Figures
- Fig. 1—
Diagnostic algorithm. ALK-1: activin-receptor-like kinase; ANA: anti-nuclear antibodies; BMPR2: bone morphogenetic protein receptor 2; CHD: congenital heart disease; CMR: cardiac magnetic resonance; CTD: connective tissue disease; CTEPH: chronic thromboembolic pulmonary hypertension; Group: clinical group (table 4⇓); HHT: hereditary haemorrhagic telangiectasia; HRCT: high-resolution computed tomography; LFT: liver function tests; P̄pa: mean pulmonary arterial pressure; PAH: pulmonary arterial hypertension; PCH: pulmonary capillary haemangiomatosis; Ppcw: pulmonary capillary wedge pressure; PFT: pulmonary function test; PH: pulmonary hypertension; PVOD: pulmonary veno-occlusive disease; RHC: right heart catheterisation; TEE: transoesophageal echocardiography; TTE: transthoracic echocardiography; US: ultrasonography; V′/Q′: ventilation/perfusion lung scan. #: refer also to table 12⇓.
- Fig. 2—
Evidence-based treatment algorithm for pulmonary arterial hypertension patients (for group 1 patients only). APAH: associated pulmonary arterial hypertension; BAS: balloon atrial septostomy; CCB: calcium channel blocker; ERA: endothelin receptor antagonist; IPAH: idiopathic pulmonary arterial hypertension; PAH: pulmonary arterial hypertension; PDE-5 I: phosphodiesterase type-5 inhibitor; s.c.: subcutaneously; WHO-FC: World Health Organization functional class. #: to maintain arterial blood O2 pressure >8 kPa (60 mmHg); ¶: under regulatory review in the European Union; +: IIa-C for WHO-FC II.
Tables
- Table 1—
Classes of recommendations
Classes of recommendations Definition Class I Evidence and/or general agreement that a given treatment 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 favour of usefulness/efficacy. Class IIb Usefulness/efficacy is less well established by evidence/opinion. Class III Evidence or general agreement that the given treatment or procedure is not useful/effective, and in some cases may be harmful. - Table 2—
Levels of evidence
Level of evidence A Data derived from multiple randomised clinical trials# or meta-analyses. Level of evidence B Data derived from a single randomised clinical trial# or large nonrandomised studies. Level of evidence C Consensus of opinion of the experts and/or small studies, retrospective studies, registries. #: or large accuracy or outcome trial(s) in the case of diagnostic tests or strategies.
- Table 3—
Haemodynamic definitions of pulmonary hypertension(PH)#
Definition Characteristics Clinical group(s)¶ PH P̄pa ≥25 mmHg All Pre-capillary PH P̄pa ≥25 mmHg 1. Pulmonary arterial hypertension Ppcw ≤15 mmHg 3. PH due to lung diseases CO normal or reduced+ 4. Chronic thromboembolic PH 5. PH with unclear and/or multifactorial mechanisms Post-capillary PH P̄pa ≥25 mmHg 2. PH due to left heart disease Ppcw >15 mmHg CO normal or reduced+ Passive TPG ≤12 mmHg Reactive (out of proportion) TPG >12 mmHg P̄pa: mean pulmonary arterial pressure; Ppcw: pulmonary capillary wedge pressure; CO: cardiac output; TPG: transpulmonary pressure gradient (P̄pa- P̄pcw). #: all values measured at rest; ¶: according to table 4; +: high CO can be present in cases of hyperkinetic conditions such as systemic-to-pulmonary shunts (only in the pulmonary circulation), anaemia, hyperthyroidism, etc.
- Table 4—
Updated clinical classification of pulmonary hypertension
1 PAH 1.1 Idiopathic 1.2 Heritable 1.2.1 BMPR2 1.2.2 ALK-1, endoglin (with or without hereditary haemorrhagic telangiectasia) 1.2.3 Unknown 1.3 Drugs and toxins induced 1.4 Associated with (APAH) 1.4.1 Connective tissue diseases 1.4.2 HIV infection 1.4.3 Portal hypertension 1.4.4 Congenital heart disease 1.4.5 Schistosomiasis 1.4.6 Chronic haemolytic anaemia 1.5 Persistent pulmonary hypertension of the newborn 1′ Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis 2 Pulmonary hypertension due to left heart disease 2.1 Systolic dysfunction 2.2 Diastolic dysfunction 2.3 Valvular disease 3 Pulmonary hypertension due to lung diseases and/or hypoxia 3.1 Chronic obstructive pulmonary disease 3.2 Interstitial lung disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern 3.4 Sleep-disordered breathing 3.5 Alveolar hypoventilation disorders 3.6 Chronic exposure to high altitude 3.7 Developmental abnormalities 4 Chronic thromboembolic pulmonary hypertension 5 PH with unclear and/or multifactorial mechanisms 5.1 Haematological disorders: myeloproliferative disorders, splenectomy 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis BMPR2: bone morphogenetic protein receptor, type 2; ALK-1: activin receptor-like kinase 1 gene; APAH: associated pulmonary arterial hypertension; PAH: pulmonary arterial hypertension. Reproduced from Dana Point 1, with permission from the publisher.
