2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension

5.1.1 Clinical presentation

The symptoms of PH are non-specific and mainly related to progressive right ventricular (RV) dysfunction. Initial symptoms are typically induced by exertion. They include shortness of breath, fatigue, weakness, angina and syncope. Less commonly patients may also describe dry cough and exercise-induced nausea and vomiting. Symptoms at rest occur only in advanced cases. Abdominal distension and ankle oedema will develop with progressing RV failure. The presentation of PH may be modified by diseases that cause or are associated with PH as well as other concurrent diseases.

In some patients the clinical presentation may be related to mechanical complications of PH and the abnormal distribution of blood flow in the pulmonary vascular bed. These include haemoptysis related to rupture of hypertrophied bronchial arteries, as well as symptoms attributable to pulmonary arterial dilatation such as hoarseness caused by compression of the left recurrent laryngeal nerve, wheeze caused by large airway compression and angina due to myocardial ischaemia caused by compression of the left main coronary artery. Significant dilation of the PA may result in its rupture or dissection, leading to signs and symptoms of cardiac tamponade.

The physical signs of PH include left parasternal lift, an accentuated pulmonary component of the second heart sound, an RV third heart sound, a pansystolic murmur of tricuspid regurgitation and a diastolic murmur of pulmonary regurgitation. Elevated jugular venous pressure, hepatomegaly, ascites, peripheral oedema and cool extremities characterize patients with advanced disease. Wheeze and crackles are usually absent.

Clinical examination may suggest an underlying cause of PH. Telangiectasia, digital ulceration and sclerodactyly are seen in scleroderma, inspiratory crackles may point towards interstitial lung disease and spider naevi, testicular atrophy, and palmar erythema suggest liver disease. When digital clubbing is encountered, PVOD, cyanotic CHD, interstitial lung disease or liver disease should be considered.

5.1.2 Electrocardiogram

An electrocardiogram (ECG) may provide supportive evidence of PH, but a normal ECG does not exclude the diagnosis. An abnormal ECG is more likely in severe rather than mild PH. ECG abnormalities may include P pulmonale, right axis deviation, RV hypertrophy, RV strain, right bundle branch block, and QTc prolongation. While RV hypertrophy has insufficient sensitivity (55%) and specificity (70%) to be a screening tool, RV strain is more sensitive [30]. Prolongation of the QRS complex and QTc suggest severe disease [31, 32]. The ECG differential diagnosis includes anterolateral myocardial ischaemia. In contrast to PH, ECG changes in ischaemia more commonly affect the lateral and inferior leads, and when present in the anterior chest leads are usually accompanied by a Q wave in V1 to V3, and rarely cause right axis deviation.

Supraventricular arrhythmias may occur in advanced disease, in particular atrial flutter, but also atrial fibrillation, with a cumulative incidence in 25% of patients after 5 years [33]. Atrial arrhythmias compromise CO and almost invariably lead to further clinical deterioration. Ventricular arrhythmias are rare.

5.1.3 Chest radiograph

In 90% of patients with IPAH the chest radiograph is abnormal at the time of diagnosis [34]. Findings in patients with PAH include central pulmonary arterial dilatation, which contrasts with ‘pruning’ (loss) of the peripheral blood vessels. Right atrium (RA) and RV enlargement may be seen in more advanced cases. A chest radiograph may assist in differential diagnosis of PH by showing signs suggesting lung disease (group 3, Table 4) or pulmonary venous congestion due to LHD (group 2, Table 4). Chest radiography may help in distinguishing between arterial and venous PH by respectively demonstrating increased and decreased artery:vein ratios [35].

Overall, the degree of PH in any given patient does not correlate with the extent of radiographic abnormalities. As for ECG, a normal chest radiograph does not exclude PH.

5.1.4 Pulmonary function tests and arterial blood gases

Pulmonary function tests and arterial blood gases identify the contribution of underlying airway or parenchymal lung disease. Patients with PAH have usually mild to moderate reduction of lung volumes related to disease severity [36, 37]. Although diffusion capacity can be normal in PAH, most patients have decreased lung diffusion capacity for carbon monoxide (DLCO). An abnormal low DLCO, defined as <45% of predicted, is associated with a poor outcome [36, 37]. The differential diagnosis of a low DLCO in PAH includes PVOD, PAH associated with scleroderma and parenchymal lung disease. Although airflow obstruction is unusual, peripheral airway obstruction can be detected. Due to alveolar hyperventilation at rest, arterial oxygen pressure (PaO₂) remains normal or is only slightly lower than normal and arterial carbon dioxide pressure (PaCO₂) is decreased [38].

COPD as a cause of hypoxic PH is diagnosed on the evidence of irreversible airflow obstruction together with increased residual volumes and reduced DLCO [39]. Arterial blood gases of COPD patients show a decreased PaO₂ with normal or increased PaCO₂ [40]. A decrease in lung volume combined with decreased diffusion capacity for carbon monoxide may indicate interstitial lung disease [39]. The severity of emphysema and of interstitial lung disease can be diagnosed using high-resolution computed tomography (CT). Combined emphysema and pulmonary fibrosis may pseudonormalize spirometry, although the DLCO is almost always reduced, emphasizing the need to interpret pulmonary function alongside lung imaging.

The prevalence of nocturnal hypoxaemia and central sleep apnoeas are high in PAH (70–80%) [41, 42]. Overnight oximetry or polysomnography should be performed where obstructive sleep apnoea syndrome or hypoventilation are considered.

5.1.5 Echocardiography

Transthoracic echocardiography is used to image the effects of PH on the heart and estimate PAP from continuous wave Doppler measurements. Echocardiography should always be performed when PH is suspected and may be used to infer a diagnosis of PH in patients in whom multiple different echocardiographic measurements are consistent with this diagnosis. When treatment of PH itself is being considered, echocardiography alone is not sufficient to support a treatment decision and cardiac catheterization is required. Detailed guidelines describing the echocardiographic assessment of the right heart can be found in documents created and/or endorsed by the European Association of Cardiovascular Imaging (EACVI), a registered branch of the ESC, and the reader is referred to these for further instruction [43, 44].

The estimation of systolic PAP is based on the peak tricuspid regurgitation velocity (TRV) taking into account right atrial pressure (RAP) as described by the simplified Bernoulli equation. RAP can be estimated by echocardiography based on the diameter and respiratory variation in diameter of the inferior vena cava (IVC): an IVC diameter <2.1 cm that collapses >50% with a sniff suggests a normal RA pressure of 3 mmHg (range 0–5 mmHg), whereas an IVC diameter >2.1 cm that collapses <50% with a sniff or <20% on quiet inspiration suggests a high RA pressure of 15 mmHg (range 10–20 mmHg). In scenarios in which the IVC diameter and collapse do not fit this paradigm, an intermediate value of 8 mmHg (range 5–10 mmHg) may be used. The EACVI recommends such an approach rather than using a fixed value of 5 or 10 mmHg for PA systolic pressure (PASP) estimations. However, given the inaccuracies of RAP estimation and the amplification of measurement errors by using derived variables, we recommend using the continuous wave Doppler measurement of peak TRV (and not the estimated PASP) as the main variable for assigning the echocardiographic probability of PH.

When peak TRV is technically difficult to measure (trivial or mild tricuspid regurgitation) some laboratories use contrast echocardiography [e.g. agitated saline administered by intravenous (i.v.) injection], which may improve the Doppler signal, allowing measurement of peak TRV velocity. Unfortunately, despite the strong correlation of TRV with a tricuspid regurgitation pressure gradient, Doppler-derived pressure estimation may be inaccurate in the individual patient. In patients with severe tricuspid regurgitation, TRV may be significantly underestimated and cannot be used to exclude PH. Overestimation may also occur [44]. PH cannot be reliably defined by a cut-off value of TRV. Consequently, estimation of PAP based solely on Doppler transthoracic echocardiography measurements is not suitable for screening for mild, asymptomatic PH. Other echocardiographic variables that might raise or reinforce suspicion of PH independent of TRV should always be sought.

Conclusions derived from an echocardiographic examination should aim to assign a level of probability of PH. This ESC Guideline suggests grading the probability of PH based on TRV at rest and on the presence of additional pre-specified echocardiographic variables suggestive of PH (Table 8A). The probability of PH may then be judged as high, intermediate or low. When interpreted in a clinical context, the echocardiographic result is required to decide the need for cardiac catheterization in individual patients. In order to facilitate and standardize assignment to the level of probability of PH, several additional echocardiographic signs are proposed in addition to criteria based on TRV (Table 8B). These signs provide assessment of the RV size and pressure overload, the pattern of blood flow velocity out of the RV, the diameter of the PA and an estimate of RAP [43–45]. Their measurement has been defined in recommendations endorsed by the EACVI [43, 44].

The recommended plan for further patient investigation based on echocardiographic probability of PH is shown in Table 9 for symptomatic patients. In the Web addendum, a similar table (Web Table IX) for screening for asymptomatic patients with risk factors for PAH or with incidental findings suggesting the possibility of PH on ECG or lung imaging is provided.

Echocardiography can be helpful in detecting the cause of suspected or confirmed PH. Two-dimensional, Doppler and contrast examinations can be used to identify CHD. High pulmonary blood flow found on pulsed wave Doppler in the absence of a detectable shunt or significant dilatation of proximal PA despite only moderate PH may warrant transoesophageal examination with contrast or cardiac magnetic resonance (CMR) imaging to exclude sinus venosus atrial septal defect and/or anomalous pulmonary venous return. In cases of suspicion of LV diastolic dysfunction, Doppler echocardiographic signs should be assessed even if their reliability is considered low. RHC should be considered when the diagnosis remains uncertain after non-invasive investigations (see section 8.1). The practical clinical value of exercise Doppler echocardiography in the identification of cases with PH limited to exercise is uncertain because of the lack of validated criteria and prospective confirmatory data.

