2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension Se eee eee ean, ieee meee EUROPEAN Sociery oFTask Force 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 the Association for European Paediatric and Congenital Cardi and the International Society for Heart and Lung Transplantation (ISHLT) ESC Chairperson ERS Chairperson Nazzareno Gal Marc Humbert? Department of Experimental, Service de Pneumologie Diagnostic & Specialty Medicine-DIMES Hopital Bic8tre (AP-HP) University of Bologna Université Paris-Sud Via Massarenti 9 78 rue du Général Ledere 40138 Bologna, Italy 94270 Le Kremlin-Bicétre, France Tel: +39 051 349 858 Tel: +33 1.45.21 7972 Fax: +39 051 344 859 Fox: +33 145 21 79 71 Email: nazzareno.galie@unibo.it Email: marc.humbert@aphp.fr ‘Task Force Members: Jean-Luc Vachiery (Belajum), Simon Gibbs (UX), Trene Lang (Austr), Adam Torbicki (Poland), Gérald Simonneau? (France), Andrew Peacock? (UK), Anton Vonk Noordegraaf (The Netherlands), Maurice Beghetti» (Switzerland), Ardeschir Ghofranie (Germany), Miguel Ange Gomez Sanchez (Spain), Georg Hansmenn® (Germany), Walter Klepetko® (Austra), Patni Lancellot (Belgium), Merco Matuce(Italy), ‘Theresa McDonagh (UK), Luc A. Pierard (Belgium), Pedro T. Trindade (Switzerland), Maurizio Zompatori¢ (Italy) and Marius Hoeper® (Germany) ‘Representing the European Respiratory Society (ERS) - *Representng the Assocation for European Paediatric and Congenital Cardiology (AEPC). “Representing the Intemabonal Socety for Heart and Lung Transplantation (ISHLT). sRepresonting the European League Against Rheumatism (EULAR). «Representing the European Sooty of Radiology @ERS @ socomerdie.ote Srpsn eat una 09697 7-19 a 10 ceoeueaniena? Sit See eee | anomie coeESC Classes of recommendations fires re tay Etereee ke) Seer Class I Conflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure. Class Ila Weight of evidence/opinion is in favour Should be considered. of usefulness/efficacy. Class Ib Usefulness/efficacy is less well May be considered. established by evidence/opinion. Class IIT “Evidence or general agreement that _Is not recommended. the given treatment or procedure is “not useful/effective, and in some cases may be harmful. ERS sano ( European Hear Journal 2016:37'67—119 -aov'10 10sveuneartieMarT ropean Respiratory Journal 2015 46: 903-975;ESC Levels of evidence Level of LTTE tee. Level of baU te U eM] Level of Evidence © Data derived from multiple randomized clinical trials or meta-analyses. Data derived from a single randomized clinical trial or large non-randomized studies. Gonsensus of opinion of the experts and/ or small studies, retrospective studies, registries. @ ERS » Esritos European Hear Journal 201637 67—119 dos 10 10s0/eunearyienva European Respiratory Journal 2015 46: 903-075;Outline + _Definitions and classifications + Pulmonary hypertension diagnosis + Diagnostic algorithm + Pulmonary arterial hypertension (Group 1) + Evaluation of severity + Treatment algorithm + Specific pulmonary (arterial) hypertension subsets + Paediatric pulmonary arterial hypertension + Pulmonary arterial hypertension associatedwith adult congenital heart disease + Pulmonary arterial hypertension associated with connective tissue disease + Pulmonary arterial hypertension associated with portal hypertension + Pulmonary arterial hypertension associated with human immunodeficiency virus infection + Pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis + Pulmonary hypertension due to left heart disease (Group 2) + Pulmonary hypertension due to lung diseases and/or hypoxia (Group 3) + Chronic thromboembolic pulmonary hypertension (Group 4.1) + Definition of a pulmonary hypertension referral centre @ERS &@ MON eae ae European Heart Journal 2016:37'6?—119 do 10 10sueuneartienvan7 Sire ‘European Respiratory Journal 2015 46: 903-975;Outline + Definitions and classifications + Pulmonary hypertension diagnos + Diagnostic algorithm + Pulmonary arterial hypertension (Group 1) + Evaluation of severity + Treatment algorithm + Specific pulmonary (arterial) hypertension subsets + Paediatric pulmonary arterial hypertension + Pulmonary arterial hypertension associatedwith adult congenital heart disease + Pulmonary arterial hypertension associated with connective tissue disease + Pulmonary arterial hypertension associated with portal hypertension + Pulmonary arterial hypertension associated with human immunodeficiency virus infection + Pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis + Pulmonary hypertension due to left heart disease (Group 2) + Pulmonary hypertension due to lung diseases and/or hypoxia (Group 3) + Chronic thromboembolic pulmonary hypertension (Group 4.1) * Definition of a pulmonary hypertension referral ““"@ E RS eer @ RESPIRATORY SOCIETY MON eae ae European Heart Journal 2016:37'6?