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## Complete Summary

#### GUIDELINE TITLE

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.

#### BIBLIOGRAPHIC SOURCE(S)

Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T,
Olschewski H, Peacock A, Pietra G, Rubin LJ, Simonneau G, Priori SG,
Garcia MA, Blanc JJ, Budaj A, Cowie M, Dean V, Deckers J, Burgos EF,
Lekakis J, Lindahl B, Mazzotta G, McGregor K, Morais J, Oto A, Smiseth
OA, Barbera JA, Gibbs S, Hoeper M, Humbert M, Naeije R, Pepke-Zaba J.
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. Eur Heart
J 2004 Dec;25(24):2243-78. \[230 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15589643)

#### GUIDELINE STATUS

This is the current release of the guideline.

### \*\* REGULATORY ALERT \*\*

#### FDA WARNING/REGULATORY ALERT

**Note from the National Guideline Clearinghouse**: This guideline
references a drug(s)/intervention(s) for which important revised
regulatory and/or warning information has been released.

-   [October 18, 2007, PDE5 inhibitors, Viagra (sildenafil citrate),
    Levitra (vardenafil HCL), Cialis
    (tadalafil)](http://www.fda.gov/medwatch/safety/2007/safety07.htm#PDE5):
    The PRECAUTION and updated Adverse Reactions Sections of the
    approved product labeling for Viagra, Levitra, and Cialis were
    revised in response to reports of sudden decreases or loss of
    hearing.

-   [August 16, 2007, Coumadin
    (Warfarin)](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Warfarin):
    Updates to the labeling for Coumadin to include pharmacogenomics
    information to explain that people\'s genetic makeup may influence
    how they respond to the drug.

-   [June 8, 2007, Troponin-I
    Immunoassay](http://www.fda.gov/medwatch/safety/2007/safety07.htm#Architect):
    Class I Recall of all lots of the Architect Stat Troponin-I
    Immunoassay. The assay may report falsely elevated or falsely
    decreased results at and near a low level, which may impact patient
    treatment.

-   [October 6, 2006, Coumadin (warfarin
    sodium)](http://www.fda.gov/medwatch/safety/2006/safety06.htm#Coumadin):
    Revisions to the labeling for Coumadin to include a new patient
    Medication Guide as well as a reorganization and highlighting of the
    current safety information to better inform providers and patients.

-   [March 2, 2006, Tracleer
    (bosentan)](http://www.fda.gov/medwatch/safety/2006/safety06.htm#Tracleer):
    Changes to the prescribing information based on cases of
    hepatotoxity reported.

### COMPLETE SUMMARY CONTENT

 \*\* REGULATORY ALERT \*\*\
 SCOPE\
 METHODOLOGY - including Rating Scheme and Cost Analysis\
 RECOMMENDATIONS\
 EVIDENCE SUPPORTING THE RECOMMENDATIONS\
 BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS\
 CONTRAINDICATIONS\
 QUALIFYING STATEMENTS\
 IMPLEMENTATION OF THE GUIDELINE\
 INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT
CATEGORIES\
 IDENTIFYING INFORMATION AND AVAILABILITY\
 DISCLAIMER

### SCOPE

#### DISEASE/CONDITION(S)

Pulmonary arterial hypertension (PAH), including idiopathic pulmonary
hypertension (IPAH) and pulmonary hypertension associated with various
conditions such as connective tissue diseases, congenital
systemic-to-pulmonary shunts, portal hypertension and human
immunodeficiency virus (HIV) infection

#### GUIDELINE CATEGORY

Diagnosis\
Evaluation\
Management\
Treatment

#### CLINICAL SPECIALTY

Cardiology\
Critical Care\
Internal Medicine\
Pulmonary Medicine\
Thoracic Surgery

#### INTENDED USERS

Physicians

#### GUIDELINE OBJECTIVE(S)

-   To provide clear and concise indications for the practical use of
    the new clinical classification of pulmonary hypertension, and a
    brief description of new pathological classification and of the
    recent pathogenetic insights

-   To propose a logical sequence of investigations for aetiology
    identification, disease assessment, and follow-up

-   To provide an evidence-based treatment algorithm for patients with
    pulmonary arterial hypertension (PAH)

#### TARGET POPULATION

Patients with pulmonary arterial hypertension (PAH)

#### INTERVENTIONS AND PRACTICES CONSIDERED

**Diagnosis/Evaluation**

1.  Symptoms and physical evaluation

2.  Screening assessments when predisposing abnormalities are present

3.  Electrocardiography (ECG)

4.  Chest radiograph

5.  Transthoracic (TT) echocardiography

6.  Pulmonary function tests

7.  Arterial blood gases (ABG)

8.  Ventilation/perfusion lung scan

9.  High resolution computed tomography (HRCT)

10. Spiral computed tomography (CT)

11. Pulmonary angiography

12. Magnetic resonance imaging

13. Blood tests and immunology

    -   Thyroid function tests

    -   Routine biochemistry

    -   Thrombophilia screen including antiphospholipid antibodies

    -   Autoimmune screen (antinuclear antibodies including
        anti-centromere antibody, anti-SCL70, and ribonucleoproteins
        (RNP)

14. Human immunodeficiency virus (HIV) test

15. Abdominal ultrasound scan

16. Exercise test:

    -   6 minute walk test (6MWT)

    -   Cardiopulmonary exercise testing (CPET) with gas exchange
        measurement

17. Haemodynamics:

    -   Right heart catheterisation + vasoreactivity

    -   Blood pressure

    -   Right atrial pressure (RAP)

    -   Systolic, diastolic, and mean pulmonary artery pressure (PAP)

    -   Pulmonary capillary wedge pressure (PWP)

    -   Cardiac output

    -   Heart rate

    -   Pulmonary and systemic vascular resistance

    -   Arterial and mixed venous oxygen saturation

    -   Superior vena cava saturation

18. Acute calcium channel blocker (CCB) vasoreactivity test

19. Open or thoracoscopic lung biopsy (considered, but not recommended)

20. Liver function tests

21. Haematocrit

22. International normalized ratio (INR)

23. Prothrombin time (PT)

**General Measures for Management**

1.  Physical activity (limitations)

2.  Supplemental oxygen during travel/high altitude

3.  Influenza and pneumococcus pneumonia vaccines

4.  Appropriate contraception in women with childbearing potential

5.  Monitoring of haemoglobin levels and appropriate treatment for
    anemia of elevated haematocrit (e.g., phlebotomy)

6.  Monitoring of concomitant medications

7.  Provision of psychological assistance

8.  In the case of elective surgery, epidural anesthesia in preference
    to general anesthesia

**Pharmacological Treatment**

1.  Oral anticoagulant treatment

2.  Diuretics

3.  Oxygen therapy

4.  Digitalis

5.  Dobutamine

6.  Calcium channel blockers (CCBs)

    -   Nifedipine

    -   Diltiazem

7.  Synthetic prostacyclin and prostacyclin analogues

    -   Intravenous (iv) epoprostenol

    -   Subcutaneous treprostinil

    -   Oral sodium beraprost

    -   Inhaled or iv iloprost

8.  Endothelin-1 (ET-1) receptor antagonists

    -   Bosentan

    -   Sitaxsentan

    -   Ambrisentan

9.  Type 5 phosphodiesterase (PDE) inhibitors

    -   Sildenafil

10. Combination therapy

    -   Epoprostenol + bosentan

    -   Epoprostenol + sildenafil

**Interventional Procedures**

1.  Balloon atrial septostomy

2.  Lung transplantation

3.  Heart and lung transplantation

**Special considerations in the following specific conditions**:
Pediatric pulmonary artery hypertension, pulmonary arterial hypertension
associated with Eisenmenger syndrome, porto-pulmonary hypertension,
pulmonary arterial hypertension associated with HIV infection, pulmonary
arterial hypertension associated with connective tissue diseases, and
pulmonary veno-occlusive disease and pulmonary capillary
haemangiomatosis.

