Consensus statement on the management of …...Consensus statement on the management of pulmonary...

Consensus statement on the management ofpulmonary hypertension in clinical practice in the UKand Ireland

National Pulmonary Hypertension Centres of the UK and Ireland

Correspondence to:Dr J Simon R Gibbs, NationalPulmonary Hypertension Service,Department of Cardiology,Hammersmith Hospital, Du CaneRoad, London W12 0HS, UK;[email protected]

1. FOREWORDI am delighted to write the foreword for thisconsensus statement which updates the‘‘Recommendations on the management of pul-monary hypertension in clinical practice’’ of 2001.The consensus statement reflects contemporarypractice in the management of this uncommon,deadly but now treatable condition in the pul-monary hypertension designated centres in the UKand Ireland. It matches and complements interna-tional guidelines, which are currently under revi-sion.

In addition to health professionals who encoun-ter affected patients within national centres or inother fields of practice, the statement is acomprehensive but readily accessible source ofinformation for commissioners and managers ofspecialised services.

Initially the evidence on which to base the careof patients with rare and deadly diseases often restson the experience and judgement of those whodeliver daily care, the collection of clinical, epide-miological and pathological data, and the assiduousconstruction of informative registers. This familiardiscipline has enabled the advances summarised inthis document.

The first challenge to health service commis-sioners is to ensure that all patients with pulmon-ary hypertension have access to appropriatetherapy as quickly as possible. Delay in makingthe diagnosis has the same consequences as delayin those with cancer. Regrettably ‘‘postcode pre-scribing’’ and its consequences still persist.

As for other uncommon conditions, continuedprogress in developing effective therapies rests onspecialised centres working in concert to developand participate in well-designed clinical trials,particularly trials of combination therapy.

This statement is a testament to the majoradvances in therapy made over the last 10 years,progress those of us who have cared for suchpatients over more than 30 years could not haveenvisaged.Professor Dame Carol M Black DBE, MD, FRCP,MACP, FMEDSCT

2. INTRODUCTIONIn 2001 the BCS Guidelines and Medical PracticeCommittee published their ‘‘Recommendations onthe management of pulmonary hypertension inclinical practice’’1 which was approved by theBritish Thoracic Society (BTS) and the BritishSociety of Rheumatology (BSR).

Lead clinicians

Gerry Coghlan, Royal Free Hospital, London, UKPaul A Corris (Co-editor), Freeman Hospital, Newcastle,UKSean Gaine, Mater Misericordae, Dublin, IrelandMichael A Gatzoulis, Royal Brompton Hospital, London,UKJ Simon R Gibbs (Chairman and co-editor),Hammersmith Hospital, London, UKSheila G Haworth, Great Ormond Street Hospital forChildren, London, UKDavid G Kiely, Royal Hallamshire Hospital, Sheffield, UKAndrew Peacock, Western Infirmary, Glasgow, UKJoanna Pepke-Zaba, Papworth Hospital, PapworthEverard, UK

Pulmonary hypertension cliniciansCarol Black, Royal Free Hospital, London, UKCharlie Elliot, Royal Hallamshire Hospital, Sheffield, UKAndrew J Fisher, Freeman Hospital, Newcastle UKClive Handler, Royal Free Hospital, London, UKLuke Howard, Hammersmith Hospital, London, UKRodney Hughes, Royal Hallamshire Hospital, Sheffield,UKDavid P Jenkins, Papworth Hospital, Papworth Everard,UKMartin Johnson, Western Infirmary, Glasgow, UKJim Lordan, Freeman Hospital, Newcastle, UKGuy MacGowan, Freeman Hospital, Newcastle UKNick Morrell, Addenbrookes Hospital, Cambridge, UKIngram Schulze-Neick, Great Ormond Street Hospital forChildren, London, UKKaren Sheares, Papworth Hospital, Papworth Everard, UKMartin Wilkins, Hammersmith Hospital, London, UKJohn Wort, Royal Brompton Hospital, London, UK

Pulmonary hypertension clinical nursespecialistsAgnes Crozier, Western Infirmary, Glasgow, UKClare Das, Royal Free Hospital, London, UKJulia De Soyza, Freeman Hospital, Newcastle, UKSinead Doherty, Mater Misericordae, Dublin, IrelandYvette Flynn, Great Ormond Street Hospital for Children,London, UKWendy Gin-Sing, Hammersmith Hospital, London, UKCarl Harries, Royal Brompton Hospital, London, UKMaureen Rootes, Papworth Hospital, Papworth Everard,UK