—119 do 10 10sueuneartienvan7 Sire ‘European Respiratory Journal 2015 46: 903-975;Outline + Definitions and classifications + Pulmonary hypertension diagnosis * Diagnostic algorithm + Pulmonary arterial hypertension (Group 1) + Evaluation of severity + Treatment algorithm + Specific pulmonary (arterial) hypertension subsets + Paediatric pulmonary arterial hypertension + Pulmonary arterial hypertension associatedwith adult congenital heart disease + Pulmonary arterial hypertension associated with connective tissue disease + Pulmonary arterial hypertension associated with portal hypertension * Pulmonary arterial hypertension associated with human immunodeficiency virus infection + Pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis + Pulmonary hypertension due to left heart disease (Group 2) + Pulmonary hypertension due to lung diseases and/or hypoxia (Group 3) + Chronic thromboembolic pulmonary hypertension (Group 4.1) + Definition of a pulmonary hypertension referral centre © ERS Bas% @ Eur Heart) 2016:37;67-219 Sue ee www.escardio.org doi:20,1093/eurheard/ehv3i7 seogeest Eur Respir 3, 2018 SipserHaemodynamic definitions of pulmonary hypertension eisai (Tiielsrotnea> PH | PAPm 225 mmHg All Pre-capillary PH Papm 225 mmHg 1. Pulmonary arterial PAWP <15 mmHg hypertension 3. PH due to lung diseases Chronic thromboembolic PH PH with unclear and/or multifactorial mechanisms a | Post-capillary PH Pam 225 mmHg PH due to left heart disease CaaS. PH with unclear and/or Isolated post-capillary PH _DPG <7 mmHg and/or | multifactorial mechanisms (Ipc-PH) | PVR $3 WUs Combined post-capillary and | DPG >7 mmHg and/or pre-capillary PH (Cpc-PH) | PVR >3 WU " ardlac output; DPG = diastale pressure gradient (diastolic PAP - mean PAWP); mPAP — mean pulmonary arterial 'e; PAWP = pulmonary artenal wedge pressure; PH = pulmonary hypertension; PVR = pulmonary vascular resistance; WW = Weed units +All values measured at rest; see also section 7. according to Table 4 ‘Wood units ae preferred to dynes. s.cm @ ERS : oe © www.escardio.org seers European Hear Journal 201637 67—119 doy 10 10s0/euneary European Respiratory Journal 2015 46: 903-075;Comprehensive clinical classification of pulmonary hypertension eae 1.1 Idiopathic 1.2 Henitable 1.2.1 BMPR2 mutation 1.2.2 Other mutations 1.3 Drugs and toxins induced 1.4 Assodated with; 1.4.1 Connective tissue disease 1.4.2 human immunodeficiency virus (HIV) infection 1.4°3 Portal hypertension 1.4:4 Congenital heart disease (Table 5) 1.415 Schistosomiasis 1’, Pulmonary veno-ocdusive disease and/or pulmonary capillary haemangiomatosis 1/1 Idiopathic 1.2 Heritable 12.1 EIF2AK4 mutanon 12.2 Other mutations 1.3 Drugs, toxins and radiation induced 1-4 Associated with: 14.1 Connective tissue disease 174.2 HIV infection 11”, Persistent pulmonary hypertension of the newborn Cesena seers ues eo fetes 2.4 Left ventricular systolic dysfunction 2.2 Left ventricular diastolic dysfunction 2.3 Valvular disease 2.4 Congenital/acquired left heart inflow/outfow tract obstruction and congenital cardiomyopathies 2.5 Congenital/acquired pulmonary veins stenosis www.escardio.org European Heart Journal 2016:37, Pana essed EiuAualh oO.) 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 ther pulmonary diseases with mixed restricave and obstructive pattem 3.4 Sleep-dsordered breathing 3.5 Alveolar hypoventilation disorders, 2.6 Chronic expasure to high altitude 3.7 Developmental lung diseases (Web Table 11) fact Tonos oe iis See fess hoes 4.1 Chrenic thromboembolic pulmonary hypertension 4.2. Other pulmonary artery obstructions 4.2.1 Angiosarcoma 4.2.2 Other intravascular tumors 42:3 artentis, 4.2.4 Congenital pulmonary arteries stenoses 4:25 Parasites (hnydatidoss) Etta een Gibesieta ses sce 5.1 Haematological disorders: chronic haemolytic anaemia, myeloproliferative disorders, splenectomy 5.2.Systemic disorders: sarcoidosis, pulmonary histiocytods, Iymphangioleiomyomatosis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: pulmonary tumoral thrombothic micreangiopathy, fibrosng medaastinibs, chronic renal failure (with/wthout dialysis), segmental pulmonary hhypertension Te een 419-aoi 10 10Geuneartienvan7 Gian ‘European Respiratory Journal 2015 46: 903-975;ety Clinical class' ation of pulmonary arterial hypertension associated with congenital heart disease 1. Eisenmenger’s syndrome Includes all large intra- and extra-cardiac defects which begin as systemic-to-pulmonary shunts and progress with time to severe elevation of PVR and to reversal (pulmonary-to- systemic) or bidirectional shunting; cyanosis, secondary erythrocytosis, and multiple organ involvement are usually present, 2. PAH associated with prevalent systemic-to-pulmonary shunts + Correctable® + Non-correctable Includes moderate to large defects; PVR Is mildly to moderately Increased, systemic-to- ulmonary shunting is still prevalent, whereas cyanosis at rest is not a feature, . PAH with small/coincidental> defects Marked elevation In PVR In the presence of small cardiac defects (usually ventricular septal defects <1 cm and atrial septal defects <2 cm of effective diameter assessed by echo), which themselves do not account for the development of elevated PVR; the clinical picture Is very similar to idiopathic PAH. Closing the defects is contra-indicated. 4. PAH after defect correction Congenital heart disease Is repaired, but PAH elther persists immediately after correction or recurs/develops months or years after correction in the absence of significant postoperative haemodynamic lesions. PAH = pulmonary artenal hypertension; PVR = pulmonary vascular resistance with surgery or Intravascular percutaneous procedure. the size applies to adult patients. However, also in adults the simple diameter may be not sufficent for defining ‘the haemodynamic relevance of the defect, and also the pressure gradient, the shunt size and direction, & the pulmonary to systemic flows ratio should be considered (Web Table IT on the web at; www.escardio.org/ guidelines). B ERS PuROPEAN @ Micon ad european Hear Jounal201637 51-19-4010 tosseumnearyjeniat7 ae European Respiratory Journal 2015 46: 903-075;Anatomical-pathophysiological ication of congenital systemic-to-pulmonary shunts 1.1 Simple pre-tricuspid