Despite the increased awareness of pulmonary arterial hypertension (PAH), patients can still experience long delays between initial symptom onset and a confirmed PAH diagnosis.[1] Registry data show that PAH patients who achieve and maintain a low-risk status with treatment have improved long-term outcomes compared with patients at higher risk.[2]
On this page, you will find guidance and recommendations from the 2015 European Respiratory Society (ERS)/European Society of Cardiology (ESC) guidelines on the diagnosis and long-term management of PAH.
Early diagnosis of pulmonary arterial hypertension (PAH) and timely therapeutic intervention is associated with improved patient outcomes. However, early diagnosis of PAH is often challenging due to the non-specific nature of early symptoms, among other factors.[1] See below for detailed guidance on the diagnostic process for PAH.[3]
PAH should be considered in the differential diagnosis of patients presenting with a constellation of exertional dyspnoea, syncope, angina and/or progressive limitation of exercise capacity. This is of particular concern in patients without apparent risk factors or symptoms/signs of common cardiovascular and respiratory disorders.[3]
Special awareness should be directed towards patients with associated conditions and/or risk factors for the development of PAH, including:[3]
• Family history
• Connective tissue disease
• Congenital heart disease
• Human immunodeficiency virus (HIV) infection
• Portal hypertension
• A history of drug or toxin intake known to induce PAH
It is recommended for patients with suspected PAH to undergo further investigation at a specialist centre, including right heart catheterisation (RHC) to definitively confirm the presence or absence of PAH.[3]
Adapted from Galiè et al. 2016[3]
Clinical history, symptoms, signs, electrocardiograms (ECG), chest radiographs, echocardiograms, pulmonary function tests (PFTs), computed tomography (CT) of the chest and ventilation/perfusion (V/Q) scans are all necessary to exclude the diagnosis of PAH due to left heart disease or lung disease, or chronic thromboembolic pulmonary hypertension (CTEPH):[3]
ECGs may provide suggestive or supportive evidence of PH by demonstrating right ventricular (RV) hypertrophy, RV strain, right axis deviation, P pulmonale and QTc prolongation.[3]
An echo provides information on right heart structure and function, and should always be performed in cases of suspected PH.[3]
Chest radiographs may show evidence of right atrial and RV enlargement, as well as pulmonary arterial dilatation. They may also show signs of the underlying disease (e.g. lung disease).[3]
Pulmonary function tests and arterial blood gas samples may help identify the contribution of underlying airway or parenchymal lung disease.[3]
CT imaging can provide information such as pulmonary arterial diameter and clues as to the type of PAH (e.g. cardiac defects, oesophageal dilation in scleroderma). High-resolution CT provides detailed views of the lung parenchyma and facilitates the diagnosis of interstitial lung disease and emphysema.[3]
A V/Q lung scan is used to exclude CTEPH. Where there is evidence of multiple segmental perfusion defects, a diagnosis of CTEPH should be suspected. The final diagnosis of CTEPH requires CT pulmonary angiography, RHC and selective pulmonary angiography.[3]
Echocardiography (echo) is a key screening tool in the diagnosis of pulmonary arterial hypertension (PAH), while right heart catheterisation (RHC) is the gold standard for confirming the diagnosis of PAH.[4][5]
Echo should always be performed when PAH is suspected. It may be used to infer a diagnosis of PAH in patients when multiple echo parameters consistent with a diagnosis of PAH are met.[3]
Echo can provide an estimate of the right ventricular systolic pressure, which is equivalent to the systolic pulmonary arterial pressure. Tricuspid regurgitation velocity (TRV) and the presence of other echocardiographic signs should be combined to estimate the probability of PAH. Ensuring adequate right heart assessment assists not only in the diagnosis of PAH but also in monitoring disease progression and/or treatment response.[3]
Based on echocardiographic parameters (peak TRV and the presence of other echocardiographic PH signs), this table gives the echocardiographic probability (low, intermediate or high) of pulmonary hypertension (PH).[3]
Adapted from Galiè et al. 2016[3]
This table describes the echocardiographic signs suggestive of PH used to assess the probability of PH.[3]
Adapted from Galiè et al. 2016[3]
*Echocardiographic signs from at least two different categories (A/B/C) from the list should be present to alter the level of echocardiographic probability of PH.[3]
RHC is required for the definitive diagnosis of PAH. RHC involves directing a catheter into the right side of the heart to assess cardiopulmonary haemodynamics.[3]
Diagnostic criteria of PAH measured by RHC:[3]
• Mean pulmonary arterial pressure (mPAP) ≥25 mmHg
• Pulmonary arterial wedge pressure (PAWP) ≤15 mmHg
• Pulmonary vascular resistance (PVR) >3 Wood units
• Excluding other causes of pre-capillary PH
The 2015 ESC/ERS guidelines recommend that patients with pulmonary arterial hypertension (PAH) undergo comprehensive multiparameter risk assessment at diagnosis to assess disease severity and guide therapeutic decisions.[3]
