Abstract
Résumé
Group 1: PAH |
1.1 Idiopathic PAH |
1.2 Heritable PAH |
1.3 Drug- and toxin-induced PAH |
1.4 PAH associated with: |
1.4.1 Connective tissue disease |
1.4.2 HIV infection |
1.4.3 Portal hypertension |
1.4.4 Congenital heart disease |
1.4.5 Schistosomiasis |
1.5 PAH long-term responders to calcium channel blockers |
1.6 PAH with overt features of venous/capillaries (PVOD/PCH) involvement |
1.7 Persistent PH of the newborn syndrome |
Group 2: PH due to left heart disease |
2.1 PH due to heart failure with preserved LVEF |
2.2 PH due to heart failure with reduced LVEF |
2.3 Valvular heart disease |
2.4 Congenital/acquired cardiovascular conditions leading to postcapillary PH |
Group 3: PH due to lung diseases and/or hypoxia |
3.1 Obstructive lung disease |
3.2 Restrictive lung disease |
3.3 Other lung disease with mixed restrictive/obstructive pattern |
3.4 Hypoxia without lung disease |
3.5 Developmental lung disorders |
Group 4: PH due to pulmonary artery obstructions |
4.1 Chronic thromboembolic PH |
4.2 Other pulmonary artery obstructions |
Group 5: PH with unclear and/or multifactorial mechanisms |
5.1 Hematological disorders |
5.2 Systemic and metabolic disorders |
5.3 Others |
5.4 Complex congenital heart disease |
Methods
Diagnosis




Echocardiography
Echocardiography for identification of PH
- Rudski L.G.
- Lai W.W.
- Afilalo J.
- et al.
- 1.We recommend transthoracic echocardiography for initial assessment of all patients with clinically suspected PH or unexplained dyspnea (Strong Recommendation, Moderate-Quality Evidence).
- 2.We recommend a complete echocardiographic assessment when PH is suspected, including estimation of sPAP using the TRV jet, measurement of inferior vena cava size, and degree of inspiratory collapse, as well as assessment of “secondary” signs of PH, such as RA or right ventricular (RV) enlargement, RV hypertrophy, septal flattening, and RV dysfunction (Strong Recommendation, Moderate-Quality Evidence).
- Rudski L.G.
- Lai W.W.
- Afilalo J.
- et al.
Echocardiography for classification of PH
- 3.We recommend transthoracic echocardiography in all PH patients to detect any abnormality of left-sided chambers or valves, which can indicate the possibility of postcapillary PH (Strong Recommendation, Moderate-Quality Evidence).
Echocardiographic prognosticators in patients with PH
- 4.We recommend that PH patients should have baseline and follow-up echocardiograms that measure systolic PAP, RA size, tricuspid regurgitation severity, and presence/severity of pericardial effusion. Additionally, indices of RV systolic function should be assessed using tricuspid annular plane systolic excursion, S', or RV index of myocardial performance, with free wall strain using 2-dimensional speckle tracking being a recommended method in laboratories with suitable equipment and expertise (Strong Recommendation, Moderate-Quality Evidence).
Recognizing PAH in high-risk groups
- 5.We recommend annual echocardiography and measurement of lung diffusing capacity for carbon monoxide to screen for PH in all patients with scleroderma (Strong Recommendation, Low-Quality Evidence).
- 6.We recommend echocardiography to screen for PH in all patients with portal hypertension being assessed for liver transplantation (Strong Recommendation, Low-Quality Evidence).
Right heart catheterization
- 7.We recommend RHC in all patients with suspected PAH or CTEPH to confirm the hemodynamic diagnosis of precapillary PH and to assess the severity of PH (Strong Recommendation, Moderate-Quality Evidence).
- 8.We recommend RHC in PH patients be performed only in centres with technical expertise and experience to accurately assess cardiopulmonary hemodynamics and to diagnose and appropriately classify the cause of PH (Strong Recommendation, Low-Quality Evidence).