shunts 1.4.1 Atrial septal defect (ASD) 1.1.1.1 Ostium secundum 1.1.1.2 Sinus venous 1.1.1.3 Ostium primum 1.1.2 Total or partial unobstructed anormalous: pulmonaty venous 1.2 Simple post-tricuspid shunts 4.2.4 Ventricular septal defect (VSD) 1.2.2 Patent ductus arteriosus 1.3 Combined shunts Descnbe combination and define predominant defect 1.4 Complex congenital heart disease 1.4.1 Complete atrioventricular septal defect 4.4.2 Truneus arteriosus 1.4.3 Single ventricle physiology with unobstructed pulmonary blood flow 1.4.4 Transposition of the great arteries with Vsb (without pulmonary stenosis) and/or patent ductus arteriosus 1.4.5 Other www.escardio.org = Ratio of pulmonary (Qp) to systemic (Qs) blood flow. ® ERS x The size applies to adult patients, European Hear Journal 2076:37'67—119-ao European Respiratory Journal 2015 46: 903-4 2. Dimension (specify for each defect if more than ore eee renee) 2.1 Haemodynamic (specify Qp/Qs)* 2.1.1 Restrictive (pressure gradient accross the defect) 2.1.2 Non-restrictive 2.2 Anatomic’ 2.2.1 Small to moderate (ASD $2.0 am and VSD < 1.0 cm) 2.2.2 Large (ASD >2.0 cm and VSD >4.0 an) 3. Direction of shunt 3.1 Predominantly systemic-to-pulmonary 8.2 Predominantly pulmonary-to-systemic 3.3 Bidirectional Peres Bist Ca eet 5.1 Unoperated 5.2 Palliated (speaty type of operation/s, age at surgery) 5.3 Repaired (specify type of operation/s, age at surgery) 0 10s/euneartenvenT ¥Developmental lung disease associated with pulmonary hypertension . Congenital diaphragmatic hernia . Bronchopulmonary dysplasia Alveolar capillary dysplasia (ACD) . ACD with misalignment of veins . Lung hypoplasia “primary” or “secondary”) 1 2, a 4. 5 6. . Surfactant protein abnormalities a. Surfactant protein B deficiency b, Surfactant protein C deficiency c. ATP-binding cassette A3 mutation d, Thyroid transcription factor I/Nkx2.1 homeobox mutation ~ Pulmonary interstitial glycogenosis o . Pulmonary alveolar proteinosis 0 |. Pulmonary lymphangiectasia @ ERS 2 @ www.escardio.org see European Hear Journal 2016:37'67—119 -aov'10 10sveuneartieMarT ‘European Respiratory Journal 2015 46: 903-975;Diagnostic investigations utilised in patients with PH + Electrocardiogram + Chest radiograph + Echocardiography + Pulmonary function tests and arterial blood gases + Ventilation/perfusion lung scan + High-resolution computed tomography, contrast enhanced computed tomography + Cardiac magnetic resonance imaging + Blood tests and immunology + Abdominal ultrasound scan + Right heart catheterization and vasoreactivity + Pulmonary Angiography wey epeardia.org: urepean Wear Jounai20163767-118- 10 s0sleuea oe. European Respiratory Journal 2015 46: 903-075;Echocardiographic probability of pulmonary hypertension in symptomatic patients with a suspicion of pulmonary hypertension according with PTRV & additional signs ate glus ble rose) zie GE) cig £238 or not measurable 52.8 or not measurable 29-3.4 Intermediate A. The ventricles Right ventricle/ left ventricle basal _| Right ventricular outflow Infetior cava diameter 21 mm diameter ratio >1.0 Doppler acceleration time with decreased inspiratory <105 misec and/or midsystolic | collapse (<50 Yewith a sniff or <20 notching owith quiet inspiration). Flattening of the interventricular Early diastolic pulmonary Right atrial area (end-systole) septum (left ventricular eccentricity _| regurgitation velocity >18 cm? index >1.1 in systole andlor diastole). | >2.2 m/sec. PA diameter >25 mm, www.escardio.org Teereroe, European Hear Journal 201637 67—119 doy 10 1050/euneary European Respiratory Journal 2015 46: 903-975;Diagnostic management according to echocardiographic probability of PH in patients with symptoms compatible with PH, with or without risk factors for PAH or CTEPH me Allternative diagnosis should be considered Alternative diagnosis, echo follow-up, shoud be considered Further investigation of PH may be recommended® Further investigation of PH (including RHC) is recommended aid Echo follow-up should be considered Further assessment of PH including RHC should be considered? Further investigation of PH® including RHC is recommended CCTEPH = chronic thromboembolic pulmonary hypertension; Echo = echocardiographic: Pa = pulmonary arterial hypertension’ Pat = pulmonary hypertension: RHC = right heart cathecerizanon. ‘Thase recommendations do nat apply to patents with diflse parenchymal lung disease or laftheart disease; Bone sameachar antl cnet iohe naive SE aaa ERS © wvew.escardio.0Fo again sonaanasreim etme Ee. European Respiratory Journal 2018 4&: 003-075;Right heart catheterization in pulmonary hypertension RHC is recommended to confirm the diagnosis of pulmonary arterial hypertension (Group 1) and to support treatment decisions. In patients with PH, it is recommended to perform RHC in expert centres (Table 34) as it is technically demanding and may be associated with serious complications. RHC should be considered in pulmonary arterial hypertension (Group 1) to assess the treatment effect of drugs (Table 12). RHC is recommended in patients with congenital cardiac shunts to support decisions on correction (Table 23). RHC is recommended in patients with PH due to left heart disease (Group 2) or lung disease (Group 3) if organ transplantation is considered . When measurement of PAWP is unreliable, left heart catheterization should be considered to measure LVEDP. RHC may be considered in patients with suspected PH and left heart disease or lung disease to assist in the differential diagnosis and support treatment decisions. RHC is indicated in patients with Chronic Thromboembolic Pulmonary Hypertension (Group 4) to confirm the diagnosis and support treatment decisions. @ ERS 2% Micon ad European Heart Journal 2016:37'6?