Copyright © 2004 by the European Society of Cardiology.
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ESC Guidelines
Guidelines on diagnosis and treatment of pulmonary arterial hypertension
The Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology
Task Force members,ESC Committee for Practice Guidelines (CPG): Silvia G. Priori (Chairperson) (Italy), Maria Angeles Alonso Garcia (Spain), Jean-Jacques Blanc (France), Andrzej Budaj (Poland), Martin Cowie (UK), Veronica Dean (France), Jaap Deckers (The Netherlands), Enrique Fernandez Burgos (Spain), John Lekakis (Greece), Bertil Lindahl (Sweden), Gianfranco Mazzotta (Italy), Keith McGregor (France), João Morais (Portugal), Ali Oto (Turkey), Otto A. Smiseth (Norway)
Document reviewers: Gianfranco Mazzotta (CPG Review Coordinator) (Italy), Joan Albert Barbera (Spain), Simon Gibbs (UK), Marius Hoeper (Germany), Marc Humbert (France), Robert Naeije (Belgium), Joanna Pepke-Zaba (UK)
Preamble
Guidelines and Expert Consensus Documents aim to present all the relevant evidence on a particular issue in order to help physicians to weigh the benefits and risks of a particular diagnostic or therapeutic procedure. They should be helpful in everyday clinical decision-making.
A great number of Guidelines and Expert Consensus Documents have been issued in recent years by the European Society of Cardiology (ESC) and by different organisations and other related societies. This profusion can put at stake the authority and validity of guidelines, which can only be guaranteed if they have been developed by an unquestionable decision-making process. This is one of the reasons why the ESC and others have issued recommendations for formulating and issuing Guidelines and Expert Consensus Documents.
In spite of the fact that standards for issuing good quality Guidelines and Expert Consensus Documents are well defined, recent surveys of Guidelines and Expert Consensus Documents published in peer-reviewed journals between 1985 and 1998 have shown that methodological standards were not complied with in the vast majority of cases. It is therefore of great importance that guidelines and recommendations are presented in formats that are easily interpreted. Subsequently, their implementation programmes must also be well conducted. Attempts have been made to determine whether guidelines improve the quality of clinical practice and the utilisation of health resources.
The ESC Committee for Practice Guidelines (CPG) supervises and coordinates the preparation of new Guidelines and Expert Consensus Documents produced by Task Forces, expert groups or consensus panels. The chosen experts in these writing panels are asked to provide disclosure statements of all relationships they may have which might be perceived as real or potential conflicts of interest. These disclosure forms are kept on file at the European Heart House, headquarters of the ESC. The Committee is also responsible for the endorsement of these Guidelines and Expert Consensus Documents or statements.
The Task Force has classified and ranked the usefulness or efficacy of the recommended procedure and/or treatments and the Level of Evidence as indicated in the tables below:
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Introduction
Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterised by a progressive increase of pulmonary vascular resistance (PVR) leading to right ventricular failure and premature death.1 The median life expectancy from the time of diagnosis in patients with idiopathic PAH (IPAH), formerly known as primary pulmonary hypertension (PPH), before the availability of disease-specific (targeted) therapy, was 2.8 years through the mid-1980s.2 PAH includes IPAH3 and pulmonary hypertension associated with various conditions such as connective tissue diseases (CTD), congenital systemic-to-pulmonary shunts, portal hypertension and Human Immunodeficiency Virus (HIV) infection.4 All these conditions share equivalent obstructive pathological changes of the pulmonary microcirculation5,6 suggesting shared pathobiological processes among the disease spectrum of PAH.7
In the past decade, we have witnessed major advances in our understanding of the mechanism of disease development, in the diagnostic process, and in the treatment of PAH.
The identification of mutations in the bone morphogenetic protein receptor 2 (BMPR2) in the majority of cases of familial PAH (FPAH) has been a major advance in the elucidation of the pathogenic sequence in PAH.8,9 A variety of cellular abnormalities has been described in the pulmonary vasculature of affected patients that may play important roles in the development and progression of PAH.7 These include pulmonary endothelial dysfunction10 characterised by altered synthesis of nitric oxide, thromboxane A2, prostacyclin and endothelin, impaired potassium channels and altered expression of the serotonin transporter in the smooth muscle cells and enhanced matrix production in the adventitia.7
The diagnosis is now more clearly defined according to a new clinical classification and with consensus reached on algorithms of various investigative tests and procedures that exclude other causes and ensure an accurate diagnosis of PAH.11 In addition, non-invasive markers of disease severity, either biomarkers or physiological tests that can be widely applied, have been proposed to reliably monitor the clinical course.11,12
Finally, the numerous controlled clinical trials performed recently in PAH can allow us to abandon a clinical-based treatment strategy and adopt an evidence-based therapy that includes new classes of drugs such as prostanoids,13 endothelin receptor antagonists14 and type 5 phosphodiesterase inhibitors.15
The present guidelines are intended to provide clear and concise indications for the practical use of the new clinical classification, and a brief description of the new pathological classification and of the recent pathogenetic insights. The diagnostic process will be discussed in order to propose a logical sequence of investigations for aetiology identification, disease assessment and follow-up. Special emphasis will be devoted to the evidence-based treatment algorithm that has been defined according to the ESC proposals for the Level of Evidence classification and the Grade of Recommendation16 for the available therapies.
Clinical classification of pulmonary hypertension
Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure (PAP) >25 mmHg at rest or >30 mmHg with exercise.17 Current classification of PH is presented in Table 1. It is a result of extensive discussion and represents a consensus accommodating our present understanding of pathophysiology as well as of clinical-based differences or similarities within PH. Understanding and correct clinical application of the classification should be aided by the following discourse.
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PH was previously classified into 2 categories: PPH or secondary PH depending on the absence or the presence of identifiable causes or risk factors.3,17 The diagnosis of PPH was one of exclusion after ruling out all causes of PH.
In 1998, during the Second World Meeting on PH held in Evian – France, a clinical-based classification of PH was proposed.18 The aim of the "Evian classification" was to individualise different categories sharing similarities in pathophysiological mechanisms, clinical presentation and therapeutic options. Such a clinical classification is essential in communicating about individual patients, in standardising diagnosis and treatment, in conducting trials with homogeneous groups of patients, and lastly in analysing novel pathobiological abnormalities in well characterised patient populations. Obviously, a clinical classification does not preclude other classifications such as a pathological classification based on histological findings, or a functional classification based on the severity of symptoms. The 2003 Third World Symposium on PAH held in Venice–Italy provided the opportunity to assess the impact and the usefulness of the Evian classification and to propose some modifications.
It was decided to maintain the general architecture and philosophy of the Evian classification. However, some modifications have been proposed, mainly: to abandon the term "primary pulmonary hypertension – PPH" and to replace it with "idiopathic pulmonary arterial hypertension – IPAH", to reclassify pulmonary veno-occlusive disease (PVOD) and pulmonary capillary haemangiomatosis (PCH), to update risk factors and associated conditions for PAH, and to propose some guidelines in order to improve the classification of congenital systemic-to-pulmonary shunts (Table 1). The aim of these modifications was to make the "Venice clinical classification" more comprehensive, easier to follow and widespread as a tool.