#### MAJOR OUTCOMES CONSIDERED

-   Sensitivity and specificity of diagnostic tests

-   Predictive value of diagnostic tests

-   Survival

-   Morbidity and mortality

-   Quality of life

-   Exercise capacity

-   Haemodynamics

-   Symptoms

-   New York Heart Association (NYHA) functional class

### METHODOLOGY

#### METHODS USED TO COLLECT/SELECT EVIDENCE

Searches of Electronic Databases

#### DESCRIPTION OF METHODS USED TO COLLECT/SELECT THE EVIDENCE

Not stated

#### NUMBER OF SOURCE DOCUMENTS

Not stated

#### METHODS USED TO ASSESS THE QUALITY AND STRENGTH OF THE EVIDENCE

Weighting According to a Rating Scheme (Scheme Given)

#### RATING SCHEME FOR THE STRENGTH OF THE EVIDENCE

**Levels of Evidence**

A.  Data derived from multiple randomised clinical trials or
    meta-analyses

B.  Data derived from a single randomised clinical trial or multiple
    trials with heterogeneous results

C.  Consensus of opinion of the experts and/or small studies,
    retrospective studies, registries

#### METHODS USED TO ANALYZE THE EVIDENCE

Systematic Review

#### DESCRIPTION OF THE METHODS USED TO ANALYZE THE EVIDENCE

**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 randomised controlled trials (RCTs) performed
with a given treatment strategy (see \"Rating Scheme for the Strength of
the Evidence\" above) and has been adapted to the specific requirements
of a rare disease. The only difference is that the Task Force did not
include in category B \"non-randomised studies\" because all these
studies in pulmonary arterial hypertension (PAH) are rather small;
therefore they are included in category C. In category B the Task Force
included the wording \"multiple randomised controlled trials with
heterogeneous results\" because this situation may happen (and has
happened) and this definition is more comprehensive even if the first
result is that \"a single randomised controlled 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.

#### METHODS USED TO FORMULATE THE RECOMMENDATIONS

Expert Consensus

#### DESCRIPTION OF METHODS USED TO FORMULATE THE RECOMMENDATIONS

Not stated

#### RATING SCHEME FOR THE STRENGTH OF THE RECOMMENDATIONS

**Class of Recommendations**

**Class I**: Evidence and/or general agreement that a given diagnostic
procedure/treatment is beneficial, useful, and effective

**Class II**: Conflicting evidence and/or a divergence of opinion about
the usefulness/efficacy of the treatment

-   **Class IIa**: Weight of evidence/opinion is in favour of
    usefulness/efficacy.

-   **Class IIb**: Usefulness/efficacy is less well established by
    evidence/opinion.

**Class III**\*: Evidence or general agreement that the treatment is not
useful/effective and in some cases may be harmful

\*Use of Class III is discouraged by the European Society of Cardiology
(ESC)

#### COST ANALYSIS

A formal cost analysis was not performed and published cost analyses
were not reviewed.

#### METHOD OF GUIDELINE VALIDATION

External Peer Review\
Internal Peer Review

#### DESCRIPTION OF METHOD OF GUIDELINE VALIDATION

Not stated

### RECOMMENDATIONS

#### MAJOR RECOMMENDATIONS

The class of recommendations (I-III) and level of evidence (A-C) are
defined at the end of the \"Major Recommendations\" field.

**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. Current
classification of PH is presented in the table below titled \"Clinical
Classification of Pulmonary Hypertension - Venice 2003.\" It is a result
of extensive discussion and represents a consensus accommodating the
European Society of Cardiology\'s 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 discussion found in the original
guideline document.

+-----------------------------------------------------------------------+
| **Table: Clinical Classification of Pulmonary Hypertension - Venice   |
| 2003**                                                                |
+=======================================================================+
| 1.  Pulmonary arterial hypertension (PAH)                             |
|                                                                       |
| > 1.1 Idiopathic (IPAH)                                               |
| >                                                                     |
| > 1.2 Familial (FPAH)                                                 |
| >                                                                     |
| > 1.3 Associated with (APAH):                                         |
| >                                                                     |
| > 1.3.1 Connective tissue disease (CTD)                               |
| >                                                                     |
| > 1.3.2 Congenital systemic pulmonary shunts                          |
| >                                                                     |
| > 1.3.3 Portal hypertension                                           |
| >                                                                     |
| > 1.3.4 Human immunodeficiency virus (HIV) infection                  |
| >                                                                     |
| > 1.3.5 Drugs and toxins                                              |
| >                                                                     |
| > 1.3.6 Other (thyroid disorders, glycogen storage disease,           |
| > Gaucher\'s disease, hereditary haemorrhagic telangiectasia,         |
| > haemoglobinopathies, myeloproliferative disorders, splenectomy)     |
| >                                                                     |
| > 1.4 Associated with significant venous or capillary involvement     |
| >                                                                     |
| > 1.4.1 Pulmonary veno-occlusive disease (PVOD)                       |
| >                                                                     |
| > 1.4.2 Pulmonary capillary haemangiomatosis (PCH)                    |
| >                                                                     |
| > 1.5 Persistent pulmonary hypertension of the newborn (PPHN)         |
+-----------------------------------------------------------------------+
| 2.  Pulmonary hypertension associated with left heart diseases        |
|                                                                       |
| > 2.1 Left-sided atrial or ventricular heart disease                  |
| >                                                                     |
| > 2.2 Left-sided valvular heart disease                               |
+-----------------------------------------------------------------------+
| 3.  Pulmonary hypertension associated with lung respiratory diseases  |
|     and/or hypoxia                                                    |
|                                                                       |
| > 3.1 Chronic obstructive pulmonary disease                           |
| >                                                                     |
| > 3.2 Interstitial lung disease                                       |
| >                                                                     |
| > 3.3 Sleep disordered breathing                                      |
| >                                                                     |
| > 3.4 Alveolar hypoventilation disorders                              |
| >                                                                     |
| > 3.5 Chronic exposure to high altitude                               |
| >                                                                     |
| > 3.6 Developmental abnormalities                                     |
+-----------------------------------------------------------------------+
| 4.  Pulmonary hypertension due to chronic thrombotic and/or embolic   |
|     disease                                                           |
|                                                                       |
| > 4.1 Thromboembolic obstruction of proximal pulmonary arteries       |
| >                                                                     |
| > 4.2 Thromboembolic obstruction of distal pulmonary arteries         |
| >                                                                     |
| > 4.3 Non-thromboembolic pulmonary embolism (tumour, parasites,       |
| > foreign material)                                                   |
+-----------------------------------------------------------------------+
| 5.  Miscellaneous                                                     |
|                                                                       |
| > Sarcoidosis, histiocytosis X, lymphangiomatosis, compression of     |
| > pulmonary vessels (adenopathy, tumour, fibrosing mediastinitis)     |
+-----------------------------------------------------------------------+

PH was previously classified into 2 categories: primary pulmonary
hypertension (PPH) or secondary PH depending on the absence or the
presence of identifiable causes or risk factors. The diagnosis of PPH
was one of exclusion after ruling out all causes of PH.