—119 do 10 10sueuneartienvan7 Sire ‘European Respiratory Journal 2015 46: 903-975;Vasoreactivity testing Vasoreactivity testing is indicated only in expert centres. \Vasoreactivity testing is recommended in patients with IPAH, HPAH and PAH associated with drugs use to detect patients who can be treated with high doses of a calcium channel blocker. A positive response to vasoreactivity testing is defined as a reduction of mean PAP 210 mmHg to reach an absolute value of mean PAP <40 mmHg with an increased or unchanged cardiac output. Nitric oxide is recommended for performing vasoreactivity testing. Intravenous epoprostenol is considered for performing vasoreactivity testing as an alternative. Adenosine should be considered for performing vasoreactivity testing as an alternative. Inhaled iloprost may be considered for performing vasoreactivity testing as an alternative. The use of oral or intravenous calcium channel blockers in acute vasoreactivity testing is not recommended. Vasoreactivity testing to detect patients who can be safely treated with high doses of a calcium channel blocker is not recommended in patients with PAH other than IPAH, HPAH and PAH associated with drugs use, and is not recommended in pulmonary hypertension Groups 2, 3, 4 and 5. @ ERS www.escardio.org ISRREFSE European Hear Journal 2016:37'67—119 -aov'10 10sveuneartieMarT Gian ‘European Respiratory Journal 2015 46: 903-975;Diagnostic Algorithm for Pulmonary Hypertension Sonnac cecal Echovardiographic. probability of PH (Table 7) ee ee ae sighs, risk factors, ECG, PF+-DLCO, choix radiograph and) iNefeneisoetstd See Er ogre leuat ate) ri eee ees Caer emer (Tecoma Teebene ae eens eee etree desistenlesats face Reterto PH expert centre Yes No. Referto PH expert centre Genta ee eee ieee rogue ery RHC (Table 9) mPAP 225 mmHg, Yes PAWP£15mmHg, PVR 28 Wood unite —ka-—_¥_—_-EEzm L, ea |} SS —, ) ro re. areas eae) 10. 10sa/euneanyen Jean Respiratory Journal 2015 46: 903-975;Diagnostic Algorithm for Pulmonary Hypertension (1) SOU eM Msn patllysany oa z El Echocardiographic probability of PH (Table 7) High orintermediate Low Cees eM aaileaetd (Table 8) Gonsider left heart disease and lung diseases DS neu wee ECG, PFT+DLCO, cholx radiograph and HRCT, arterial blood gases (Table 8) WE stale Ceres Jung diseases confirmed? Beton PHIRV dysfunction enon Galasso ieee Mismatched perfusion Cees Bee sea ur tesa Refer to PH expert centre Refer to PH expert centre sropean Heart Uo aPratbeneayDiagnostic Algorithm for Pulmonary Hypertension (2) V/Q scan eure ut (a ees Yes Refer to PH Ra expert centre Grapes Com eure ey Glee ete apes ely + Pulp Cees cs —_—_EB So (oleae Idiopathic Genel PVOD/PCH Ge s0sc/eunear} 46: 903-975: RHC (Table 8) mPAP =25 mmHg, PAWP £15mmHg, PVR >3 Wood units Consider OueetecdDiagnostic strategy Echocardiography is recommended as a first-line non-invasive diagnostic investigation in case of suspicion of PH. Ventilation/perfusion or perfusion lung scan is recommended in patients with unexplained PH to exclude CTEPH. Contrast CT angiography of the PA is recommended in the workup of patients with CTEPH. Routine biochemistry, haematology, immunology, HIV testing and thyroid function tests are recommended in all patients with PAH to identify the specific associated condition. Abdominal ultrasound is recommended for the screening of portal hypertension. Lung function test with DLCO is recommended in the initial evaluation of patients with PH. High-resolution CT should be considered in all patients with PH. Pulmonary angiography should be considered in the work-up of patients with CTEPH. Open or thoracoscopic lung biopsy is not recommended in patients with PAH. @ERS = @ wwewnescardio.0rg —— syegeanheatJouna201637 67-110 a ososaeumeaenat ae ‘European Respiratory Journal 2015 46: 903-975;Suggested assessment and timing for the follow-up of patients with pulmonary arterial hypertension Es Ei Sa eso esis Pia) ess ete eiere runes | cite Donen uses | duis) |e Medical assessment and determination of functional class | s + * cs 0G + + + + + 6MWT/Borg dyspnoea score + + of + a CPET + ia +9 ECHO oe ff i fs Basic lab + + + + + Extended lab + + + + Blood gas analysise + + + ze Right heart catheterization a ce aoa +4 Basic lab includes blood count, INR (in patients receiving vitamin K antagonists), serum creatinine, sod um, potassium, ASAT/ALAT (in patients receiving ERAs), bilirubin and BNP/ NT-proBNP. "Extended lab includes basic lab plus TSH, troponin, uric acid, iron status ({ron, ferritin, soluble transferrin receptor) and other variables according to individual patient needs. ‘From arterial or arterialized capillary blood; may be replaced by peripheral oxygen saturation in stable patients or if BGA is not avallable.¢should be considered. “Some centres perform RHCs at regular Intervals during falow-up. @ ERS sansrow @ wey epeardia.org: urepean Hear Jounai201637 67-118 10 10sleumeanyjeniat? oe. European Respiratory Journal 2015 46: 903-4Evaluation of severity of pulmonary arterial hypertension and clinical response to therapy It is recommended to evaluate the severity of PAH patients with a panel of data derived from clinical assessment, exercise tests, biochemical markers and echocardiographic and haemodynamic evaluations (Tables 12 and 13). It is recommended to perform regular follow-up assessments every 3-6 months in stable patients (Table 12). Achievement/maintenance of a low-risk profile (Table 13) is recommended as an adequate treatment response for patients with PAH. Achievement/maintenance of an intermediate-risk profile (Table 13) should be considered an inadequate treatment response for most patients with PAH. @ERS @ Mec orca nad European Heart Journal 2016:37'6?