Idiopathic pulmonary arterial hypertension
The term PPH was retained in the Evian classification because of its common use and familiarity, and because it was emblematic of 50 years of intense scientific and clinical research. However, the use of the term "primary" facilitated the reintroduction of the term "secondary" that was abandoned in the Evian version because it was used to describe very heterogeneous conditions. In order to avoid any possible confusion in Venice it was decided that the first category termed "pulmonary arterial hypertension – PAH" should include three main subgroups: [1.1] idiopathic pulmonary arterial hypertension – IPAH, [1.2] familial pulmonary arterial hypertension – FPAH and [1.3] pulmonary arterial hypertension related to risk factors or associated conditions – APAH.
Risk factors and associated conditions
A risk factor for PH is any factor or condition that is suspected to play a predisposing or facilitating role in the development of the disease. Risk factors may include drugs and chemicals, diseases or phenotype (age, gender). The term of "associated conditions" is used when a statistically significantly increased incidence of PAH is found with a given predisposing factor, without, however, meeting "Koch's postulate" for causal relationship. Since the absolute risk of known risk factors for PAH is generally low, individual susceptibility or genetic predisposition is likely to play an important role. During the Evian meeting in 1998, different risk factors and associated conditions were categorised according to the strength of their association with PH and their probable causal role. "Definite" indicates an association based on several concordant observations including a major controlled study or an unequivocal epidemic. "Very likely" indicates several concordant observations (including large case series and studies) that are not attributable to identified causes. "Possible" indicates an association based on case series, registries or expert opinions. "Unlikely" indicates risk factors that were suspected but for which controlled studies failed to demonstrate any association.
According to the strength of the evidence, Table 2 summarises, risk factors and associated conditions already known19 and novel "possible" risk factors for PAH that were identified recently, according to several case series or case reports. The new possible risk factors include haematological conditions such as asplenia secondary to surgical splenectomy,20 sickle cell disease,21 β-thalassaemia22 and chronic myeloproliferative disorders23 (polycythaemia vera, essential thrombocytaemia and myelofibrosis with myeloid metaplasia accompanying chronic myeloid leukaemia or the myelodysplastic syndrome). Possible risk factors include also rare genetic or metabolic diseases such as type 1a glycogen storage disease (Von Gierke disease),24 Gaucher's disease25 and hereditary haemorrhagic telangiectasia (Osler–Weber–Rendu disease).26
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Pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis
In the Evian classification, PVOD was included in the pulmonary venous hypertension category that consists predominantly of left-sided heart diseases and PCH was included in the last and heterogeneous group of PH caused by diseases that directly affect the pulmonary vasculature. The similarities in the pathological features and clinical presentation, along with the possible occurrence of pulmonary oedema during epoprostenol therapy, suggest that these disorders may overlap. Accordingly, it seems logical to include PVOD and PCH within the same group, most appropriately within the category of PAH. In fact, the clinical presentation of PVOD and PCH is generally similar to that of IPAH and the risk factors or conditions associated with PAH and PVOD/PCH are similar and include the scleroderma spectrum of the disease, HIV infection, and the use of anorexigens. Thus, in the new clinical classification (Table 1), the PAH Clinical classification group 1 includes another subgroup termed PAH associated with significant venous or capillary involvement (Clinical class 1.4).
Classification of congenital systemic-to-pulmonary shunts
The proposed classification of congenital systemic-to-pulmonary shunts takes into account the type and the dimensions of the defect, the presence of associated extracardiac abnormalities and the correction status (Table 3). All these factors are relevant for the development of PH and Eisenmenger physiology and the prognosis.
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Eisenmenger syndrome can be caused by simple or complex (about 30% of cases) congenital heart defects.27 Among simple defects, ventricular septal defects appear to be the most frequent, followed by atrial septal defects and patent ductus arteriosus.27 It is calculated that 10% of patients with ventricular septal defects of any size that are older than 2 years can develop Eisenmenger syndrome as compared to 4–6% of subjects with atrial septal defects.28,29 For patients with large defects, almost all cases with truncus arteriosus, 50% of cases with ventricular septal defects and 10% of those with atrial septal defects will develop PAH and pulmonary vascular disease.30 In patients with atrial septal defects, those with sinus venosus defects have an higher incidence of PAH (16%) as compared to ostium secundum defects (4%).31
The development of PAH with pulmonary vascular disease appears to be related to the size of the defect. In fact, with small- to moderate-size ventricular septal defects only 3% of patients develop PH.32,33 In contrast with larger defects (>1.5 cm in diameter), 50% will be affected. In case of small defects (ventricular septal defects <1 cm and atrial septal defects <2 cm of effective diameter assessed by echo) the exact pathophysiological role of the heart defect on the development of PAH is unknown.
In some patients severe PAH can be detected after "successful" correction of the heart defect. In many of these cases it is not clear if irreversible pulmonary vascular lesions were already present before the surgical intervention or if the pulmonary vascular disease has progressed despite a successful correction. Usually an early correction prevents the subsequent development of PAH.
Pathology of pulmonary arterial hypertension
PAH includes various forms of PH of different aetiologies but similar clinical presentation, and in many cases similar response to medical treatment. Histopathological changes in various forms of PAH are qualitatively similar5 but with quantitative differences in the distribution and prevalence of pathological changes in the different components of the pulmonary vascular bed (arterioles, capillaries or veins). The following updated pathological classification has been proposed at the Third World Symposium on PAH of Venice (Table 4).6
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Pulmonary arteriopathy
The main histopathological features of pulmonary arteriopathy include medial hypertrophy, intimal thickening, adventitial thickening and complex lesions.
Medial hypertrophy is an increase in the cross sectional area of the media of pre and intra-acinar pulmonary arteries. It is due to both hypertrophy and hyperplasia of smooth muscle fibers as well as increase in connective tissue matrix and elastic fibers in the media of muscular arteries.
Intimal thickening may be concentric laminar, eccentric or concentric non-laminar. Ultrastructurally and immuno-histochemically the intimal cells show features of fibroblasts, myofibroblasts and smooth muscle cells.
Adventitial thickening occurs in most cases of PAH but it is more difficult to evaluate.
Complex lesions. The plexiform lesion is a focal proliferation of endothelial channels lined by myofibroblasts, smooth muscle cells and connective tissue matrix. These lesions are at an arterial branching point or at the origin of a supernumerary artery, distally to marked obliterative intimal thickening of the parent artery. The frequency of the plexiform lesions in PAH remains undetermined. Arteritis may be associated with plexiform lesions and it is characterised by a necrosis of the arterial wall with fibrinoid insudation and infiltration with inflammatory cells.
All the above changes are seen typically in clinical classification (Table 1) groups 1.1 (IPAH), 1.2 (FPAH) and 1.3 (APAH).
Pulmonary occlusive venopathy (also called pulmonary veno-occlusive disease)
Pulmonary occlusive venopathy accounts for a relatively small proportion of cases of PH; main histo-pathological features consist of extensive and diffuse occlusion of pulmonary venules and veins of various sizes. The luminal occlusion can be either solid or eccentric. In addition, the media may be thickened. In pulmonary occlusive venopathy, large amounts of haemosiderin are found both within the cytoplasm of alveolar macrophages and type II pneumocytes, as well as deposits in the interstitium. The capillary vessels are engorged and prominent and they may be so tortuous as to mimic pulmonary capillary haemangiomatosis. Pulmonary arterioles can show remodelling with medial hypertrophy and intimal fibrosis. Plexiform lesions and fibrinoid arteritis are not described in pulmonary occlusive venopathy. The pulmonary interstitium frequently shows oedema in the lobular septa, which may progress to interstitial fibrosis. Lymphatics within the lung and pleura are also dilated. These changes are seen typically in clinical classification (Table 1) group 1.4.1 (PVOD).