**[Diagnostic Strategy]{.underline}**

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 (see figure 2 of the
original guideline document):

I.  Clinical suspicion of PH

II. Detection of PH

III. PH clinical class identification

IV. PAH evaluation (type, functional capacity, haemodynamics)

**Clinical Suspicion of PH**

The clinical suspicion of PH should arise in any case of breathlessness
without overt signs of specific heart of 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
PH* can also include fatigue, weakness, angina, syncope, and abdominal
distension. Symptoms at rest are reported only in very advanced cases.

The *physical signs of PH* 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 pre-disposing
abnormalities some experts support a rationale for periodic screening
assessments to identify asymptomatic patients in the early stage of PH
(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 PH**

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 (TTE).

*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. However, the ECG has
inadequate sensitivity (55%) and specificity (70%) to be a screening
tool for detecting significant PAH. 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. 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 PVOD.

*TTE*

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=4v^2^ + RAP. RAP is either a standardised value or estimated value
from characteristics of the inferior vena cava or from jugular venous
distension. Tricuspid regurgitant jets can be assessed in the majority
(74%) of patients with PH. Most studies report a high correlation
(0.57-0.93) between TTE and right heart catheterisation (RHC)
measurements of PASP. However, in order to minimise false positives 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 [+]{.underline} 5 mmHg (range
15-57 mmHg). RVSP increases with age and body mass index. 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/sec (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 (New York Heart Association \[NYHA\] 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.

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.

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 (see
table above). 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 computed tomography (HRCT),
spiral computed tomography (CT), and pulmonary angiography.

*PFTs and Arterial Blood Gases*

PFTs and arterial blood gas sampling can identify the contribution of
underlying airway of parenchymal lung disease. Patients with PAH usually
have decreased lung diffusion capacity for carbon monoxide (DL~CO~)
(typically in the range of 40-80% predicted) and mild to moderate
reduction of lung volumes. The arterial oxygen tension (PaO~2~) is
normal or slightly lower than normal, and arterial carbon dioxide
tension (PaCO~2~) is decreased as a result of alveolar hyperventilation.
Chronic obstructive pulmonary diseases as a cause of hypoxic PH, is
diagnosed on the evidence of irreversible airflow obstruction, usually
by measuring the forced expired volume in one second (FEV1). These
patients often have a normal or increased PaCO~2~ together with airflow
limitation and increased residual volumes and reduced DL~CO~. Emphysema
is now diagnosed using HRCT. A decrease in lung volume together with a
decrease in DL~CO~ may indicate a diagnosis of interstitial lung disease
(ILD). Again the HRCT is the principle way of assessing the severity of
interstitial lung disease. If clinically suspected, screening overnight
oximetry and polysomnography 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). 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. A caveat is that
unmatched perfusion defects are also seen in veno-occlusive disease.
Such a patient requires careful further investigation (see the section
below titled \"HRCT of the Lung\"). In patients with parenchymal lung
disease the perfusion defects are *matched* by ventilation defects.

*HRCT of the Lung*

HRCT provides detailed views of the lung parenchyma and facilitates the
diagnosis of interstitial lung disease 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 interlobular septa suggest PVOD; additional findings
are lymphadenopathy, pleural shadows, and effusions. Diffuse bilateral
thickening of the interlobular septae and the presence of small,
centrilobular, poorly circumscribed nodular opacities suggest PCH.

*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.

Traditional pulmonary angiography is still required in the work-up of
CTEPH to better identify patients that can benefit from the intervention
of endarterectomy. Pulmonary angiography is more accurate in the
identification of distal obstruction 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. However, additional experience is needed before
introducing this tool in the routine assessment of patients with PAH.

**PAH 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 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-SCL 70, and
ribonucleoproteins (RNP). About one third of patients with IPAH have
positive but low antinuclear antibody titre ([\<]{.underline}1:80
dilutions). Patients with a substantially elevated antinuclear
antibodies 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. Portal
hypertension can be confirmed by the detection of an increased gradient
between free and occluded (wedge) hepatic vein pressure at the time of
right heart catheterisation (RHC) (see Porto-pulmonary hypertension).

*Exercise Capacity*

The objective assessment of exercise capacity in patients with PAH is an
important instrument for evaluating disease severity and treatment
effect. The most commonly used exercise tests for PH are the six-minute
walk test (6MWT) and cardiopulmonary exercise testing (CPET) with gas
exchange measurement.

The 6MWT is technically simple and inexpensive. It is predictive of
survival in IPAH and also correlates inversely with NYHA functional
status severity. 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. 6MWT is the traditional
\"primary\" end point for the great majority of controlled clinical
trials performed in PAH.

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 VO~2~, reduced peak work rate, reduced ratio of VO~2~
increase to work rate increase, reduced anaerobic threshold; and reduced
peak oxygen pulse; they show also increased volume of expired gas (VE)
and VCO~2~ slope representative of ventilatory insufficiency. Peak VO~2~
is correlated with the prognosis of PAH patients.

CPET has been used in recent multicentre trials, but it failed to
confirm improvements observed with 6MWT. 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 [\<]{.underline}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.

Elevated mean RAP, mean PAP, and reduced cardiac output and central
venous O~2~ 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 equation
that has also been utilised for assessing the long-term effects of new
treatments on survival. 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. It is
generally accepted that patients who may benefit from long-term CCB can
be identified by an acute vasodilator challenge performed during RHC.
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 of CCB.

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. Currently the agents used in
acute testing are intravenous (iv) prostacyclin or adenosine and inhaled
nitric oxide. Half-lives, dose ranges, increments, and duration of
administration for these compounds are provided in Table 5 in the
original guideline titled \"Route of administration, half-lives, dose
ranges, increments and duration of administration of the most used
substances on pulmonary vasoreactivity tests.\"

A positive acute vasoreactive response (*positive acute responders*) is
defined as a reduction of mean PAP [\>]{.underline}10 mmHg to reach an
absolute value of mean PAP [\<]{.underline}40 mmHg with an increase or
unchanged cardiac output. Generally, only about 10-15% of IPAH will meet
these criteria. 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 responders 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.
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. 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 (see
table below).

+-----------------------------------------------------------------------+
| **Table: Prognostic Parameters in Patients with IPAH**                |
+=======================================================================+
| Clinical parameters                                                   |
|                                                                       |
| -   NYHA functional classification                                    |
|                                                                       |
| -   NYHA functional class on chronic epoprostenol treatment           |
|                                                                       |
| -   History of right heart failure                                    |
+-----------------------------------------------------------------------+
| Exercise capacity                                                     |
|                                                                       |
| -   6MWT distance                                                     |
|                                                                       |
| -   6MWT distance on chronic epoprostenol treatment                   |
|                                                                       |
| -   Peak VO~2~                                                        |
+-----------------------------------------------------------------------+
| Echocardiographic parameters                                          |
|                                                                       |
| -   Pericardial effusion                                              |
|                                                                       |
| -   Right atrial size                                                 |
|                                                                       |
| -   Left ventricular eccentricity index                               |
|                                                                       |
| -   Doppler right ventricular (Tei) index                             |
+-----------------------------------------------------------------------+
| Haemodynamics                                                         |
|                                                                       |
| -   RAP                                                               |
|                                                                       |
| -   Mean PAP                                                          |
|                                                                       |
| -   Cardiac output                                                    |
|                                                                       |
| -   Mixed venous O~2~ saturation                                      |
|                                                                       |
| -   Positive acute response to vasoreactivity tests                   |
|                                                                       |
| -   Fall in PVR \<30% after 3 months of epoprostenol                  |
+-----------------------------------------------------------------------+
| Blood tests                                                           |
|                                                                       |
| -   Hyperuricaemia                                                    |
|                                                                       |
| -   Baseline Brain natriuretic peptide                                |
|                                                                       |
| -   Brain natriuretic peptide after 3 months therapy                  |
|                                                                       |
| -   Troponin - detectable, especially persistent leakage              |
|                                                                       |
| -   Plasma norepinephrine                                             |
|                                                                       |
| -   Plasma endothelin-1                                               |
+-----------------------------------------------------------------------+