- Table 5—
Important definitions
PH is a haemodynamic and pathophysiological condition defined as an increase in P̄pa ≥25 mmHg at rest as assessed by right heart catheterisation (table 3). PH can be found in multiple clinical conditions (table 4). The definition of PH on exercise as a P̄pa >30 mmHg as assessed by right heart catheterisation is not supported by published data. PAH (group 1) is a clinical condition characterised by the presence of pre-capillary PH (table 3) in the absence of other causes of pre-capillary PH such as PH due to lung diseases, chronic thromboembolic PH, or other rare diseases (table 4). PAH includes different forms that share a similar clinical picture and virtually identical pathological changes of the lung microcirculation (table 4). PH: pulmonary hypertension; P̄pa: mean pulmonary arterial pressure; PAH: pulmonary arterial hypertension.
- Table 6—
Clinical classification of congenital, systemic-to-pulmonary shunts associated with pulmonary arterial hypertension (PAH)
A. Eisenmenger's syndrome Eisenmenger's syndrome includes all systemic-to-pulmonary shunts due to large defects leading to a severe increase in PVR and resulting in a reversed (pulmonary-to-systemic) or bidirectional shunt. Cyanosis, erythrocytosis and multiple organ involvement are present. B. PAH associated with systemic-to-pulmonary shunts In these patients with moderate-to-large defects, the increase in PVR is mild to moderate, systemic-to-pulmonary shunt is still largely present, and no cyanosis is present at rest. C. PAH with small# defects In cases with small defects (usually ventricular septal defects <1 cm and atrial septal defects <2 cm of effective diameter assessed by echocardiography) the clinical picture is very similar to idiopathic PAH. D. PAH after corrective cardiac surgery In these cases, congenital heart disease has been corrected but PAH is either still present immediately after surgery or has recurred several months or years after surgery in the absence of significant post-operative residual congenital lesions or defects that originate as a sequela to previous surgery. PVR: pulmonary vascular resistance. #: the size applies to adult patients.
- Table 7—
Anatomical–pathophysiological classification of congenital systemic-to-pulmonary shunts associated with pulmonary arterial hypertension
1 Type 1.1 Simple pre-tricuspid shunts 1.1.1 ASD 1.1.1.1 Ostium secundum 1.1.1.2 Sinus venosus 1.1.1.3 Ostium primum 1.1.2 Total or partial unobstructed anomalous pulmonary venous return 1.2 Simple post-tricuspid shunts 1.2.1 VSD 1.2.2 Patent ductus arteriosus 1.3 Combined shunts Describe combination and define predominant defect 1.4 Complex congenital heart disease 1.4.1 Complete atrioventricular septal defect 1.4.2 Truncus arteriosus 1.4.3 Single ventricle physiology with unobstructed pulmonary blood flow 1.4.4 Transposition of the great arteries with VSD (without pulmonary stenosis) and/or patent ductus arteriosus 1.4.5 Other 2 Dimension (specify for each defect if more than one congenital heart defect exists) 2.1 Haemodynamic (specify Qp/Qs)# 2.1.1 Restrictive (pressure gradient across the defect) 2.1.2 Nonrestrictive 2.2 Anatomical¶ 2.2.1 Small to moderate (ASD ≤2.0 cm and VSD ≤1.0 cm) 2.2.2 Large (ASD >2.0 cm and VSD >1.0 cm) 3 Direction of shunt 3.1 Predominantly systemic-to-pulmonary 3.2 Predominantly pulmonary-to-systemic 3.3 Bidirectional 4 Associated cardiac and extracardiac abnormalities 5 Repair status 5.1 Unoperated 5.2 Palliated (specify type of operation(s), age at surgery) 5.3 Repaired (specify type of operation(s), age at surgery) ASD: atrial septal defect; VSD: ventricular septal defect. #: ratio of pulmonary (Qp) to systemic (Qs) blood flow; ¶: the size applies to adult patients. Modified from the Evian-Venice classification 2003 13, with permission from the publisher.