Invited individuals and organisationsGeoffey Carroll, Medical Director, Health CommissionWalesPulmonary Hypertension Association (UK)Iain Armstrong, Royal Hallamshire Hospital, Sheffield, UKBritish Congenital Cardiac AssociationJohn Gibbs, Leeds General Infirmary Leeds, UKBritish Society of Human GeneticsRichard Trembath, Guy’s Hospital, London, UK

Pulmonary hypertension

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Subsequently the National Pulmonary Hypertension Centresof the UK and Ireland Physicians Committee was constituted torepresent all of the designated centres. This statement is issuedby this Committee and represents the views of healthcareprofessionals who provide expert management of pulmonaryhypertension (PH) in designated centres.

Major advances in the clinical management of PH have beenmade in the time which has elapsed since the 2001 publication.The purpose of this consensus statement is to update the 2001recommendations to reflect contemporary clinical practice indesignated centres routinely managing PH in the UK andIreland. It is published to inform other health care professionals,commissioners and managers who are responsible for deliveringhealthcare.

Since 2001 formal guidelines for the management ofpulmonary arterial hypertension (PAH) have been publishedby the European Society of Cardiology (ESC)2 and the AmericanCollege of Chest Physicians (ACCP).3–6 Both of these guidelinesare in the process of being updated for publication in 2008–2009.Furthermore the clinical nomenclature was revised7 and clinicalpractice recommendations made8–10 at the 3rd WorldSymposium on Pulmonary Arterial Hypertension in 2004.These will also be updated in 2008 at the 4th WorldSymposium.

We have not sought to replicate international guidelines andthus there is no grading of evidence or recommendations.Instead this consensus statement is intended to complementthese PAH guidelines with specific emphasis on UK and Irishpractice, as well as to extend them to other forms of PH. Werecognise that in such a rapidly advancing field of clinicalpractice there will be a need to revise this statement in duecourse.

2.1 Evolution of treatmentPatients with PAH who do not receive disease-targeted therapyhave a poor quality of life (QoL) and high mortality at ratessimilar to many cancers. In 1996 the first randomised trial ofdrug therapy in PAH demonstrated benefit with epoprostenol,establishing this as therapy for severe idiopathic pulmonaryarterial hypertension (IPAH) in World Health Organization(WHO) functional classes III and IV.11

Over the last 10 years randomised, placebo controlled trials ofother prostacyclin analogues, endothelin receptor antagonistsand phosphodiesterase inhibitors have shown significant benefitto patients with PAH, with improved survival and functionalclass.

In the UK designated centres, the number of patients on thesetreatments in both clinical practice and clinical trials on 31March was 638 in 2004, 912 in 2005, 1242 in 2006 and 1499 in2007. This represents a total of 24.9 patients treated per millionpopulation based on the size of the UK population in mid2005.12 It is expected that this number will increase as patientssurvive longer, more patients come to medical attention and theindications for disease-targeted therapy expands.

2.2 Centres designated to manage pulmonary hypertensionThe purpose of designated centres is to provide best clinicalpractice, well coordinated patient care, clinical research, andadvice for those who are managing patients but are notspecialists in PH. Care is provided by multiprofessional teamsfor inpatients, day cases and outpatients with 24 h cover.

Centres designated to manage PH are shown in table 1. Thereare seven hospitals in England, one in Scotland and one in

