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Guidelines for the diagnosis and treatment of pulmonary hypertension

N. Galiè, M. M. Hoeper, M. Humbert, A. Torbicki, J-L. Vachiery, J. A. Barbera, M. Beghetti, P. Corris, S. Gaine, J. S. Gibbs, M. A. Gomez-Sanchez, G. Jondeau, W. Klepetko, C. Opitz, A. Peacock, L. Rubin, M. Zellweger, G. Simonneau
European Respiratory Journal 2009 34: 1219-1263; DOI: 10.1183/09031936.00139009
N. Galiè
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M. M. Hoeper
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M. Humbert
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A. Torbicki
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J-L. Vachiery
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J. A. Barbera
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M. Beghetti
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P. Corris
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S. Gaine
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J. S. Gibbs
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M. A. Gomez-Sanchez
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G. Jondeau
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W. Klepetko
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C. Opitz
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A. Peacock
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L. Rubin
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M. Zellweger
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G. Simonneau
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  • Figure1
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  • Fig. 1—
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    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—
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    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

  • Figures
  • Table 1—

    Classes of recommendations

    Classes of recommendationsDefinition
    Class IEvidence and/or general agreement that a given treatment or procedure is beneficial, useful, effective.
    Class IIConflicting evidence and/or a divergence of opinion about the usefulness/efficacy of the given treatment or procedure.
     Class IIaWeight of evidence/opinion is in favour of usefulness/efficacy.
     Class IIbUsefulness/efficacy is less well established by evidence/opinion.
    Class IIIEvidence 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 AData derived from multiple randomised clinical trials# or meta-analyses.
    Level of evidence BData derived from a single randomised clinical trial# or large nonrandomised studies.
    Level of evidence CConsensus 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)#

    DefinitionCharacteristicsClinical group(s)¶
    PHP̄pa ≥25 mmHgAll
    Pre-capillary PHP̄pa ≥25 mmHg1. Pulmonary arterial hypertension
    Ppcw ≤15 mmHg3. PH due to lung diseases
    CO normal or reduced+4. Chronic thromboembolic PH
    5. PH with unclear and/or multifactorial mechanisms
    Post-capillary PHP̄pa ≥25 mmHg2. PH due to left heart disease
    Ppcw >15 mmHg
    CO normal or reduced+
     PassiveTPG ≤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 BenfluorexPossible Cocaine Phenylpropanolamine St John’s Wort Chemotherapeutic agents Selective serotonin reuptake inhibitors Pergolide
    Likely Amphetamines l-tryptophan MethamphetaminesUnlikely 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 PHIB
    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 PHIIaC
     Tricuspid regurgitation velocity 2.9–3.4 m·s−1, PA systolic pressure 37–50 mmHg with/without additional echocardiographic variables suggestive of PHIIaC
    Echocardiographic diagnosis: PH likely
     Tricuspid regurgitation velocity >3.4 m·s−1, PA systolic pressure >50 mmHg, with/without additional echocardiographic variables suggestive of PHIB
    Exercise Doppler echocardiography is not recommended for screening of PHIIIC
    • #: 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