- Table 8—
Updated risk level of drugs and toxins known to induce pulmonary arterial hypertension
Definite Aminorex Fenfluramine Dexfenfluramine Toxic rapeseed oil Benfluorex Possible Cocaine Phenylpropanolamine St John’s Wort Chemotherapeutic agents Selective serotonin reuptake inhibitors Pergolide Likely Amphetamines l-tryptophan Methamphetamines Unlikely Oral contraceptives Oestrogen Cigarette smoking - Table 9—
Arbitrary criteria for estimating the presence of pulmonary hypertension(PH) based on tricuspid regurgitation peak velocity and Doppler-calculated pulmonary arterial (PA) systolic pressure at rest (assuming a normal right atrial pressure of 5 mmHg) and on additional echocardiographic variables suggestive of PH
Class# Level¶ Echocardiographic diagnosis: PH unlikely Tricuspid regurgitation velocity ≤2.8 m·s−1, PA systolic pressure ≤36 mmHg and no additional echocardiographic variables suggestive of PH I B Echocardiographic diagnosis: PH possible Tricuspid regurgitation velocity ≤2.8 m·s−1, PA systolic pressure ≤36 mmHg, but presence of additional echocardiographic variables suggestive of PH IIa C Tricuspid regurgitation velocity 2.9–3.4 m·s−1, PA systolic pressure 37–50 mmHg with/without additional echocardiographic variables suggestive of PH IIa C Echocardiographic diagnosis: PH likely Tricuspid regurgitation velocity >3.4 m·s−1, PA systolic pressure >50 mmHg, with/without additional echocardiographic variables suggestive of PH I B Exercise Doppler echocardiography is not recommended for screening of PH III C #: class of recommendation; ¶: level of evidence.
- Table 10—
Route of administration, half-life, dose ranges, increments and duration of administration of the most commonly used agents for pulmonary vasoreactivity tests
Drug Route Half-life Dose range# Increments¶ Duration+ Epoprostenol Intravenous 3 min 2–12 ng·kg−1·min−1 2 ng·kg−1·min−1 10 min Adenosine Intravenous 5–10 s 50–350 μg·kg−1·min−1 50 μg·kg−1·min−1 2 min Nitric oxide Inhaled 15–30 s 10–20 p.p.m. 5 min§ #: initial dose and maximal tolerated dose suggested (maximal dose limited by side-effects such as hypotension, headache, flushing, etc.); ¶: increments of dose by each step; +: duration of administration on each step; §: for NO, a single step within the dose range is suggested.
- Table 11—
Recommendations for right heart catheterisation(RHC; A) and vasoreactivity testing (B)
Class# Level¶ A. RHC is indicated in all patients with PAH to confirm the diagnosis, to evaluate the severity and when PAH specific drug therapy is considered I C RHC should be performed for confirmation of efficacy of PAH-specific drug therapy IIa C RHC should be performed for confirmation of clinical deterioration and as baseline for the evaluation of the effect of treatment escalation and/or combination therapy IIa C B. Vasoreactivity testing is indicated in patients with IPAH, heritable PAH and PAH associated with anorexigen use to detect patients who can be treated with high doses of a CCB I C A positive response to vasoreactivity testing is defined as a reduction of P̄pa ≥10 mmHg to reach an absolute value of P̄pa ≤40 mmHg with an increased or unchanged CO I C Vasoreactivity testing should be performed only in referral centres IIa C Vasoreactivity testing should be performed using nitric oxide as vasodilator IIa C Vasoreactivity testing may be performed in other types of PAH IIb C Vasoreactivity testing may be performed using i.v. epoprostenol or i.v. adenosine IIb C The use of an oral or i.v. CCB in acute vasoreactivity testing is not recommended III C Vasoreactivity testing to detect patients who can be safely treated with high doses of a CCB is not recommended in patients with other PH groups (groups 2, 3, 4 and 5) III C PAH: pulmonary arterial hypertension; IPAH: idiopathic PAH; CCB: calcium channel blocker; P̄pa: mean pulmonary arterial pressure; CO: cardiac output; PH: pulmonary hypertension. #: class of recommendation; ¶: level of evidence.
- Table 12—
Probability of pulmonary arterial hypertension(PAH) diagnosis and suggested management according to the echocardiographic diagnosis of pulmonary hypertension (PH; table 9), symptoms and additional clinical information
Low probability for PAH diagnosis Class# Level¶ Echocardiographic diagnosis of “PH unlikely”, no symptoms: no additional work-up is recommended I C Echocardiographic diagnosis of “PH unlikely”, presence of symptoms and of associated conditions or risks factors for group1–PAH: echocardiographic follow-up is recommended I C Echocardiographic diagnosis of “PH unlikely”, presence of symptoms and absence of associated conditions or risks factors for group 1–PAH: evaluation of other causes for the symptoms is recommended I C Intermediate probability for PAH Echocardiographic diagnosis of “PH possible”, no symptoms and absence of associated conditions or risks factors for group 1–PAH: echocardiographic follow-up is recommended I C Echocardiographic diagnosis of “PH possible”, presence of symptoms and of associated conditions or risks factors for group 1–PAH: RHC may be considered IIb C Echocardiographic diagnosis of “PH possible”, presence of symptoms and absence of associated conditions or risks factors for group 1–PAH: alternative diagnosis and echocardiographic follow-up may be considered. If symptoms at least moderate RHC may be considered IIb C High probability for PAH Echocardiographic diagnosis of “PH likely”, with symptoms and presence/absence of associated conditions or risks factors for group 1–PAH: RHC is recommended I C Echocardiographic diagnosis of “PH likely”, without symptoms and presence/absence of associated conditions or risks factors for group 1–PAH: RHC should be considered IIa C RHC: right heart catheterisation. #: class of recommendation; ¶: level of evidence.
