PH are
(e) cardiologist or PH physician with expertise in RHC and va-
poorly understood and may include pulmonary vasoconstriction,
soreactivity testing
proliferative vasculopathy, extrinsic compression, intrinsic occlu-
(f) access to psychological and social work support
sion, high-output cardiac failure, vascular obliteration and left heart
(g) appropriate on-call cover and expertise
failure as causes (Web Table VIII).
2. For expert referral centres, access to the following facilities is
These patients need careful diagnosis. Treatment is tailored for
recommended:
that diagnosis; treatment of PH is secondary. The axiom should
be ‘Treat the lung not the pressure’. There are no RCTs regarding (a) a ward where staff has special expertise in PH
the use of PAH-approved drugs in the treatment of group 5 disor- (b) an intensive therapy unit with relevant expertise
ders.450 Of particular importance is that some of the diseases de- (c) a specialist outpatient service
scribed in Web Table VII may have a venous component (PVOD) (d) emergency care
that could be made worse by the use of pulmonary arterial (e) diagnostic investigations including echocardiography, CT
vasodilators. scanning, nuclear scanning, MR imaging, ultrasound, exercise
testing, lung function testing and a cardiac catheterization
laboratory
12. Definition of a pulmonary (f) access to the full range of specific PAH and CTEPH drug ther-
hypertension expert referral apy available in their country
3. Expert referral centres are recommended to have established
centre networks (e.g. expert referral criteria, patient pathway and
PAH is a rare disease. Since, in general, medical centres with a high clinical management protocols) with other services that may
volume of patients tend to obtain the best outcomes, the establish- not necessarily be on the same site:452
ment of expert referral centres is clinically and economically highly (a) genetics
desirable and supported by patient organisations. The purpose of a (b) CTD
expert referral centre is to receive new referrals and undertake (c) family planning
assessment and investigation of all causes of PH, routinely manage (d) PEA
appropriate patients with PAH- and CTEPH-specific drug therap- (e) lung transplantation
ies, work closely with other healthcare providers to obtain the (f) adult CHD
4. Expert referral centres should consider undertaking a pro- 13. To do and not to do messages
gramme of clinical audit of adherence to guidelines and clinical
outcomes that includes survival analysis. Audits should also carry from the guidelines
out comparisons within the same country where there is more
than one expert referral centre.
5. Expert referral centres should consider participating in collab-
orative clinical research in PAH and CTEPH that includes phase
II and phase III clinical trials. Pulmonary hypertension diagnosis
6. Expert referral centres should consider raising awareness about Right heart catheterization is recommended to
expert referral criteria and provide regular education about all confirm the diagnosis of pulmonary arterial
I C
aspects of PH to appropriate healthcare professionals. In parti- hypertension (PAH - Group 1) and to support
treatment decisions
cular, education should be aimed at junior doctors in training
as well as senior colleagues. Vasoreactivity testing is recommended in patients
7. Expert referral centres should consider participating in the devel- with IPAH, HPAH and PAH induced by drugs use
I C
to detect patients who can be treated with high
opment and running of a network of PH centres within their own doses of a calcium channel blocker
country where there is more than one expert referral centre.
Pulmonary arterial hypertension severity
8. Expert referral centres should consider having a link to their