    DrugRouteHalf-lifeDose range#Increments¶Duration+
    EpoprostenolIntravenous3 min2–12 ng·kg−1·min−12 ng·kg−1·min−110 min
    AdenosineIntravenous5–10 s50–350 μg·kg−1·min−150 μg·kg−1·min−12 min
    Nitric oxideInhaled15–30 s10–20 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 consideredIC
     RHC should be performed for confirmation of efficacy of PAH-specific drug therapyIIaC
     RHC should be performed for confirmation of clinical deterioration and as baseline for the evaluation of the effect of treatment escalation and/or combination therapyIIaC
    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 CCBIC
     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 COIC
     Vasoreactivity testing should be performed only in referral centresIIaC
     Vasoreactivity testing should be performed using nitric oxide as vasodilatorIIaC
     Vasoreactivity testing may be performed in other types of PAHIIbC
     Vasoreactivity testing may be performed using i.v. epoprostenol or i.v. adenosineIIbC
     The use of an oral or i.v. CCB in acute vasoreactivity testing is not recommendedIIIC
     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)IIIC
    • 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 diagnosisClass#Level¶
     Echocardiographic diagnosis of “PH unlikely”, no symptoms: no additional work-up is recommendedIC
     Echocardiographic diagnosis of “PH unlikely”, presence of symptoms and of associated conditions or risks factors for group1–PAH: echocardiographic follow-up is recommendedIC
     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 recommendedIC
    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 recommendedIC
     Echocardiographic diagnosis of “PH possible”, presence of symptoms and of associated conditions or risks factors for group 1–PAH: RHC may be consideredIIbC
     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 consideredIIbC
    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 recommendedIC
     Echocardiographic diagnosis of “PH likely”, without symptoms and presence/absence of associated conditions or risks factors for group 1–PAH: RHC should be consideredIIaC
    • RHC: right heart catheterisation. #: class of recommendation; ¶: level of evidence.

  • Table 13—

    Recommendations for diagnostic strategy

    StatementClass#Level¶
    Ventilation/perfusion lung scan is recommended in patients with unexplained PH to exclude CTEPHIC
    Contrast CT angiography of the PA is indicated in the work-up of patients with CTEPHIC
    Routine biochemistry, haematology, immunology and thyroid function tests are indicated in all patients with PAH, to identify the specific associated conditionIC
    Abdominal ultrasound is indicated for the screening of portal hypertensionIC
    High-resolution CT should be considered in all patients with PHIIaC
    Conventional pulmonary angiography should be considered in the work-up of patients with CTEPHIIaC
    Open or thoracoscopic lung biopsy is not recommended in patients with PAHIIIC
    • 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 IPatients 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 IIPatients 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 IIIPatients 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 IVPatients 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 prognosisDeterminants of prognosisWorse prognosis
    NoClinical evidence of RV failureYes
    SlowRate of progression of symptomsRapid
    NoSyncopeYes
    I, IIWHO-FCIV
    Longer (>500 m)#6-MWTShorter (<300 m)
    Peak O2 consumption >15 mL·min−1·kg−1Cardiopulmonary exercise testingPeak O2 consumption <12 mL·min−1·kg−1
    Normal or near-normalBNP/NT-proBNP plasma levelsVery elevated and rising
    No pericardial effusion TAPSE¶ >2.0 cmEchocardiographic findings¶Pericardial effusion TAPSE¶ <1.5 cm
    RAP <8 mmHg and CI ≥2.5 L·min−1·m−2HaemodynamicsRAP >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 therapyIn 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

    StatementClass#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)IC
    It is recommended to perform regular follow-up every 3–6 months (table 16) also in stable patients with PAHIC
    A goal-oriented treatment strategy is recommended in patients with PAHIC
    • PAH: pulmonary arterial hypertension. #: class of recommendation; ¶: level of evidence.

  • Table 18—

    Recommendations for general measures

    StatementClass#Level¶
    It is recommended to avoid pregnancy in patients with PAHIC
    Immunisation of PAH patients against influenza and pneumococcal infection is recommendedIC
    Physically deconditioned PAH patients should be considered for supervised exercise rehabilitationIIaB
    Psychosocial support should be considered in patients with PAHIIaC
    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)IIaC
    Epidural anaesthesia instead of general anaesthesia should be utilised, if possible, for elective surgeryIIaC
    Excessive physical activity that leads to distressing symptoms is not recommended in patients with PAHIIIC
    • PAH: pulmonary arterial hypertension; WHO-FC: World Health Organization functional class. #: class of recommendation; ¶: level of evidence.