**[Treatment]{.underline}**

The treatment of PAH has been traditionally characterised by few and
difficult options. Recently, there has been 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
there are now 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 (see \"Rating Scheme
for the Strength of the Evidence\" above) as suggested by the Committee
for Practice Guidelines of the European Society of Cardiology. In
addition, the Grade of Recommendation (see \"Rating Scheme for the
Strength of the Recommendations\") will be provided 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,
information will be provided concerning current country-specific
regulatory approval and labelling for each compound. Finally, an
evidence-based treatment algorithm will be proposed 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**

Both components Grade of Recommendation and Level of Evidence are
provided in order to give a complete profile for each treatment (see
table below). 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 in Table 11 of the original guideline document.

**Table: Grading of Recommendations and Level of Evidence for Efficacy
in IPAH**

  ------------------------------------------------------------------------------------
  **Treatment**            **Grade of                               **Level of
                           Recommendation**                         Evidence**
  ------------------------ ------------------ ---------- ---------- ------------------
                           **Ia**             **IIa**    **IIb**    

  General measures                            X                     C

  Oral anticoagulants^a^                      X                     C

  Diuretics                X                                        C

  Digoxin                                                X          C

  Oxygen^b^                                   X                     C

  CCBs^c^                  X                                        C

  Epoprostenol             X                                        A

  Treprostinil                                X                     B

  Iloprost (inhalation)                       X                     B

  Iloprost (iv)                               X                     C

  Beraprost                                              X          B

  Bosentan                 X^d^                                     A

  Sitaxsentan^e^                                                    B

  Ambrisentan^e^                                                    C

  Sildenafil               X^d^                                     A

  Combination therapy                                    X          C

  Balloon atrial                              X                     C
  septostomy                                                        

  Lung transplantation     X                                        C
  ------------------------------------------------------------------------------------

Notes\
^a^ IIa for IPAH, IIb for other PAH conditions\
^b^ If arterial oxygen saturation \<90%\
^c^ Only in patient responders to acute reactivity tests, I for IPAH,
IIb for other PAH conditions\
^d^ IIa B in NYHA class IV\
^e^ These drugs are currently available only for patients enrolled in
RCTs and no grade of recommendation is given.

**General Measures**

General measures include strategies devoted to limit the deleterious
impact of some circumstances and external agents on patients 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 1,500 and 2,000 meters.
Commercial airplanes are pressurised to equivalent altitude between
1,600 and 2,500 meters 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 therapy* -
Pregnancy and delivery in PAH patients is associated with an increased
rate of deterioration and death. Even if successful pregnancies have
been reported in IPAH patients, 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 European
Society of Cardiology (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%. 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. 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.

*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, their use may further reduce
glomerular filtration rate in patients with low cardiac output and
pre-renal azotemia. 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
angiotensin-converting enzyme (ACE)-inhibitors and beta-blockers has not
been confirmed in patients with PAH. 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) 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.

*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 latter 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 hours) 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 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 thrombophilic predisposition and of thrombotic
changes in the pulmonary microcirculation and in the elastic pulmonary
arteries.

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. The design of these
studies was not randomised and only IPAH and anorexigens-related PAH
patients were included in the studies.

The target International Normalized Ratio (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. 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. 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 the 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. 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; 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. 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**

*CCBs*

The evidence for medial hypertrophy in the small pulmonary arteries
together with the reduction of PVR obtained by vasodilator drugs led
Paul Wood many years ago 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. In
these studies, the control group consisted of non-vasoreactive patients
who may have a poorer prognosis \"per se\" as compared to vasoreactive
individuals. However, there is no clear evidence for this hypothesis and
it would appear unethical to withhold a therapy with a 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.

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).
It is advisable, in vasoreactive patients, to start with reduced doses
(i.e., 30 mg of slow-release nifedipine twice a day \[bid\] or 60 mg of
diltiazem three times a day \[tid\]) 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. There are no reports
on efficacy, tolerability, and effective doses of new generation CCBs
such as amlodipine and felodipine.

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. 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.

**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*

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 IPAH and in PAH associated with the scleroderma spectrum of diseases,
and is summarised in Table 12 of the original guideline document.
Epoprostenol improves symptoms, exercise capacity, and haemodynamics in
both clinical conditions and is the only treatment to be shown in RCTs
to improve survival in IPAH.

Recently two large series of IPAH patients treated with epoprostenol
have been reported. The data showed that survival was about 65% at three
years and it was related to the severity at baseline, as well as to the
three-month response to therapy. The authors suggested that lung
transplantation should be considered in a subset of patients who remain
in NYHA functional class III or IV or in those who cannot achieve a
significant exercise and haemodynamic improvement after three months of
epoprostenol therapy, or both.

Long-term treatment with epoprostenol is imitated at a dose ranging from
2 to 4 ng/kg/min and increased at a rate limited by side effects
(flushing, headache, diarrhoea, leg pain). Target doses for the first
two to four weeks is usually around 10 to 15 ng/kg/min and periodic dose
increases are then required to maximise efficacy and to maintain the
results because of possible tolerance to the drug. Optimal dose is
variable between individual patients ranging in the majority between 20
and 40 ng/kg/min, but the current strategy for increases is different
among centres. In two large recently published series of patients
treated with epoprostenol, mean dose was 21 [+]{.underline} 7 and 27
[+]{.underline} 8 ng/kg/min, respectively.

Adverse effects with chronic epoprostenol treatment are common and
include flushing, jaw pain, diarrhoea, headache, backache, foot and leg
pain, abdominal cramping, nausea, and rarely hypotension. The incidence
of side effects may relate to how aggressive the dose is initially up
titrated. Dose reduction is required only if the intensity is moderate
to severe. Recurrence of side effects may be experienced after dose
increases but usually they are mild and self-limiting over time without
dose changes. In some cases ascites has been reported that may be
related to an increased permeability of the peritoneal membrane induced
by epoprostenol. Adverse events related to the delivery system are more
serious and are essentially linked to pump malfunction, local site
infection, catheter obstruction, and sepsis. In two large series, 0.14
and 0.19 episodes of sepsis per patients-year were reported and 8 deaths
(2.8%) out of a total of 340 subjects were directly related to catheter
infections. Localised infections can also occur, such as small exit site
reactions, tunnel infections, and cellulitis. Rare events are
pneumothorax and haemothorax that occur during catheter insertion.
Abrupt interruption of the epoprostenol infusion should be avoided, as
this may, in some patients, lead to a rebound worsening of their PH with
symptomatic deterioration and even death. Management of patients on
chronic epoprostenol therapy requires a considerable infrastructure,
including experienced nurses and physicians.