national and/or European PH patients’ associations. It is recommended to evaluate the severity of
PAH patients with a panel of data derived from
The recommendations for pulmonary hypertension expert referral clinical assessment, exercise tests, biochemical
markers, and echocardiographic and I C
centres are reported in the Table 35.
haemodynamic evaluation (Tables 13 and 14) and
to perform regular follow-up assessments every
3-6 months in stable patients /Table 14)
Table 35 Recommendations for pulmonary
Pulmonary arterial hypertension general measures
hypertension expert referral centres
It is recommended to avoid pregnancy in patients
I C
with PAH
a b
Recommendations Class Level Pulmonary arterial hypertension therapy
It is recommended for expert referral centres It is recommended for expert referral centres to
to provide care by a multiprofessional team provide care by a multi-professional team (cardiology
(cardiology and respiratory medicine and respiratory medicine physicians, clinical nurse I C
I C
physicians, clinical nurse specialist, specialist, radiologists, psychological and social work
radiologists, psychological and social work support, appropriate on-call expertise)
support, appropriate on-call expertise)
Initial approved drugs monotherapy is
It is recommended for expert referral centres recommended in treatment naı̈ve, low or
to have direct links and quick referral patterns I A
intermediate risk patients with pulmonary arterial
to other services (such as CTD, family I C hypertension (Table 19)
planning, PEA, lung transplantation, adult
congenital heart disease) Initial approved oral drugs combination therapy is
recommended in treatment naı̈ve, low or
It should be considered that a expert referral I B
intermediate risk patients with pulmonary arterial
centre follow at least 50 patients with PAH hypertension (Table 20)
or CTEPH and should receive at least two IIa C
new referrals per month with documented Sequential drugs combination therapy is
PAH or CTEPH recommended in patients with inadequate
I B
treatment response to initial monotherapy or to
It should be considered that a expert referral initial double combination therapy (Table 21)
centre perform at least 20 vasoreactivity
IIa C Recommendations for left heart disease and lung diseases
tests in IPAH, HPAH or DPAH patients per
year The use of PAH approved therapies is not
Expert referral centres should participate in recommended in patients with pulmonary III C
collaborative clinical research in PAH, IIa C hypertension due to left heart disease or lung diseases
including phase II and phase III clinical trials Recommendations for chronic thromboembolic
pulmonary hypertension
CTD ¼ connective tissue disease; CTEPH ¼ chronic thromboembolic Surgical pulmonary endarterectomy in deep
pulmonary hypertension; DPAH ¼ drug-induced pulmonary arterial hypothermia circulatory arrest is recommended
hypertension; HPAH ¼ heritable pulmonary arterial hypertension;
for patients with CTEPH and it is recommended
IPAH ¼ idiopathic pulmonary arterial hypertension; PAH ¼ pulmonary arterial
that the assessment of operability and decisions I C
hypertension; PEA ¼ pulmonary endarterectomy.
a
Class of recommendation. regarding other treatment strategies (drugs
b
Level of evidence. therapy or balloon pulmonary angioplasty) be
c
Reference(s) supporting recommendations. made by a multidisciplinary team of experts
ology, Pavel Jansa; Denmark: Danish Society of Cardiology, Jens

14. Web addenda Erik Nielsen-Kudsk; Estonia: Estonian Society of Cardiology, Ly
All Web figures and Web tables are available in the Web addenda at: Anton; Finland: Finnish Cardiac Society, Pertti Jääskeläinen;
http://www.escardio.org/Guidelines-&-Education/Clinical-Practice- France: French Society of Cardiology, Fabrice Bauer; Georgia:
Guidelines/Pulmonary-Hypertension-Guidelines-on-Diagnosis- Georgian Society of Cardiology, Archil Chukhrukidze; Germany:
and-Treatment-of German Cardiac Society, Christian Opitz; Greece: Hellenic Car-
diological Society, George Giannakoulas; Hungary: Hungarian
Society of Cardiology, Kristóf Karlócai; Iceland: Icelandic Society
15. Appendix of Cardiology, Hjörtur Oddsson; Ireland: Irish Heart Foundation,
ESC Committee for Practice Guidelines (CPG): Jose Luis Sean Gaine; Israel: Israel Heart Society, Doron Menachemi; Italy:
Zamorano (Chairperson) (Spain), Victor Aboyans (France), Stephan Italian Federation of Cardiology, Michele Emdin; Kyrgyzstan:
Achenbach (Germany), Stefan Agewall (Norway), Lina Badimon Kyrgyz Society of Cardiology, Talant Sooronbaev; Latvia: Latvian
(Spain), Gonzalo Barón-Esquivias (Spain), Helmut Baumgartner Society of Cardiology, Ainars Rudzıtis; Lithuania: Lithuanian Soci-
(Germany), Jeroen J. Bax (The Netherlands), Héctor Bueno (Spain), ety of Cardiology, Lina Gumbiene; Luxembourg: Luxembourg
Scipione Carerj (Italy), Veronica Dean (France), Çetin Erol (Turkey), Society of Cardiology, Frederic Lebrun; Malta: Maltese Cardiac
Donna Fitzsimons (UK), Oliver Gaemperli (Switzerland), Paulus Society, Josef Micallef; Moldavia: Moldavian Society of Cardiology,
Kirchhof (Germany/UK), Philippe Kolh (Belgium), Patrizio Lancellot- Victor Botnaru; Morocco: Moroccan Society of Cardiology, Latifa