Pulmonary microvasculopathy (also called pulmonary capillary haemangiomatosis)
Pulmonary microvasculopathy is another rare condition characterised by localised capillary proliferation within the lung. The distribution of pulmonary microvasculopathy is usually panlobar and patchy. The abnormal proliferating capillaries infiltrate the walls of arteries and veins invading muscular walls and occluding the lumen. In the areas of capillary proliferation, pulmonary haemosiderosis, characterised by haemosiderin-laden macrophages and type II pneumocytes, is also present. Similar to pulmonary occlusive venopathy, the pulmonary arteries in pulmonary microvasculopathy show marked muscular hypertrophy and intimal thickening. These changes are seen typically in clinical classification (Table 1) group 1.4.2 (PCH).
Finally, there are unclassifiable conditions with atypical histopathological features or inadequate sampling of blood vessels.
Pathogenesis of pulmonary arterial hypertension
The exact processes that initiate the pathological changes seen in PAH are still unknown even if we now understand more of the mechanisms involved. It is recognised that PAH has a multi-factorial pathobiology that involves various biochemical pathways and cell types. The increase of PVR is related to different mechanisms including vasoconstriction, obstructive remodelling of the pulmonary vessel wall, inflammation and thrombosis.
Pulmonary vasoconstriction is believed to be an early component of the pulmonary hypertensive process.34 Excessive vasoconstriction has been related to abnormal function or expression of potassium channels in the smooth muscle cells35 and to endothelial dysfunction.10 Reduced plasma levels of a vasodilator and antiproliferative substance such as Vasoactive Intestinal Peptide has been shown in patients with PAH.36
Endothelial dysfunction leads to chronically impaired production of vasodilators such as nitric oxide (NO) and prostacyclin along with overexpression of vasoconstrictors such as thromboxane A2 (TxA2) and endothelin-1 (ET-1).10 Many of these abnormalities both elevate vascular tone and promote vascular remodelling.
The process of pulmonary vascular remodelling involves all layers of the vessel wall and is characterised by proliferative and obstructive changes that involve several cell types including endothelial, smooth muscle and fibroblasts.6,7 In addition, in the adventitia there is increased production of extracellular matrix including collagen, elastin, fibronectin, and tenascin.37 Angiopoietin-1, an angiogenic factor essential for vascular lung development, seems to be upregulated in cases of PH correlating directly with the severity of the disease.38
Also inflammatory cells and platelets may play a significant role in PAH. In fact, inflammatory cells are ubiquitous in PAH pathological changes and pro-inflammatory cytokines are elevated in the plasma of PAH patients.39 Alterations in the metabolic pathways of serotonin, a pulmonary vasoconstrictor substance stored in platelets, have also been detected in PAH patients.40
Prothrombotic abnormalities have been demonstrated in PAH patients41 and thrombi are present in both microcirculation and elastic pulmonary arteries.6 In fact, fibrinopeptide A levels that reflect thrombin activity,42 and TxA2 levels,43 are both elevated in patients with IPAH.
Despite the identification of mutations in the BMPR2 in the majority of cases of familial PAH,8,9 the pathobiological links between this genetic abnormality and the development of pulmonary vascular hypertensive disease have not been clarified. On the other hand, the high frequency of "true" sporadic IPAH cases and reduced penetrance of familial PAH (only 20% of BMPR2 gene mutation carriers manifest the disease), suggests that additional triggers are required for the development of the condition. Mechanisms could be second somatic mutations within an unstable BMPR-2 pathway,44 polymorphisms for genes related to PAH [serotonin transporter gene (5HTT),40 nitric oxide synthase (ec-NOS) gene45 and carbamyl-phosphate synthase (CPS) gene46] or any stimulus able to disrupt pulmonary vascular cells growth control. In addition there may be further genes, possibly related to the BMP/TGF-βv pathway, to be identified. Indeed, mutations in the TGF-βv receptors, activin-receptor-like kinase 1 (ALK-1) and endoglin, have been identified in PAH patients with a personal or family history of hereditary haemorrhagic telangiectasia, i.e. Osler–Weber–Rendu.26,47
Even if many pathobiological mechanisms have been identified in the cells and tissues of PAH patients, the exact interactions between these mechanisms in initiating and progressing the pathological processes are not well understood. Possible theoretical pathways (Fig. 1) include the classical interaction between genetic predisposition and risk factors that may induce changes in different cell types (smooth muscle cells, endothelial cells, inflammatory cells, platelets) and in the extracellular matrix of pulmonary microcirculation. The imbalance between thrombogenic, mitogenic, proinflammatory and vasoconstrictive factors as opposed to anticoagulant, antimitotic and vasodilating mechanisms may initiate and perpetuate interacting processes such as vasoconstriction, proliferation, thrombosis and inflammation in the lung microcirculation. These mechanisms are responsible for the initiation and progression of pathological obstructive changes typical of PAH. The consequent increase of PVR leads to right ventricular overload and eventually to right ventricular failure and death.
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Future studies are required to find which, if any, of these abnormalities initiates PAH and which are best targeted to cure the disease.
Diagnostic strategy
The diagnostic process of PH requires a series of investigations that are intended to make the diagnosis, to clarify the clinical class of PH and the type of PAH and to evaluate the functional and haemodynamic impairment. For practical purposes it can be useful to adopt a sequential approach that includes four stages (Fig. 2):
- I. Clinical suspicion of pulmonary hypertension
- II. Detection of pulmonary hypertension
- III. Pulmonary hypertension clinical class identification
- IV. Pulmonary arterial hypertension evaluation (type, functional capacity, haemodynamics)
- II. Detection of pulmonary hypertension
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Clinical suspicion of pulmonary hypertension
The clinical suspicion of PH should arise in any case of breathlessness without overt signs of specific heart or lung disease or in patients with underlying lung or heart disease whenever there is increasing dyspnoea unexplained by the underlying disease itself. The symptoms of PH48 can also include fatigue, weakness, angina, syncope, and abdominal distension. Symptoms at rest are reported only in very advanced cases.
The physical signs of PH48 may require experience to be appreciated. They include left parasternal lift, accentuated pulmonary component of S2, pansystolic murmur of tricuspid regurgitation, diastolic murmur of pulmonary insufficiency and right ventricular S3. Jugular vein distension, hepatomegaly, peripheral oedema, ascites and cool extremities characterise patients in a more advanced state with right ventricular failure at rest. Central cyanosis (and sometime peripheral cyanosis and mixed forms) may also be present. Lung sounds are usually normal.
The clinical suspicion is raised when symptoms and signs are present in subjects with conditions that can be associated with PAH such as CTD, portal hypertension, HIV infection and congenital heart diseases with systemic-to-pulmonary shunts. In the presence of these predisposing abnormalities some experts support a rationale for periodic screening assessments to identify asymptomatic patients in the early stage of PH49 (see Specific Conditions below).
Finally, PH can be suspected when abnormal electrocardiographic, chest radiograph or echocardiographic findings, are detected in the course of procedures performed for other clinical reasons.
Detection of pulmonary hypertension
The detection phase requires investigations that are able to confirm the diagnosis of PH. They include the electrocardiogram (ECG), the chest radiograph and transthoracic Doppler-echocardiography.
ECG
The ECG may provide suggestive or supportive evidence of PH by demonstrating right ventricular hypertrophy and strain, and right atrial dilation. Right ventricular hypertrophy on ECG is present in 87% and right axis deviation in 79% of patients with IPAH.48 However, the ECG has inadequate sensitivity (55%) and specificity (70%) to be a screening tool for detecting significant PAH.50 A normal ECG does not exclude the presence of severe PH.