—119 do 10 10sueuneartienvan7 Sire ‘European Respiratory Journal 2015 46: 903-975;PAH general treatment measures It is recommended to avoid pregnancy in patients with PAH. Immunization of PAH patients against influenza and pneumococcal infection is recommended. Psychosocial support is recommended in patients with PAH. Supervised exercise training should be considered in physically deconditioned PAH patients under medical therapy. In-flight ©, administration should be considered for patients in WHO-FC III and IV and those with arterial blood O, pressure consistently less than 8 kPa (60 mmHg). In elective surgery, epidural rather than general anaesthesia should be preferred whenever possible. Excessive physical activity that leads to distressing symptoms is not recommended in patients with PAH. @ ERS 2 @ wey epeardia.org: urepean Wer Jouna!20163767-118-d 1010s oes. European Respiratory Journal 2015 46: 903-075;PAH supportive therapy Diuretic treatment is recommended in PAH patients with signs of RV failure and fluid retention. Continuous long-term ©, therapy is recommended in PAH patients when arterial blood O, pressure is consistently less than 8 kPa (60 mmHg). Oral anticoagulant treatment may be considered in patients with IPAH, HPAH and PAH due to use of anorexigens. Correction of anaemia and/or iron status may be considered in PAH patients. The use of angiotensin-converting enzyme inhibitors, angiotensin-2 receptor antagonists, beta-blockers and ivabradine is not recommended in patients with PAH unless required by co-morbidities (i.e. high blood pressure, coronary artery disease or left heart failure). @ERS Bs @ European Hear Journal 2016:37'67—119 -aov'10 10sveuneartieMarT Gian ‘European Respiratory Journal 2015 46: 903-975;Calcium channel blocker therapy in patients who respond to the acute vasoreactivity test High doses of CCBs are recommended in patients with IPAH, HPAH and DPAH responder to acute vasoreactivity testing. Close follow-up with complete reassessment after 3-4 months of therapy (including RHC) is recommended in patients with IPAH, HPAH and DPAH treated by high doses of CCB. Continuation of high doses CCB treatment is recommended in patients with IPAH, HPAH and DPAH in WHO-FC I or II with marked haemo- dynamic improvement (near normalization). Initiation of specific PAH therapy is recommended in patients in WHO- FC III or IV or those without marked haemodynamic improvement (near normalization) after high doses CCB treatment. High doses of CCBs are not indicated in patients without vasoreactivity study or non-responders, unless standard doses are prescribed for other indications (e.g.,Raynaud phenomenon). @ ERS 2 @ Micon ad European Heart Journal 2016:37'6?—119 do 10 10sueuneartienvan7 Sire ropean Respiratory Journal 2015 46: 903-975;Calcium channel blockers Ambrisentan A Endothelin receptor Faocentan A antagonists == Macitentan? Sildenafil Phosphodiesterase . type-5 Inhibitors gecesi Vardenafil* 7 Guanylate eydase . stimulators See : Prostanoids Epoprostenol _| intravenous! ny Inhaled Tloprost Intravenous* subcutaneous Inhaled* B Treprostinil Intravenous Oral* Beraprost® B IP-receptor agonists Selexipag (oral)* ‘Only in responders to 20 Soautanesus form ‘hie drug isnot aoprovedby the EMA at the time of publication ofthese guid due to drugs Class Ha for AH condone. - fr arugs wth detonctrstecrecucton in al cause moray. Cass for sioosthic Pal, ert ‘Time to dinal worening 28 primary ‘In pavente nat tolerating theEfficacy of initial drug combination therapy, for PAH (Group 1) Ambrisentan + tadalafile Other ERA + PDE-Si Bosentan + sildenafil +i.v. epoprostenol Bosentan + i.v. epoprostenol - - Other ERA or PDE-5i + s.c. trepostinil - - Other ERA or PDE-Si + other i.v. prostacyclin analogues ‘Time to clinica falure as prmary end-point in RCTs or crags with demonstrated reduction i al-catse mortality (prospectively defined) @ERS 2 @ MON eae ae European Heart Journal 2016:37'6?—119 do 10 10sueuneartienvan7 ‘European Respiratory Journal 2015 46: 903-975;Macitentan added to sildenafil Riociguat added to bosentan Selexipag added to ERA and/or PDE-5i Sildenafil added to epoprostenol Treprostinil inhaled added to sildenafil or bosentan Tloprost inhaled added to bosentan Tadalafil added to bosentan Ambrisentan added to sildenafil Bosentan added to epoprostenol Bosentan added to sildenafil Sildenafil added to bosentan Other double combinations Other triple combinations Riociguat added to sildenafil or other PDE-Si www.escardio.org Laan European Rest 101637 67-119 dos 10 10sR/eUNeArHENV y Jourral 2015 46: 903-975;Efficacy of intensive care unit management, balloon atrial septostomy & lung transplantation for PAH (Group 1) Hospitalization in intensive care unit is recommended in PH patients with high heart rate (>110 b/min), low blood pressure (Systolic blood pressure <90 mmHg), low urine output and rising lactate levels due or not due to comorbidities. Inotropic support is recommended in hypotensive patients. Lung transplantation is recommended soon after inadequate clinical response on maximal medical therapy. Ballon atrial septostomy may be considered where available after failure of maximal medical therapy. www.escardio.org European Hear Journal 2016:37'67—119 -aov'10 10sveuneartieMarT ERS tenis ‘European Respiratory Journal 2015 46: 903-975;32 Treatment Algorithm for Pulmonary Arterial Hypertension | Qa -------. General measures (Table 18) ‘Supportive therapy (Table 16) CCB Therapy ‘Acute vaso reactivity test (1PAH/HPAH/DPAH only) (Table 17) Non vas reactive Lowor intermediate-isk (WHO-FC IMI) High-risk (WHO.