5.1.6 Ventilation/perfusion lung scan

A ventilation/perfusion (V/Q) lung scan should be performed in patients with PH to look for CTEPH. The V/Q scan has been the screening method of choice for CTEPH because of its higher sensitivity compared with CT pulmonary angiogram (CTPA), especially in inexperienced centres [47]. A normal- or low-probability V/Q scan effectively excludes CTEPH with a sensitivity of 90–100% and a specificity of 94–100%; however, many V/Q scans are not diagnostic. While in PAH the V/Q lung scan may be normal, it may also show small peripheral unmatched and non-segmental defects in perfusion. A caveat is that unmatched perfusion defects may also be seen in other pulmonary vascular disease such as PVOD. While a V/Q scan is still recommended as the screening test of choice, ventilation scans are often replaced with either a recent chest radiograph or a recent high-resolution CT of the lungs, but such practices are not really evidence-based. Also, CT is preferred in many centres since it is more readily available. A few studies suggest that single photon emission CT, also a nuclear medicine technique, could be superior to V/Q planar scan and CTPA, but these results need more extensive evaluation [48]. More recently, newer techniques such as three-dimensional magnetic resonance (MR) perfusion mapping, have been demonstrated to be as sensitive as traditional perfusion scintigraphy in screening for CTEPH; MR can also be used as a radiation-free modality to assess both ventilation and perfusion in CTEPH [49].

5.1.7 High-resolution computed tomography, contrast-enhanced computed tomography, and pulmonary angiography

CT imaging is a widely available tool that can provide important information on vascular, cardiac, parenchymal and mediastinal abnormalities. It may suggest the diagnosis of PH (PA or RV enlargement), identify a cause of PH such as CTEPH or lung disease, provide clues as to the form of PAH (e.g. oesophageal dilation in SSc or congenital cardiac defects such as anomalous pulmonary venous drainage) and also provide prognostic information [50].

CT may raise a suspicion of PH in symptomatic patients or those examined for unrelated indications by showing an increased PA diameter (≥29 mm) and pulmonary:ascending aorta diameter ratio (≥1.0). A segmental artery:bronchus ratio >1 : 1 in three or four lobes has been reported to have high specificity for PH [51, 52].

High-resolution CT provides detailed views of the lung parenchyma and facilitates the diagnosis of interstitial lung disease and emphysema. High-resolution CT may also be very helpful where there is a clinical suspicion of PVOD. Characteristic changes of interstitial oedema with diffuse central ground-glass opacification and thickening of interlobular septa support the diagnosis of PVOD; additional findings may include lymphadenopathy, pleural shadows and effusions [53]. Pulmonary capillary haemangiomatosis is suggested by diffuse bilateral thickening of the interlobular septa and the presence of small, centrilobular, poorly circumscribed nodular opacities. However, ground-glass abnormalities are also present in PAH, occurring in more than one-third of patients [50].

Contrast CT angiography of the PA is helpful in determining whether there is evidence of surgically accessible CTEPH. It can delineate the typical angiographic findings in CTEPH, such as complete obstruction, bands and webs and intimal irregularities, as accurately and reliably as digital subtraction angiography [54, 55]. With this technique, collaterals from bronchial arteries can be identified.

Traditional pulmonary angiography is required in most patients for the workup of CTEPH to identify those who may benefit from pulmonary endarterectomy (PEA) or BPA [56, 57]. Angiography can be performed safely by experienced staff in patients with severe PH using modern contrast media and selective injections. Angiography may also be useful in the evaluation of possible vasculitis or pulmonary arteriovenous malformations, but CT angiography has similar or even higher accuracy for both diagnoses, and is less invasive [58, 59].

5.1.8 Cardiac magnetic resonance imaging

CMR imaging is accurate and reproducible in the assessment of RV size, morphology and function and allows non-invasive assessment of blood flow, including stroke volume, CO, pulmonary arterial distensibility and RV mass.

In patients with suspected PH, the presence of late gadolinium enhancement, reduced pulmonary arterial distensibility and retrograde flow have high predictive value for the identification of PH; however, no single CMR measurement can exclude PH [60–62]. In patients with PH, CMR may also be useful in cases of suspected CHD if echocardiography is not conclusive.

Contrast-enhanced and unenhanced MR angiography have a potential in the study of the pulmonary vasculature in patients with suspected CTEPH, particularly in clinical scenarios such as suspected chronic embolism in pregnant women, young patients or when iodine-based contrast media injection is contraindicated [63].

CMR provides useful prognostic information in patients with PAH both at baseline and at follow-up [64–66].

5.1.9 Blood tests and immunology

Blood tests are not useful in diagnosing PH, but are required to identify the aetiology of some forms of PH as well as end organ damage. Routine biochemistry, haematology and thyroid function tests are required in all patients, as well as a number of other specific blood tests. Liver function tests may be abnormal because of high hepatic venous pressure, liver disease and/or endothelin receptor antagonist (ERA) therapy. Hepatitis serology should be performed if clinical abnormalities are noted. Thyroid disease is common in PAH and may develop during the course of the disease. This should always be considered in cases of abrupt deterioration.

Serological testing is required to detect underlying CTD, hepatitis and human immunodeficiency virus (HIV). Up to 40% of patients with IPAH have elevated antinuclear antibodies usually in a low titre (1:80). It is important to look for evidence of SSc since this disease has a relatively high prevalence of PAH. Limited scleroderma typically has antinuclear antibodies, including anti-centromere, dsDNA, anti-Ro, U3-RNP, B23, Th/To and U1-RNP. Diffuse scleroderma is typically associated with a positive U3-RNP. Patients with systemic lupus erythematosus may have anticardiolipin antibodies.

Patients with CTEPH should undergo thrombophilia screening, including antiphospholipid antibodies, anticardiolipin antibodies and lupus anticoagulant. HIV testing is required in PAH. N-terminal pro-brain natriuretic peptide (NT-proBNP) may be elevated in patients with PH and is an independent risk predictor in these patients.

5.1.10 Abdominal ultrasound scan

Similar to blood tests, abdominal ultrasound may be useful for identification of some of the clinical entities associated with PAH. Abdominal ultrasound may confirm but not formally exclude portal hypertension. The use of contrast agents and the addition of a colour Doppler examination may improve the accuracy of the diagnosis [67]. Portal hypertension can be reliably confirmed or excluded by measurement of the gradient between free and occluded (wedge) hepatic vein pressure at the time of RHC [68].

5.1.11 Right heart catheterization and vasoreactivity

RHC is required to confirm the diagnosis of PAH and CTEPH, to assess the severity of haemodynamic impairment and to undertake vasoreactivity testing of the pulmonary circulation in selected patients (Table 10). When performed at expert centres, these procedures have low morbidity (1.1%) and mortality (0.055%) rates [69]. The threshold to perform left heart catheterization in addition to RHC should be low in patients with clinical risk factors for coronary artery disease or heart failure with preserved ejection fraction, as well as in patients with echocardiographic signs of systolic and/or diastolic LV dysfunction. Specific recommendations for catheterization of patients with LHD or lung disease in addition to Table 10 are described in Tables 31 and 33, respectively. Measurement of LV end-diastolic pressure is also important to avoid misclassification of patients with an elevated PAWP when this is unexpected and may be inaccurate [absence of risk factors for heart failure with preserved ejection fraction, normal left atrial (LA) size and absence of echocardiographic markers of elevated LV filling pressures].

The interpretation of invasive haemodynamics should be made in the context of the clinical picture and imaging, in particular echocardiography. Cardiac catheterization should be performed after the completion of other investigations so that it can answer specific questions that may arise from these investigations and avoid an unnecessary procedure where an alternative diagnosis is revealed.

RHC is a technically demanding procedure that requires meticulous attention to detail to obtain clinically useful information. To obtain high-quality results and to be of low risk to patients, the procedure should be limited to expert centres. Particular attention should be paid to the following issues:

• The external pressure transducer should be zeroed at the mid-thoracic line in a supine patient, halfway between the anterior sternum and the bed surface [70]. This represents the level of the LA.

• Pressure measurements should be made in the PA, PA wedge position, RV and RA. Where a balloon catheter is used, it should be inflated in the RA, from where the catheter should be advanced until it reaches the PAWP position. Repeated deflations and inflations of the balloon in the end pulmonary arteries should be avoided because this has been associated with rupture of the pulmonary arteries. The PAWP is a surrogate of LA pressure and should be recorded as the mean of three measurements. Blood sampling should also be considered with the balloon inflated in the wedge position to confirm that a true PAWP measurement has been taken, as this should have the same saturation as systemic blood. All pressure measurements should be determined at the end of normal expiration (breath holding is not required). Alternatively, assuming that negative inspiratory and positive expiratory intrathoracic pressures cancel each other out, averaging pulmonary vascular pressures over several respiratory cycles is also acceptable, except in dynamic hyperinflation states [70]. Ideally, high-fidelity tracings that can be printed on paper should be used rather than small moving traces on a cardiac monitor. Non-invasive blood pressure should be recorded at the time of the procedure if left heart catheterization is not undertaken.