Abbreviations

ACCP: American College of Chest PhysiciansALK-1: activin receptor-like kinase 1APAH: associated pulmonary arterial hypertensionATS: American Thoracic SocietyBCS: British Cardiovascular SocietyBLT: bilateral lung transplantationBMPRII: bone morphogenetic protein receptor type IIBNP: brain natriuretic peptideBSR: British Society of RheumatologyBTS: British Thoracic SocietycAMP: cyclic adenosine monophosphateCAMPHOR: Cambridge Pulmonary Hypertension Outcome ReviewCCAD: Central Cardiac Audit DatabasecGMP: cyclic guanosine monophosphateCOPD: chronic obstructive pulmonary diseaseCPET: cardiopulmonary exercise testCT: computed tomography scanCTD: connective tissue diseaseCTEPH: chronic thromboembolic pulmonary hypertensionDLCO: lung diffusing capacityECG: electrocardiogramERA: endothelin receptor antagonistETA: endothelin AETB: endothelin BESC: European Society of CardiologyFPAH: familial pulmonary arterial hypertensionGOSHC: Great Ormond Street Hospital for ChildrenGP: general practitionerGUCH: grown-up congenital heart diseaseHIV: human immunodeficiency virusHRQoL: health-related quality of lifeILD: interstitial lung diseaseINR: international normalised ratioIPAH: idiopathic pulmonary arterial hypertensionISHLT: International Society of Heart and Lung TransplantationIVC: inferior vena cavaLTOT: long term oxygen therapyMCTD: mixed connective tissue diseaseMR: magnetic resonanceNCG: National Commissioning Group (formerly NSCAG)NHS: National Health ServiceNO: nitric oxideNSCAG: National Specialist Commissioning Advisory GroupNSD: National Service DivisionNYHA: New York Heart AssociationPAH: pulmonary arterial hypertensionPAP: pulmonary arterial pressurePASP: pulmonary arterial systolic pressure (estimated by echocardio-graphy)PCH: pulmonary capillary haemangiomatosisPCT: Primary Care TrustPCWP: pulmonary capillary wedge pressurePDE: phosphodiesterasePEA: pulmonary endarterectomyPFO: patent foramen ovalePH: pulmonary hypertensionPro-NT BNP: pro-N terminal brain natriuretic peptidePVOD: pulmonary veno-occlusive diseasePVR: pulmonary vascular resistanceQoL: quality of lifeSCG: Specialist Commissioning GroupSLE: systemic lupus erythematosisSLT: single lung transplantationSSc: sclerodermaTGFb: transforming growth factor bTR: tricuspid regurgitationVIP: vasoactive intestinal polypeptideWHO: World Health Organization


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Ireland. Wales and Northern Ireland refer patients to UK centresand may develop their own or satellite centres in the future. Thisdirectory of centres is kept current at www.thephdirectory.com.

Formal designation of centres was undertaken by theNational Specialist Commissioning Advisory Group (NSCAG)of the Department of Health in England in 2001, the NationalService Division (NSD) of the Scottish Parliament in Scotland in1998, and the Health Service Executive in Ireland. NSCAG wasreplaced by the National Commissioning Group (NCG) in 2007.These centres are monitored by their designating bodies byregular site visits and audit against agreed Standards of Care.Audit data will become centralised in the National HealthService (NHS) in 2008 when it is collected from all designatedcentres by the Central Cardiac Audit Database (CCAD).

2.3 Commissioning of pulmonary hypertension in EnglandIn England, PH is included within the list of defined specialistservices issued by the Department of Health. For adults, thismeans that Primary Care Trusts (PCTs) are required tocommission the service through formal collaborative arrange-ments established by the Specialist Commissioning Group(SCG) responsible for their area.

At national level specialist commissioners are working withthe six designated adult centre lead clinicians to formulateservice development strategies and policies aimed at ensuring aconsistent and dynamic approach in the future.

Funding of expensive disease-targeted therapies is provided onan individual patient basis by PCTs to whom applications must

be made for each patient by a designated centre. Some PCTshave formed consortia to fund the cost of treatment accordingto strict criteria without the need for individual applications.

For children, NCG not only designates but funds the serviceand drug therapies. The Pulmonary Endarterectomy (PEA)Service is separately NCG designated and centrally funded.

2.4 Commissioning of pulmonary hypertension in ScotlandThe Scottish Pulmonary Vascular Unit is commissioned toprovide services for Scotland and is centrally funded by theNSD.

2.5 Commissioning of pulmonary hypertension in IrelandA single PH Unit has been commissioned to provide a service forthe whole of the Republic of Ireland and is centrally funded on ayearly basis by the Health Service Executive.

2.6 Collection of audit dataCurrently all designated centres collect audit data in localdatabases. In 2008 the UK data will be centralised in the CCAD,part of the National Clinical Audit Support Programme of theNHS.

3. NOMENCLATURE3.1 Clinical classificationThe clinical classification of PH is key to making an accuratediagnosis and guides treatment. It was updated in 20047 (box 1).

The classification is based upon groups of diseases causing PHwhich demonstrate similarities in clinical presentation, patho-physiology and therapeutic options.

The broad influence of the clinical classification on manage-ment is seen in table 2.

3.2 Functional classThe severity of PH is assessed according to a modification of theNew York Heart Association (NYHA) functional classification13

shown in box 2. It has long been recognised that symptomaticseverity is related to prognosis14 and this remains so incontemporary practice (fig 1)15 emphasising the need for earlyreferral for investigation and treatment.