  • Table 19—

    Recommendations for supportive therapy

    StatementClass#Level¶
    Diuretic treatment is indicated in PAH patients with signs of RV failure and fluid retentionIC
    Continuous long-term O2 therapy is indicated in PAH patients when arterial blood O2 pressure is consistently <8 kPa (60 mmHg)+IC
    Oral anticoagulant treatment should be considered in patients with IPAH, heritable PAH and PAH due to use of anorexigensIIaC
    Oral anticoagulant treatment may be considered in patients with APAHIIbC
    Digoxin may be considered in patients with PAH who develop atrial tachyarrhythmias to slow ventricular rateIIbC
    • 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 drugMechanism of interactionInteracting drugInteraction
    Ambrisentan?CyclosporineKetoconazoleCaution is required in the co-administration of ambrisentan with ketoconazole and cyclosporine
    BosentanCYP3A4 inducerSildenafilSildenafil levels fall 50%; bosentan levels increase 50%. May not require dose adjustments of either drug.
    CYP3A4 substrateCyclosporineCyclosporine levels fall 50%; bosentan levels increase fourfold. Combination contraindicated.
    CYP3A4 substrateErythromycinBosentan levels increase. May not require dose adjustment of bosentan during a short course.
    CYP3A4 substrateKetoconazoleBosentan levels increase two-fold.
    CYP3A4 substrate + bile salt pump inhibitorGlibenclamideIncrease incidence of elevated aminotransferases. Potential decrease of hypoglycaemic effect of glibenclamide. Combination indicated.
    CYP2C9 and CYP3A4 substrateFluconazole, amiodaroneBosentan levels considerably increase. Combination potentially contraindicated.
    CYP2C9 and CYP3A4 inducersRifampicin, phenytoinBosentan levels decrease by 58%. Need for dose adjustment uncertain.
    CYP2C9 inducerHMG CoA reductase inhibitorsSimvastatin levels reduce 50%; similar effects likely with atorvastatin. Cholesterol level should be monitored.
    CYP2C9 inducerWarfarinIncreases warfarin metabolism, may need to adjust warfarin dose. Intensified monitoring of warfarin recommended following initiation but dose adjustment usually necessary.
    CYP2C9 and CYP3A4 inducersHormonal contraceptivesHormone levels decrease. Contraception unreliable.
    SitaxentanCYP2C9 inhibitorWarfarinInhibits warfarin metabolism, warfarin dose needs to be reduced by 80% when initiating sitaxentan and INR monitoring intensified.
    ? inhibition of OATP transporterCyclosporineIncreases sitaxen levels; combination contraindicated.
    SildenafilCYP3A4 substrateBosentanSildenafil levels fall 50%; bosentan levels increase 50%. May not require dose adjustment of either drug.
    CYP3A4 substrateHMG CoA reductase inhibitorsMay increase simvastatin/atorvastatin levels through competition for metabolism. Sildenafil levels may increase. Possible increased risk of rhabdomyolysis.
    CYP3A4 substrateHIV protease inhibitorsRitonavir and saquinovir increase sildenafil levels markedly. Sildenafil dose adjustments are usually required.
    CYP3A4 inducerPhenytoinSildenafil level may fall.
    CYP3A4 substrateErythromycinSildenafil levels increase may not require dose adjustment for a short course.
    CYP3A4 substrateKetoconazoleSildenafil levels increase. May not require dose adjustment.
    CYP3A4 substrateCimetidineSildenafil levels increase. May not require dose adjustment.
    cGMPNitratesNicorandilProfound systemic hypotension, combination contraindicated.
    TadalafilCYP3A4 substrateBosentanTadafil plasma levels decrease by 42%, no significant changes in bosentan levels. May not require dose adjustment.
    cGMPNitratesNicorandilProfound 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/treatmentClasses of recommendation–level of evidence
    WHO-FC IIWHO-FC IIIWHO-FC IV
    Calcium channel blockersI–C#I–C#–
    Endothelin receptor antagonistsAmbrisentanI–AI–AIIa–C
    BosentanI–AI–AIIa–C
    SitaxentanIIa–CI–AIIa–C
    Phosphodiesterase type-5 inhibitorsSildenafilI–AI–AIIa–C
    Tadalafil¶I–BI–BIIa–C
    ProstanoidsBeraprost–IIb–B–
    Epoprostenol (intravenous)–I–AI–A
    Iloprost (inhaled)–I–AIIa–C
    Iloprost (intravenous)–IIa–CIIa–C
    Treprostinil (subcutaneous)–I–BIIa–C
    Treprostinil (intravenous)–IIa–CIIa–C
    Treprostinil (inhaled)¶–I–BIIa–C
    Initial drugs combination therapy––IIa–C
    Sequential drugs combination therapyIIa–CIIa–BIia–B
    Balloon atrial septostomy–I–CI–C
    Lung transplantation–I–CI–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