• Blood samples for oximetry should be taken from the high superior vena cava, IVC and PA at a minimum. Systemic arterial blood oxygen (O₂) saturation should also be determined. A stepwise assessment of O₂ saturation should be performed in every patient with a pulmonary arterial O₂ saturation >75% and whenever a left-to-right shunt is suspected.

• CO should be measured using thermodilution or the direct Fick method. Thermodilution measured in triplicate is the preferred method because it can provide reliable measurements even in patients with low CO and/or severe tricuspid regurgitation [71]. In patients with intracardiac shunts, thermodilution may be inaccurate because of early recirculation of the injectate. The direct Fick method requires direct measurement of O₂ uptake, a technique that is not widely available. The indirect Fick method, which uses estimated values of O₂ uptake, is acceptable but lacks reliability.

• Pulmonary vasoreactivity testing for identification of patients suitable for high-dose calcium channel blocker (CCB) treatment is recommended only for patients with IPAH, HPAH or drug-induced PAH. It should be performed at the time of RHC. In all other forms of PAH and PH the results can be misleading and responders are rare. Inhaled nitric oxide (NO) at 10–20 parts per million (ppm) is the standard of care for vasoreactivity testing, but i.v. epoprostenol, i.v. adenosine or inhaled iloprost can be used as alternatives (Web Table IV). A positive acute response is defined as a reduction of the mean PAP ≥10 mmHg to reach an absolute value of mean PAP ≤40 mmHg with an increased or unchanged CO. Only about 10% of patients with IPAH will meet these criteria. The use of CCBs, O₂, phosphodiesterase type 5 inhibitors or other vasodilators for acute vasoreactivity testing is discouraged.

• Interpretation of the PAWP at a single point in time needs to be performed in a clinical context. In many patients with LHD, PAWP may be reduced to <15 mmHg with diuretics [72–74]. For this reason, the effect of an acute volume challenge on left heart filling pressures has been considered [75]. Limited data suggest that a fluid bolus of 500 ml appears to be safe and may discriminate patients with PAH from those with LV diastolic dysfunction [76, 77]. Further evaluation of administering a fluid challenge is required before this can be considered for routine clinical practice. Similarly, exercise haemodynamics to identify patients with LV diastolic dysfunction is likely to be useful [2, 78, 79], but lacks standardisation and requires further evaluation [17]. Furthermore, PAWP may underestimate LV end-diastolic pressure [80].

• Derived variables calculated from the RHC measurements should include transpulmonary pressure gradient (TPG) and PVR. A PVR >3 WU is required for the diagnosis of PAH [1]. PVR is commonly used but has the disadvantage of being a composite variable that is highly sensitive to changes in both flow and filling pressure and may not reflect changes in the pulmonary circulation at rest [81, 82]. The DPG between the mean PAWP and diastolic PAP is less affected by flow and filling pressures [81] but may not be of prognostic value [83]. DPG may have a role in patients suspected of having PH related to LHD, as discussed in section 8 [4].

• Coronary angiography may be required in the presence of angina, risk factors for coronary artery disease and listing for PEA or lung transplantation. It may identify left main stem coronary artery compression by an enlarged PA as well as coronary artery disease.

Recommendations for right and left heart catheterization and vasoreactivity testing are summarised in the Tables 10 and 11.

5.1.12 Genetic testing

The availability of molecular genetic diagnosis has opened up a new field for patient care, including genetic counselling for PAH (developed in section 6.3.1.8) [26]. Genetic testing and counselling follows strict local regulations that set the conditions for prescribing and conducting reviews of the genetic characteristics of a patient. The ethical principles are to inform patients properly to avoid harm, to allow patients to preserve their autonomy (disclosure about the process, risks and benefits of the genetic test without external pressures) and to allow equal access to genetic counselling and testing. Patients with sporadic or familial PAH or PVOD/PCH should be advised about the availability of genetic testing and counselling because of the strong possibility that they carry a disease-causing mutation. Trained professionals should offer counselling and testing to the patient. Genetic counselling and BMPR2 mutation screening (point mutations and large rearrangements) should be offered by referral centres to patients with IPAH considered to be sporadic or induced by anorexigens and to patients with a family history of PAH. When no BMPR2 mutations are identified in familial PAH patients or in IPAH patients <40 years old, or when PAH occurs in patients with a personal or familial history of hereditary haemorrhagic telangiectasia, screening of the ACVRL1 and ENG genes may be performed. If no mutations in the BMPR2, ACVRL1 and ENG genes are identified, screening of rare mutations may be considered (KCNK3, CAV1, etc.).

Patients with sporadic or familial PVOD/PCH should be tested for EIF2AK4 mutations [28]. The presence of a bi-allelic EIF2AK4 mutation is sufficient to confirm a diagnosis of PVOD/PCH without performing a hazardous lung biopsy for histological confirmation.

6.2.1 Clinical parameters, imaging and haemodynamics

Clinical assessment remains a key part of the evaluation of patients with PH, as it provides valuable information for determining disease severity, improvement, deterioration or stability. Elementary parts of history taking between follow-up visits include changes in exercise capacity, episodes of chest pain, arrhythmia, haemoptysis or syncope and changes in medications, as well as adherence to the prescribed drugs. Physical examination provides information on the presence or absence of peripheral or central cyanosis, enlarged jugular veins, oedema, ascites and pleural effusions and on heart rate, rhythm and blood pressure.

The World Health Organization functional class (WHO-FC) (Web Table V), despite its interobserver variability [95], remains one of the most powerful predictors of survival, not only at diagnosis, but also during follow-up [96–98]. A worsening FC is one of the most alarming indicators of disease progression, which should trigger further diagnostic studies to identify the causes of clinical deterioration [97, 99].

As RV function is a key determinant of exercise capacity and outcome in patients with PH, echocardiography remains an important follow-up tool. In contrast to common belief, the estimated systolic PAP (PAPs) at rest is usually not prognostic and not relevant for therapeutic decision making [96, 97, 100]. An increase in PAPs does not necessarily reflect disease progression and a decrease in PAPs does not necessarily signal improvement. A comprehensive echocardiographic assessment includes a description of chamber sizes, particularly of the RA and RV area, the magnitude of tricuspid regurgitation, the LV eccentricity index and RV contractility, which can be determined by several variables, including RV longitudinal systolic strain/strain rate and RV fractional area change, Tei index and tricuspid annular plane systolic excursion (TAPSE) [101–108].

Three-dimensional echocardiography may achieve a better estimation than standard two-dimensional assessment, but underestimations of volumes and ejection fractions have been reported [109].

Speckle tracking improves the quantification of RV function [110]. Given the complex geometry of the RV, none of these variables alone is sufficient to describe RV function, and the overall impression of an experienced physician is often more important than single variables. Echocardiography during exercise provides additional information on RV function. Of note, a marked increase (>30 mmHg) of PAPs during exercise reflects better RV function and is associated with a better long-term outcome than a modest or no increase [111]. This so-called contractile reserve has recently been shown to be an independent prognostic marker in patients with severe PH [111].

CMR imaging is more accurate for the assessment of RV morphology and function than echocardiography and also allows measurement of stroke volume and CO. A number of CMR prognostic markers have been identified, including increased RV volume, reduced LV volume, reduced RV ejection fraction and reduced stroke volume. There is some evidence that follow-up CMR studies may have utility in the long-term management of PAH by identifying RV failure prior to the development of clinical features [64, 66, 112, 113].

Haemodynamics assessed by RHC provide important prognostic information, both at the time of diagnosis and during follow-up. RA pressure, cardiac index (CI) and mixed venous oxygen saturation (SvO₂) are the most robust indicators of RV function and prognosis, whereas PAPm provides little prognostic information (except for CCB responders) [96, 97, 99, 100, 114]. Non-invasive assessment of CO by rebreathing techniques [71] or bioreactance [115] has not yet been sufficiently validated to allow routine clinical use and therapeutic decision making.

There are still uncertainties around the optimal timing of follow-up RHC. Strategies vary between centres, from regular invasive haemodynamic assessments to a predominantly non-invasive follow-up strategy. There is no evidence that an approach involving regular RHC is associated with better outcomes than a predominantly non-invasive follow-up strategy. However, there is consensus among experts that RHC should be performed whenever therapeutic decisions can be expected from the results, which may include changes in medications and/or decisions regarding listing for transplantation.

6.2.2 Exercise capacity

The 6-minute walking test (6MWT), a submaximal exercise test, remains the most widely used exercise test in PH centres. The test is easy to perform, inexpensive and familiar to patients and centres. As with all PH assessments, 6MWT results must always be interpreted in the clinical context. The 6-minute walking distance (6MWD) is influenced by several factors, including sex, age, height, weight, co-morbidities, need for O₂, learning curve and motivation. Nevertheless, test results are usually given in absolute numbers rather than percent predicted. Absolute values, but not changes in 6MWD, provide prognostic information, but there is no single threshold that is applicable for all patients (see below) [96, 99, 116–118]. It is recommended to use the Borg score at the end of the 6MWT to determine the level of effort. In addition, some studies suggest that adding peripheral O₂ measurements and heart rate response may improve the prognostic relevance, but these findings await independent confirmation [119, 120].

Cardiopulmonary exercise testing (CPET) is usually performed as a maximal exercise test and provides important information on exercise capacity as well as on gas exchange, ventilator efficacy and cardiac function during exercise. Most PH centres use an incremental ramp protocol, although the test has not yet been standardized for this patient population. Patients with PAH show a typical pattern with a low end-tidal partial pressure of carbon dioxide (pCO₂), high ventilator equivalents for carbon dioxide (VE/VCO₂), low oxygen pulse (VO₂/HR) and low peak oxygen uptake (peak VO₂) [121]. Several variables determined by CPET provide prognostic information, although peak VO₂ is most widely used for therapeutic decision making [106, 122–125]. The diagnostic and prognostic information provided by CPET add to that provided by the 6MWT [122].