4. PATHOPHYSIOLOGY AND GENETICS OF PULMONARYARTERIAL HYPERTENSION: LINKS TO TREATMENTSThe pathology of PAH is characterised by luminal obliterationof small pulmonary arteries. This process of vascular remodel-ling involves proliferation of smooth muscle cells, fibroblastsand endothelial cells in the vessel wall.16–18 In severe forms of PH,the formation of a neointima is observed forming concentricintimal lesions. Abnormal endothelial cell proliferation results inthe formation of plexiform lesions (fig 2). The most severeforms of precapillary PH are usually pathologically indistin-guishable.

A number of mediators and growth factors have been shownto be involved in driving the cellular changes. Increasedcirculating and local expression of endothelin-1 is observed inpatients with PAH.19 20 As well as being a potent vasoconstric-tor, endothelin stimulates smooth muscle and fibroblastproliferation via the endothelin A (ETA) and/or endothelin B(ETB) receptors, which are increased in small hypertensivepulmonary arteries.21 Circulating levels of serotonin are alsoelevated in PAH.22 Serotonin stimulates mitogenesis of vascularcells via serotonin receptors, including 5HT2A, 5HT2B and5HT1B.18 In human pulmonary artery smooth muscle cells, a

Table 1 Designated pulmonary hypertension centres in the UK andIreland

Designated centrelocation Contact details

Glasgow, Scotland Scottish Pulmonary Vascular Unit, Western Infirmary,Glasgow, G11 6NTTel: 0141 211 6327 Fax: 0141 211 6334Website: www.spvu.co.uk

Newcastle-upon-Tyne,England

Northern Pulmonary Vascular Unit, Regional CardiothoracicCentre, Freeman Hospital, Newcastle upon Tyne, NE7 7DNTel: 0191 223 1084 or 0191 244 8608Fax: 0191 223 1691

Sheffield, England Pulmonary Vascular Unit, Royal Hallamshire Hospital,Glossop Road, Sheffield, S10 2JFTel: 0114 271 2590 Fax: 0114 271 1718

Cambridge, England Pulmonary Vascular Diseases Unit, Papworth Hospital NHSTrust, Papworth Everard, Cambridge CB3 8RETel: 01480 830 541 Fax: 01480 831 315Website: www.papworth-hospital.org.uk

London, England Pulmonary Hypertension Service, Hammersmith Hospital,Du Cane Road, London, W12 0HSTel: 0208 383 2330 Fax: 0208 383 2331Website: www.pulmonary-hypertension.org.uk

London, England Royal Brompton Pulmonary Hypertension and AdultCongenital Heart Centre,Sydney Street, London SW3 6NPTel: 0207 351 8362 Fax: 0207 351 8629Website: www.rbht.nhs.uk

London, England Royal Free Hospital, Pond Street, London, NW3 2QGTel: 0207 794 0500 ext 8648.Website: www.royalfree.nhs.uk

London, England UK Pulmonary Hypertension Service for Children, GreatOrmond Street Hospital,London, WC1N 1EHTel 0207 405 9200 Ext.1005, 1007, 8495

Dublin, Ireland Mater Misericordiae University HospitalEccles Street, Dublin 7Tel 00 353 1803 44 20Website: www.mater.ie





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major proliferative pathway involves activation of mitogenactivated protein kinases via the serotonin transporter.23

Increased expression of the transporter is found in hypertensivearteries.

A relative deficiency of vasodilator pathways is observed insevere PAH, an imbalance which enhances the activity ofmitogenic and vasoconstrictor pathways. Patients with PAHproduce less endothelial-derived prostacyclin, and have reducedexpression of nitric oxide (NO) synthase and vasoconstrictivethromboxane.24 More recent studies have also shown adeficiency of the neuropeptide vasodilator vasoactive intestinalpolypeptide (VIP) in the lungs of patients with PAH.25 Many ofthe important vasodilator pathways also exert antiproliferativeeffects on vascular cells. The deficiency of these key vasodilatorpathways has provided the rationale for therapies.

Other important pathways involved in the process ofpulmonary vascular remodelling include changes in potassium

channel (Kv1.5 and 2.1) expression, activation of vascularelastases, and increased expression of inflammatory cytokinesand chemokines.18

The genetics of PAH is described in section 5.3.1.