Reference level | The choice of reference level can lead to substantial variability in measured pressures, with mid-thoracic height best approximating the level of the left atrium. 51 See Figure 4A |
Wedge pressure | Mean PAP may be determined at end-expiration, or with a mean throughout the respiratory cycle. With obesity or obstructive lung disease, respiratory swings in intrathoracic pressure can be substantial, affecting interpretation of the hemodynamics. Computer-derived mean pressure measurements instead of end-expiratory pressures can change PH classification in 25%-30% of patients. 52 ,53 We recommend pressure measurement at end expiration. Values should be taken using examination of traces containing several respiratory cycles and not the automatic digital estimation by recording devices. See Figure 4B |
When a reliable assessment of pulmonary arterial wedge pressure is not possible, consideration should be given to performing a left heart catheterization to obtain a left ventricular end diastolic pressure. This is particularly important when mixed etiologies of PH are being considered | |
Cardiac output | Although most accurate, the direct Fick estimation of cardiac output is rarely feasible. The commonly used techniques are the TD and indirect Fick methods. They correlate with direct Fick, but the agreement between methods is only fair. 54 ,55 Because TD correlates better with RV function and mortality, it should be used56 ,57 |
Additional manoeuvres |
|
Cardiac magnetic resonance
- Kreitner K.F.
- Wirth G.M.
- Krummenauer F.
- et al.
- 9.We suggest CMR imaging in PAH patients when accessible to assess right ventricle size and function to help guide management (Weak Recommendation, Moderate-Quality Evidence).
Approach to Management of PAH
Parameter | Low risk | Intermediate risk | High risk |
---|---|---|---|
WHO/NYHA functional class | I-II | III | IV |
Clinical right heart failure | Absent | Absent | Present |
Syncope | No | Occasional | Repeated |
Symptom progression | No | Slow | Rapid |
Six-minute walk distance, m | > 440 | 165-440 | < 165 |
NT pro-BNP, ng/mL or BNP, ng/L | < 300 | 300-1400 | > 1400 |
< 50 | 50-300 | > 300 | |
RAP, mm Hg | < 8 | 8-14 | > 14 |
CI, L/min/m2 | >2.5 | 2.0-2.4 | <2.0 |
SvO2 | > 65% | 60%-65% | < 60% |
Echo/CMR RA area, cm2 | < 18 | 18-26 | > 26 |
Pericardial effusion | None | None or minimal | Present |
CPET peak VO2, mL/min/kg | > 15 | 11-15 | < 11 |
VE/VCO2 slope | < 36 | 36-45 | > 45 |
- Galie N.
- Humbert M.
- Vachiery J.L.
- et al.
Supportive measures
- 10.We recommend general supportive (education, psychosocial support, contraception) measures in all PAH patients to improve understanding and self-management (Strong Recommendation, Low-Quality Evidence).
- 11.We recommend supervised exercise rehabilitation be considered in PAH patients to improve functional capacity and health-related quality of life (HRQoL; Strong Recommendation, Moderate-Quality Evidence).
- 12.We suggest general medical therapeutic measures (diuretics for volume overload, and oxygen for resting hypoxemia) in all PAH patients (Weak Recommendation, Low-Quality Evidence).
Anticoagulation
- 13.We suggest systemic anticoagulation with warfarin in selected PAH patients (idiopathic PAH [IPAH], heritable PAH [HPAH], drug- and toxin-induced [DPAH]) in the absence of elevated bleeding risk (Weak Recommendation, Low-Quality Evidence). We recommend against systemic anticoagulation in patients with PAH associated with connective tissue disease, CHD, portal hypertension, and HIV (Strong Recommendation, Low-Quality Evidence).
Calcium channel blockers
- 14.We recommend acute vasodilator testing (with inhaled NO, intravenous [I.V.] epoprostenol or adenosine) in selected PAH patients (IPAH, HPAH, DPAH) (Strong Recommendation, Low-Quality Evidence). Marked vasodilator responsiveness (decrease in mean PAP ≥ 10 mm Hg to < 40 mm Hg and stable/increased cardiac output) identifies a subgroup of patients more likely to respond to high-dose CCBs, which should be initiated in PH expert centres (Strong Recommendation, Low-Quality Evidence).