6.2.3 Biochemical markers

There is still no specific marker for PAH or pulmonary vascular remodelling, although a wide variety of biomarkers have been explored in the field. These can be grouped into markers of vascular dysfunction [asymmetric dimethylarginine (ADMA), endothelin-1, angiopoeitins, von Willebrand factor] [126–131], markers of inflammation (C-reactive protein, interleukin 6, chemokines) [132–135], markers of myocardial stress (atrial natriuretic peptide, brain natriuretic peptide (BNP)/NT-proBNP, troponins) [97, 118, 136–139], markers of low CO and/or tissue hypoxia [pCO₂, uric acid, growth differentiation factor 15 (GDF15), osteopontin] [38, 140–142] and markers of secondary organ damage (creatinine, bilirubin) [97, 137]. This list is constantly growing, but so far BNP and NT-proBNP remain the only biomarkers that are widely used in the routine practice of PH centres as well as in clinical trials. BNP/NT-proBNP levels correlate with myocardial dysfunction and provide prognostic information at the time of diagnosis and during follow-up assessments [143]. They are not specific for PH, but can be elevated in almost any heart disease. BNP/NT-proBNP levels tend to have a high variability and should be interpreted in the clinical context. There are no clear advantages of using BNP versus NT-proBNP. BNP appears to have a slightly tighter correlation with pulmonary haemodynamics and is less affected by kidney function, whereas NT-proBNP seems to be a stronger predictor of prognosis [137].

6.2.4 Comprehensive prognostic evaluation and risk assessment

Regular assessment of patients with PAH in expert PH centres is strongly recommended. A comprehensive assessment is required since there is no single variable that provides sufficient diagnostic and prognostic information. The most important questions to be addressed at each visit are (i) is there any evidence of clinical deterioration since the last assessment?; (ii) if so, is clinical deterioration caused by progression of PH or by a concomitant illness?; (iii) is RV function stable and sufficient?; and (iv) is the current status compatible with a good long-term prognosis, i.e. does the patient meet the low-risk criteria (see below)?

In order to answer these questions, a multidimensional approach is needed. Table 13 lists the variables that are most frequently used in PH centres. Not all of them need to be assessed at each visit. However, the basic programme should include determination of the FC and at least one measurement of exercise capacity, e.g. 6MWD or CPET. It is also recommended to obtain some information on RV function, either by measuring BNP/NT-proBNP or by performing echocardiography. Most of the proposed variables and cut-off values are based on expert opinion. They may provide prognostic information and may be used to guide therapeutic decisions, but application to individual patients must be done carefully. The indicated mortality rates are crude estimates and the depicted variables have been studied mostly in patients with IPAH. Not all variables may be in the same risk group, and it is the comprehensive assessment of individual patients that should guide treatment decisions. The individual risk is further modified by other factors, such as the rate of disease progression and the presence or absence of signs of right heart failure, or syncope, and also by co-morbidities, age, sex, background therapy, and PAH subtype, among others.

Finally, the assessment of PAH patients should provide information on co-morbidities and disease complications. ECGs should be obtained on a regular basis to detect clinically relevant arrhythmias, which occur frequently in this patient population [33]. Patients with PAH occasionally present with progressive hypoxaemia and may be candidates for long-term O₂ therapy. In addition, a low PaCO₂ is associated with reduced pulmonary blood flow and has prognostic implications [38]. Thus arterial or capillary blood gases provide important information and should be part of the regular clinical assessment, at least in cases of clinical deterioration. Alternatively the peripheral O₂ saturation may be used, but it is less reliable and does not provide information on PaCO₂. The recommended basic laboratory workup (in addition to BNP/NT-proBNP) includes blood counts and international normalized ratio (INR) (in patients receiving vitamin K antagonists), as well as serum sodium, potassium, creatinine, uric acid, aspartate aminotransferase (ASAT), alanine aminotransferase (ALAT) (in patients receiving ERAs) and bilirubin. In addition, troponin, uric acid, iron status and thyroid function should be checked at least once a year or whenever the patient presents with clinical worsening. Tables 14 and 15 provide detailed recommendations on the follow-up assessment of patients with PAH.

6.2.5 Definition of patient status

Based on the comprehensive assessment described in the last section, the patient can be classified as low risk, intermediate risk or high risk for clinical worsening or death (Table 13). Of course, there are several other factors that have an impact on disease manifestation and prognosis that cannot be affected by PAH therapy, including age, sex, underlying disease and co-morbidities. Although reliable individual predictions are always difficult, patients categorized as low risk have an estimated 1-year mortality <5%. Basically these patients present with non-progressive disease in WHO-FC I or II with a 6MWD >440 m and no signs of clinically relevant RV dysfunction. The estimated 1-year mortality in the intermediate-risk group is 5–10%. These patients typically present in WHO-FC III, with moderately impaired exercise capacity and signs of RV dysfunction, but not with RV failure. Patients in the high-risk group have an estimated 1-year mortality >10%. These patients present in WHO-FC III or IV with progressive disease and signs of severe RV dysfunction, or with RV failure and secondary organ dysfunction.

The variables shown in Table 13 may not behave consistently, i.e. they may fall into different risk categories. Again, it is the overall assessment that should drive therapeutic decisions.

6.2.6 Treatment goals and follow-up strategy

The overall treatment goal in patients with PAH is achieving a low-risk status (Table 13), which is usually associated with good exercise capacity, good quality of life, good RV function and a low mortality risk. Specifically, this means bringing and/or keeping the patient in WHO-FC II whenever possible. In most patients, this will be accompanied by a near-normal or normal 6MWD. Several treatment goals for the 6MWD have been proposed including >380 m, >440 m and >500 m [96, 99, 116–118, 144]. All of these numbers are based on survival analyses from selected cohorts or on expert opinion. The present guidelines adopt a threshold of >440 m as suggested during the 5th World Symposium on Pulmonary Hypertension [145], because this number was derived from the largest cohort investigated so far [99]. Nevertheless, individual factors must be considered and lower values may be acceptable in elderly patients or patients with co-morbidities, whereas even values >440 m may not be sufficient in younger, otherwise healthy patients. Especially in those patients, CPET should be regularly used, as it provides more objective information on exercise capacity and RV performance.

It should be noted that these treatment goals are not always realistic and may not be achievable in patients with advanced disease, patients with severe co-morbidities or very old patients.

6.3.1 General measures

Patients with PAH require sensible advice about general activities of daily living and need to adapt to the uncertainty associated with a serious chronic life-threatening disease. The diagnosis usually confers a degree of social isolation [150]. Encouraging patients and their family members to join patient support groups can have positive effects on coping, confidence and outlook. The recommendations for general measures are reported in the Table 16.

6.3.2 Supportive therapy

The recommendations for supportive therapy are reported in Table 17.

6.3.3 Specific drug therapy

6.3.4 Combination therapy

Combination therapy—using two or more classes of drugs simultaneously—has been used successfully in the treatment of systemic hypertension and heart failure. It is also an attractive option for the management of PAH, because three separate signalling pathways known to be involved in the disease can be addressed by specific drugs: the prostacyclin pathway (prostanoids), the endothelin pathway (ERAs) and the NO pathway (PDE-5is and sGCs).

The experience with combination therapy is increasing and a recent meta-analysis on six RCTs with combination therapy including 858 patients has been published [244]; compared with the control group, combination therapy reduced the risk of clinical worsening {relative risk [RR] 0.48 [95% confidence interval (CI) 0.26, 0.91], P = 0.023}, increased the 6MWD significantly by 22 m and reduced mean PAP, RAP and PVR. The incidence of serious adverse events was similar in the two groups [RR 1.17 (95% CI 0.40, 3.42), P = 0.77]. The reduction in all-cause mortality was not statistically significant. However, the incidence of mortality in RCTs with PAH medications is relatively low and to achieve statistical significance a sample size of several thousand patients may be required [244].

Combination therapy may be applied sequentially or initially (upfront).

Sequential combination therapy is the most widely utilised strategy both in RCTs and in clinical practice: from monotherapy there is an addition of a second and then a third drug in cases of inadequate clinical results or in cases of deterioration. A structured prospective programme to evaluate the adequacy of clinical results is the so-called goal-oriented therapy, a treatment strategy that uses known prognostic indicators as treatment targets. The therapy is considered adequate only if the targets are met. The key difference between goal-oriented therapy and non-structured approaches is that patients who are stabilised, or even those who improve slightly, can still receive additional therapy if treatment goals are not met. The goal-oriented treatment strategy utilises different targets, including WHO-FC I or II, and the near-normalization of resting CI and/or of NT-proBNP plasma levels. A recent study has confirmed a better prognosis in patients achieving these goals as compared with patients who did not [97].

Recommendations and evidence on the use of specific drugs for initial combination therapy and for sequential combination therapy for PAH according to WHO-FC are provided in Table 20 and Table 21, respectively.