5. OBJECTIVES AND PRIORITIES FOR INVESTIGATION

5.1 Definition of pulmonary hypertensionPH is defined as a mean pulmonary arterial pressure (PAP) of.25 mm Hg at rest or .30 mm Hg on exercise at cardiaccatheterisation.26 PAH also requires a pulmonary capillarywedge pressure (PCWP) (15 mm Hg and a pulmonary vascularresistance (PVR) >240 dynes/s/cm5.2

5.2 When to suspect pulmonary hypertensionThe principal symptoms of PH are non-specific and the clinicalsigns subtle until patients present with advanced disease.26 As aconsequence the diagnosis is most readily made where asystematic approach is taken to investigation, and high riskpatients are targeted with screening programmes.

Box 1: Revised clinical classification of pulmonaryhypertension (Venice 2003) following the previous Evianclassification (described in the 2001 BCSrecommendations)

1. Pulmonary arterial hypertension (PAH)1.1. Idiopathic (IPAH)1.2. Familial (FPAH)1.3. Associated with (APAH):1.3.1. Collagen vascular disease1.3.2. Congenital systemic-to-pulmonary shunts1.3.3. Portal hypertension1.3.4. HIV infection1.3.5. Drugs and toxins1.3.6. Other (thyroid disorders, glycogen storage disease,Gaucher’s disease, hereditary haemorrhagic telangiectasia,haemoglobinopathies, myeloproliferative disorders, splenectomy)1.4. Associated with significant venous or capillary involvement1.4.1. Pulmonary veno-occlusive disease (PVOD)1.4.2. Pulmonary capillary haemangiomatosis (PCH)1.5. Persistent pulmonary hypertension of the newborn

2. Pulmonary hypertension with left heart disease2.1. Left-sided atrial or ventricular heart disease2.2. Left-sided valvular heart disease

3. Pulmonary hypertension associated with lung diseasesand/or hypoxaemia3.1. Chronic obstructive pulmonary disease3.2. Interstitial lung disease3.3. Sleep disordered breathing3.4. Alveolar hypoventilation disorders3.5. Chronic exposure to high altitude3.6. Developmental abnormalities

4. Pulmonary hypertension due to chronic thrombotic and/orembolic disease4.1. Thromboembolic obstruction of proximal pulmonary arteries4.2. Thromboembolic obstruction of distal pulmonary arteries4.3. Non-thrombotic pulmonary embolism (tumour, parasites,foreign material)

5. MiscellaneousSarcoidosis, histiocytosis X, lymphangiomatosis, compression ofpulmonary vessels (adenopathy, tumour, fibrosing mediastinitis)

Table 2 Clinical classification of pulmonary hypertension (PH) as aguide to treatment

Classification Treatment

Pulmonary arterialhypertension

Disease-targeted therapies (but caution in veno-occlusive disease)

PH with left heart disease Medical, interventional and surgical therapies forchronic heart failure, coronary artery disease, valvedisease and pericardial disease

PH associated with lungdiseases and/or hypoxaemia

Therapy to treat the primary lung disorder

Oxygen

Disease-targeted therapies when pulmonaryhypertension out of proportion to lung disease

PH due to chronic thromboticand/or embolic disease

Pulmonary endarterectomy (PEA) for proximal disease

Disease-targeted therapies for distal disease (seesection 6.4.8.7), significant residual post-PEApulmonary hypertension or late redevelopment ofsymptomatic pulmonary hypertension post-PEA

Miscellaneous Specific to individual diseases

Box 2: Functional classification of pulmonary hypertensionmodified after the New York Heart Association functionalclassification according to the World Health Organization1998

c Class I: Patients with pulmonary hypertension but withoutresulting limitation of physical activity. Ordinary physicalactivity does not cause undue dyspnoea or fatigue, chest painor near syncope.

c Class II: Patients with pulmonary hypertension resulting inslight limitation of physical activity. They are comfortable atrest. Ordinary physical activity causes undue dyspnoea orfatigue, chest pain or near syncope.

c Class III: Patients with pulmonary hypertension resulting inmarked limitation of physical activity. They are comfortable atrest. Less than ordinary activity causes undue dyspnoea orfatigue, chest pain or near syncope.

c Class IV: Patients with pulmonary hypertension with inabilityto carry out any physical activity without symptoms. Thesepatients manifest signs of right heart failure. Dyspnoea and/orfatigue may even be present at rest. Discomfort is increasedby any physical activity.