-FC IM) rere cal Ci Rae N (Table 19) Cee y (Table 18) eee Uy (Table 19) Ee Inadequate clrical response Consider referal for (Table 14) lung transplantation Double or triple sequential combination (Table 20) Inadequate dinical response (Table 14) Consider listing for lung transplantation (Table 21) @ERS oe @ socomerdie.ote Srpsn eat una 09697 7-19 a 10 ceoeueaniena? Sit See eee | anomie coePaediatric pulmonary hypertension ‘APH diagnostic algorithm work-up is recommended for diagnosis? and definition of the specific aetiology group in paediatric PH patients. A PAH? specific therapeutic algorithm is recommended in paediatric PH patients. Combination therapy should be considered in paediatric PH patients. Specific paediatric determinants of risk should be considered. ulmonary arterial hypertension. PH = pulmonary hypertension, +See Ivy D et al 1 Am Coll Cardiol 2013;62(25):0117-D125, @ERS Bs @ European Hear Journal 2016:37'67—119 -aov'10 109veunearyienvanT Gian ‘European Respiratory Journal 2015 46: 903-975;Pulmonary arterial hypertension associated with adult congenital heart disease Individual patient evaluation in tertiairy centres PVR = pulmonary vascular resistance, PvRi = pulmonary vascular resistance inde. Wu = Weod units. with surgery or intravascular percutaneous procedure. @ ERS ees @ MON eae ae European Heart Journal 207637 61-119 Ao 10 10saeuneartenvar7 m ‘European Respiratory Journal 2015 46: 903-975;Pulmonary arterial hypertension associated with congenital heart disease Bosentan is recommended in WHO-FC III patients with Eisenmenger’s syndrome. Other ERAs, PDE-Si, and prostanoids should be considered in patients with Eisenmenger’s syndrome. In the absence of significant haemoptysis, oral anticoagulant treatment may be considered in patients with PA thrombosis or signs of heart failure. The use of supplemental O, therapy should be considered in cases in which it produces a consistent increase in arterial oxygen saturation and reduces symptoms. If symptoms of hyperviscosity are present, phlebotomy with isovolumic replacement should be considered, usually when the haematocrit is >65%. The use of supplemental iron treatment may be considered in patients with low ferritin plasma levels. Combination drug therapy may be considered in patients with Eisenmenger's syndrome. The use of CCBs is not recommended in patients with Eisenmenger’s syndrome. www.escardio.org European Hear Journal 201637 67—119 -aot'10 10sveuneartiema1T ‘European Respiratory Journal 2015 46: 903-975;Pulmonary arterial hypertension associated with connective tissue disease In patients with PAH associated with CTD the same treatment algorithm as for patients with IPAH is recommended. Resting echocardiography is recommended as a screening test in asymptomatic SSc patients with systemic sclerosis, followed by annual screening with echocardiography, DLCO and biomarkers. RHC is recommended in all cases of suspected PAH associated with CTD. Oral anticoagulation may be considered on an individual basis and in the presence of thrombophilic predisposition. CID = connective nssue disease PAH = Idiopathic pulmonary arterial hypertension. PAH = pulmonary arterial hypertension. RHC = right heart catheterization. @ERS = @ www.escardio.org ipa ab oi Ava a mieecaeicee ae sn uma 2018376719 to orePulmonary arterial hypertension associated with portal hypertension Echocardiographic assessment for signs of PH is recommended in symptomatic patients with liver disease or portal hypertension and in all candidates for liver transplantation. It is recommended that patients affected by PAH associated with portal hypertension are referred to centres with expertise in managing both conditions. It is recommended that the treatment algorithm for patients with other forms of PAH is applied to patients with PAH associated with portal hypertension, taking into account the severity of liver disease. Anticoagulation is not recommended in patients with pulmonary hypertension associated with portal hypertension. Liver transplantation may be considered in selected patients responding well to PAH therapy. Liver transplantation is contraindicated in patients with severe and uncontrolled PAH. @ERS 2 @ wey epeardia.org: urepean Wer Jouna!20163767-118-d 1010s oes. European Respiratory Journal 2015 46: 903-075;Pulmonary arterial hypertension associated with human immunodeficiency virus infection Echocardiographic screening in asymptomatic HIV patients to detect PH is not recommended. In patients with PAH associated with HIV infection, the same treatment algorithm as for patients with PAH should be considered, taking into consideration comorbidities and drug-drug interactions. Anticoagulation is not recommended for lack of data on the efficacy to risk ratio. @ERS ss @ www.escardio.org european Hear Joumnai2016.7 67-119 ao: 10 10sveuneanjenia17 ial ‘European Respiratory Journal 2015 46: 903-975;Pulmonary veno-occlusive disease A combination of clinical findings, physical examination, bronchoscopy and radiological findings is recommended to