The rationale for initial or upfront combination therapy is based on the known mortality of PAH, which is reminiscent of many malignancies, and the fact that malignancies and critical medical illnesses (heart failure, malignant hypertension) are not treated with a stepwise approach to therapy, but rather with pre-emptive combination therapy. The experience in RCTs with initial combination therapy started with the small BREATHE-2 (Web Table VID) study, which failed to demonstrate any significant difference between patients treated initially with the combination epoprostenol and bosentan as compared with epoprostenol alone [198]. In a more recent experience, 23 treatment-naive PAH patients were treated with the initial combination of epoprostenol and bosentan and compared with a matched historical control group treated with epoprostenol [245]. The study showed a statistically significant greater decrease in PVR in the initial combination therapy group, but this haemodynamic benefit did not translate into a statistically significant difference in survival or in transplant-free survival. A pilot study on an initial triple combination in 19 WHO-FC class III and IV patients has provided preliminary evidence of the long-term benefits of upfront triple combination therapy in patients with severe PAH [246]. A recent multicentre, multinational, blinded, placebo-controlled trial (Web Table VID) compared first-line monotherapy with tadalafil or monotherapy with ambrisentan with upfront combination therapy with tadalafil and ambrisentan in de novo WHO-FC II and III PAH patients [247]. The primary endpoint was a composite of clinical failure events (including death, hospitalization, PAH progression and unsatisfactory clinical status). The study was positive, with a 50% reduction in events in the combination group. In addition, improvements were observed in exercise capacity, rate of satisfactory clinical response and NT-proBNP plasma levels [247].

6.3.5 Drug interactions

Significant drug interactions involving the disease-targeted therapies for PAH are shown in Web Table VII. This table highlights known important interactions but does not include theoretical untested interactions, which may still be clinically important. In addition, updated official prescribing information for each compound should be read.

Bosentan is an inducer of cytochrome P450 isoenzymes CYP3A4 and CYP2C9. Plasma concentrations of drugs metabolised by these isoenzymes will be reduced when co-administered with bosentan. Bosentan is also metabolised by these enzymes so that their inhibition may increase the plasma concentration of bosentan. In addition to interactions shown in Web Table VII, a combination of a potent CYP3A4 inhibitor (ketoconazole, ritonavir) and/or a CYP2C9 inhibitor (e.g. amiodarone, fluconazole) with bosentan may cause a significant increase in plasma bosentan levels and thus is contraindicated. Interactions may theoretically occur with itraconazole, tacrolimus, sirolimus, carbamazepine, phenytoin, phenobarbitone, dapsone and St John's wort.

Sildenafil is metabolised by cytochrome P450 isoenzymes CYP3A4 (major route) and CYP2C9 (minor route). There is an increase in sildenafil bioavailability and reduced clearance with CYP3A4 substrates and inhibitors and CYP3A4 substrates plus beta-adrenoceptor blockers. CYP3A4 inducers such as carbamazepine, phenytoin, phenobarbital, rifampicin and St John's wort may significantly lower sildenafil levels. Sildenafil levels are modestly increased by fresh grapefruit juice, a weak inhibitor of CYP3A4.

Finally, care is needed when PAH-targeted medications are co-administered with antihypertensive drugs such as beta-adrenoceptor blockers, angiotensin-converting enzyme inhibitors, etc., to avoid excessive systemic hypotension.

6.3.6 Balloon atrial septostomy

The creation of an inter-atrial right-to-left shunt can decompress the right heart chambers and increase LV preload and CO [253, 254]. In addition, this improves systemic O₂ transport despite arterial O₂ desaturation [253] and decreases sympathetic hyperactivity. The recommended technique is graded balloon dilation atrial septostomy, which produces equivalent improvements in haemodynamics and symptoms but reduced risk compared with the original blade technique. Other techniques are considered experimental [255].

A careful pre-procedure risk assessment ensures reduced mortality. Balloon atrial septostomy (BAS) should be avoided in end-stage patients presenting with a baseline mean RAP >20 mmHg and O₂ saturation at rest <85% on room air. Patients should be on optimal medical therapy, which may include preconditioning with i.v. inotropic drugs, prior to considering BAS. Published reports suggest a benefit in patients who are in WHO-FC IV with right heart failure refractory to medical therapy or with severe syncopal symptoms [253, 254]. It may also be considered in patients awaiting lung transplantation with unsatisfactory clinical response on maximal medical therapy or when medical therapy is not available. Studies show improvements in CI and decreases in RAP with improvement in 6MWD [253, 254]. The impact of BAS on long-term survival has not been established in RCTs [253, 254]. BAS should be regarded as a palliative or bridging procedure to be performed only in centres with experience in the method [256]. Since BAS is performed very rarely, it has not been included in the treatment algorithm (Figure 2).

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FIGURE 2

Evidence based treatment algorithm for pulmonary arterial hypertension patients (for group 1 patients only; see description in the text). CCB: calcium channel blockers; DPAH: drug-induced PAH; HPAH: heritable PAH; IPAH: idiopathic PAH; i.v.: intravenous; PAH: pulmonary arterial hypertension; PCA: prostacyclin analogues; WHO-FC: World Health Organization functional class. ^aSome WHO-FC III patients may be considered high risk (see Table 13). ^bInitial combination with ambrisentan plus tadalafil has proven to be superior to initial monotherapy with ambrisentan or tadalafil in delaying clinical failure. ^cIntravenous epoprostenol should be prioritised as it has reduced the 3 months rate for mortality in high risk PAH patients also as monotherapy. ^dConsider also balloon atrial septostomy.

6.3.7 Advanced right ventricular failure

6.3.8 Transplantation

The advent of disease-targeted therapy for severe PAH has reduced and delayed patient referral for lung transplant programmes [256]. The long-term outcomes of medically treated patients remain uncertain and transplantation should continue to be an important option for those who fail on such therapy and remain in WHO-FC III or IV [96, 107]. Delayed referral in combination with the length of the waiting time, due to the shortage of organ donors, may increase the mortality of patients on the waiting list and their clinical severity at the time of transplantation.

The overall 5-year survival following transplantation for PAH was considered to be 45–50%, with evidence of continued good quality of life [266]. More recent data show that survival is increased to 52–75% at 5 years and to 45–66% at 10 years [267–269].

Considering the above information, it seems reasonable to consider eligibility for lung transplantation after an inadequate clinical response to the initial monotherapy and to refer the patient soon after an inadequate clinical response is confirmed on maximal combination therapy (Figure 2). Also the aetiology of PAH may help the decision making since the prognosis varies according to the underlying condition. In fact, PAH associated with CTD has a worse prognosis than IPAH, even when treated with prostanoids, while patients with PAH associated with CHD have a better survival. The poorest prognosis is seen in patients with PVOD and PCH because of the lack of effective medical treatments; these patients should be listed for transplantation at diagnosis.

Both heart–lung and double-lung transplantation have been performed for PAH, although the threshold for unrecoverable RV systolic dysfunction and/or LV diastolic dysfunction is unknown. Currently the vast majority of patients worldwide receive bilateral lungs, as indicated by the International Society for Heart and Lung Transplantation Registry figures [270]. Patients with Eisenmenger syndrome due to simple shunts have been treated with isolated lung transplantation and repair of the cardiac defect or by heart–lung transplantation [266].

While registry data initially supported a survival benefit of heart–lung transplantation for patients with PH associated with a ventricular septal defect [271], experience with isolated bilateral lung transplantation has increased and more recent data support a role for this approach combined with repair of the defect [272].

Recent reports indicate that veno-arterial ECMO may be employed in awake end-stage PH patients for bridging to lung transplantation [263].

6.3.9 Treatment algorithm

A treatment algorithm for PAH patients is shown in Figure 2. The classes of recommendation and levels of evidence for the PAH treatments are shown in Tables 19 (monotherapy), 20 (initial combination therapy), 21 (sequential combination therapy) and 22 (ICU and interventions). Definitions of clinical response to treatments are reported in Table 15. It is recognized that the therapeutic approach to PAH may vary depending on the local availability (and expertise) of therapeutic options in various hospitals and clinical settings. Accordingly, Tables 19, 20, 21 and 22 provide the necessary evidence for alternative evidence-based therapeutic strategies. In these tables only the compounds officially approved for PAH or undergoing regulatory approval in at least one country are included. A four-level hierarchy for endpoints in RCTs has been proposed by experts according to the level of evidence regarding efficacy [273, 274]. According to this hierarchy, drugs or combinations of drugs with time to clinical failure or to clinical worsening as the primary endpoint in RCTs or drugs with a demonstrated reduction in all-cause mortality (prospectively defined) have been highlighted with a footnote in Tables 19, 20 and 21. The PAH treatment algorithm does not apply to patients in other clinical groups, and in particular it does not apply to patients with PH associated with group 2 (LHD) or group 3 (lung diseases). In addition, the different treatments have been evaluated by RCTs mainly in IPAH, HPAH, PAH due to drugs and in PAH associated with CTD or with CHD (surgically corrected or not).

Treatment algorithm description (Figure 2)

• After confirmation of the diagnosis of the treatment-naive PAH patient in an expert centre, the suggested initial approach is the adoption of general measures and the initiation of supportive therapy if needed (Tables 16 and 17).

• Acute vasoreactivity testing should be performed only in patients with IPAH, HPAH and PAH associated with drugs or toxins use. Vasoreactive patients should be treated with high doses (progressively titrated) of CCB; adequate response should be confirmed after 3–4 months of treatment (Table 18). Patient responders without an adequate clinical response to CCB treatment should be treated with approved PAH medications according to the non-vasoreactive patient's treatment strategy.

• Non-responders to acute vasoreactivity testing who are at low or intermediate risk (Table 13) can be treated with either initial monotherapy (Table 19) or initial oral combination therapy (Table 20).

• If initial monotherapy is chosen, since head-to-head comparisons among different compounds are not available, no evidence-based first-line monotherapy can be proposed. In this case the choice of the drug may depend on a variety of factors, including the approval status, labelling, route of administration, side-effect profile, potential interaction with background therapies, patient preferences, co-morbidities, physician experience and cost.