Chest radiograph
In 90% of IPAH patients the chest radiograph is abnormal at the time of diagnosis.48 Findings include central pulmonary arterial dilatation which contrasts with 'pruning' (loss) of the peripheral blood vessels. Right atrial and ventricular enlargement may be seen and it progresses in more advanced cases. The chest radiograph allows associated moderate-to-severe lung disease or pulmonary venous hypertension due to left heart abnormalities to be reasonably excluded. However, a normal chest radiograph does not exclude mild post capillary pulmonary hypertension including left-heart disease or pulmonary veno-occlusive disease.
Transthoracic Doppler-echocardiography
Transthoracic Doppler-echocardiography (TTE) is an excellent non-invasive screening test for the patient with suspected PH. TTE estimates pulmonary artery systolic pressure (PASP) and can provide additional information about the cause and consequences of PH. PASP is equivalent to right ventricular systolic pressure (RVSP) in the absence of pulmonary outflow obstruction. RVSP is estimated by measurement of the systolic regurgitant tricuspid flow velocity v and an estimate of right atrial pressure (RAP) applied in the formula: RVSP=4v2+RAP. RAP is either a standardised value, or estimated value from characteristics of the inferior vena cava51 or from jugular venous distension. Tricuspid regurgitant jets can be assessed in the majority (74%) of patients with PH.52 Most studies report a high correlation (0.57–0.93) between TTE and right heart catheterisation (RHC) measurements of PASP.53 However, in order to minimise false positives54 it is important to identify specific values for the definition of PH as assessed by TTE.
The range of RVSP among healthy controls has been well characterised. Among a broad population of male and female subjects ranging from 1 to 89 years old, RVSP was reported as 28±5 mmHg (range 15–57 mmHg). RVSP increases with age and body mass index.55 According to these data mild PH can be defined as a PASP of approximately 36–50 mmHg or a resting tricuspid regurgitant velocity of 2.8–3.4 m/s (assuming a normal RAP of 5 mmHg). It should be noted that also with this definition a number of false positive diagnoses can be anticipated especially in aged subjects and confirmation with RHC is required in symptomatic patients (NYHA class II–III). In asymptomatic subjects (NYHA class I) a concomitant CTD should be excluded and echocardiography should be repeated in six months. It should be noted that defining the level for an elevated RVSP does not define the point at which an increased RVSP is clinically important, is predictive of future consequences and/or requires specific treatments. Also the possibility of false negative Doppler-echocardiographic results should be considered in case of high clinical suspicion.56
Additional echocardiographic and Doppler parameters are important for diagnosis confirmation and assessment of severity of PH including right and left ventricular dimensions and function, tricuspid, pulmonary and mitral valve abnormalities, right ventricular ejection and left ventricular filling characteristics, inferior vena cava dimensions and pericardial effusion size.57,58
Besides identification of PH, TTE also allows a differential diagnosis of possible causes and virtually starts the phases III and IV of the diagnostic process. TTE can recognise left heart valvular and myocardial diseases responsible for pulmonary venous hypertension (Clinical Class 2), and congenital heart diseases with systemic-to-pulmonary shunts can be easily identified (Clinical Class 1.3.2). The venous injection of agitated saline as contrast medium can help the identification of patent foramen ovale or small sinus venosus type atrial septal defects that can be overlooked on the standard TTE examination. Trans-oesophageal echocardiography (TEE) is rarely required and is usually used to confirm the presence, and assess the exact size, of small atrial septal defects.
Pulmonary hypertension clinical class identification
The next step after the detection of PH is the identification of the Clinical Class according to the clinical classification of Venice (Table 1).1 This is accomplished by the use of essential tests such as TTE (as specified above), pulmonary function tests (PFT) (including arterial blood gas sample) and ventilation and perfusion (V/Q) lung scan. If required, in particular circumstances additional tests can be performed such as chest high resolution CT (HRCT), spiral CT and pulmonary angiography.
Pulmonary function tests and arterial blood gases
PFTs and arterial blood gas sampling can identify the contribution of underlying airway or parenchymal lung disease. Patients with PAH usually have decreased lung diffusion capacity for carbon monoxide (DLCO) [typically in the range of 40–80% predicted] and mild to moderate reduction of lung volumes. The arterial oxygen tension (PaO2) is normal or only slightly lower than normal and arterial carbon dioxide tension (PaCO2) is decreased as a result of alveolar hyperventilation. Chronic obstructive pulmonary disease as a cause of hypoxic PH, is diagnosed on the evidence of irreversible airflow obstruction,59 usually by measuring the forced expired volume in one second (FEV1). These patients often have a normal or increased PaCO2 together with airflow limitation and increased residual volumes and reduced DLCO. Emphysema is now diagnosed using HRCT. A decrease in lung volume together with a decrease in DLCO may indicate a diagnosis of interstitial lung disease (ILD). Again the HRCT is the principle way of assessing the severity of ILD.60 If clinically suspected, screening overnight oximetry and polisomnography will exclude significant obstructive sleep apnoea/hypopnoea and nocturnal desaturation.
Ventilation and perfusion (V/Q) lung scan
In PAH the lung V/Q scans may be entirely normal. However, they may also show small peripheral non-segmental defects in perfusion. These are normally ventilated and thus represent V/Q mismatch. Lung V/Q scan provides a means of diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH, Clinical Class 4).61 In CTEPH the perfusion defects are usually found in lobar and segmental regions leading to segmental defects in the perfusion image. As these areas are normally ventilated, the perfusion defects are described as being unmatched by ventilation defects. V/Q scanning showed sensitivity of 90–100% with specificity of 94–100% for distinguishing between IPAH and CTEPH.61 A caveat is that unmatched perfusion defects are also seen in veno-occlusive disease. Such a patient requires careful further investigation (see section on HRCT). In patients with parenchymal lung disease the perfusion defects are matched by ventilation defects.
High resolution CT of the lung
HRCT provides detailed views of the lung parenchyma and facilitates the diagnosis of ILD and emphysema. The presence of interstitial markings similar to those seen with advanced left ventricular failure such as diffuse central ground-glass opacification and thickening of interolobular septa suggest pulmonary veno-occlusive disease; additional findings are lymphadenopathy, pleural shadows and effusions.62 Diffuse bilateral thickening of the interlobular septae and the presence of small, centrilobular, poorly circumscribed nodular opacities suggest pulmonary capillary haemangiomatosis.
Contrast enhanced spiral CT of the lung, pulmonary angiography and magnetic resonance imaging
Contrast-enhanced spiral (or helical) CT is indicated in pulmonary hypertensive patients when the V/Q lung scintigraphy shows segmental or sub-segmental defects of perfusion with normal ventilation, i.e. evidence of a V/Q mismatch and may demonstrate central chronic pulmonary thromboemboli. CT features of chronic thromboembolic disease are complete occlusion of pulmonary arteries, eccentric filling defects consistent with thrombi, recanalisation, and stenoses or webs.63,64
Traditional pulmonary angiography is still required in the work-up of CTEPH to better identify patients that can benefit from the intervention of endarterectomy.61 Pulmonary angiography is more accurate in the identification of distal obstructions and it is indicated also in cases of inconclusive contrast-enhanced spiral CT in patients with clinical and lung scintigraphy suspicion of CTEPH. This procedure can be safely performed by experienced staff in patients with severe PH. Useful technical details include the utilisation of modern contrast media, right and left main branch selective injections and multiple views.