diagnose PVOD/PCH. Identification of a bi-allelic EIF2AK4 mutation is recommended to confirm a diagnosis of heritable PVOD/PCH without histological confirmation. Referral of eligible patients with PVOD/PCH to a transplant centre for evaluation is indicated as soon as the diagnosis is established. Patients with PVOD/PCH should be managed only in centres with extensive experience in PH due to the risk of lung oedema after the initiation of PAH therapy. | @ ERS 2 @© European Hear Journal 2016:37'67—119 -aov'10 10sveuneartieMarT ropean Respiratory Journal 2015 46: 903-975;Examples of key factors suggestive of Group 2 pulmonary hypertension Chinical presentation Echocardiography (aleersseures ‘Age >65 years Structural left heart abnormality ECG + Disease of left heart valves, *LVH and/or LAH + LAenlargement (>4.2 cm) + AF/Atib + Bowing of the IAS to the right + LBBB + LV dysfunction + Presence of Q waves + Concentric LV hypertrophy and/or increased LV mass ‘Symptoms of left heart failure | Doppler indices of increased filling ‘Other Imaging pressures: + Kerley B lines + Increased E/e" + Pleural effusion + >Type 2-3 mitral flow abnormality + Pulmonary oedema + enlargement Features of metabolic syndrome | Absence of; + RV dysfunction + Mid systolic notching of the PA flow + Pericardial effusion History of heart disease (past or current) Persistent atrial fibrillation TAS = inter-atrial septum; LA = left atrum; left ventricle; “ERS BO European Hear Journal 2016:37'67—119 -aov'10 109veunearyienvanT Gian ‘European Respiratory Journal 2015 46: 903-975;Management of pulmonary hypertension in left heart disease Optimization of the treatment of the underlying condition is recommended before considering assessment of PH-LHD (i.e. treating structural heart disease). It is recommended to identify other causes of PH (i.e. COPD, SAS, PE, CTEPH) and to treat them when appropriate before considering assessment of PH-LHD. It is recommended to perform invasive assessment of PH in patients on optimized volume status. Patients with PH-LHD and a severe pre-capillary component as indicated by a high DPG and/or high PVR should be referred to an expert PH centre for a complete diagnostic work-up and an individual treatment decision. The importance and role of vasoreactivity testing is not established in PH-LHD, except in patients who are candidates for heart transplantation and/or LV assist device implantation. The use of PAH approved therapies is not recommended in PH-LHD. @ERS 2 @ wey epeardia.org: european Hear Joumnai2016.7 67-119 ao: 10 10sveuneanjenia17 Be ‘European Respiratory Journal 2015 46: 903-975;Haemodynaniic classification of pulmonary hypertension associated with lung disease Hae mOdysanice (ight peaeeatsetenzanon) Gomslasy COPD/IPF/CPFE without PH PAPm <25 mmHg COPD/IPF/CPFE with PH PAPm 225 mmHg COPD/IPF/CPFE with severe PH | PAPm >35 mmHg, or PAPm >25 mmi4 in the presence of a low cardiac output (CI <2.5 L/min, not explained by other causes) = cardiac index. chronic obstructive pulmenary disease combined pulmonary fibrasis and emphysema iopathic pulmonary fibrosis, PH = pulmonary hypertenson. @ ERS ze @® wey epeardia.org: urepean Her Jounai201637 67-118 10 10sveuneanjehvat? oe. /Saielen e e o athes i esEe Pulmonary hypertension due to lung diseases Echocardiography is recommended for the non-invasive diagnostic assessment of suspected PH in patients with lung disease. In patients with echocardiographic signs of severe PH and/or severe right ventricular dysfunction referral to an expert centre is recommended. The optimal treatment of the underlying lung disease, including long- term O, therapy in patients with chronic hypoxaemia, is recommended in patients with PH due to lung diseases. Referral to PH expert centre should be considered for patients with signs of severe PH/severe RV failure for individual-based treatment. RHC is not recommended for suspected PH in patients with lung disease, unless therapeutic consequences are to be expected (e.g. lung transplantation, alternative diagnoses such as PAH or CTEPH, potential enrolment in a clinical trial). The use of drugs approved for PAH is not recommended in patients with PH due to lung diseases. @ERS oe @ Micon ad European Heart Journal 2016:37'6?-119 aot 10 10sweumeare! European Respiratory Journal 2015 46: 903-075;Diagnostic algorithm for chronic thromboembolic PH sues te sn yo ceusaEl Echovardiographic probability of PH (Table 7) High or intermediate probability of PH ale) Mismatched perfusion defects? oredr essi9 petits Kane Refer to PHICTEPH Work-up for PHIPAH expert centre (Figure 4) (Cin slate jeus}e)bY Gina esr cure ty) DP enue Uyeutisee bY s0sa/euneanyen 46: 903-975:c Treatment algorithm for chronic thromboembo! Lifetong anticoagulation Operability assessment by a multidisciplinary CTEPH team Technically non-operable eee) Ciera eed eran Geet ateuee treat Persistent sever transplantation symptomatic PI BPA= talon palo ant, CTEPH chr oaboantole puora'yrypataion: PH = panonay gota ‘Tecrialy pra pas wan non-occopa bere alc cored a0 fr SPA rons viv dca hry and ZPA as imi concur @ERS @ socomerdie.ote Srpsn eat una 09697 7-19 a 10 ceoeueaniena? Sit See eee | anomie coe LiChronic thromboembolic pulmonary hypertension In PE survivors with exercise dyspnoea, CTEPH should be considered. Life-long anticoagulation is recommended in alll patients with CTEPH. It is recommended that in all patients with CTEPH the assessment of operability and decisions regarding other treatment strategies be made by a