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Clinical suspicion should arise in any patient presenting withbreathlessness without overt signs of specific heart or pulmon-ary disease, particularly in diseases which may be associatedwith PH (box 1). While breathlessness is the most commonsymptom, patients may also present with chest pain, syncope,fatigue, weakness and abdominal distension.26 Frequently thereis a delay of up to 3 years between first symptom and diagnosisand this interval has remained the same over the last 10 years.27

The precordial signs of PH include right ventricular lift,accentuated pulmonary component of the second heart sound, apansystolic murmur of tricuspid regurgitation, a diastolicmurmur of pulmonary regurgitation and a right ventricularthird sound. Jugular venous distension, hepatomegaly, periph-eral oedema, ascites and cold extremities characterise patients in

a more advanced state with right ventricular failure at rest;central cyanosis may also be present. Ankle swelling occurs latein the natural history of the disease.

When faced with breathlessness of unknown cause, spiro-metry is a useful screening test to exclude common respiratorydisease. A chest x ray and ECG should be performed since thesetests are abnormal in 80–90% of patients presenting withsymptoms caused by established PH.1 The ECG may demon-strate right ventricular hypertrophy and strain and right atrialdilatation. The ECG alone has inadequate sensitivity (55%) andspecificity (70%) to be a screening tool for detecting PH.28

Doppler echocardiography is the most useful non-invasiveinvestigation and allows an estimate of pulmonary arterialsystolic pressure (PASP).29 Its sensitivity and specificity inidentifying PH depends on the population and limitations relateprimarily to technical aspects of this technique. The estimatedupper limit for PASP in 95% of normal subjects is 37.2 mm Hg.30

A PASP .40 mm Hg was found in 6% of those .50 years oldand 5% of those with a body mass index (BMI) .30 kg/m.Twenty-eight per cent of normal subjects have a PASP.30 mm Hg, and the expected upper limit of PASP may be ashigh as 40 mm Hg in older or obese subjects. Mild PH has beendefined as a peak tricuspid regurgitation (TR) velocity of 2.8–3.4 m/s with a normal right atrial pressure.2

Computed tomographic (CT) scanning also provides usefulinformation on right ventricular and pulmonary artery size,raising the possibility of PH which had not otherwise beensuspected.

RECOMMENDATIONS1. PH should be considered in all patients presenting with

breathlessness in the absence of an alternative cause ofcardiorespiratory disease. The presence of progressive breath-lessness associated with chest pain or syncope shouldparticularly alert the clinician to this diagnosis.

2. While ECG and chest x ray are often abnormal atpresentation, the sensitivity of these investigations is suchthat normal appearances do not exclude PH.

Figure 1 Survival of patients with idiopathic pulmonary arterialhypertension based upon functional class (FC) at clinical presentation.NYHA, New York Heart Association. Reproduced with permission fromSitbon O, et al. J Am Coll Cardiol 2002;40:780–8 (fig 2, panel A only).

Figure 2 Pathophysiology of pulmonaryarterial hypertension (PAH) and itsrelationship to treatment. ANP, atrialnatriuretic peptide; AMP, adenosinemonophosphate; ATP, adenosinetriphosphate; BNP, brain natriureticpeptide; GMP, guanosinemonophosphate; GTP, guanosinetriphosphate; NO, nitric oxide; PDE,phosphodiesterase; VIP, vasoactiveintestinal polypeptide.





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3. Spirometry should be performed to detect common respira-tory diseases.

4. Doppler echocardiography is the best screening investigationfor PH.

5.3 Screening at risk populations for pulmonary hypertension

5.3.1 Genetic screening for pulmonary arterial hypertensionIncident data from specialist centres indicate the minimumfrequency of recognised familial pulmonary arterial hyperten-sion (FPAH) as 5–10% of referrals. Risk for FPAH is conferred bya heterozygous loss of function mutation of receptor membersof the TGFb superfamily, most commonly defects in the geneencoding the type II receptor, BMPRII.31 32 Rarely, mutations ofthe type I receptor, ALK-l, have been detected in PAH subjectswho may also exhibit the clinical features characteristic ofhereditary haemorrhagic telangiectasia.33 A significant propor-tion of sporadic cases (classified as IPAH) have germline TGFbmutations34 while the frequency of detectable mutationsappears lower in childhood onset disease.35 Incidence andprevalence data for populations for FPAH/IPAH have not beenreported.

An evidence base for the management of ‘‘at risk’’ individualsfor PAH requires further research and will require modificationshould disease prevention or modification strategies emerge.The provision of information regarding risk and opportunitiesfor risk resolution in monogenic disorders is a recognisedfunction of genetic services, which should be extended toFPAH kindreds.