Based on a number of determinants, including World Health Organization (WHO) functional class (FC), exercise capacity and haemodynamics, the risk status of patients can be categorised as either low, intermediate or high. This corresponds to an estimated 1-year mortality of <5%, 5–10% or >10%, respectively. There is no single variable that can provide sufficient prognostic information on its own, and a multidimensional approach to investigations and imaging is required.[3]
Adapted from Galie et al. 2016[3]
WHO FC is one of the parameters that can be used to evaluate the clinical severity of PAH. This system grades PAH severity according to the functional status of the patient, linking symptom severity and activity limitations. The grades range from FC I, where PAH does not affect patients' day-to-day activities, to FC IV, where patients are severely functionally impaired, even at rest.[6] FC remains a powerful predictor of outcomes in patients with PAH.[3]
Adapted from McGoon et al. 2004[6]
The severity of PAH can also be graded by patients' exercise capacity. Two approaches to this are the 6-minute walk distance (6MWD) and cardiopulmonary exercise testing (CPET).[3]
The 6MWD is an important test in PAH management as it provides a measure of the patient's functional status and any limitations. Furthermore, it is a simple test to perform, being both inexpensive and convenient. In addition to distance walked, dyspnoea on exertion and oxygen saturation can also be recorded, which can provide further information regarding the patient's functional status.[3][7]
CPET assesses lung gas exchange and gives a more sensitive and comprehensive measure of exercise capacity than the 6MWD. CPETs are maximal stress tests that measure a patient’s exercise capacity, as well as gas exchange, ventilatory efficacy and cardiac function during exercise. It is required that a patient exercises to a level that progressively increases their symptoms to the maximum workload they can tolerate. It is therefore difficult to perform in patients with advanced disease. CPET may not be suitable for patients with more severe disease, as they may not tolerate the increased workload due to risk of syncope and discomfort.[3]
Although there is no cure, advances in treatment strategies and increased therapeutic options have offered an improvement in prognosis and survival for patients with pulmonary arterial hypertension (PAH).[8][9]
Given the progressive nature of PAH, the overall treatment goal for patients is to achieve or maintain a low-risk status, which is associated with good exercise capacity, good quality of life, good right ventricular function and a low mortality risk.[3]
In a database study of treatment-naïve patients newly diagnosed with PAH, patients with a low-risk status at baseline had better survival outcomes up to 5 years from diagnosis compared with those at intermediate or high risk.[10]
Adapted from Hoeper et al. 2017[10]
The current treatment strategy for PAH patients can be divided into three main steps:[3]
The initial approach includes general measures, supportive therapy, referral to specialist centres and acute vasoreactivity testing for the indication of chronic calcium channel blocker (CCB) therapy
The second step includes initial therapy with high-dose CCB in vasoreactive patients or drugs approved for PAH in non-vasoreactive patients, according to the prognostic risk of the patient and the grade of recommendation and level of evidence for each compound or combination of compounds
The third step is related to the response to the initial treatment strategy; in the case of an inadequate response, the role of combinations of approved drugs and lung transplantation are proposed
Adapted from Galiè et al. 2016[3]
The treatment process for pulmonary arterial hypertension (PAH) patients is characterised by a complex strategy, beginning with general measures and supportive therapy. Depending on risk status, patients may then be initiated on PAH-specific therapy, either as monotherapy or in initial or sequential combination therapy. Surgical intervention should be considered for patients with severe PAH who do not respond to treatment with PAH-specific therapies.[3]
General measures include physical activity and supervised rehabilitation. Patients should be encouraged to remain active within their symptom limits. There are also recommendations on caution when considering pregnancy, prevention and prompt treatment of chest infections and awareness of the potential effects of high altitude.[3] View the 2015 ESC/ERS guidelines to learn more about the general measures for patients with PAH.
A range of supportive treatment options have been shown to provide symptomatic benefit for patients with PAH:[3]
Patients with idiopathic PAH are at increased risk of venous thromboembolism, supporting the role of anticoagulants for these patients.[3]
Clinical experience shows clear symptomatic benefit in patients with fluid overload due to decompensated right heart failure.[3]
This may provide symptomatic relief, although there is no evidence to support benefit in the long term, except in patients with consistently low oxygen saturations.[3]
Digoxin has been shown to improve cardiac output in the short term but there is no long-term evidence to support its use.[3]
View the 2015 ESC/ERS guidelines to learn more about supportive therapy for patients with PAH.