Even if RCTs with epoprostenol have been performed only in IPAH and PAH
associated with scleroderma, favourable results have also been shown in
uncontrolled experiences in other subsets such as paediatric IPAH
systemic lupus erythematosus and other CTD, PAH associated with
congenital heart defects with systemic to pulmonary shunts either
repaired or not, in porto-pulmonary hypertension in PAH associated to
Gaucher\'s disease and to HIV infection. There is no consensus among
experienced physicians on the effectiveness of epoprostenol in patients
with inoperable CTEPH even if some positive effects have been shown.

Epoprostenol in Europe has not been registered through the centralised
procedure of the European Union (European Agency for the Evaluation of
Medicinal Products \[EMEA\]) but is approved in different European
countries on a local basis for IPAH in NYHA class III and IV.
Epoprostenol is approved by the Food and Drug Administration (FDA) in
the USA and Canada for IPAH and PAH associated with CTD in NYHA class
III and IV.

**Grade of Recommendation = I; Level of Evidence = A for IPAH and PAH
associated with CTD\
Grade of Recommendation = IIa; Level of Evidence = C for other PAH
conditions**

Four RCTs have been performed with prostacyclin analogues and are
summarised in Table 13 of the original guideline document.

*Trepostinil* - Trepostinil is a tricyclic benzidine analogue of
epoprostenol, with sufficient chemical stability to be administered at
ambient temperature in a physiological solution. These characteristics
allow the administration of the compound by iv as well as subcutaneous
route. The subcutaneous administration of treprostinil can be
accomplished by micro-infusion pumps (Mini-Med pump®) and small
subcutaneous catheters similar to those utilised for the administration
of insulin in diabetic patients. In this case, the problems linked to a
permanent central venous line, such as infections, are avoided and the
management of the system is much simpler.

The effects of continuous subcutaneous administration of treprostinil in
PAH were studied in the largest worldwide RCT performed in this
condition and showed improvements in exercise capacity, haemodynamics,
and clinical events. The greatest exercise improvement was observed in
patients who were more compromised at baseline and in subjects who could
tolerate upper quartile dose (dose \>13.8 ng/kg/min). One earlier pilot
controlled study was performed with treprostinil in 26 PAH patients and
showed trends in the improvement of 6MWD and in the reduction of PVR.

Infusion site pain was the most common side effects of treprostinil
leading to discontinuation of the treatment in 8% of cases on active
drug and limiting dose increase in an additional proportion of patients.
Overall mortality was 3% and no difference was detected between
treatment groups. Preliminary reports have shown the possibility to
transition patients from iv epoprostenol to subcutaneous treprostinil.

In 2002, the FDA approved the use of treprostinil in NYHA class II, III,
and IV patients with PAH.

**Grade of Recommendation = IIa; Level of Evidence = B for PAH**

*Sodium beraprost* - Sodium beraprost is the first chemically stable and
orally-active prostacyclin analogue. It is absorbed rapidly in fasting
conditions, peak concentration is reached after 30 min, and elimination
half-life is 35-40 min after single oral administration.

The orally-active prostacyclin analogue beraprost has been evaluated in
PAH patients in two RCTs in Europe and in the United States. In the
first study the drug was administered orally four times a day at the
highest tolerated dose (median dose 80 micrograms four times a day
\[qid\]) and an increase in exercise capacity was seen only in IPAH
subjects after 3 months. In the second randomised trial that lasted 12
months, improvement in exercise capacity was observed at 3 and 6 months
but not thereafter. No haemodynamic improvements were observed in the
long-term study and clinical events were reduced only at the 6 month
evaluation.

Beraprost sodium has been approved in Japan and South-Korea for IPAH but
its development appears to have been stopped in the USA and in Europe.

**Grade of Recommendation = IIb; Level of Evidence = B for IPAH**

*Inhaled iloprost* - Iloprost is a chemically stable prostacyclin
analogue available for iv, oral and aerosol administration. Iloprost is
a chemically stable prostacyclin analogue available for iv, oral and
aerosol administration. Inhaled therapy for PAH is an attractive concept
that has the theoretical advantage to be selective for the pulmonary
circulation. In fact, since intra-acinar pulmonary arteries are closely
surrounded by alveolar units, it is possible to vasodilate these vessels
by an alveolar deposition of vasodilators. It is critical that
aerosolised particles be small enough (diameter 3-5 micrometers) to
ensure alveolar deposition.

After a single inhalation of iloprost a reduction of 10-20% of mean
pulmonary artery pressure was observed and lasted for 45-60 min. The
short duration of action requires frequent inhalations (from 6 to 12
times daily) to obtain a persistent effect with long-term
administration. With Jet nebulisers, the duration of each inhalation
takes about 15 min; with alternative devices such as ultrasound
nebulisers the inhalation time can be reduced to about 5 min.

Inhaled iloprost has been evaluated in one RCT in which daily repetitive
iloprost inhalations (6-9 times 2.5-5 micrograms/inhalation, median 30
micrograms daily) were compared to placebo inhalation in patients with
PAH and CTEPH (see table 13 of the original guideline document). The
study showed an increase in exercise capacity and improvement in
symptoms, PVR, and clinical events in IPAH patients only. Overall,
inhaled iloprost was well tolerated: cough occurred more frequently in
the iloprost group as well as flushing and headache.

A long-term, uncontrolled study on 25 patients with IPAH treated for at
least one year with inhaled iloprost 100-150 micrograms daily has been
also reported: the data showed a mean increase of 85 meters of the six
minutes walk, a reduction of 7 mmHg in mean pulmonary artery pressure,
and an increase in cardiac index of 0.6 L/min/m^2^. In a small study on
8 patients with PH and lung fibrosis, the acute administration of
inhaled iloprost caused marked pulmonary vasodilation with maintenance
of gas exchange and systemic arterial pressure showing a possible
usefulness in this particular subset of patients.

Inhaled iloprost treatment has been approved by the EMEA in Europe for
NYHA Class III IPAH and in Australia and New Zealand for PAH and
non-operable CTEPH class III and IV.

**Grade of Recommendation = IIa; Level of Evidence = B for IPAH**

*Intravenous iloprost* - Continuous iv administration of iloprost
appears to be as effective as epoprostenol in a small series of patients
with PAH and CTEPH. Iloprost presents the advantage of being stable at
room temperature and does not need to be reconstituted and refrigerated.

Continuous iv administration has been approved in New Zealand for NYHA
class III and IV PAH.

**Grade of Recommendation = IIa; Level of Evidence = C for PAH**

*Endothelin-1 (ET-)1 Receptor Antagonists*

Currently three RCTs with endothelin-1 receptor antagonists have been
performed in PAH patients at the time of writing (see Table 14 of the
original guideline document):

*Bosentan* - Bosentan is an oral active dual ET~A~ and ET~B~-receptor
antagonist and is the first molecule of this class of drugs to be
synthesised. Bosentan has been evaluated in PAH in two RCTs that have
shown improvement in exercise capacity, functional class, haemodynamics,
echocardiographic, and Doppler variable, and time to clinical worsening.
In the larger BREATHE-1 study, patients were randomised 1:1:1 to receive
placebo or 62.5 mg of bosentan twice daily for 4 weeks followed by
either bosentan 125 mg bid or 250 mg bid for a minimum of 12 weeks.
Although both bosentan dosages induced a significant treatment effect,
the placebo-corrected improvement tended to be more pronounced for the
250 mg bid than for the 125 mg bid dosage (+54 meters and +35 meters of
6MWT treatment effect, respectively). However, no formal dose response
for efficacy could be ascertained. Although a similar treatment effect
was achieved in patients with IPAH and in those with PAH associated with
scleroderma, bosentan improved the walking distance from baseline in
IPAH patients (+46 meters in the bosentan group versus -5 meters in the
placebo group) whereas it prevented walk distance deterioration in the
scleroderma patients (+3 meters in the bosentan group versus -40 meters
in the placebo group). Increases in hepatic aminotransferases occurred
in 10% of the subjects and were found to be dose-dependent and
reversible after dose reduction or discontinuation. In fact, abnormal
hepatic function was more frequent and severe in the 250 mg dose group
and a decrease in transaminase concentrations was observed in all cases
in which the bosentan dose was reduced. Based on these results, the
recommended target therapeutic dose of bosentan was confirmed as 125 mg
twice daily. The most likely mechanism for the liver enzyme changes with
bosentan treatment is a dose-dependent competition by bosentan and its
metabolites with the biliary excretion of bile salts, resulting in a
retention of bile salts that can be cytotoxic to hepatocytes.