Magnetic resonance imaging is increasingly used in patients with PAH for the evaluation of pathological and functional changes of both heart and pulmonary circulation.63 However, additional experience is needed before introducing this tool in the routine assessment of patients with PAH.
Pulmonary arterial hypertension evaluation (type, exercise capacity, haemodynamics)
When the Clinical Class of PAH (Clinical Class 1) has been determined, additional investigations may be required for the exact identification of the type of PAH and for the assessment of exercise capacity and haemodynamics.
Blood tests and immunology
Routine biochemistry, haematology and thyroid function tests are required. Thrombophilia screen should be performed including antiphospholipid antibodies (lupus anticoagulant, anticardiolipin antibodies). CTD are diagnosed primarily on clinical and laboratory criteria and an autoimmune screen consists of antinuclear antibodies (ANA), including anti-centromere antibody, anti-SCL70 and RNP. About one third of patients with IPAH have positive but low antinuclear antibody titre (⩽1:80 dilutions).65 Patients with a substantially elevated ANA and/or suspicious clinical features require further serological assessment and rheumatology consultation. Finally, all patients should be consented for and undertake a HIV serology test.
Abdominal ultrasound scan
Liver cirrhosis and/or portal hypertension can be reliably excluded by the use of abdominal ultrasound scan. The colour-Doppler examination also allows the differentiation between passive portal hypertension, due to right heart failure, from portal hypertension caused by an increase in the trans-hepatic venous gradient associated with liver cirrhosis. The use of contrast agents may improve the diagnosis.66 Portal hypertension can be confirmed by the detection of an increased gradient between free and occluded (wedge) hepatic vein pressure at the time of RHC (see Porto-pulmonary hypertension).67
Exercise capacity
The objective assessment of exercise capacity in patients with PAH is an important instrument for evaluating disease severity68,69 and treatment effect.70,71 The most commonly used exercise tests for PH are the six-minute walk test and cardiopulmonary exercise testing with gas exchange measurement.
The six-minute walk test (6MWT) is technically simple and inexpensive.72 It is predictive of survival in IPAH and also correlates inversely with NYHA functional status severity.68 6MWT is usually combined with the Borg score that assesses the subjective level of dyspnoea with the exercise. Reduction of arterial oxygen saturation >10% during 6MWT increases mortality risk 2.9 times over a median follow-up of 26 months.73 6MWT is the traditional "primary" end point for the great majority of controlled clinical trials performed in PAH.70
Cardiopulmonary exercise testing (CPET) allows measurement of ventilation and pulmonary gas exchange during exercise testing providing additional "pathophysiologic" information to that derived from standard exercise testing. PAH patients show reduced peak VO2, reduced peak work rate, reduced ratio of VO2 increase to work rate increase, reduced anaerobic threshold and reduced peak oxygen pulse; they show also increased VE and VCO2 slope representative of ventilatory inefficiency.69 Peak VO2 is correlated with the prognosis of PAH patients.69
CPET has been used in recent multicentre trials but it failed to confirm improvements observed with 6MWT.74,75 A possible explanation for these findings is that CPET is technically more difficult than 6MWT and its results may be influenced by the experience of the centres. An alternative explanation may relate to a lack of sensitivity of CPET in measuring response to treatment which has less effect on maximal as opposed to submaximal exercise.
Haemodynamics
RHC is required to confirm the diagnosis of PAH, to assess the severity of the haemodynamic impairment and to test the vasoreactivity of the pulmonary circulation. The following parameters should always be assessed: heart rate, RAP, PAP (systolic, diastolic and mean), pulmonary capillary wedge pressure (PWP), cardiac output (by thermodilution, or the Fick method in cases of systemic-to-pulmonary shunts), blood pressure, pulmonary and systemic vascular resistance, arterial and mixed venous oxygen saturation (and superior vena cava saturation in cases of systemic-to-pulmonary shunts).
PAH is defined by a mean PAP >25 mmHg at rest or >30 mmHg with exercise, by a PWP ⩽15 mmHg and by PVR >3 mmHg/l/min (Wood units). Left heart catheterisation is required in the rare circumstances in which a reliable PWP cannot be measured.
Confirmation of diagnosis by RHC is required in cases of symptomatic patients (NYHA class II and III) with mild PH as assessed by Doppler echocardiography (see above for definition) to identify subjects needing further diagnostic and therapeutic procedures. The assessment of PWP may allow the distinction between arterial and venous PH in patients with concomitant left heart diseases.
RHC is important also in patients with definite moderate-to-severe PAH because the haemodynamic variables have prognostic relevance.2
Elevated mean RAP, mean PAP and reduced cardiac output and central venous O2 saturation identify IPAH patients with the worst prognosis. Haemodynamic measurements have been used to estimate the natural history of IPAH in an individual patient by the use of a prediction equation2 that has also been utilised for assessing the long-term effects of new treatments on survival.76–78 However, this formula has been derived by patients on conventional therapy followed up almost 15–20 years ago that may not represent an appropriate "control" group for current PAH populations.
Uncontrolled studies have suggested that long-term administration of calcium-channel blockers (CCB) prolongs survival in the rare case of acutely responsive patients compared with unresponsive patients.79 It is generally accepted that patients who may benefit from long-term CCB can be identified by an acute vasodilator challenge performed during RHC.80 However, it has been proposed that the definitive recognition of patients who benefit from CCB treatment requires both (1) the demonstration of a positive acute vasoreactive response and (2) the confirmation of a sustained response to long term treatment to CCB.81
Acute vasodilator testing should only be done using short-acting pulmonary vasodilators at the time of the initial RHC in experienced centres to minimise the potential risks.82 Currently the agents used in acute testing are intravenous (iv) prostacyclin or adenosine and inhaled nitric oxide.83,84 Half-lives, dose ranges, increments and duration of administration for these compounds are provided in Table 5.
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A positive acute vasoreactive response (positive acute responders) is defined as a reduction of mean PAP ⩾10 mmHg to reach an absolute value of mean PAP ⩽40 mmHg with an increase or unchanged cardiac output.11,81,85 Generally, only about 10–15% of IPAH will meet these criteria.81,83 Positive acute responders are most likely to show a sustained response to long-term treatment with high doses of CCB and are the only patients that can safely be treated with this type of therapy. An empiric treatment with CCB without acute vasoreactivity test is strongly discouraged due to possible severe adverse effects.
Positive long-term responders to high dose CCB treatment are defined as patients being in NYHA functional class I or II with near normal haemodynamics after several months of treatment with CCB alone. Only about a half of IPAH positive acute responders are also positive long-term responders81 to CCB and only in these cases the continuation of CCB as single treatment is warranted.
The usefulness of acute vasoreactivity tests and long-term treatment with CCB in patients with PAH associated with underlying processes, such as CTD or congenital heart disease, is less clear as compared to IPAH.81,86 However, experts suggest also in these cases to test patients for acute vasoreactivity and to look for a long-term response to CCB in appropriate subjects.
Lung biopsy
Open or thoracoscopic lung biopsy entails substantial risks of morbidity and mortality. Because of the low likelihood of altering the diagnosis and treatment, routine biopsy is discouraged.
Assessment of severity
Several variables have been shown to predict prognosis in IPAH when assessed at baseline or after targeted treatments.71 Very little information is available in other conditions such as PAH associated with CTD, congenital systemic to pulmonary shunts, HIV infection or portal hypertension. In these circumstances, additional factors may contribute to the overall outcome. In fact, PAH associated with CTD disorders has a worse prognosis than IPAH patients, whereas patients with PAH associated with congenital systemic-to-pulmonary shunts have a more slowly progressive course than IPAH patients.