• Since head-to-head comparison between initial combination therapy with ambrisentan plus tadalafil has proven to be superior to initial monotherapy with ambrisentan or tadalafil in delaying clinical failure, a higher grade of recommendation has been given to this initial combination (Table 20) [247].

• In non-vasoreactive and treatment-naive patients at high risk (Table 13), initial combination therapy including i.v. prostacyclin analogues should be considered (Table 20). I.V. epoprostenol should be prioritised since it has reduced the 3-month rate of mortality in high-risk PAH patients also as monotherapy (Table 19) [149]. Alternative types of initial combination therapy may be considered (Table 20).

• In case of inadequate clinical response to initial combination therapy or initial monotherapy (Table 15), sequential double or triple combination therapy is recommended according to Table 21. The combination of riociguat and PDE-5i is contraindicated.

• In case of inadequate clinical response with sequential double combination therapy, triple combination therapy should be attempted (Tables 20 and 21).

• It seems reasonable to consider eligibility for lung transplantation after an inadequate clinical response to the initial monotherapy or initial combination therapy and to refer the patient for lung transplantation soon after the inadequate clinical response is confirmed on maximal combination therapy. BAS should be regarded as a palliative or bridging procedure in patients deteriorating despite maximal medical therapy.

6.3.10 Diagnosis and treatment of pulmonary arterial hypertension complications

6.3.11 End of life care and ethical issues

The clinical course of PH is one of progressive deterioration interspersed with episodes of acute decompensation. It is difficult to predict when patients will die since death may come either suddenly or slowly because of progressive heart failure. It has been shown that physicians caring for patients tend to be overoptimistic in their prognostication and frequently misunderstand their patients' wishes.

Open and sensitive communication with patients allows advanced planning and discussion of their fears, concerns and wishes, which is essential to good care. Opportunities to discuss prognosis should be created at the time of initial diagnosis. Recognition that cardiopulmonary resuscitation in severe PH has a poor outcome may enable a do-not-resuscitate order. This may increase the chance of patients being in their preferred place of care at the end of life.

Patients approaching the end of life require frequent assessment of their full needs by a multidisciplinary team. Attention should be given to controlling the distressing symptoms and prescribing appropriate drugs while withdrawing unnecessary medication. Well-informed psychological, social and spiritual support is also vital. Specialist palliative care should be consulted about patients whose needs are beyond the expertise of the PH team.

PH is a disease that may be severely life-limiting. In addition to psychological and social support, there should be proactive advanced care planning with referral to specialist palliative care services when appropriate.

7.1.1 Diagnosis

Dyspnoea, fatigue and failure to thrive are common symptoms; syncope is more common in children, but overt RV failure is a late event and the child may die of sudden death before the occurrence of RV failure [284, 287]. A specific diagnostic workup has been recently recommended, and even if some causes are rare, they should be excluded before a definite diagnosis of IPAH [284]. A thorough family and personal history, including pregnancy, delivery and postnatal details, is essential [290]. Diagnosis must be confirmed by heart catheterization, and vasoreactivity testing should be performed. Recent reports suggest that cardiac catheterization may be a greater risk in children compared with adults, with younger age (<1 year) and worse FC (WHO-FC IV) as risk factors. Cardiac catheterization performed in expert centres is recommended [290]. The general scheme of the diagnostic algorithm for adult patients with PH (Figure 1) may also be adopted in children, with some adaptation related to the different epidemiology [9].

As in adults, clinical evidence of RV failure, progression of symptoms, WHO-FC III/IV and elevated BNP levels are recognized as being associated with higher risk of death. In children, failure to thrive, haemodynamic parameters such as the PAPm:systemic artery pressure ratio, RAP >10 mmHg and PVR index >20 WU/m² have also been associated with a higher risk of death, while the 6MWD was not a prognostic parameter.

7.1.2 Therapy

There is a lack of randomized trials in paediatrics, making it difficult to deliver strong guidelines [291, 292]. A specific treatment algorithm, similar to that used in adults (Figure 2), has been recommended. Determinants of risk and risk stratification have also been suggested [9]. CCBs are used in responders, but close follow-up is mandatory, as some patients may fail long-term therapy.

Indications for epoprostenol are similar to those for adults. The optimal dose varies between patients and thus individual adaptation is required [293, 294]. Use of i.v. iloprost and trepostinil, as well as subcutaneous trepostinil [295], has been reported. Oral beraprost is used in some countries, but lack of proof of efficacy is a problem. Inhaled iloprost is difficult to deliver, but some reports have shown efficacy, mostly in combination with other therapies [296].

Bosentan pharmacokinetics have been assessed in two studies [297, 298]. Several uncontrolled studies have shown positive results similar to adults, with survival rates around 80–90% at 1 year [298]. A paediatric formulation is available in Europe [299]. Data with ambrisentan are scarce and a study is ongoing.

Sildenafil has shown efficacy [300] and has been approved in Europe for children 1–17 years of age. Increased mortality using high doses has raised concerns; therefore high doses should not be used in children (high individual doses of sildenafil on a three daily dosing not recommended: >10 mg/dose with a bodyweight of 8–20 kg, >20 mg/dose in children with a bodyweight >20 kg or >1 mg/kg/dose in infants and small children) [301].

Data on tadalafil also suggest efficacy [302]; a trial is currently under way to define the specific dosage for children.

An increasing number of paediatric patients are on combination therapies even though evidence is still limited [303].

RV decompression strategies include atrioseptostomy [304], ductal stenting in cases of patent ductus arteriosus [305] and a surgical Potts shunt [306]. Transcatheter Potts shunt creation has also been proposed [307]. Lung transplantation remains an important option for paediatric PH patients.

Specific goals for treatment should be applied for children. Some have been extrapolated from defined risk factors in children but still require validation in large cohorts [9]. Recently FC, TAPSE and NT-proBNP have been recognized as treatment goals [308].

The recommendations for paediatric PH are reported in the Table 23.

7.2.1. Diagnosis

As indicated in Table 6, the clinical presentation of adult patients with PAH may differ. Eisenmenger syndrome is a multisystem disorder and the most severe form of PAH in adult CHD. The signs and symptoms of Eisenmenger syndrome result from PH, low arterial O₂ saturation and haematological changes, including secondary erythrocytosis, thrombocytopenia and at times leucopenia. They include dyspnoea, fatigue and syncope. In patients with PAH associated with adult CHD without reversal of the shunt, the degree of cyanosis and erythrocytosis may be mild to moderate. Eisenmenger syndrome patients also present with haemoptysis, cerebrovascular accidents, brain abscesses, coagulation abnormalities and sudden death. Subjects with Eisenmenger syndrome have reduced life expectancy, although many survive into their third or fourth decade, with some even surviving up to their seventh decade [312]. In patients listed for lung or heart–lung transplantation when no medical treatment was available, Eisenmenger syndrome had better survival compared with IPAH, with a 3-year survival rate of 77% compared with 35% for untreated IPAH [313]. In a recent study on the different clinical groups of PAH patients associated with CHD (Table 6), the worst survival was observed in patients with PAH after defect repair or with small/coincidental defects as compared with patients with Eisenmenger syndrome or those with prevalent systemic-to-pulmonary shunts [314]. Improved survival may result from preservation of RV function, as the RV does not undergo remodelling at birth and remains hypertrophied [315]. The RV is also relieved by the right-to-left shunt, sustaining CO at the expense of hypoxaemia and cyanosis.

Of all patients with CHD, those with Eisenmenger syndrome are the most severely compromised in terms of exercise intolerance [314, 316].

Patients with CHD (in particular those without shunts) may also develop PH due to LHD (group 2, Table 4) or concomitant lung diseases (group 3, Table 4). In these cases, a comprehensive diagnostic workup, as reported in the section 7.1.1, is recommended.

7.2.2. Therapy

Operability may be considered in patients with prevalent systemic-to-pulmonary shunting (Table 6). The criteria for shunt closure based on baseline PVR have been proposed (Table 24) based on available literature data [317–319]. Additional criteria include the type of the defect, age, the PVR:SVR ratio and the Qp:Qs ratio [320]. No prospective data are available on the usefulness of vasoreactivity testing, closure test or lung biopsy for operability assessment [320]. Surgical or percutaneous intervention is contraindicated in patients with Eisenmenger syndrome and likely is useless in patients with small/coincidental defects.

The medical treatment strategy for patients with PAH associated with CHD, and in particular for subjects with Eisenmenger syndrome, is mainly based on the clinical experience of experts rather than being formally evidence-based [311]. A specific treatment algorithm has been proposed [309].

PAH associated with CHD patients should be managed in specialised centres. Patient education, behavioural modifications and awareness of potential medical risk factors are important aspects of management.

Patients with PAH associated with CHD may present with clinical deterioration in different circumstances, such as during non-cardiac surgery requiring general anaesthesia, dehydration, lung infections and at high altitudes. It is recommended to avoid strenuous exercise, but mild activities seem to be beneficial. Pregnancy is associated with very high risk to both the mother and foetus and should be discouraged. Hence effective contraception is mandatory. Dual contraception is indicated in patients taking ERAs in light of the interaction with progesterone-based compounds.

Long-term home O₂ therapy may improve symptoms but has not been shown to modify survival, at least when given only at night [179]. The use of supplemental O₂ therapy is recommended in cases in which it produces a consistent increase in arterial O₂ saturation and reduces symptoms.