- Table 13—
Recommendations for diagnostic strategy
Statement Class# Level¶ Ventilation/perfusion lung scan is recommended in patients with unexplained PH to exclude CTEPH I C Contrast CT angiography of the PA is indicated in the work-up of patients with CTEPH I C Routine biochemistry, haematology, immunology and thyroid function tests are indicated in all patients with PAH, to identify the specific associated condition I C Abdominal ultrasound is indicated for the screening of portal hypertension I C High-resolution CT should be considered in all patients with PH IIa C Conventional pulmonary angiography should be considered in the work-up of patients with CTEPH IIa C Open or thoracoscopic lung biopsy is not recommended in patients with PAH III C PH: pulmonary hypertension; CTEPH: chronic thromboembolic pulmonary hypertension; CT: computed tomography; PA: pulmonary artery; PAH: pulmonary arterial hypertension. #: class of recommendation; ¶: level of evidence.
- Table 14—
Functional classification of pulmonary hypertension modified after the New York Heart Association functional classification according to the World Health Organization
Class I Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope. Class II Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope. Class III Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea or fatigue, chest pain, or near syncope. Class IV Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may even be present at rest. Discomfort is increased by any physical activity. Reproduced from 76, with permission from the publishers.
- Table 15—
Parameters with established importance for assessing disease severity, stability and prognosis in pulmonary arterial hypertension
Better prognosis Determinants of prognosis Worse prognosis No Clinical evidence of RV failure Yes Slow Rate of progression of symptoms Rapid No Syncope Yes I, II WHO-FC IV Longer (>500 m)# 6-MWT Shorter (<300 m) Peak O2 consumption >15 mL·min−1·kg−1 Cardiopulmonary exercise testing Peak O2 consumption <12 mL·min−1·kg−1 Normal or near-normal BNP/NT-proBNP plasma levels Very elevated and rising No pericardial effusion TAPSE¶ >2.0 cm Echocardiographic findings¶ Pericardial effusion TAPSE¶ <1.5 cm RAP <8 mmHg and CI ≥2.5 L·min−1·m−2 Haemodynamics RAP >15 mmHg or CI ≤2.0 L·min−1·m−2 RV: right ventricular; WHO-FC: World Health Organization functional class; 6-MWT: 6-min walking test; BNP: brain natriuretic peptide; NT-proBNP: N-terminal proBNP; TAPSE: tricuspid annular plane systolic excursion; RAP: right atrial pressure; CI: cardiac index. #: depending on age; ¶: TAPSE and pericardial effusion have been selected because they can be measured in the majority of the patients. Reproduced from McLaughlin and McGoon 94, with permission from the publisher.
- Table 16—
Suggested assessments and timing for the follow-up of patients with pulmonary arterial hypertension
At baseline (prior to therapy) Every 3–6 months# 3–6 months after initiation or changes in therapy In case of clinical worsening Clinical assessment WHO-FC ECG ✓ ✓ ✓ ✓ 6-MWT¶ ✓ ✓ ✓ ✓ Cardiopulmonary exercise testing¶ ✓ ✓ ✓ BNP/NT-proBNP ✓ ✓ ✓ ✓ Echocardiography ✓ ✓ ✓ RHC ✓+ ✓§ ✓§ WHO-FC: World Health Organization functional class; ✓: assessment is suggested; 6-MWT: 6-min walking test; BNP: brain natriuretic peptide; NT-proBNP: N-terminal proBNP; RHC: right heart catheterisation. #: intervals should to be adjusted to individual patients needs; ¶: usually one of the two exercise tests is performed; +: is recommended (table 11A); §: should be performed (table 11A).
- Table 17—
Recommendations for evaluation of severity and follow-up
Statement Class# Level¶ It is recommended to evaluate the severity of PAH patients with a panel of data derived from clinical evaluation, exercise tests, biochemical markers, and echocardiographic and haemodynamic assessments (table 15) I C It is recommended to perform regular follow-up every 3–6 months (table 16) also in stable patients with PAH I C A goal-oriented treatment strategy is recommended in patients with PAH I C PAH: pulmonary arterial hypertension. #: class of recommendation; ¶: level of evidence.