    TreatmentCountryLabelling
    AetiologyWHO-FC
    Calcium channel blockers–––
    AmbrisentanUSA, CanadaPAHII–III–IV
    European UnionPAHII–III
    Bosentan#European UnionPAHII–III
    USA, CanadaPAHII–III–IV
    SitaxentanEuropean UnionPAHIII
    SildenafilUSA, CanadaPAHII–III–IV
    European UnionPAHII–III
    Tadalafil¶USAPAHII–III–IV
    BeraprostJapan, KoreaPAHII–III–IV
    Epoprostenol (intravenous)Europe+PAHIII–IV
    USA, CanadaIPAH and PAH–CTDIII–IV
    Iloprost (inhaled)European UnionIPAHIII
    USAPAHIII–IV
    Iloprost (intravenous)New ZealandIPAH, PAH–CTD and CTEPHIII–IV
    Treprostinil (subcutaneous)USAPAHII–III–IV
    CanadaPAHIII–IV
    European Union§IPAHIII
    Treprostinil (intravenous)USAƒPAHII–III–IV
    CanadaPAHIII–IV
    Treprostinil (inhaled)¶USAPAHIII
    • 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)

    StatementClass#Level¶
    The PH diagnostic work-up proposed for adults should also be considered in childrenIIaC
    The PAH therapeutic algorithm proposed for adults should also be considered in childrenIIaC
    • PH: pulmonary hypertension. #: class of recommendation; ¶: level of evidence.

  • Table 25—

    Recommendations for pulmonary arterial hypertension(PAH) associated with congenital cardiac shunts

    StatementClass#Level¶
    The ERA bosentan is indicated in WHO-FC III patients with Eisenmenger's syndromeIB
    Other ERAs, phosphodiesterase type-5 inhibitors, and prostanoids should be considered in patients with Eisenmenger's syndromeIIaC
    In the absence of significant haemoptysis, oral anticoagulant treatment should be considered in patients with PA thrombosis or signs of heart failureIIaC
    The use of supplemental O2 therapy should be considered in cases in which it produces a consistent increase in arterial oxygen saturation and reduces symptomsIIaC
    If symptoms of hyperviscosity are present, phlebotomy with isovolumic replacement should be considered usually when the haematocrit is >65%IIaC
    Combination therapy may be considered in patients with Eisenmenger's syndromeIIbC
    The use of CCBs is not recommended in patients with Eisenmenger's syndromeIIIC
    • 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)

    StatementClass#Level¶
    In patients with PAH associated with CTD the same treatment algorithm as in patients with IPAH is recommendedIA
    Echocardiographic screening for the detection of PH is recommended in symptomatic patients with scleroderma spectrum of diseasesIB
    Echocardiographic screening for the detection of PH is recommended in symptomatic patients with all other CTDsIC
    RHC is indicated in all cases of suspected PAH associated with CTD, in particular if specific drug therapy is consideredIC
    Oral anticoagulation should be considered on an individual basisIIaC
    Echocardiographic screening for the detection of PH may be considered in asymptomatic patients with the scleroderma spectrum of diseaseIIbC
    • 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

    StatementClass#Level¶
    Echocardiographic screening for the detection of PH is recommended in symptomatic patients with liver diseases and/or in candidates for liver transplantationIB
    In patients with PAH associated with portal hypertension the same treatment algorithm as in patients with IPAH should be considered, taking into consideration comorbiditiesIIaC
    Anticoagulation is not recommended in patients with increased risk of bleedingIIIC
    Significant PAH is a contraindication to liver transplantation if P̄pa is ≥35 mmHg and/or PVR is ≥250 dynes·s−1·cm−5IIIC
    • 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

    StatementClass#Level¶
    Echocardiography is indicated in patients with unexplained dyspnoea to detect HIV-related cardiovascular complicationsIC
    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 interactionsIIaC
    Anticoagulation is not recommended in patients with increased risk of bleedingIIIC
    • IPAH: idiopathic PAH. #: class of recommendation; ¶: level of evidence.