Twenty-nine patients received bosentan in an extension study: patients
assessed at month 6 maintained the improvement in walk distance, and
long-term treatment with bosentan for \>1 year was associated with an
improvement in haemodynamic parameters and NYHA functional class.

Oral bosentan has also recently been proposed as a transition therapy in
patients displaying severe and/or unbearable side effects of prostanoid
therapy including sepsis with iv epoprostenol.

An open-label uncontrolled single and multiple-dose study has been
performed in children 4-17 years of age with PAH (BREATHE-3) to assess
pharmacokinetics, tolerability, and safety of oral bosentan. In this
preliminary study a significant improvement in haemodynamics was
observed after 12 weeks of treatment in the 18 enrolled children either
with bosentan alone or in combination with epoprostenol.

Due to the potential increase in liver enzymes, the FDA requires that
liver function tests be performed at least monthly in patients receiving
bosentan. In addition, the EMEA recommended to monitor monthly liver
function tests, and currently these data are collected in an
internet-based program (TRAX). Also, the haemoglobin/haematocrit should
be checked regularly because bosentan use may also be associated with
the development of anaemia, which seems typically to be mild. Fluid
retention and lower limb oedema have been also reported in patients
treated with bosentan. Careful attention must be paid to the use of
adequate contraception in women of childbearing age due to the potential
teratogenic effects of bosentan. In addition bosentan may decrease the
efficacy of hormonal contraceptive techniques, and for this reason they
should not be used alone. There is concern that the endothelin
antagonists as a class may be capable of causing testicular atrophy and
male infertility. Younger males who may consider conceiving should be
counselled regarding this possibility prior to taking these drugs.

Bosentan has been approved for the treatment of NYHA class III and IV
PAH patients in the USA and Canada. In Europe it has been approved by
the EMEA for the treatment of NYHA class III patients specifying that
efficacy has been demonstrated only in IPAH patients and PAH associated
with scleroderma without significant lung fibrosis.

**Grade of Recommendation = I; Level of Evidence = A for NYHA class III
IPAH and PAH associated with scleroderma without significant lung
fibrosis\
Grade of Recommendation = IIa; Level of Evidence = B for NYHA class IV
IPAH and PAH associated with scleroderma without significant lung
fibrosis**

*Sitaxsentan* - Sitaxsentan, a selective orally-active ET~A~-receptor
antagonist has been assessed in PAH patients in one RCT on 178 patients
with NYHA class II, III, and IV PAH. Aetiology included IPAH and PAH
associated with CTD or congenital heart diseases. Patients were
randomised 1:1:1 to placebo, sitaxsentan 100 mg, or sitaxsentan 300 mg
given orally once daily for 12 weeks. The study demonstrated
improvements in exercise capacity, haemodynamics, and clinical events.
Incidence of abnormal liver function tests, which reversed in all cases,
was 0% for 100 mg, and 9.5% for 300 mg. An additional pilot study with
this compound in 20 PAH patients has shown similar results.

Sitaxsentan may increase the INR or prothrombin time (PT), due to the
inhibition of CYP2C9 P450 enzyme, the principal hepatic enzyme involved
in the metabolism of warfarin. This interaction can be managed by
reducing the warfarin dose to achieve the desired INR.

A second RCT is currently ongoing with sitaxsentan to further explore
both efficacy and side effects profile and to achieve approval from
regulatory agencies. No grade of recommendation is given for sitaxsentan
because it is currently available only for patients enrolled in RCTs.

**Grade of Recommendation = Currently not given; Level of Evidence = B**

*Ambrisentan* - Ambrisentan, a selective orally-active ET~A~-receptor
antagonist has thus far been evaluated in a pilot blinded
dose-comparison study in 64 PAH patients. Preliminary results show
improvements in exercise capacity and haemodynamics that appear similar
to the results observed with the other ET-1 receptor antagonists. Two
RCTs are currently ongoing with ambrisentan to further explore both
efficacy and side effects profile to achieve approval from regulatory
agencies. No grade of recommendation is given for ambrisentan because it
is currently available only for patients enrolled in RCTs.

**Grade of Recommendation = Currently not given; Level of Evidence = C**

*Type 5 Phosphodiesterase (PDE) Inhibitors*

*Sildenafil* - Sildenafil is an orally-active, potent, and selective
inhibitor of cyclic guanosine monophosphate (cGMP)-PDE type 5 that
exerts its pharmacological effect by increasing the intracellular
concentration of cGMP. The increase of this nucleotide induces
relaxation and antiproliferative effects on vascular smooth muscle
cells. PDE-5 is selectively abundant in the pulmonary circulation, and
PDE-5 gene expression and activity are increased in chronic PH. This
suggests that sildenafil may have a preferential effect of the lung
vasculature.

A number of uncontrolled studies have reported favourable effects of the
orally-active type 5 PDE inhibitor sildenafil in PAH, CTEPH and PH
associated with lung fibrosis. The drug at a dose ranging from 25 to 75
mg tid appears to improve both cardiopulmonary haemodynamics and
exercise capacity. These studies report relatively few minor side
effects (e.g., headache, nasal congestion, and visual disturbances). A
RCT with a cross-over design has been recently published: sildenafil
25-100 mg tid administered in 22 NYHA II and III PAH patients improved
symptoms after 6 weeks, the exercise capacity as assessed by the
Naughton protocol on the treadmill (from 475 [+]{.underline} 168 sec of
exercise time at the end of placebo phase to 686 [+]{.underline} 224 sec
at the end of sildenafil phase), and the haemodynamics. The results of a
pivotal RCT of 278 NYHA II and III PAH patients were recently presented
at the American College of Chest Physicians meeting at the end of
October 2004. The data show that mean placebo-corrected treatment
effects on 6MWT were around 45 meters for 20, 40, and 80 mg sildenafil 3
times daily. All sildenafil doses reduced mean PAP at week 12 by about 3
to 5 mmHG. At the time of writing sildenafil treatment has not yet been
approved by any regulatory agency for treatment of PAH. Currently,
treatment with sildenafil should be considered in patients with PAH, who
have failed or are not candidates for other approved therapies.

**Grade of Recommendation = I; Level of Evidence = A**

*Combination Therapy*

Combination therapy is an attractive option to address the multiple
pathophysiological mechanisms that are present in PAH. Combination
therapy can be pursued by the simultaneous initiation of two (or more)
treatments or by the addition of a second (or third) treatment to a
previous therapy that may be considered insufficient. Which of these two
strategies is the best choice is currently unknown.