- Table 18—
Recommendations for general measures
Statement Class# Level¶ It is recommended to avoid pregnancy in patients with PAH I C Immunisation of PAH patients against influenza and pneumococcal infection is recommended I C Physically deconditioned PAH patients should be considered for supervised exercise rehabilitation IIa B Psychosocial support should be considered in patients with PAH IIa C In-flight O2 administration should be considered for patients in WHO-FC III and IV and those with arterial blood O2 pressure consistently <8 kPa (60 mmHg) IIa C Epidural anaesthesia instead of general anaesthesia should be utilised, if possible, for elective surgery IIa C Excessive physical activity that leads to distressing symptoms is not recommended in patients with PAH III C PAH: pulmonary arterial hypertension; WHO-FC: World Health Organization functional class. #: class of recommendation; ¶: level of evidence.
- Table 19—
Recommendations for supportive therapy
Statement Class# Level¶ Diuretic treatment is indicated in PAH patients with signs of RV failure and fluid retention I C Continuous long-term O2 therapy is indicated in PAH patients when arterial blood O2 pressure is consistently <8 kPa (60 mmHg)+ I C Oral anticoagulant treatment should be considered in patients with IPAH, heritable PAH and PAH due to use of anorexigens IIa C Oral anticoagulant treatment may be considered in patients with APAH IIb C Digoxin may be considered in patients with PAH who develop atrial tachyarrhythmias to slow ventricular rate IIb C PAH: pulmonary arterial hypertension; RV: right ventricle/ventricular; IPAH: idiopathic PAH; APAH: associated PAH. #: class of recommendation; ¶: level of evidence; +: see also recommendations for PAH associated with congenital cardiac shunts (table 25).
- Table 20—
Potentially significant drug interactions with pulmonary arterial hypertension(PAH)-targeted therapies
PAH drug Mechanism of interaction Interacting drug Interaction Ambrisentan ? CyclosporineKetoconazole Caution is required in the co-administration of ambrisentan with ketoconazole and cyclosporine Bosentan CYP3A4 inducer Sildenafil Sildenafil levels fall 50%; bosentan levels increase 50%. May not require dose adjustments of either drug. CYP3A4 substrate Cyclosporine Cyclosporine levels fall 50%; bosentan levels increase fourfold. Combination contraindicated. CYP3A4 substrate Erythromycin Bosentan levels increase. May not require dose adjustment of bosentan during a short course. CYP3A4 substrate Ketoconazole Bosentan levels increase two-fold. CYP3A4 substrate + bile salt pump inhibitor Glibenclamide Increase incidence of elevated aminotransferases. Potential decrease of hypoglycaemic effect of glibenclamide. Combination indicated. CYP2C9 and CYP3A4 substrate Fluconazole, amiodarone Bosentan levels considerably increase. Combination potentially contraindicated. CYP2C9 and CYP3A4 inducers Rifampicin, phenytoin Bosentan levels decrease by 58%. Need for dose adjustment uncertain. CYP2C9 inducer HMG CoA reductase inhibitors Simvastatin levels reduce 50%; similar effects likely with atorvastatin. Cholesterol level should be monitored. CYP2C9 inducer Warfarin Increases warfarin metabolism, may need to adjust warfarin dose. Intensified monitoring of warfarin recommended following initiation but dose adjustment usually necessary. CYP2C9 and CYP3A4 inducers Hormonal contraceptives Hormone levels decrease. Contraception unreliable. Sitaxentan CYP2C9 inhibitor Warfarin Inhibits warfarin metabolism, warfarin dose needs to be reduced by 80% when initiating sitaxentan and INR monitoring intensified. ? inhibition of OATP transporter Cyclosporine Increases sitaxen levels; combination contraindicated. Sildenafil CYP3A4 substrate Bosentan Sildenafil levels fall 50%; bosentan levels increase 50%. May not require dose adjustment of either drug. CYP3A4 substrate HMG CoA reductase inhibitors May increase simvastatin/atorvastatin levels through competition for metabolism. Sildenafil levels may increase. Possible increased risk of rhabdomyolysis. CYP3A4 substrate HIV protease inhibitors Ritonavir and saquinovir increase sildenafil levels markedly. Sildenafil dose adjustments are usually required. CYP3A4 inducer Phenytoin Sildenafil level may fall. CYP3A4 substrate Erythromycin Sildenafil levels increase may not require dose adjustment for a short course. CYP3A4 substrate Ketoconazole Sildenafil levels increase. May not require dose adjustment. CYP3A4 substrate Cimetidine Sildenafil levels increase. May not require dose adjustment. cGMP NitratesNicorandil Profound systemic hypotension, combination contraindicated. Tadalafil CYP3A4 substrate Bosentan Tadafil plasma levels decrease by 42%, no significant changes in bosentan levels. May not require dose adjustment. cGMP NitratesNicorandil Profound systemic hypotension, combination contraindicated. HMG CoA: 3-hydroxy-3-methylglutary coenzyme A; OATP: organic anion transporter proteins; cGMP: cyclic guanosine monophosphate. The table is adapted from National Pulmonary Hypertension Centres of the UK and Ireland, “Consensus Statement on the Management of Pulmonary Hypertension in Clinical Practice in the UK and Ireland” 180, wih permmission from the publisher.