In practice, the prognostic value of a single variable in the individual patient may be less than the value of multiple concordant variables (Table 6).
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Clinical variables
Among clinical variables, baseline NYHA functional classification has a definite prognostic predictive value in patients with IPAH on conventional treatment.2 This predictive value is conserved when NYHA classification is assessed either before or 3 months after the initiation of epoprostenol treatment.77,87 History of right heart failure before the initiation of epoprostenol treatment has a negative predictive value.87 The World Health Organisation (WHO) classification proposed in Evian is an adaptation of the NYHA system for PAH and many clinicians refer to both classifications which are nearly identical as NYHA/WHO functional classification (Table 7).11,12
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Exercise capacity
Several authors have shown that the 6MWT is of great prognostic value in PAH: Miyamoto et al.68 showed that patients with IPAH walking less than 332 m had a significantly lower survival rate than those walking farther. In another study it has been calculated that there is an 18% reduction in the risk of death per additional 50 m walked in patients with IPAH.73 Preliminary data show also that arterial oxygen desaturation >10% during 6MWT increases mortality risk 2.9 times over a median follow-up of 26 months.73 Patients in NYHA functional class III or IV walking ⩽250 m before the initiation of epoprostenol or <380 m after three months of epoprostenol treatment portend a worst prognosis as compared to patients walking farther.87 Absolute change of 6MWT distance with epoprostenol has not been found to be of prognostic value.
Peak VO2 <10.4 ml/kg/min as assessed by CPET is correlated with a worse prognosis in PAH patients.69
Echocardiographic parameters
The presence and size of a pericardial effusion as assessed by TTE has a clear prognostic relevance in patients with IPAH.88,89 In addition, right atrial size and left ventricular eccentricity index are predictive of the outcome of IPAH subjects.89
Doppler right ventricular90 index, i.e. Tei index, is a variable which assesses both systolic and diastolic function of the right ventricle and has been found to have prognostic relevance in PAH.91
Haemodynamics
Elevated mean RAP and PAP at baseline, as well as reduced cardiac output and central venous O2 saturation, identify IPAH patients with a worst prognosis.2 Patients with a positive acute response to vasoreactivity tests have a better prognosis when compared to non-responders.79,83,92
On univariate analysis, the baseline haemodynamic variables associated with a poor outcome in IPAH patients subsequently treated with epoprostenol are reported to be RAP >12 mmHg, and mean pulmonary artery pressure <65 mmHg87 even if this last finding has not been confirmed by other series.77 After 3 months of epoprostenol, a fall in PVR <30% relative to baseline is associated with a poor prognosis.87
Blood tests
Hyperuricaemia occurs with high frequency in patients with PH and correlates with haemodynamic abnormalities, e.g. elevated RAP and increased mortality in IPAH.93 Brain natriuretic peptide is elevated in right ventricular pressure overload and correlates with severity of right ventricular dysfunction and mortality in PAH.94
Additional neurohormonal plasma levels correlate with survival e.g. norepinephrine95 and ET-1.96 Recently troponin97 levels both at baseline and after targeted treatments have been found to have prognostic relevance in PAH patients.
Treatment
The treatment of PAH has been traditionally characterised by few and difficult options.98 Recently, we have faced a dramatic change from the slow progress in the past decades to the remarkable number of randomised controlled trials (RCT) accomplished in the last few years. However we have also inherited different treatments that are generally accepted to be efficacious (e.g. oral anticoagulants, oxygen, CCBs), although not supported by RCT and not formally approved by Regulatory Agencies for the specific PAH indication.
The objective of this section is to review each form of therapy according to the Level of Evidence classification as suggested by the Committee for Practice Guidelines of the European Society of Cardiology.16 In addition, we will provide the Grade of Recommendation16 that will take into account the clinical efficacy of treatments that, for different reasons, have not been tested in RCTs such as oral anticoagulants, oxygen, CCBs, balloon atrial septostomy and/or lung transplantation. Furthermore, we will provide information concerning current country-specific regulatory approval and labelling for each compound. Finally, we will propose an evidence-based treatment algorithm85 that is intended to provide a guide to the selective use of each form of therapy.
Introduction to level of evidence and grade of recommendation
The grading system for the Level of Evidence is substantially based on the number of favourable RCTs performed with a given treatment strategy16 (Table 8) and has been adapted to the specific requirements of a rare disease. The only difference is that we did not include in category B "non-randomised studies" because all these studies in PAH are rather small therefore they are included in category C. In category B we included the wording "multiple randomised clinical trials with heterogeneous results" because this situation may happen (and has happened) and this definition is more comprehensive even if the final result is that "a single randomised clinical trial" resulted positive. The analysis takes into consideration the studies and the RCTs on PAH patients published in peer-reviewed journals or presented in recent major meetings.
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The grading system for the Level of Evidence based on the number of RCTs may present some limitations that need to be taken into account and possibly corrected.99 In fact, the level of evidence may change over time as a result of additional studies performed. In addition, the grading system does not address the sample sizes of the RCTs as "small" RCTs are given the same weight as larger ones. Moreover, the Level of Evidence for efficacy should not be confused with the Level of Clinical Efficacy, which depends on the net pharmacodynamic effects of the compound and on possible side effects and shortcomings (e.g. complexity of the route of administration). For example, a treatment strategy with better results but with only one or no RCTs is rated respectively B or C, as compared with a therapy with poorer results and greater side effects assessed in more than one RCT that can be rated as A. Also regulatory agencies may grant approval to a given treatment on the basis of a single RCT with an appropriate sample size and pre specified adequate statistical requirements.
Accordingly, the Grade of Recommendation (Table 9) was based on the Level of Clinical Efficacy that is expected from the therapeutic procedure.
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Finally, both components Grade of Recommendation and Level of Evidence are provided in order to give a complete profile for each treatment (Table 10). No grade of recommendation is given for drugs that are currently available only for patients enrolled in RCTs. Country-specific regulatory approval status and labelling for each compound is also provided (Table 11).
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General measures
General measures include strategies devoted to limit the deleterious impact of some circumstances and external agents on patient with PAH. As for other clinical conditions, the impact of these measures has not been tested scientifically and the recommendations are based on the experts' opinion.
Grade of Recommendation=IIa; Level of Evidence=C
Physical activity – It is unclear whether physical activity may have a negative impact on the evolution of PAH. However, potentially hazardous symptoms like severe dyspnoea, syncope and chest pain should be clearly avoided. Exercise should be limited to a symptom-free level in order to maintain adequate skeletal muscles conditioning. Physical activity after meals or in extreme temperatures should be avoided. Appropriate adjustments of daily activities may improve quality of life and reduce the frequency of symptoms.
Travel/altitude – Hypoxia may aggravate vasoconstriction in PAH patients and it is advisable to also avoid mild degrees of hypobaric hypoxia that start at altitudes between 1500 and 2000 m. Commercial airplanes are pressurised to equivalent altitude between 1600 and 2500 m and supplemental oxygen in PAH patients should be considered. Before planning to travel, information on nearest PH clinics should be collected.
Prevention of infections – Patients with PAH are susceptible to develop pneumonia that is the cause of death in 7% of cases. Pulmonary infections are poorly tolerated and need to be promptly recognised and treated. Vaccine strategies are recommended for influenza and pneumococcus pneumonia. Any persistent fever in patients with iv catheter for continuous administration of epoprostenol should raise the suspicion of catheter infection.