The use of oral anticoagulant treatment in Eisenmenger syndrome is controversial: a high incidence of PA thrombosis and stroke is reported, but there is also an increased risk of haemorrhage and haemoptysis [321]. No data exist on this issue and thus definite recommendations cannot be made. Oral anticoagulant treatment may be considered in patients with PA thrombosis, signs of heart failure and absent or only mild haemoptysis [321].

Secondary erythrocytosis is beneficial for adequate O₂ transport and delivery and routine phlebotomy should be avoided. If symptoms of hyperviscosity are present, phlebotomy with isovolumic replacement should be performed, usually when the haematocrit is >65%. Iron deficiency should be corrected. No clear data support the use of CCBs in patients with Eisenmenger syndrome and the empirical use of CCBs is dangerous and should be avoided.

One RCT is available with specific drug therapy in Eisenmenger syndrome patients: bosentan has been shown to improve 6MWT and decrease PVR after 16 weeks of treatment in WHO-FC III patients. Although a beneficial effect of bosentan has been shown on exercise capacity and quality of life in this group of patients, an effect on mortality remains uncertain [200]. Long-term follow-up (40 weeks) showed sustained improvement [322]. Bosentan is currently approved in Europe for WHO-FC III Eisenmenger syndrome patients.

Experiences with other ERAs [323] and the PDE-5is sildenafil [314] and tadalafil [324] show favourable functional and haemodynamic results in patients with PAH associated with CHD and Eisenmenger syndrome.

The use of i.v. epoprostenol has been reported in Eisenmenger syndrome patients, with favourable effects on haemodynamics and exercise capacity, although central lines expose the patients to the risk of paradoxical embolism and sepsis [223]. No data are available on the use of other prostanoids.

There are a few published data on combination therapy, but the rationale is the same as in IPAH [207, 314]. The use of PAH therapy to achieve the operability criteria in PAH with systemic-to-pulmonary cardiovascular shunts (Table 24), allowing defect correction (‘treat-to-close’ concept), is not supported by available data.

Heart–lung or lung transplantation with heart surgery is an option in special cases not responsive to medical treatment, but is limited by organ availability. Short- and long-term survival rates following heart–lung transplantation are similar to other forms of PAH. The prolonged estimated survival of patients with Eisenmenger syndrome makes the decision as to if and when patients should be listed difficult [309].

Recommendations for PAH associated with CHD are reported in the Table 25.

7.3.1. Diagnosis

Compared with IPAH, patients with CTD and PAH are mainly women (female:male ratio 4:1), are older (mean age at diagnosis >60 years), may present concomitant disorders (interstitial lung disease, LHD) and have shorter survival times [326, 330, 334–336]. The unadjusted risk of death for SSc-PAH compared with IPAH is 2.9 and the predictors of outcome are broadly similar as for IPAH [336]. Symptoms and clinical presentation are very similar to IPAH and occasional patients thought to have IPAH can be identified as having an associated CTD by immunological screening tests. High-resolution tomography of the chest is helpful for evaluating the presence of associated interstitial lung disease and/or PVOD [326, 332, 337]. An isolated reduction of DLCO is a frequent abnormality in SSc associated with PAH [327, 338].

Resting echocardiography is recommended as a screening test in asymptomatic SSc patients, followed by annual screening with echocardiography, DLCO and biomarkers [325]. A two-step composite score has been proposed in the DETECT study to select patients who should have RHC [327]. Specific recommendations for screening/early detection are provided in Web Table IX. The cost-effectiveness of these strategies has not been clarified as compared with symptom-based detection. Echocardiography is recommended in the presence of symptoms in other CTDs. As in other forms of PAH, RHC is recommended in all cases of suspected PAH associated with CTD to confirm the diagnosis, determine severity and rule out left-sided heart disease.

7.3.2 Therapy

Treatment of patients with CTD-associated PAH is more complex than that of IPAH. Immunosuppressive therapy combining glucocorticosteroids and cyclophosphamide may result in clinical improvement in patients with PAH associated with systemic lupus erythematosus or mixed CTD [339].

Long-term favourable response to CCB treatment is reported in <1% of cases [189]. In SSc, the long-term risk:benefit ratio of oral anticoagulation is less favourable than in IPAH because of an increased risk of bleeding [175].

Treatment of patients with CTD and PAH should follow the same treatment algorithm as in IPAH (Figure 2). This recommendation is based on the fact that patients with CTD have been included in most of the major RCTs for regulatory approval of PAH therapy, including those with combination therapy.

Subgroup analysis of patients with SSc enrolled in the RCTs performed with bosentan, macitentan, sildenafil, riociguat and subcutaneous treprostinil have shown favourable effects. In some of these trials the magnitude of the response in the PAH subgroup associated with CTD was lower than in IPAH [340]. The choice of PAH therapy in the context of SSc and its generalized microangiopathy must take into account other vascular damage such as past/current digital ulcers.

Continuous i.v. epoprostenol therapy was shown to improve exercise capacity, symptoms and haemodynamics in a 3-month RCT in SSc-PAH [222]. However, retrospective analysis shows a better effect of i.v. epoprostenol on survival in IPAH as compared with SSc-PAH. This may be due, at least in part, to co-morbidities such as cardiopulmonary involvement.

SSc should not be considered as an a priori contraindication for lung transplantation [341]. A multidisciplinary approach optimizing SSc patient management before, during and after surgery is recommended [341]. Indications and contraindications for transplantation have to be adapted to the specificities of SSc with a special focus on digestive (gastro-oesophageal reflux disease and intestinal disease), cardiac, renal and cutaneous involvement.

The recommendations for PAH associated with CTD are reported in the Table 26.

7.4.1 Diagnosis

In general, the signs and symptoms of PoPH are similar or identical to most other forms of PAH, with progressive dyspnoea on exertion being the chief complaint. The clinical picture may be obscured by the presence and severity of the underlying liver disease. The diagnostic assessment follows the same recommendations as for other forms of PH, keeping in mind that the co-existence of portal hypertension and PH does not mean that these patients necessarily suffer from PoPH [344]. A complete diagnostic workup including RHC is required to assess disease severity, haemodynamic profile and other potential causes of PH, including lung disease, LHD or chronic thromboembolic disease. As a group, patients with PoPH tend to have a higher CI and a lower PVR than patients with IPAH [347], but there is a wide overlap.

7.4.2 Therapy

The mortality risk of patients with PoPH is at least as high as in IPAH [347, 348] and these patients should be referred to centres with expertise in managing both PAH and liver disease. In general, treatment follows the general rules for other forms of PAH, but there are important considerations. Patients with PoPH often have an elevated bleeding risk and anticoagulation is usually not recommended for these patients. Beta-blockers, which are frequently used to lower the portal pressure, should be avoided in patients with PoPH, as they worsen haemodynamics and exercise in this patient population [349].

Patients with PoPH have been excluded from almost all RCTs in the PAH field (except for the PATENT study, which included 13 patients with PoPH). Anecdotal reports suggest that ERAs, PDE-5is, sGC stimulators and prostacyclin analogues may be used in this patient population [214, 350–356]. This includes potentially hepatotoxic drugs such as bosentan, but it should be noted that this compound tends to accumulate in patients with severely impaired liver function (i.e. Child–Pugh class B and C) [356]. Newer ERAs (ambrisentan, macitentan) have a theoretical advantage over bosentan, as the risk of drug-associated liver toxicity is lower [194, 201, 357], but both drugs have not been systematically evaluated in patients with PoPH.

The presence of PH is of particular importance in patients undergoing liver transplantation [358]. Mild PH with normal or near-normal PVR in the presence of high CO is usually well tolerated and tends to be reversible after transplantation [359]. PAH, in contrast, has been identified as a major risk factor in the setting of liver transplantation. In a series from the Mayo Clinic, the mortality rate was 100% in patients with a PAPm ≥50 mmHg and 50% in patients with a PAPm between 35 and 50 mmHg and a PVR ≥250 dyn·s·cm⁻⁵ [359]. Therefore patients evaluated for liver transplantation should be screened for signs of PH, even in the absence of corresponding clinical symptoms. In the past, significant PAH was considered a contraindication for liver transplantation, but anecdotal reports suggest that pretreating these patients with PAH drugs might improve the outcome after liver transplantation [360–363]. There is not yet sufficient evidence to allow general recommendations and the transplant decision should be made by multidisciplinary teams in expert centres. A few specialized centres offer combined liver–lung or liver–heart–lung transplantation for carefully selected patients [364].

The recommendations for PAH associated with portal hypertension are reported in the Table 27.

7.5.1 Diagnosis

HIV-associated PAH shares a similar clinical presentation with IPAH. At the time of diagnosis, a majority of patients are in an advanced New York Heart Association (NYHA)-FC III or IV. Patients may present with other risk factors for PAH, such as liver disease (chronic hepatitis B or C), exposure to drugs or toxins or PE due to i.v. drug abuse. Patients with HIV-associated PAH are more likely to be male and i.v. drug abusers. Animal research supports the notion that the additive effect of cocaine on HIV infection might play a role in the development of pulmonary arteriopathy. Because of its low prevalence, asymptomatic HIV-infected patients should not be screened for PAH. However, echocardiography must be performed in patients with unexplained dyspnoea to detect HIV-related cardiovascular complications such as myocarditis, cardiomyopathy or PAH. RHC confirmation is mandatory to establish the diagnosis of HIV-related PAH and the absence of LHD [369]. PAH is an independent risk factor for death in HIV-infected patients.