The efficacy and safety of the concurrent initiation of bosentan and
epoprostenol were investigated in 33 NYHA class III and IV PAH
randomised either to an epoprostenol + placebo group or an
epoprostenol + bosentan group (BREATHE-2). Improved haemodynamics,
exercise capacity, and functional class were observed in both groups.
Data shows that there was a trend for a greater (though non-significant)
improvement in all haemodynamic parameters in the epoprostenol +
bosentan group. However, an increase of adverse events was observed in
the combination group as compared to epoprostenol alone.

Further RCT is ongoing or planned that will explore the effects of the
addition of sildenafil to patients already on epoprostenol.

In patients with PAH who were deteriorating despite chronic treatment
with non-parenteral prostanoids, addition of bosentan or sildenafil to
the ongoing treatment resulted in favourable improvements in pulmonary
haemodynamics and exercise capacity in uncontrolled studies.

**Grade of Recommendations = IIb; Level of Evidence = C**

**Interventional Procedures**

*Balloon Atrial Septostomy*

Several experimental and clinical observations have suggested that an
inter-atrial defect might be of benefit in the setting of severe PH. In
fact the presence of an atrial septal defect would allow right-to-left
shunting to increase systemic output that, in spite of the fall in
systemic arterial oxygen saturation will produce an increase in systemic
oxygen transport. Furthermore, the shunt at the atrial level would allow
decompression of the right atrium and right ventricle, alleviating signs
and symptoms of right heart failure.

The role of balloon atrial septostomy in the treatment of PAH patients
is uncertain because its efficacy has been reported only in small series
and case reports, totalling approximately 120 published cases. In most
circumstances, this intervention has been performed in severely ill
patients as a palliative bridge to lung transplantation, which may
explain a procedure mortality rate ranging from 5 to 15%. In addition to
symptomatic and haemodynamic improvement, an increase in survival as
compared with historical control groups has also been shown. At present,
balloon atrial septostomy is indicated for advanced NYHA class III and
class IV patients with recurrent syncope and/or right heart failure
despite all available medical treatments; septostomy is used either as a
palliative bridge to lung transplantation or as the sole treatment
modality when other options are not available. Balloon atrial septostomy
should be performed only in experienced centres to reduce the procedural
risks.

**Grade of Recommendation = IIa; Level of Evidence = C**

*Lung Transplantation*

Lung and heart-lung transplantation in PAH has been assessed only in
prospective uncontrolled series, since formal RCTs are considered
unethical in the absence of alternative treatment options.

The 3- and 5-year survival after lung and heart-lung transplantation is
approximately 55% and 45%, respectively.

Both single and bilateral lung transplantation have been performed for
IPAH, and these operations have been combined with repair of cardiac
defects for the Eisenmenger syndrome. Recipient survival rates have been
similar after single and bilateral transplantation for PAH, and if
technically feasible, either of these operations is an acceptable choice
for most cases of PAH. However, many transplant centres currently prefer
to perform bilateral lung transplantation in part because there are
generally fewer postoperative complications. In patients with
Eisenmenger syndrome and in those with end-stage heart failure, the
option of heart-lung transplantation should be carefully considered for
some complex defects, and in cases of ventricular septal defects, a
survival advantage of heart lung transplantation has been shown.

Lung and heart-lung transplantation are indicated in PAH patients with
advanced NYHA class III and class IV symptoms that are refractory to
available medical treatments. The unpredictability of the period of the
waiting list and donor organ shortage complicate the decision-making
regarding the appropriate timing of listing for transplantation.

**Grade of Recommendation = I; Level of Evidence = C**

**[Specific Conditions]{.underline}**

See the original guideline document for a discussion of the treatment of
\"Specific Conditions\" including: paediatric PAH, PAH associated with
Eisenmenger syndrome, porto-pulmonary hypertension, PAH associated with
HIV infection, PAH associated with CTDs, and PVOD and PCH.

**[Definitions]{.underline}**

**Class of Recommendations**

**Class I**: Evidence and/or general agreement that a given diagnostic
procedure/treatment is beneficial, useful and effective

**Class II**: Conflicting evidence and/or a divergence of opinion about
the usefulness/efficacy of the treatment

-   **Class IIa**: Weight of evidence/opinion is in favour of
    usefulness/efficacy.

-   **Class IIb**: Usefulness/efficacy is less well established by
    evidence/opinion.

**Class III**\*: Evidence or general agreement that the treatment is not
useful/effective and in some cases may be harmful

\*Use of Class III is discouraged by the European Society of Cardiology
(ESC)

**Levels of Evidence**

A.  Data derived from multiple randomised clinical trials or
    meta-analyses

B.  Data derived from a single randomised clinical trial or multiple
    trials with heterogeneous results

C.  Consensus of opinion of the experts and/or small studies,
    retrospective studies, registries

#### CLINICAL ALGORITHM(S)

An evidence-based algorithm is provided for the treatment of pulmonary
arterial hypertension (PAH), New York Heart Association (NYHA) Class
III/IV.

### EVIDENCE SUPPORTING THE RECOMMENDATIONS

#### TYPE OF EVIDENCE SUPPORTING THE RECOMMENDATIONS

The type of supporting evidence is identified and graded for selected
recommendations (see \"Major Recommendations\").

### BENEFITS/HARMS OF IMPLEMENTING THE GUIDELINE RECOMMENDATIONS

#### POTENTIAL BENEFITS

-   Appropriate diagnosis and treatment of pulmonary arterial
    hypertension

-   Appropriate diuretic treatment in case of right heart failure allows
    clear symptomatic and clinical benefits in patients with pulmonary
    arterial hypertension (PAH) even if specific randomised controlled
    trials (RCTs) have not been performed.

#### POTENTIAL HARMS

-   Limiting factors for dose increase of calcium channel blockers
    (CCBs) are usually systemic hypotension and lower limb peripheral
    oedema.

-   Adverse effects with chronic epoprostenol treatment are common and
    include flushing, jaw pain, diarrhoea, headache, backache, foot and
    leg pain, abdominal cramping, nausea, and rarely hypotension. The
    incidence of side effects may relate to how aggressive the dose is
    initially up titrated. Dose reduction is required only if the
    intensity is moderate to severe. Recurrence of side effects may be
    experienced after dose increases but usually they are mild and
    self-limiting over time without dose changes. In some cases ascites
    has been reported that may be related to an increased permeability
    of the peritoneal membrane induced by epoprostenol. Adverse events
    related to the delivery system are more serious and are essentially
    linked to pump malfunction, local site infection, catheter
    obstruction and sepsis. Localised infections can also occur such as
    small exit site reactions, tunnel infections and cellulitis. Rare
    events are pneumothorax and haemothorax that occur during catheter
    insertion.

-   Infusion site pain was the most common side effect reported for
    treprostinil, leading to the discontinuation of treatment in 8% of
    cases on active drug and limiting does increase in an additional
    proportion of patients.

-   Studies with sildenafil in patients with pulmonary arterial
    hypertension reported such minor side effects as headache, nasal
    congestion, and visual disturbances.

-   Due to the potential increase in liver enzymes, the United States
    Food and Drug Administration (FDA) requires that liver function
    tests be performed at least monthly in patients receiving bosentan.
    In addition, the European Agency for the Evaluation of Medicinal
    Products (EMEA) recommended to monitor monthly liver function tests,
    and currently these data are collected in an internet-based program
    (TRAX). Also, the haemoglobin/haematocrit should be checked
    regularly because bosentan use may also be associated with the
    development of anaemia, which seems typically to be mild. Fluid
    retention and lower limb oedema have been also reported in patients
    treated with bosentan. Careful attention must be paid to the use of
    adequate contraception in women of childbearing age due to the
    potential teratogenic effects of bosentan. In addition bosentan may
    decrease the efficacy of hormonal contraceptive techniques, and for
    this reason they should not be used alone. There is concern that the
    endothelin antagonists as a class may be capable of causing
    testicular atrophy and male infertility.