Pregnancy, birth control and post-menopausal hormonal therapy100 – Pregnancy and delivery in PAH patients are associated with an increased rate of deterioration and death.101,102 Even if successful pregnancies have been reported in IPAH patients,103 an appropriate method of birth control is highly recommended in women with childbearing potential. There is consensus among guidelines from the American Heart Association, and the American College of Cardiology which recommend that pregnancy be avoided or terminated in women with cyanotic congenital heart disease, PH, and Eisenmenger syndrome. The Expert consensus document of the ESC on the management of cardiovascular diseases during pregnancy outlines that severe pulmonary vascular diseases has long been known to carry a maternal mortality of 30–50%.104 However, there is no agreement among experts on the most appropriate birth control method in these subjects. The safety of hormonal contraception is questioned for its influence on prothrombotic changes. On the other hand, the current availability of low-oestrogen dose products, and concomitant oral anticoagulant treatment may limit the risk of these agents. In addition recent studies of large numbers of patients failed to reveal any relationship between intake of hormonal contraceptive agents and PAH.105 Some experts suggest the use of oestrogen-free products or surgical sterilisation or barrier contraceptives. It is not clear if the use of hormonal therapy in post-menopausal women with PAH is advisable or not. Probably it can be suggested only in case of intolerable menopausal symptoms and in conjunction with anticoagulation.
Haemoglobin levels – Patients with PAH are highly sensitive to reductions in haemoglobin levels. Any kind of mild anaemia should be promptly treated. On the other hand, patients with long-standing hypoxia, such as those with right-to-left shunts, tend to develop erythrocytosis with elevated levels of haematocrit. In these circumstances, phlebotomies are indicated (see section on Eisenmenger syndrome) if haematocrit is above 65% in symptomatic patients (headache, poor concentration) to reduce adverse effects of hyperviscosity.106
Concomitant medications – Care is needed to avoid drugs that interfere with oral anticoagulants or increase the risk of gastrointestinal bleeding. Even if non-steroid anti-inflammatory drugs seem not to be associated to PAH in a case-control study,105 their use may further reduce glomerular filtration rate in patients with low cardiac output and pre-renal azotaemia. Anorexigens that have been linked to the development of PAH are no longer available on the market. The effects of the new generation serotonin-related anorexigens are unknown but no reports of pulmonary-related side effects are available up to now. The efficacy of current treatments for chronic "biventricular" heart failure like ACE-inhibitors and beta-blockers has not been confirmed in patients with PAH.107 On the other hand, the empiric use of these treatments, even at low doses, may result in severe side effects like hypotension and right heart failure and should be discouraged.
Psychological assistance – Patients with PAH have a median age of about 40 years and exercise limitation may interfere considerably with their previous life-style. In addition, information on the severity of the disease may be obtained from many non-professional sources. Such sources may not be up-to date or may be confusing or inappropriately explicit. For this reason, many PAH patients are affected by a variable degree of anxiety and/or depression that can have a profound impact on their quality of life. The role of the PAH expert is important in supporting patients with adequate information (breaking bad news)108 and in referring them to psychologists or psychiatrists when needed. Also support groups for patients and families coordinated or not by psychologists or psychiatrists are useful in improving the understanding and the acceptance of the disease condition.109
Elective surgery – Even if appropriate studies are lacking it is expected that elective surgery has an increased risk in patients with PAH. In addition, the risk should increase with the severity of NYHA functional class and in cases of thoracic and abdominal interventions. It is not clear which type of anaesthesia is advisable but probably epidural is better tolerated than general anaesthesia. The later should be performed by experienced anaesthetists with the support of PH experts for deciding the most appropriate treatment in case of complications. Patients on iv epoprostenol and subcutaneous treprostinil treatment should have fewer problems than subjects on oral or inhaled treatments. The latter may suffer from temporary obstacles to the drug administration like fasting, general anaesthesia and assisted ventilation. In case a prolonged period of withdrawal is foreseen (more than 12–24 h) it is advisable to provisionally shift to iv treatments and revert to the original therapy subsequently. Anticoagulant treatment should be interrupted for the shortest possible time and deep venous thrombosis prophylaxis should be performed.
Pharmacological treatment
Oral anticoagulant treatment
The rationale for the use of oral anticoagulant treatment in patients with PAH is based on the presence of traditional risk factors for venous thromboembolism like heart failure and sedentary lifestyle as well as on the demonstration of thrombophylic predisposition41,42 and of thrombotic changes in the pulmonary microcirculation5,6 and in the elastic pulmonary arteries.110
The evidence for favourable effects of oral anticoagulant treatment in patients with IPAH or PAH associated to anorexigens is based on retrospective analysis of single centre studies.79,111,112 The design of these studies was not randomised and only IPAH and anorexigens-related PAH patients were included in the studies.
The target INR in patients with IPAH varies somewhat being 1.5–2.5 in most centres of North America and 2.0–3.0 in European centres.
The evidence supporting anticoagulation in patients with IPAH may be extrapolated to other patients with PAH provided that the risk/benefit ratio is carefully considered.
For example, it is generally thought that the risk of gastrointestinal bleeding may be higher in patients with PAH associated with CTD. Patients with PAH associated with congenital heart disease with intracardiac shunts are at increased risk of hemoptysis but they may be also at increased risk for paradoxical embolism in pulmonary artery and cerebral vein thrombosis.27 Patients with porto-pulmonary hypertension may be at increased risk for gastrointestinal bleeding due to the presence of varices and low platelet counts. Patients with PAH receiving therapy with chronic iv epoprostenol are anticoagulated in the absence of contraindications, due in part to the additional risk of catheter-associated thrombosis.
In recent RCTs, oral anticoagulants were administered in 51–86% of subjects. Interestingly, the highest prevalence of oral anticoagulant treatment was seen in the trials involving mainly IPAH patients in NYHA class III and IV, while the lowest prevalence was observed in the trial that included only patients with scleroderma.113 It should be emphasised that there is no evidence of any difference in efficacy of oral anticoagulant therapy according to functional class or other measures of severity.
Grade of Recommendation=IIa; Level of Evidence=C for IPAH. Grade of Recommendation=IIb; Level of Evidence=C for other PAH conditions.
Diuretics
Patients with decompensated right heart failure develop fluid retention that leads to increased central venous pressure, abdominal organ congestion, peripheral oedema and in advanced cases also ascites. Appropriate diuretic treatment in case of right heart failure allows clear symptomatic and clinical benefits in patients with PAH even if specific RCTs have not been performed. In the recent RCTs on new targeted treatments, 49–70% of patients were treated with diuretics. However, the lack of trials with specific classes of diuretics in PAH and the individual variability in responses leave the choice of the type and the dose of drug to be used in individual cases to the experience of the physician. Serum electrolytes and indices of renal function should be followed closely in patients receiving diuretic therapy.
Grade of Recommendation=I; Level of Evidence=C.
Oxygen
Most patients with PAH (except those with associated congenital heart disease) present with only mild degrees of arterial hypoxaemia at rest. The pathophysiological mechanisms in this case include a low mixed venous oxygen saturation caused by low cardiac output and only minimally altered ventilation perfusion matching. In some patients with profound hypoxaemia, a secondary opening of a patent foramen ovale can be found. In patients with PAH associated with congenital cardiac defects, hypoxaemia is related to reversal of left-to-right shunting and is refractory to increased inspired oxygen.