ti (Belgium), Gregory Y.H. Lip (UK), Petros Nihoyannopoulos (UK), Oukerraj; Norway: Norwegian Society of Cardiology, Arne
Massimo F. Piepoli (Italy), Piotr Ponikowski (Poland), Marco Roffi K. Andreassen; Poland: Polish Cardiac Society, Marcin Kurzyna;
(Switzerland), Adam Torbicki (Poland), Antonio Vaz Carneiro (Por- Portugal: Portuguese Society of Cardiology, Maria João Ribeiro
tugal), Stephan Windecker (Switzerland). Leite Baptista; Romania: Romanian Society of Cardiology,
ESC National Cardiac Societies actively involved in the re- Ioan Mircea Coman; Russia: Russian Society of Cardiology, Olga
view process of the 2015 ESC/ERS Guidelines for the diagnosis Moiseeva; Serbia: Cardiology Society of Serbia, Branislav
and treatment of pulmonary hypertension: S. Stefanović; Slovakia: Slovak Society of Cardiology, Iveta Šimko-
Albania: Albanian Society of Cardiology, Sokol Myftiu; vá; Sweden: Swedish Society of Cardiology, Gerhard Wikström;
Austria: Austrian Society of Cardiology, Diana Bonderman; Switzerland: Swiss Society of Cardiology, Markus Schwerzmann;
Azerbaijan: Azerbaijan Society of Cardiology, Ibrahimov Firdovsi; The Former Yugoslav Republic of Macedonia: Macedonian
Belarus: Belorussian Scientific Society of Cardiologists, Irina FYR Society of Cardiology, Elizabeta Srbinovska-Kostovska;
Lazareva; Belgium: Belgian Society of Cardiology, Michel De The Netherlands: Netherlands Society of Cardiology, Arie
Pauw; Bosnia & Herzegovina: Association of Cardiologists of P. J. van Dijk; Tunisia: Tunisian Society of Cardiology and Cardio-
Bosnia & Herzegovina, Šekib Sokolović; Bulgaria: Bulgarian Vascular Surgery, Abdallah Mahdhaoui; Turkey: Turkish Society of
Society of Cardiology, Vasil Velchev; Croatia: Croatian Cardiac Cardiology, Cihangir Kaymaz; UK: British Cardiovascular Society,
Society, Maja Čikeš; Cyprus: Cyprus Society of Cardiology, Josef Gerry Coghlan; Ukraine: Ukrainian Association of Cardiology,
Antoniou Moutiris; Czech Republic: Czech Society of Cardi- Yuriy Sirenko.
The CME text ‘2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension’ is accredited by the European Board for Accreditation in Cardiology (EBAC).
EBAC works according to the quality standards of the European Accreditation Council for Continuing Medical Education (EACCME), which is an institution of the European Union of
Medical Specialists (UEMS). In compliance with EBAC/EACCME Guidelines, all authors participating in this programme have disclosed any potential conflicts of interest that might cause
a bias in the article. The Organizing Committee is responsible for ensuring that all potential conflicts of interest relevant to the programme are declared to the participants prior to the
CME activities.
CME questions for this article are available at: European Heart Journal http://www.oxforde-learning.com/eurheartj and European Society of Cardiology http://www.escardio.
org/guidelines.
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European Heart Journal Advance Access published October 21, 2015

European Heart Journal ESC/ERS GUIDELINES

2015 ESC/ERS Guidelines for the diagnosis

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6.3.7 Advanced right ventricular failure . . . . . . . . . . . . . 28

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Table 1 Classes of recommendations

Classes of Suggested wording to use

Class I Evidence and/or general Is recommended/is

Class II Conflicting evidence and/or a

Class IIa Weight of evidence/opinion is in Should be considered

Class IIb Usefulness/efficacy is less well May be considered

Class III Evidence or general agreement Is not recommended

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appropriate and/or necessary. It is also the health professional’s re-

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Table 3 Haemodynamic definitions of pulmonary hypertensiona

Characteristicsa Clinical group(s)b

PH PAPm ≥25 mmHg All

Pre-capillary PH PAPm ≥25 mmHg 1. Pulmonary arterial hypertension

Post-capillary PH PAPm ≥25 mmHg 2. PH due to left heart disease

Isolated post-capillary PH DPG <7 mmHg and/or

Combined post-capillary and pre-capillary PH DPG ≥7 mmHg and/or

regard to pathological findings (absence of plexiform lesions),

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obstruction and congenital cardiomyopathies

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Table 9 Diagnostic management suggested according to echocardiographic probability of pulmonary hypertension in

Without risk factors or With risk factors or

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† Derived variables calculated from the RHC measurements

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Symptoms, signs, history suggestive of PH

Echocardiographic probability of PH (Table 8)

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Yes Diagnosis of left heart diseases or Yes

Treat underlying V/Q scana Refer to PH

PAH likely Consider other

Heritable Idiopathic Idiopathic Heritable

Figure 1 Diagnostic algorithm.

common clinical groups of PH [group 2 (LHD) and group 3 (lung

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Table 13 Risk assessment in pulmonary arterial hypertension

RAP <8 mmHg RAP 8–14 mmHg RAP >14 mmHg

Medical assessment and

6MWT/Borg dyspnoea score + + + + +

Blood gas analysisd + + + +

Right heart catheterization + +f +e +e

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6.2.5 Definition of patient status

patient in WHO-FC II whenever possible. In most patients, this

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on prognosis. Exercise training programmes should be implemented 6.3.1.5 Psychosocial support

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