- Table 21—
Recommendations for efficacy of specific drug therapy, balloon atrial septostomy and lung transplantation for pulmonary arterial hypertension(group 1) according to World Health Organization functional class (WHO-FC)
Measure/treatment Classes of recommendation–level of evidence WHO-FC II WHO-FC III WHO-FC IV Calcium channel blockers I–C# I–C# – Endothelin receptor antagonists Ambrisentan I–A I–A IIa–C Bosentan I–A I–A IIa–C Sitaxentan IIa–C I–A IIa–C Phosphodiesterase type-5 inhibitors Sildenafil I–A I–A IIa–C Tadalafil¶ I–B I–B IIa–C Prostanoids Beraprost – IIb–B – Epoprostenol (intravenous) – I–A I–A Iloprost (inhaled) – I–A IIa–C Iloprost (intravenous) – IIa–C IIa–C Treprostinil (subcutaneous) – I–B IIa–C Treprostinil (intravenous) – IIa–C IIa–C Treprostinil (inhaled)¶ – I–B IIa–C Initial drugs combination therapy – – IIa–C Sequential drugs combination therapy IIa–C IIa–B Iia–B Balloon atrial septostomy – I–C I–C Lung transplantation – I–C I–C #: only in responders to acute vasoreactivity tests, I for idiopathic pulmonary arterial hypertension (PAH), heritable PAH and PAH due to anorexigens; IIa for APAH conditions; ¶: under regulatory review in the European Union.
- Table 22—
Definition of inadequate response to pulmonary arterial hypertension(PAH) treatments (see also section 7.2.5 and 7.2.6)
Inadequate clinical response for patients who were initially in WHO-FC II or III: (1) Resulting clinical status defined as stable and not satisfactory (2) Resulting clinical status defined as unstable and deteriorating Inadequate clinical response for patients who were initially in WHO-FC IV: (1) No rapid improvement to WHO-FC III or better (2) Resulting clinical status defined as stable and not satisfactory WHO-FC: World Health Organization functional class.
- Table 23—
Country-specific regulatory approval and labelling for pulmonary arterial hypertension (PAH)-specific drug therapy
Treatment Country Labelling Aetiology WHO-FC Calcium channel blockers – – – Ambrisentan USA, Canada PAH II–III–IV European Union PAH II–III Bosentan# European Union PAH II–III USA, Canada PAH II–III–IV Sitaxentan European Union PAH III Sildenafil USA, Canada PAH II–III–IV European Union PAH II–III Tadalafil¶ USA PAH II–III–IV Beraprost Japan, Korea PAH II–III–IV Epoprostenol (intravenous) Europe+ PAH III–IV USA, Canada IPAH and PAH–CTD III–IV Iloprost (inhaled) European Union IPAH III USA PAH III–IV Iloprost (intravenous) New Zealand IPAH, PAH–CTD and CTEPH III–IV Treprostinil (subcutaneous) USA PAH II–III–IV Canada PAH III–IV European Union§ IPAH III Treprostinil (intravenous) USAƒ PAH II–III–IV Canada PAH III–IV Treprostinil (inhaled)¶ USA PAH III WHO-FC: World Health Organization functional class; IPAH: idiopathic PAH; CTD: connective tissue disease; CTEPH: chronic thromboembolic pulmonary hypertension. #: specifically approved also for PAH associated with congenital systemic-to-pulmonary shunts and Eisenmenger's physiology; ¶: under regulatory review in the European Union; +: epoprostenol in Europe has not been registered through the centralised procedure of the European Medicines Agency (EMEA) but it is approved in different European countries on a national basis; §: treprostinil in Europe has not been registered through the centralised procedure of the EMEA but it is approved in France and in other countries through the mutual recognition process on a national basis; ƒ: in the case of intolerance of the subcutaneous form.
- Table 24—
Recommendations for paediatric pulmonary arterial hypertension(PAH)
Statement Class# Level¶ The PH diagnostic work-up proposed for adults should also be considered in children IIa C The PAH therapeutic algorithm proposed for adults should also be considered in children IIa C PH: pulmonary hypertension. #: class of recommendation; ¶: level of evidence.