No consistent data are currently available on the effects of long-term oxygen treatment in PAH. Although improvement in PH with low-flow supplemental oxygen has been reported in some PAH patients, this has not been confirmed in controlled studies. However, it is generally considered important to maintain oxygen saturation at greater than 90% at all times. More controversial is the use of oxygen treatment in patients with PAH associated with cardiac shunts. In fact, in a controlled study on Eisenmenger syndrome patients, nocturnal oxygen therapy had no effect on haematological variables, quality of life or survival.114 In any case, the effect of continuous oxygen administration in these cases is unknown.
Grade of Recommendation=IIa; Level of Evidence=C
Digitalis and dobutamine
Since the depression of myocardial contractility seems to be one of the primary events in the progression of right heart failure, inotropic agents have been considered for the treatment of this condition. Short-term iv administration of digoxin in IPAH produces a modest increase in cardiac output and a significant reduction in circulating norepinephrine levels;115 however, no data are available on the effects of long-term treatment. Accordingly, the use of digitalis in PAH patients with refractory right heart failure is based primarily on the judgment of the physician rather than on scientific evidence of efficacy. Digitalis may be used in the rare PAH patients with atrial fibrillation or atrial flutter to slow ventricular rate. Digoxin was administered in 18–53% of patients enrolled in recent RCTs in PAH. Patients with end stage PAH are treated with iv dobutamine in most expert centres.116 This treatment often results in clinical improvement that may persist for a variable period of time, like in advanced left heart failure.
Grade of Recommendation=IIb; Level of Evidence=C.
Calcium-channel blockers
The evidence for medial hypertrophy in the small pulmonary arteries together with the reduction of PVR obtained by vasodilator drugs lead Paul Wood many years ago34 to elaborate the "vasoconstrictive" hypothesis as the basis for understanding the pathogenesis and the pathophysiology of IPAH. It is now clear that only in a minority of patients with IPAH a clinically significant reduction of pulmonary artery pressure associated with long-term clinical benefits can be achieved by the use of traditional vasodilators such as CCBs.
Favourable clinical and prognostic effects of high doses of CCBs in vasoreactive patients (see in the "Diagnosis and Assessment" section for definition of positive acute vasoreactive response) with IPAH have been shown in single centre, non-randomised, non-controlled studies.81,79,92,117 In these studies, the control group consisted of non-vasoreactive patients who may have a poorer prognosis "per se" as compared to vasoreactive individuals.92 However, there is no clear evidence for this hypothesis and it would appear unethical to withhold a therapy with high-dose CCB from a patient with a consistent reduction of pulmonary artery pressure by acute pharmacological testing and to perform a placebo-controlled clinical trial in these subjects.98
The CCBs that have been predominantly used in reported studies are nifedipine and diltiazem and the choice can be based upon the patient's heart rate at baseline (relative bradycardia favouring nifedipine, and relative tachycardia favouring diltiazem). The doses of these drugs that have shown efficacy in IPAH are relatively high i.e. up to 120–240 mg/day for nifedipine and 240–720 mg/day for diltiazem.79 It is advisable, in vasoreactive patients, to start with reduced doses (i.e. 30 mg of slow-release nifedipine bid or 60 mg of diltiazem tid) to be increased cautiously and progressively in the subsequent weeks to the maximal tolerated regimen. Limiting factors for dose increase are usually systemic hypotension and lower limb peripheral oedema. In some cases the addition of digoxin and/or diuretics can decrease the CCB side effects.119 There are no reports on efficacy, tolerability and effective doses of new generation CCBs such as amlodipine and flodpine.
As reported above ("Diagnosis and Assessment" section) generally, only about 10–15% of IPAH will meet the criteria for a positive acute vasoreactive response and only about half of them will also be clinical and haemodynamic long-term responders to CCB treatment. It is commonly accepted that only in these cases the continuation of CCBs as single treatment is warranted.
The usefulness of acute vasoreactivity tests and long-term treatment with CCBs in patients with PAH associated with CTD or congenital heart disease is less clear as compared to IPAH.81,86 However, experts suggest also in these cases to test patients for acute vasoreactivity and to treat cautiously the vasoreactive ones with oral CCB, monitoring them closely to determine both the efficacy and safety of such therapy.
Favourable results of long-term administration of high doses of calcium-channel antagonists have also been shown in children with IPAH.118
Grade of Recommendation=I; Level of Evidence=C for IPAH. Grade of Recommendation=IIb; Level of Evidence=C for other PAH conditions.
Synthetic prostacyclin and prostacyclin analogues
Prostacyclin is produced predominantly by endothelial cells and it induces potent vasodilatation of all vascular beds studied. This compound is the most potent endogenous inhibitor of platelet aggregation and it appears also to have both cytoprotective and antiproliferative activities.120 A dysregulation of the prostacyclin metabolic pathways has been shown in patients with PAH as assessed by a reduction of prostacyclin synthase expression in the pulmonary arteries and of prostacyclin urinary metabolites.13 Even if it is not clear if the dysregulation of the prostacyclin metabolic pathways has a causative role or is merely a consequence of PH, it represents a convincing rationale for the therapeutic use of prostacyclin in PAH patients. Initially, the clinical use of "prostacyclin", i.e. epoprostenol, was based on its pulmonary vasodilator properties that were shown in short term trials, and this acute effect is currently utilised in testing the vasoreactivity of pulmonary circulation. On the other hand, even patients who do not manifest acute vasodilator response to epoprostenol have shown clinical and haemodynamic improvement with chronic treatment.121 In fact, long-term iv administration of epoprostenol lowers PVR beyond the level achieved in the acute vasoreactivity tests.84 The hypotheses to explain these results are based on the inhibitory effects of prostacyclin on vascular growth, remodelling and obliteration that can facilitate the partial restoration of altered functions of the pulmonary microcirculation. However the precise mechanism of action of prostacyclin administration in PAH is unknown and is likely to be multifactorial. It may include relaxation of vascular smooth muscle cells (acute), inhibition of platelet aggregation, normalisation of aggregation abnormalities, dispersion of platelets aggregates, improvement of endothelial cells injury, inhibition of vascular cells migration and proliferation facilitating reverse remodelling of pulmonary vascular changes, improvement of pulmonary clearance of ET-1, direct inotropic effect, enhanced peripheral O2 utilisation by skeletal muscles and exercise haemodynamic improvements.13
The clinical use of prostacyclin in patients with PAH has been extended by the synthesis of stable analogues that possess different pharmacokinetic properties but share qualitatively similar pharmacodynamic effects. Originally, the experience on humans has been collected with epoprostenol that is a synthetic salt of prostacyclin.
Epoprostenol – Epoprostenol is available as a stable, freeze-dried preparation that needs to be dissolved together with an alkaline buffer (glycine), which allows a solution to be infused intravenously. Epoprostenol has a short half-life in the circulation (3–5 min), is rapidly converted to stable breakdown products or metabolites and is stable at room temperature for only 8 h; this explains why it needs to be administered by continuous iv route by means of infusion pumps (e.g. CADD® pump) and permanent tunnelised catheters (Hickman). The epoprostenol is kept cool by using cold packs, which allows the infusion to be changed daily. The use of subcutaneous catheters with reservoirs and transcutaneous needles (used in intermittent treatments) is discouraged.
The efficacy of continuous iv administration of epoprostenol (synthetic prostacyclin) has been tested in 3 unblinded, controlled clinical trials in IPAH121,122 and in PAH associated with the scleroderma spectrum of diseases,113 and is summarised in Table 12. Epoprostenol impro