Indications for clinical and molecular genetic screening inIPAH remain unclear and require further research. Empiricaldata suggest low disease risks to first and second degree relativesin IPAH. Presentation in childhood raises specific parentalconcern for occurrence of disease in siblings (recurrence risk)and/or the unborn child (offspring risk) which may requirereferral for specialist genetic counselling. Mutation analysis hasprovided no insight into the clinical variability of PAH,particularly age of onset which may vary significantly withinfamilies.35 36 The genetic basis of associated forms of PAHremains unclear.

RECOMMENDATIONS5. Recognised familial cases of PAH should be offered family-

based risk assessment including genetic counselling.6. Molecular genetic testing may be indicated in FPAH

following comprehensive genetic counselling for (a) resolu-tion of individual risk and (b) family planning. Jointmanagement of ‘‘at risk’’ individuals within recognisedfamilies between genetic services and specialist PAH centresis indicated. Clinical monitoring of at risk relatives isindicated for early detection of disease and management ofsymptoms. The frequency at which this should be conductedis unknown.

7. Close (first degree) relatives of index IPAH patients should beprovided with written information of the genetic basis of thedisorder, including recognition of the low (,5%) recurrenceand offspring risk. The role of clinical monitoring in thisgroup is unknown.

8. Parental anxiety regarding recurrence and/or offspring riskfollowing childhood onset presentation with IPAH is anindication for genetic services referral with provision forclinical assessment of ‘‘at risk’’ family members.

5.3.2 Associated pulmonary arterial hypertensionPAH is commonly seen in association with connective tissuedisease (CTD),37 congenital heart disease,38 sickle cell disease,39

portal hypertension40 and HIV infection.41 This has resulted in anumber of screening regimens to identify PAH in at risk groupsranging from investigating patients with symptoms of breath-lessness to interval screening of asymptomatic individuals.

RECOMMENDATIONS9. Screening of breathless patients should be performed in

diseases where PAH is a known complication. Right heartcatheterisation should be undertaken when Doppler echo-cardiography measures a peak TR velocity of >2.8 m/s witha normal right atrial pressure (equivalent to 36 mm Hg).

5.3.2.1 Connective tissue diseasePulmonary hypertension is a well known complication of CTD,particularly in limited cutaneous scleroderma (SSc) where theprevalence in this group is 12%,42 and mixed CTD (MCTD)with U1 RNP antibodies.43 PAH is recognised by an increasedDoppler peak TR velocity at echocardiography and reduced lungdiffusing capacity (DLCO).37 44 45

RECOMMENDATIONS10. Screening should be performed annually in patients with

limited cutaneous SSc or MCTD with U1 RNP antibodies,using echocardiography and DLCO. Right heart catheterisa-tion should be performed in all cases with a peak TRvelocity of >2.8 m/s on echocardiography or a reduction inDLCO of 50% in the absence of interstitial lung disease(ILD). Patients with other CTDs are screened only in thepresence of symptoms.

5.3.2.2 Porto-pulmonary hypertensionThe prevalence of PAH in patients undergoing liver transplanta-tion is 4.0–3.5%.46 In addition porto-systemic shunts increasethe risk of developing PAH.47

RECOMMENDATIONS11. All patients with portal hypertension and cirrhosis should

undergo echocardiography if liver transplantation isplanned.

5.3.2.3 Haemolytic anaemiaPAH is increasingly recognised in congenital haemolyticanaemias including sickle cell disease39 and thalassaemia.48 49 Itis not yet clear whether these patients benefit from PAHdisease-targeted therapies.

RECOMMENDATIONS12. Screening for PAH is not routine in patients with haemolytic

anaemia.

5.3.2.4. HIV infectionPAH is a rare complication of HIV with a cumulative incidenceof 0.57% on an annual incidence of 0.1%.41

RECOMMENDATIONS13. Screening for PAH is not routine in patients with HIV

infection.





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5.3.3. Pulmonary embolismChronic thromboembolic pulmonary hypertension (CTEPH) isa complication of venous thromboembolism. Up to 4% ofpatients with idiopathic pulmonary embolism may developCTEPH.50 Patients at greatest risk include those with previousepisodes of venous thromboembolism, massive and sub-massivepulmonary embolism,51 an elevated PASP on admission orelevated pressure 2 months following initial presentation.

RECOMMENDATIONS14. Patients with previous venous thromboembolism who are

breathless should undergo echocardiography. Patients withmassive or sub-massive pulmonary thromboembolismshould undergo echocardiography 6–12 weeks followingthe index event. Where echocardiography is inconclusiveand symptoms persist, consider contrast CT thorax.