### CONTRAINDICATIONS

#### CONTRAINDICATIONS

-   Significant pulmonary arterial hypertension (PAH) can substantially
    increase the risk associated with liver transplantation and usually
    PAH is a contraindication if mean pulmonary artery pressure (PAP) is
    [\>]{.underline}35 mmHg and/or pulmonary vascular resistance is
    [\>]{.underline}250 dynes sec cm.

-   In HIV-associated PAH, therapeutic options are less well established
    as compared to other forms of PAH. Oral anticoagulation is often
    contraindicated because of frequent reduced platelet counts,
    difficulty with compliance and potential drug interactions between
    HIV medications and warfarin.

### QUALIFYING STATEMENTS

#### QUALIFYING STATEMENTS

The grading systems for the Level of Evidence based on the number of
randomised controlled trials (RCTs) may present some limitations that
need to be taken into account and possibly corrected. 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.

### IMPLEMENTATION OF THE GUIDELINE

#### DESCRIPTION OF IMPLEMENTATION STRATEGY

An implementation strategy was not provided.

#### IMPLEMENTATION TOOLS

Clinical Algorithm\
Personal Digital Assistant (PDA) Downloads\
Pocket Guide/Reference Cards\
Slide Presentation

For information about
[availability](#identifying-information-and-availability), see the
\"Availability of Companion Documents\" and \"Patient Resources\" fields
below.

### INSTITUTE OF MEDICINE (IOM) NATIONAL HEALTHCARE QUALITY REPORT CATEGORIES

#### IOM CARE NEED

End of Life Care\
Living with Illness

#### IOM DOMAIN

Effectiveness

### IDENTIFYING INFORMATION AND AVAILABILITY

#### BIBLIOGRAPHIC SOURCE(S)

Galie N, Torbicki A, Barst R, Dartevelle P, Haworth S, Higenbottam T,
Olschewski H, Peacock A, Pietra G, Rubin LJ, Simonneau G, Priori SG,
Garcia MA, Blanc JJ, Budaj A, Cowie M, Dean V, Deckers J, Burgos EF,
Lekakis J, Lindahl B, Mazzotta G, McGregor K, Morais J, Oto A, Smiseth
OA, Barbera JA, Gibbs S, Hoeper M, Humbert M, Naeije R, Pepke-Zaba J.
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. Eur Heart
J 2004 Dec;25(24):2243-78. \[230 references\]
[PubMed](http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15589643)

#### ADAPTATION

Not applicable: The guideline was not adapted from another source.

#### DATE RELEASED

2004

#### GUIDELINE DEVELOPER(S)

European Society of Cardiology - Medical Specialty Society

#### SOURCE(S) OF FUNDING

European Society of Cardiology

#### GUIDELINE COMMITTEE

Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension
of the European Society of Cardiology

#### COMPOSITION OF GROUP THAT AUTHORED THE GUIDELINE

*Task Force Members*: Nazzarebo Galiè (*Chairperson*) (Italy); Gerald
Simonneau (*Co-Chairperson*) (France); Adam Torbicki (Poland); Robyn
Barst (USA); Philippe Dartevelle (France); Shelia Haworth (UK); Tim
Higenbottam (UK); Horst Olschewski (Germany); Andrew Peacock (UK);
Giuseppe Pietra (Switzerland) Lewis J. Rubin (USA)

*European Society of Cardiology (ESC) Committee for Practice Guidelines
Members*: 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)

#### FINANCIAL DISCLOSURES/CONFLICTS OF INTEREST

Not stated

#### GUIDELINE STATUS

This is the current release of the guideline.

#### GUIDELINE AVAILABILITY

Electronic copies: Available from the [European Society of Cardiology
(ESC) Web
site](http://www.escardio.org/guidelines-surveys/esc-guidelines/Pages/pulmonary-arterial-hypertension.aspx).

Print copies: Available from Elsevier Science Ltd. European Heart
Journal, ESC Guidelines - Reprints, 32 Jamestown Road, London, NW1 7BY,
United Kingdom. Tel: +44.207.424.4422; Fax: +44 207 424 4515; Web site:
<http://www.eurheartj.org/>

#### AVAILABILITY OF COMPANION DOCUMENTS

The following are available:

-   Diagnosis and treatment of pulmonary arterial hypertension. Pocket
    guideline. Electronic copies: Available from the [European Society
    of Cardiology (ESC) Web
    site](http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/PAH-pocket.aspx).
    Also available for PDA download from the [ESC Web
    site](http://pocketgram.net/escardio/).

-   Guidelines on diagnosis and treatment of pulmonary arterial
    hypertension. Slide set. Electronic copies: Available in Portable
    Document Format (PDF) from the [European Society of Cardiology (ESC)
    Web
    site](http://www.escardio.org/guidelines-surveys/esc-guidelines/GuidelinesDocuments/guidelines-PAH-slides.pdf).

-   Recommendations for guidelines production. A document for Task Force
    Members responsible for the production and updating of ESC
    guidelines. 2006 Jun 28. 21 p. Available from the [ESC Web
    site](http://www.escardio.org/guidelines-surveys/esc-guidelines/about/Pages/rules-writing.aspx).

Print copies: Available from Oxford University Press, Great Clarendon
Street, Oxford, OX2 6DP, UK, Tel: +44 (0) 1865 353263, Fax: +44 (0) 1865
353774, Web site: <http://www.eurheartj.org/>.

#### PATIENT RESOURCES

None available

#### NGC STATUS

This NGC summary was completed by ECRI on March 11, 2005. This summary
was updated by ECRI on July 15, 2005 following the FDA advisory on
Cialis, Levitra, and Viagra. This summary was updated by ECRI on March
8, 2006 following the FDA advisory on Tracleer (bosentan). This summary
was updated by ECRI on March 6, 2007 following the FDA advisory on
Coumadin (warfarin sodium). This summary was updated by ECRI Institute
on July 12, 2007 following the U.S. Food and Drug Administration (FDA)
advisory on Troponin-1 Immunoassay. This summary was updated by ECRI
Institute on September 7, 2007 following the revised U.S. Food and Drug
Administration (FDA) advisory on Coumadin (warfarin). This summary was
updated by ECRI Institute on November 6, 2007, following the updated
U.S. Food and Drug Administration advisory on Viagra, Cialis, Levitra,
and Revatio.

#### COPYRIGHT STATEMENT

This summary is based on the original guideline, which is subject to the
guideline developer\'s copyright restrictions.

### DISCLAIMER

#### NGC DISCLAIMER

The National Guideline Clearinghouse™ (NGC) does not develop, produce,
approve, or endorse the guidelines represented on this site.

All guidelines summarized by NGC and hosted on our site are produced
under the auspices of medical specialty societies, relevant professional
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Guidelines represented on the NGC Web site are submitted by guideline
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Inclusion Criteria which may be found at
<http://www.guideline.gov/about/inclusion.aspx> .

NGC, AHRQ, and its contractor ECRI Institute make no warranties
concerning the content or clinical efficacy or effectiveness of the
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Readers with questions regarding guideline content are directed to
contact the guideline developer.

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© 1998-2008 National Guideline Clearinghouse

Date Modified: 11/10/2008