multidisciplinary team of experts. Surgical PEA in deep hypothermia circulatory arrest is recommended for patients with CTEPH. Riociguat is recommended in symptomatic patients who have been classified as having persistent/recurrent CTEPH after surgical treatment or inoperable CTEPH by a CTEPH team including at least one experienced PEA surgeon. Off-label use of drugs approved for PAH may be considered in symptomatic patients who have been classified as having persistent/ recurrent CTEPH after surgical treatment or inoperable CTEPH by a CTEPH team including at least one experienced PEA surgeon. Interventional BPA may be considered in patients who are technically non-operable, or carry an unfavourable risk-benefit ratio for PEA. ‘Screening for CTEPH in asymptomatic survivors of PE is currently not recommended. {BPA Galen pulronary srgoplany, CTEPH = crone rorboerbalcpulmonary/hypevanstn PE = plmonayy bol eo sical @ERS Le @ Mec orca nad european Hear Jounal201637 51-19-4010 tosseumnearyjeniat7 poet Pee eee ij aed ib erDefinition of a pulmonary hypertension referral centre It is recommended for referral centres to provide care by a multi- professional team (cardiology and respiratory medicine physicians, clinical nurse specialist, radiologists, psychological and social work support, appropriate on-call expertise). It is recommended for referral centres to have direct links and quick referral patterns to other services (such as CTD service, family planning service, PEA service, lung transplantation service, adult congenital heart disease service). It should be considered for a referral centre to follow at least 50 patients with PAH or CTEPH and should receive at least two new referrals per month with documented PAH or CTEPH. It should be considered for a referral centre perform at least 20 vaso- reactivity tests in IPAH, HPAH or DPAH patients per year. Referral centres should participate in collaborative clinical research in PAH, which includes phase II and phase III clinical trials. @ ERS 2 @ Micon ad european Hear Jounal 20165751119 4010 tosseumearet ae Pee eee ij aed ib erThe Ten Commandments 1. Right heart catheterization is recommended to confirm the diagnosis of pulmonary arterial hypertension (PAH - Group 1) and to support treatment decisions. 2. Vasoreactivity testing performed during right heart catheterization is recommended in patients with idiopathic PAH, heritable PAH and PAH induced by drugs or toxins use to detect patients who can be treated with high doses of a calcium channel blocker. 3. It is recommended to evaluate the severity of PAH patients with a panel of data derived from clinical assessment, exercise tests, biochemical markers, and echocardiographic and haemodynamic evaluation and to perform regular follow-up assessments every 3-6 months in stable patients. It is recommended to avoid pregnancy in patients with PAH. 5. It is recommended for referral centres to provide care by a multi- professional team (cardiology and respiratory medicine physicians, clinical nurse specialist, radiologists, psychological and social work support, appropriate on-call expertise). @ERS 8" @ socemerdia.cte Srpsn eat Juma 09697 7-19 a 10 oeoeueaniena? Se. See eee | anomie coeThe Ten Commandments 10. www.escardio.org Initial drugs monotherapy or initial oral drugs combination therapy is recommended in treatment naive, low or intermediate risk patients with PAH. Sequential drugs combination therapy is recommended in PAH patients with inadequate treatment response to initial monotherapy or to initial oral drugs combination therapy. Initial combination therapy including an intravenous prostacyclin analogue is recommended in high risk PAH patients. The use of PAH approved therapies is not recommended in patients with pulmonary hypertension due to left heart disease or lung diseases. Surgical pulmonary endarterectomy in deep hypothermia circulatory arrest is recommended for patients with CTEPH and it is recommended that the assessment of operability and decisions regarding other treatment strategies (drugs therapy or balloon pulmonary angioplasty) be made by a multidisciplinary team of experts. @ERS Bs @ European Hear Journal 2016:37'67—119 -aov'10 10sveuneartieMarT ‘European Respiratory Journal 2015 46: 903-975;Ie Full Text published in: Eur Heart J & Eur Respir J EUROPEAN RESPIRATORY journal (Q 2015 ESCIERS Guidelines for the diagnosis ESPIRATORY jourrial and treatment of pulmonary hypertension “Te Joe Tas Force fr he Dag and Treatment of Paironary Store Tiperentn oe aropan acy Cag (36) sl the ‘loan Renrtry Seay RS). Sra Enders Racin fr European Pea and Congeneat www.escardio.org/guidelines @ERS 2 @ Micon ad european Hear Jounal201637 51-19-4010 tosseumnearyjeniat7 ae European Respiratory Journal 2015 46: 903-075;Pocket Guideli idelines and their Interacti ive App <> ESC POCKET GUIDELINES | ie fo race Gude Comnit an gate caren EOP roimpette qvay of ot FREES @ERS PULMONARY, HYPERTENSIONESC DISCLAIMER The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating. The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of health care or therapeutic strategies. Health professionals are encouraged to take the ESC 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 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 the patient's caregiver where appropriate and/or necessary. Nor do the ESC Guidelines exempt health professionals from taking careful and full consideration of 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. @ www.escardio.org eer or