PAH-targeted medications available in Canada
Prostacyclin pathway
Drug family | Drug name | Trade name | Route of delivery | Typical dosing | Notable side effects | Health Canada approved | Recommendation/level of evidence |
---|---|---|---|---|---|---|---|
Prostacyclin pathway agents | Epoprostenol | Flolan, Caripul | Continuous I.V. infusion | 10-30 ng/kg/min | Flushing, headache, diarrhea, jaw/bone pain, nausea, hypotension, central line complications, rebound PH | Yes | I/A |
Treprostinil | Remodulin | Continuous SC/I.V. infusion | 20-80 ng/kg/min | Flushing, headache, diarrhea, jaw/bone pain, nausea, hypotension, infusion site pain | Yes | I/B, IIb/C | |
Orenitram | Oral | 3-6 mg bid | Flushing, headache, diarrhea, jaw/bone pain, nausea | No | IIb/B | ||
Tyvaso | Inhaled | 54 μg qid | Flushing, headache, diarrhea, jaw/bone pain, nausea, cough | No | I/B | ||
Iloprost | Ventavis | Inhaled | 5 μg 6-9 times daily | No | I/B | ||
Selexipag | Uptravi | Oral | 200-1600 μg bid | Flushing, headache, diarrhea, jaw/bone pain, nausea | Yes | I/B | |
Endothelin receptor antagonists | Bosentan | Tracleer, generic | Oral | 125 mg bid | Hepatotoxicity, anemia, fluid retention | Yes | I/A |
Ambrisentan | Volibris | Oral | 10 mg daily | Yes | I/A | ||
Macitentan | Opsumit | Oral | 10 mg daily | Yes | I/B | ||
Nitric oxide pathway agents | Sildenafil | Revatio, generic | Oral | 20-80 mg tid | Headaches, flushing, fluid retention | Yes | I/A |
Tadalafil | Adcirca | Oral | 40 mg daily | Yes | I/B | ||
Riociguat | Adempas | Oral | 1.0-2.5 mg tid | Hypotension, headache, gastroesophageal reflux | Yes | I/B |
- Galie N.
- Humbert M.
- Vachiery J.L.
- et al.
Endothelin receptor antagonists
NO-cyclic GMP pathway
Risk-Based Assessment and Treatment Strategies
- Galie N.
- Humbert M.
- Vachiery J.L.
- et al.
- Galie N.
- Humbert M.
- Vachiery J.L.
- et al.
Limitations to Access and Therapy
- 15.We recommend that all PAH patients be assessed in a recognized PH centre to confirm the diagnosis, direct institution of PH-targeted therapies, and evaluate the response to treatment (Strong Recommendation, Low-Quality Evidence).
- 16.We recommend initial oral monotherapy (ERA, PDE-5i, or sGCs) only in low-risk (Table 3) treatment-naive PAH patients (Strong Recommendation, High-Quality Evidence).
- 17.We recommend initial dual oral combination therapy in intermediate-risk treatment-naive PAH patients (Strong Recommendation, High-Quality Evidence).
- 18.We recommend initial combination therapy including I.V. epoprostenol in high-risk patients who are candidates for such therapies (Strong Recommendation, Low-Quality Evidence). We suggest initial combination therapy including I.V./subcutaneous treprostinil in high-risk PAH patients who are candidates for such therapies (including NYHA FC IV; Weak Recommendation, Low-Quality Evidence).
- 19.We recommend regular reassessment of all PAH patients using a panel of measures (clinical, functional, hemodynamic, and/or right ventricle size/function [Table 3]; Strong Recommendation, Low-Quality Evidence).
Initial/combination therapy | No head-to-head trials or other data support any specific initial choice of therapy |
There are no reliable factors that predict the likelihood of an individual PAH patient responding to any specific individual or combination of PH-targeted medical therapies | |
The use of ambrisentan with tadalafil in upfront combination therapy is supported by a randomized controlled trial. 90 Other initial therapeutic combinations can be considered, but are less well supported by clinical evidence | |
Most combinations of the 4 classes of drugs are acceptable, except the combination of PDE-5i and sGCs which is contraindicated because of the risk of systemic hypotension | |
Follow-up | Regular comprehensive reassessment of all PAH patients is required to assess response to therapy and establish individual risk for poor clinical outcomes (worse functional status, hospitalization, need for transplantation, or death) |
Reassessment should occur within 3-4 months of institution of initial therapy or any change in therapy. In PAH patients who achieve low-risk status, reassessment could be every 6-12 months, depending on geographic access to the PH expert centre | |
Risk assessment | The definitions of low, intermediate, and high-risk patient profiles include a combination of measures that appear in Table 3. There are various approaches on the parameters that should be included and how to weight each parameter 84 , 85 , 86 , 87 , 88 , 89 |
After initial PH-targeted therapy, patients who improve to low-risk status upon reassessment can safely continue their individual current maintenance therapy |
Which PH Patients Should Not Be Treated With PAH-targeted Medications?