- Table 25—
Recommendations for pulmonary arterial hypertension(PAH) associated with congenital cardiac shunts
Statement Class# Level¶ The ERA bosentan is indicated in WHO-FC III patients with Eisenmenger's syndrome I B Other ERAs, phosphodiesterase type-5 inhibitors, and prostanoids should be considered in patients with Eisenmenger's syndrome IIa C In the absence of significant haemoptysis, oral anticoagulant treatment should be considered in patients with PA thrombosis or signs of heart failure IIa C The use of supplemental O2 therapy should be considered in cases in which it produces a consistent increase in arterial oxygen saturation and reduces symptoms IIa C If symptoms of hyperviscosity are present, phlebotomy with isovolumic replacement should be considered usually when the haematocrit is >65% IIa C Combination therapy may be considered in patients with Eisenmenger's syndrome IIb C The use of CCBs is not recommended in patients with Eisenmenger's syndrome III C ERA: endothelin receptor antagonist; WHO-FC: World Health Organization functional class; PA: pulmonary arterial; CCB: calcium channel blockers. #: class of recommendation; ¶: level of evidence.
- Table 26—
Recommendations for pulmonary arterial hypertension(PAH) associated with connective tissue disease (CTD)
Statement Class# Level¶ In patients with PAH associated with CTD the same treatment algorithm as in patients with IPAH is recommended I A Echocardiographic screening for the detection of PH is recommended in symptomatic patients with scleroderma spectrum of diseases I B Echocardiographic screening for the detection of PH is recommended in symptomatic patients with all other CTDs I C RHC is indicated in all cases of suspected PAH associated with CTD, in particular if specific drug therapy is considered I C Oral anticoagulation should be considered on an individual basis IIa C Echocardiographic screening for the detection of PH may be considered in asymptomatic patients with the scleroderma spectrum of disease IIb C IPAH: idiopathic PAH; PH: pulmonary hypertension; RHC: right heart catheterisation. #: class of recommendation; ¶: level of evidence.
- Table 27—
Recommendations for pulmonary arterial hypertension(PAH) associated with portal hypertension
Statement Class# Level¶ Echocardiographic screening for the detection of PH is recommended in symptomatic patients with liver diseases and/or in candidates for liver transplantation I B In patients with PAH associated with portal hypertension the same treatment algorithm as in patients with IPAH should be considered, taking into consideration comorbidities IIa C Anticoagulation is not recommended in patients with increased risk of bleeding III C Significant PAH is a contraindication to liver transplantation if P̄pa is ≥35 mmHg and/or PVR is ≥250 dynes·s−1·cm−5 III C PH: pulmonary hypertension; IPAH: idiopathic PAH; P̄pa: mean pulmonary arterial pressure; PVR: pulmonary vascular resistance. #: class of recommendation; ¶: level of evidence.
- Table 28—
Recommendations for pulmonary arterial hypertension(PAH) associated with HIV infection
Statement Class# Level¶ Echocardiography is indicated in patients with unexplained dyspnoea to detect HIV-related cardiovascular complications I C In patients with PAH associated with HIV infection, the same treatment algorithm as in patients with IPAH should be considered, taking into consideration comorbidities and drug–drug interactions IIa C Anticoagulation is not recommended in patients with increased risk of bleeding III C IPAH: idiopathic PAH. #: class of recommendation; ¶: level of evidence.
- Table 29—
Recommendations for pulmonary veno-occlusive disease
Statement Class# Level¶ Referral of patients with PVOD to a transplant centre for evaluation is indicated as soon as the diagnosis is established I C Patients with PVOD should be managed only in centres with extensive experience in PAH due to the risk of lung oedema after the initiation of PAH-specific drug therapy IIa C PVOD: pulmonary veno-occlusive disease; PAH: pulmonary arterial hypertension. #: class of recommendation; ¶: level of evidence.
- Table 30—
Factors favouring diagnosis of left ventricular diastolic dysfunction in the presence of pulmonary hypertension as assessed by Doppler echocardiography
Clinical features Age >65 yrs Elevated systolic blood pressure Elevated pulse pressure Obesity, metabolic syndrome Hypertension Coronary artery disease Diabetes mellitus Atrial fibrillation Echocardiography Left atrial enlargement Concentric remodelling of the LV (relative wall thickness >0.45) LV hypertrophy Presence of echocardiographic indicators of elevated LV filling pressure 64, 226 Interim evaluation (after echocardiography) Symptomatic response to diuretics Exaggerated increase in systolic blood pressure with exercise Re-evaluation of chest radiograph consistent with heart failure 226 LV: left ventricle. Modified from Hoeper et al.227, with permission from the publisher.