  • Table 29—

    Recommendations for pulmonary veno-occlusive disease

    StatementClass#Level¶
    Referral of patients with PVOD to a transplant centre for evaluation is indicated as soon as the diagnosis is establishedIC
    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 therapyIIaC
    • 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

    StatementClass#Level¶
    The optimal treatment of the underlying left heart disease is recommended in patients with PH due to left heart diseaseIC
    Patients with “out of proportion” PH due to left heart disease (table 3) should be enrolled in RCTs targeting PH specific drugsIIaC
    Increased left-sided filling pressures may be estimated by Doppler echocardiographyIIbC
    Invasive measurements of Ppcw or LV end-diastolic pressure may be required to confirm the diagnosis of PH due to left heart diseaseIIbC
    RHC may be considered in patients with echocardiographic signs suggesting severe PH in patients with left heart diseaseIIbC
    The use of PAH specific drug therapy is not recommended in patients with PH due to left heart diseaseIIIC
    • 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

    StatementClass#Level¶
    Echocardiography is recommended as a screening tool for the assessment of PH due to lung diseasesIC
    RHC is recommended for a definite diagnosis of PH due to lung diseasesIC
    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 diseasesIC
    Patients with “out of proportion” PH due to lung diseases should be enrolled in RCTs targeting PAH-specific drugsIIaC
    The use of PAH-specific drug therapy is not recommended in patients with PH due to lung diseasesIIIC
    • 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)

    StatementClass#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)IC
    In patients with CTEPH lifelong anticoagulation is indicatedIC
    Surgical pulmonary endarterectomy is the recommended treatment for patients with CTEPHIC
    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 endarterectomyIiaC
    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 comorbiditiesIiaC
    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 endarterectomyIibC
    • 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

    StatementClass#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)IC
    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)IC
    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 CTEPHIIaC
    Referral centres should perform at least 20 vasoreactivity tests in PAH patients per yearIIaC
    Referral centres should participate in collaborative clinical research in PAH, which includes phase II and phase III clinical trialsIIaC
    • CTD: connective tissue disease; PEA: pulmonary endarterectomy; PAH: pulmonary arterial hypertension; CTEPH: chronic thromboembolic pulmonary hypertension. #: class of recommendation; ¶: level of evidence.

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Guidelines for the diagnosis and treatment of pulmonary hypertension
N. Galiè, M. M. Hoeper, M. Humbert, A. Torbicki, J-L. Vachiery, J. A. Barbera, M. Beghetti, P. Corris, S. Gaine, J. S. Gibbs, M. A. Gomez-Sanchez, G. Jondeau, W. Klepetko, C. Opitz, A. Peacock, L. Rubin, M. Zellweger, G. Simonneau
European Respiratory Journal Dec 2009, 34 (6) 1219-1263; DOI: 10.1183/09031936.00139009

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Guidelines for the diagnosis and treatment of pulmonary hypertension
N. Galiè, M. M. Hoeper, M. Humbert, A. Torbicki, J-L. Vachiery, J. A. Barbera, M. Beghetti, P. Corris, S. Gaine, J. S. Gibbs, M. A. Gomez-Sanchez, G. Jondeau, W. Klepetko, C. Opitz, A. Peacock, L. Rubin, M. Zellweger, G. Simonneau
European Respiratory Journal Dec 2009, 34 (6) 1219-1263; DOI: 10.1183/09031936.00139009
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  • 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
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  • 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension
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