PH due to left heart disease (group II PH)
- Fang J.C.
- DeMarco T.
- Givertz M.M.
- et al.
- 20.We recommend that the management of patients with group II PH should focus on efforts to optimize ventricular filling pressures and treat the underlying causes of and contributors to left heart disease (Strong Recommendation, Low-Quality Evidence).
- 21.We recommend against the routine use of PAH-targeted therapies in patients with group II (post-capillary) PH (Strong Recommendation, Low-Quality Evidence).
PH due to lung disease and/or hypoxia (group III PH)
- 22.We recommend against routine RHC and against the use of PAH-targeted therapy in patients with mild-moderate World Health Organization group III PH in the absence of RV failure (Strong Recommendation, Moderate-Quality Evidence).
- 23.We suggest that patients with moderate-severe World Health Organization group III PH (and/or features of RV failure) be referred to a PH centre (Strong Recommendation, Low-Quality Evidence).
Diagnosis and Management of CTEPH (Group IV PH)
- 24.We recommend that patients with residual dyspnea or exercise intolerance after at least 3 months of uninterrupted anticoagulation post acute PE be assessed for CTEPH with echocardiography and V/Q lung scan (Strong Recommendation, Low-Quality Evidence).
- 25.We strongly recommend that the possibility of CTEPH be assessed with initial V/Q scanning in patients being evaluated for PH (Strong Recommendation, Low-Quality Evidence).
- 26.We recommend that all potential CTEPH patients be referred to a local expert PH centre for establishment of a formal diagnosis of CTEPH and assessment for the most appropriate treatment (Strong Recommendation, Moderate-Quality Evidence)
- 27.We strongly recommend that all CTEPH patients be evaluated for PEA in consultation with a PEA centre (Strong Recommendation, Moderate-Quality Evidence).
- 28.We recommend treatment with riociguat monotherapy in all patients with symptomatic inoperable or residual/recurrent CTEPH post-PEA (Strong Recommendation, Moderate-Quality Evidence). We do not currently recommend for or against combination PH-targeted medical therapy in CTEPH patients.
- 29.We suggest CTEPH patients who are ineligible for or decline PEA be considered for balloon pulmonary angioplasty (Weak Recommendation, Low-Quality Evidence).
- •Either planar or single-photon emission computed tomography or nuclear V/Q scan are acceptable modalities to screen for CTEPH.
- •A normal perfusion (Q) scan effectively rules out the possibility of CTEPH.
- •A negative computed tomography pulmonary angiogram does not effectively rule out CTEPH.
- •Macitentan improved hemodynamics and functional capacity in inoperable CTEPH patients in a phase II placebo-controlled RCT,121but is not yet Health Canada-approved for this indication.
- •Low-quality evidence suggests a possible benefit of other PAH-targeted medications (I.V. epoprostenol, subcutaneous treprostinil, oral bosentan, oral sildenafil).124
Lung Transplantation for PH
- 30.We recommend that PH patients (especially PAH and CTEPH) with persistent severe PH (NYHA FC III or IV, and/or RV failure) despite maximal medical therapy be referred for lung transplantation assessment (Strong Recommendation, Moderate-Quality Evidence).
- 31.We suggest that PH patients with refractory RV failure and/or hemodynamic instability be considered for extracorporeal life support as a “bridge” to definitive PH therapy (Weak Recommendation, Moderate-Quality Evidence).
Summary
Secondary Panel
References
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The disclosure information of the authors and reviewers is available from the CCS on their guidelines library at www.ccs.ca.
This statement was developed following a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian panel comprised of multidisciplinary experts on this topic with a mandate to formulate disease-specific recommendations. These recommendations are aimed to provide a reasonable and practical approach to care for specialists and allied health professionals obliged with the duty of bestowing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The statement is not intended to be a substitute for physicians using their individual judgement in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.