- Table 31—
Recommendations for pulmonary hypertension(PH) due to left heart disease
Statement Class# Level¶ The optimal treatment of the underlying left heart disease is recommended in patients with PH due to left heart disease I C Patients with “out of proportion” PH due to left heart disease (table 3) should be enrolled in RCTs targeting PH specific drugs IIa C Increased left-sided filling pressures may be estimated by Doppler echocardiography IIb C Invasive measurements of Ppcw or LV end-diastolic pressure may be required to confirm the diagnosis of PH due to left heart disease IIb C RHC may be considered in patients with echocardiographic signs suggesting severe PH in patients with left heart disease IIb C The use of PAH specific drug therapy is not recommended in patients with PH due to left heart disease III C RCT: randomised controlled trial; Ppcw: pulmonary capillary wedge pressure; LV: left ventricular; RHC: right heart catheterisation; PAH: pulmonary arterial hypertension. #: class of recommendation; ¶: level of evidence.
- Table 32—
Recommendations for pulmonary hypertension(PH) due to lung diseases
Statement Class# Level¶ Echocardiography is recommended as a screening tool for the assessment of PH due to lung diseases I C RHC is recommended for a definite diagnosis of PH due to lung diseases I C The optimal treatment of the underlying lung disease including long-term O2 therapy in patients with chronic hypoxaemia is recommended in patients with PH due to lung diseases I C Patients with “out of proportion” PH due to lung diseases should be enrolled in RCTs targeting PAH-specific drugs IIa C The use of PAH-specific drug therapy is not recommended in patients with PH due to lung diseases III C RHC: right heart catheterisation; RCT: randomised controlled trial; PAH: pulmonary arterial hypertension. #: class of recommendation; ¶: level of evidence.
- Table 33—
Recommendations for chronic thromboembolic pulmonary hypertension(CTEPH)
Statement Class# Level¶ The diagnosis of CTEPH is based on the presence of pre-capillary PH (P̄pa ≥25 mmHg, Ppcw ≤15 mmHg, PVR >2 Wood units) in patients with multiple chronic/organised occlusive thrombi/emboli in the elastic pulmonary arteries (main, lobar, segmental, subsegmental) I C In patients with CTEPH lifelong anticoagulation is indicated I C Surgical pulmonary endarterectomy is the recommended treatment for patients with CTEPH I C Once perfusion scanning and/or CT angiography show signs compatible with CTEPH, the patient should be referred to a centre with expertise in surgical pulmonary endarterectomy Iia C The selection of patients for surgery should be based on the extent and location of the organised thrombi, on the degree of PH, and on the presence of comorbidities Iia C PAH-specific drug therapy may be indicated in selected CTEPH patients such as patients not candidates for surgery or patients with residual PH after pulmonary endarterectomy Iib C PH: pulmonary hypertension; P̄pa: mean pulmonary arterial pressure; Ppcw: pulmonary capillary wedge pressure; PVR: pulmonary vascular resistance; CT: computed tomography; PAH: pulmonary arterial hypertension. #: class of recommendation; ¶: level of evidence.
- Table 34—
Recommendations for a pulmonary hypertension referral centre
Statement Class# Level¶ Referral centres are required to provide care by a multiprofessional team (cardiology and respiratory medicine physicians, clinical nurse specialist, radiologists, psychological and social work support, appropriate on-call expertise) I C Referral centres are required 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) I C A referral centre should follow at least 50 patients with PAH or CTEPH and should receive at least two new referrals per month with documented PAH or CTEPH IIa C Referral centres should perform at least 20 vasoreactivity tests in PAH patients per year IIa C Referral centres should participate in collaborative clinical research in PAH, which includes phase II and phase III clinical trials IIa C CTD: connective tissue disease; PEA: pulmonary endarterectomy; PAH: pulmonary arterial hypertension; CTEPH: chronic thromboembolic pulmonary hypertension. #: class of recommendation; ¶: level of evidence.
Jump To
- Article
- PREAMBLE
- 1. INTRODUCTION
- 2. DEFINITIONS
- 3. CLINICAL CLASSIFICATION OF PULMONARY HYPERTENSION
- 4. PATHOLOGY OF PULMONARY HYPERTENSION
- 5. PATHOBIOLOGY OF PULMONARY HYPERTENSION
- 6. GENETICS, EPIDEMIOLOGY AND RISK FACTORS OF PULMONARY HYPERTENSION
- 7. PULMONARY ARTERIAL HYPERTENSION (GROUP 1)
- 8. PULMONARY VENO-OCCLUSIVE DISEASE AND PULMONARY CAPILLARY HAEMANGIOMATOSIS (GROUP 1′)
- 9. PULMONARY HYPERTENSION DUE TO LEFT HEART DISEASE (GROUP 2)
- 10. PULMONARY HYPERTENSION DUE TO LUNG DISEASES AND/OR HYPOXIA (GROUP 3)
- 11. CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION (GROUP 4)
- 12. DEFINITION OF A PULMONARY ARTERIAL HYPERTENSION REFERRAL CENTRE
- Statement of interest
- Acknowledgments
- Footnotes
- References
- Figures & Data
- Info & Metrics