7.5.2 Therapy

In the absence of specific recommendations, treatment of HIV-PAH follows guidelines for the treatment of IPAH together with HAART. On multivariate analysis, a CI >2.8 l/min/m² and a CD4 lymphocyte count >200 cells/ml are independent predictors of survival [225]. Anticoagulation is not routinely recommended because of an increased risk of bleeding, anticipated compliance issues and drug interactions. Patients with HIV-related PAH appear to be non-responders to acute vasodilator challenge and thus should not receive CCBs [189]. Uncontrolled studies suggest that prostacyclins may improve exercise tolerance, haemodynamics and symptoms in HIV-related PAH [218]. An open-label study reported the effects of bosentan in patients with HIV-related PAH, showing an improvement in all efficacy measures, including 6MWT and invasive haemodynamics [370]. Sporadic cases have been included in the ambrisentan RCTs [194]. Hepatic tolerability was similar to previously reported observations in other forms of PAH. The interpretation of these studies is limited by the small sample size and their open-label nature. In the case of sildenafil, the dose should be reduced if ritonavir and saquinavir are co-administered due to drug–drug interactions. HIV infection is generally considered an exclusion criterion for lung transplantation, even though in some centres specific programmes have been implemented. Of note, cases of reversible disease have been described in HIV-PAH patients treated with HAART and specific therapies. This finding, together with the decreased incidence of HIV-PH in the modern management era, may indicate that aggressive management improves outcomes in this patient population. Further studies are needed to understand the underlying reasons of improved outcomes in these patients.

The recommendations for PAH associated with HIV infection are reported in the Table 28.

7.6.1 Diagnosis

The diagnosis of PVOD/PCH can be established with a high probability by the combination of clinical suspicion, physical examination, bronchoscopy and radiological findings [371]. This non-invasive approach may avoid the need to perform a hazardous lung biopsy (the gold standard to confirm a histological diagnosis of PVOD/PCH), which is no longer recommended in most cases [371]. In heritable cases, identification of a bi-allelic EIF2AK4 mutation is sufficient to confirm a diagnosis of PVOD/PCH without histological confirmation [28, 376]. Most patients complain of dyspnoea on exertion and fatigue, a clinical presentation that is indistinguishable from PAH [371, 374]. Physical examination may reveal digital clubbing and bi-basal crackles on lung auscultation, these being unusual in PAH [371]. Case series indicate that patients with PVOD/PCH are more severely hypoxaemic and have much lower DLCO levels than in other forms of PAH [92, 371]. This can be explained by the presence of chronic interstitial pulmonary oedema and pulmonary capillary proliferation typical of PVOD/PCH.

Chest radiography may reveal Kerley B lines, mediastinal lymph node enlargement and peripheral interstitial infiltrate, in addition to other signs of PH [92, 371]. High-resolution CT of the chest is the investigation of choice. Typical findings suggestive of PVOD/PCH are the presence of subpleural thickened septal lines, centrilobular ground-glass opacities and mediastinal lymphadenopathy [92, 371]. The association of these three findings was found to be 100% specific for PVOD/PCH in cases of PAH, with 66% sensitivity. In addition, their presence appears to closely correlate with the risk of pulmonary oedema with PAH drugs. V/Q lung scanning is not useful in discriminating PVOD/PCH from IPAH [377].

Because PVOD/PCH may be associated with occult alveolar haemorrhage, bronchoscopy with bronchoalveolar lavage may be a useful tool in the diagnostic strategy. In a retrospective study, the results of bronchoalveolar lavage performed in 19 patients with PAH or PVOD/PCH were analysed. Compared with IPAH, the eight cases of PVOD presented with a significantly elevated cell count, a higher percentage of hemosiderin-laden macrophages and a markedly elevated Golde score [378].

The haemodynamic presentation of PVOD is similar to IPAH [92, 371]. Importantly, PAWP is almost invariably normal, because the pathological changes occur in small venulae and capillaries and do not affect the larger pulmonary veins [92, 371]. Vasoreactivity testing may be complicated by acute pulmonary oedema [92, 371].

7.6.2 Therapy

There is no established medical therapy for PVOD/PCH [92]. Most importantly, vasodilators and, in particular, i.v. epoprostenol must be used with great caution because of the high risk of severe drug-induced pulmonary oedema [92, 373]. However, there are reports of sustained clinical improvement in individual patients treated with these medications [379]. High-dose diuretics, O₂ therapy and slow increases in epoprostenol doses are recommended [379]. Therefore therapy for PVOD/PCH should be undertaken only at centres with extensive experience in the management of PH and patients should be fully informed about the risks. Investigational use of angiogenesis inhibitors such as interferon alfa-2a has been considered in these patients but is not currently recommended [379]. The only curative therapy for PVOD/PCH is lung transplantation, and there are no reports of recurrence of disease following transplantation. Eligible patients with PVOD/PCH should be referred to a transplant centre for evaluation as soon as the diagnosis is established [379].

The recommendations for PVOD/PCH are reported in the Table 29.

10.2.1 Surgical

PEA is the treatment of choice for CTEPH (Figure 4). In Europe, in-hospital mortality is currently as low as 4.7% [430], and even lower in high-volume single centres [431]. The majority of patients experience substantial relief from symptoms and near normalization of haemodynamics [430–432]. In contrast to surgical embolectomy for acute PE, treatment of CTEPH necessitates a true bilateral endarterectomy through the medial layer of the pulmonary arteries, which is performed under deep hypothermia and circulatory arrest [431], without the need for cerebral perfusion [433].

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FIGURE 4

Treatment algorithm for chronic thromboembolic pulmonary hypertension. BPA: balloon pulmonary angioplasty; CTEPH: chronic thromboembolic pulmonary hypertension; PH: pulmonary hypertension. ^aTechnically operable patients with non-acceptable risk/benefit ratio can be considered also for BPA. ^bIn some centers medical therapy and BPA are initiated concurrently.

Operability of patients with CTEPH is determined by multiple factors that cannot easily be standardized; these are related to the suitability of the patient, the expertise of the surgical team and available resources. General criteria include preoperative WHO-FC II–IV and surgical accessibility of thrombi in the main, lobar or segmental pulmonary arteries. Advanced age per se is not a contraindication for surgery. There is no PVR threshold or measure of RV dysfunction that can be considered to preclude PEA.

Postoperative ECMO is recommended as a standard of care in PEA centres for severe cases [434–436]. Early postoperative reperfusion oedema may require veno-arterial ECMO, and severe persistent PH may be bridged to emergency lung transplantation with veno-venous ECMO.

Patients who do not undergo PEA or suffer from persistent or recurrent PH after PEA (post-PEA PH) face a poor prognosis.

10.2.2 Medical

Optimal medical treatment for CTEPH consists of anticoagulants and diuretics, and O₂ in cases of heart failure or hypoxaemia. Lifelong anticoagulation is recommended, even after PEA, though no data exist on the efficacy and safety of new oral anticoagulants. Although there is no consensus, routine cava filter placement is not justified by the available evidence. Pulmonary microvascular disease in CTEPH has provided the rationale for off-label use of drugs approved for PAH [25]. Some non-randomized studies have provided evidence for improvement in exercise capacity and haemodynamics [437–439]. Medical treatment of CTEPH with targeted therapy may be justified in technically non-operable patients or in the presence of an unacceptable surgical risk:benefit ratio (Figure 2). Patients with persistent or recurrent PH after PEA may also be candidates for targeted medical therapy. The use of targeted therapy in operable patients with severe haemodynamic compromise as a bridge to PEA has not yet been supported by scientific evidence.

The dual endothelin antagonist bosentan was evaluated in 157 patients with inoperable CTEPH or persistent/recurrent PH after PEA over 16 weeks; the primary combined endpoint of a decrease in PVR and an increase in the 6MWD was not met [440]. However, an oral sGC stimulator, riociguat, was administered to 261 of 446 screened patients with non-operable CTEPH or persistent/recurrent PH after PEA for 16 weeks and led to a mean increase of 39 m in the 6MWD (P < 0.001, primary endpoint) and to a least squares mean difference of 246 dyn·cm·s⁻⁵ in PVR (P < 0.001, secondary endpoint); the time to clinical worsening remained unchanged [441].

Preoperative medical treatment is uncertain because the magnitude of effects was small in one RCT [442]. One retrospective study indicated no difference in outcome, but there was a delay in surgery for patients treated medically [442]. Prospective RCTs are needed in patients with potential treatment benefit; for example, patients with a high PVR and technically challenging anatomy.

After PEA, patients should be followed in CTEPH centres, with at least one haemodynamic assessment to be considered at 6–12 months after the intervention.

10.2.3 Interventional

In 2001 Feinstein et al. [443]. published a series of 18 patients with non-operable CTEPH who had been subjected to balloon dilatation of the pulmonary arteries. Despite a significant decrease in PAPm, 11 patients developed reperfusion pulmonary oedema and 3 required mechanical ventilation. Recently, Japanese investigators have refined BPA by using smaller balloons, by cautiously limiting the number of balloon inflations per session to one or two pulmonary vascular segments and by the use of intravascular imaging [444–446]. An average number of 4.8 sessions is needed per patient to improve parameters of RV function [57]. A careful approach with targeting only one lobe during each session and very cautious balloon sizing have reduced the incidence of reperfusion pulmonary oedema to 2% in individual centres [447]. While BPA is still not extensively used, [448]. it is rapidly gaining attention worldwide. BPA should only be performed in experienced and high-volume CTEPH centres.

The recommendations for CTEPH are summarised in Table 34.

An algorithm for the treatment of CTEPH is provided in Figure 4.