The majority of PAH-specific therapies target one of three major pathways known to be involved in the pathogenesis of PAH.[11]
Combination therapy is a recommended treatment option for patients with PAH, whereby two or more classes of drug are used together to simultaneously target multiple PAH pathogenic pathways.[3][11]
Adapted from Humbert et al. 2014[11]
The endothelin-1 expression level is upregulated in patients with PAH, causing potent vasoconstriction and smooth muscle cell proliferation. ERAs act by blocking the binding of endothelin to its receptors to prevent this process.[12]
Clinical trials have shown that treatment with ERAs has a beneficial effect on exercise capacity, haemodynamics and long-term outcomes.[13][14][15]
These oral agents act on the nitric oxide pathway to induce vasodilation and also have antiproliferative effects on vascular smooth muscle cells.[3]
Clinical trials have shown that treatment with PDE-5i has favourable effects on symptoms, exercise capacity and haemodynamics.[3]
sGCs and PDE-5i should not be used in combination due to the risk of hypotension and other side effects.[3]
These agents act by helping to correct the deficiency of endogenous prostacyclin seen in patients with PAH. Prostacyclin induces potent vasodilation and inhibition of platelet aggregation, and has both cytoprotective and antiproliferative effects.[3]
Clinical trials have shown that treatment with these agents has a positive effect on symptoms, exercise capacity, haemodynamics and long-term outcomes.[3]
There is growing evidence to support targeting multiple pathogenic signalling pathways in PAH through combination therapy.[3] Sequential combination of an ERA (macitentan) with a PDE-5i, as well as initial combination with an ERA (ambrisentan) and a PDE-5i, has been shown to significantly delay disease progression and improve long-term outcomes.[13][14] Similarly, targeting three separate PAH signalling pathways with triple therapy has also been shown to result in improved long-term outcomes for patients with PAH.[16][17]
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For patients with severe PAH who do not respond to treatment with advanced therapies, surgery may be the only option. Balloon atrial septostomy (creating a right-to-left shunt through the atria) can reduce the strain on the right heart and improve cardiac output, improving a patient's functional status.[3]
Lung transplantation may offer increased survival and continued good quality of life. Given the waiting time and shortage of organ donations, referral for transplantation should not be delayed until a patient is in critical need.[3]
After being diagnosed and initiated on pulmonary arterial hypertension (PAH) therapy, patients should continue to undergo regular risk assessment at follow-up (every 3–6 months) to assess disease progression and response to therapy. Per guideline-recommended treatment algorithm, if patients are not achieving the goal of a low-risk status, the role of combinations of approved drugs and lung transplantation are proposed.[3]
In a retrospective study of a cohort of patients with incident PAH, patients with more low-risk criteria at follow-up had considerably better long-term outcomes, including transplant-free survival, compared with patients with less low-risk criteria.[2]
Adapted from Boucly et al. 2017[2]
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BNP, B-type natriuretic peptide; CCB, calcium channel blocker; CI, cardiac index; CMR, cardiac magnetic resonance; CPET, cardiopulmonary exercise testing; CTEPH, chronic thromboembolic pulmonary hypertension; DLCO, carbon monoxide diffusing capacity; DPAH, drug-induced pulmonary arterial hypertension; ECG, electrocardiogram; ERA, endothelin receptor antagonist; ERS, European Respiratory Society; ESC, European Society of Cardiology; ET, endothelin; FC, functional class; HIV, human immunodeficiency virus; HPAH, heritable pulmonary arterial hypertension; HRCT, high-resolution computed tomography; IP, prostacyclin; IPAH, idiopathic pulmonary arterial hypertension; mPAP, mean pulmonary arterial pressure; NO, nitric oxide; NT-proBNP, N-terminal pro-B-type natriuretic peptide; PAH, pulmonary arterial hypertension; PAWP, pulmonary arterial wedge pressure; PDE-5i, phosphodiesterase type-5 inhibitor; PFT, pulmonary function test; PH, pulmonary hypertension; PVR, pulmonary vascular resistance; RA, right atrium; RAP, right atrial pressure; RHC, right heart catheterisation; RV, right ventricular; SvO2, mixed venous oxygen saturation; 6MWD, 6-minute walk distance; sGCs, soluble guanylate cyclase stimulator; TRV, tricuspid regurgitation velocity; VE/VCO2, ventilatory equivalents for carbon dioxide; VO2, oxygen consumption; WHO, World Health Organization
CP-220227 | May 2021