5.4 Criteria for referral to pulmonary hypertension centresReferrals are accepted at designated centres where screeninginvestigations suggest PH for which there is not a cardiac orrespiratory cause. Right heart catheterisation is not encouragedbefore referral unless individual cases are discussed with adesignated centre, and the referring physician routinely under-takes right heart catheterisation with vasodilator studies.

RECOMMENDATIONS15. Adults with confirmed or suspected PAH, CTEPH, a

miscellaneous cause of PH, or where the cause of PH isunclear should be referred to a designated centre. Referralshould be considered in cases of PH in hypoxic lung diseaseor cardiac disease, but only if symptoms or estimated PASPat echocardiography seems excessive (.60 mm Hg) or thepatient has another disease which may be associated withPAH.

16. Children should be referred to the UK Children’s Service ifthey have confirmed or suspected IPAH or FPAH. The UK

Children’s Service will also accept referral of and/or beavailable to give advice for all children with persistentneonatal PH beyond the first month of life, sustained,postoperative PH, inoperable congenital heart disease withPH, parenchymal lung disorders/disease with PH, miscella-neous causes of PH, or PH of uncertain cause.

17. All patients should have an ECG, chest x ray, transthoracicechocardiogram, and spirometry in adults. If possible, allpatients should be seen by a consultant in cardiology orrespiratory medicine before referral to a designated centre.

18. Patients with PH may deteriorate rapidly. It is importantthat referrals are not delayed in order to undertake moreextensive investigation if it is clear that PH is the dominantproblem.

5.5 Investigation at pulmonary hypertension centresThe purpose of investigation is to confirm or exclude thediagnosis of PH, and if present to determine the aetiology andseverity of PH (table 3 and box 3).

5.5.1. Cardiac and lung imagingThe purpose of cardiac imaging is to determine if a cardiac causeof pulmonary hypertension is present, and assess severity. Theparticular advantage of non-invasive imaging is that it is safe,quick and simple to follow serially. Echocardiography can beperformed at the bedside. Transoesophageal echocardiography isnot routinely required but may be needed if congenital heartdisease is suspected.

Lung imaging is used to detect CTEPH or parenchymal lungdisease. Different techniques are used to achieve a diagnosis ofCTEPH52 (fig 3). Parenchymal lung disease can be assessed onhigh resolution CT (table 3).

RECOMMENDATIONS19. New patients require detailed investigation including cardiac

and lung imaging to determine the aetiology and severity ofPH.

5.5.2 Exercise testingA number of exercise test protocols have been used to assessexercise capacity although none are ideal.

The role of the 6 min walking test (6MWT) in the assessmentof PH is firmly established. Guidelines describe how to performthis.53 Baseline values for distance walked correlate withfunctional class, pulmonary haemodynamics, cardiopulmonaryexercise testing (CPET) variables and survival.54 Serial valueshave proven to be a useful outcome measure in the majority ofdrug trials in PH.2 It is not an absolute change in walk distancefollowing treatment that is predictive of survival but achieving athreshold distance.15 The sensitivity to change diminishes as thedistance walked increases, particularly .450 m, and conse-quently may be less useful for patients in WHO functionalclasses I and II.55

Variants of the 6MWT include the shuttle test and enduranceshuttle.56 57

The incremental CPET is well standardised although techni-cally more complex to perform.58 Baseline values have beenshown to be predictive of disease severity and survival(including peak oxygen consumption, systolic blood pressureat peak exercise, the ventilatory equivalent for carbon dioxideand end-tidal carbon dioxide partial pressure).59 60 The test canhelp with differential diagnosis because patients with PH showcharacteristic changes.59 61 The significant disadvantage with the

Table 3 Imaging investigations recommended in the assessment ofpulmonary hypertension (PH)

Investigation Comments

Chest x ray May show increase in cardiac chambers, increasedpulmonary artery size, hypoperfused areas of lung andevidence of parenchymal lung disease

High resolutioncomputed tomography(CT) scan of lungs

May show parenchymal lung disease, mosaic perfusion (asign of pulmonary vascular embolism or thrombosis but forwhich there are other causes such as air trapping), andfeatures of pulmonary venous hypertension

CT pulmonaryangiography

Used to look for enlargement of pulmonary arteries, fillingdefects and webs in the arteries. Detects enlarged bronchialcirculation

Ventilation perfusionscanning

More sensitive for chronic pulmonary thromboembolismthan CTPA but not helpful when there is underlyingparenchymal lung disease

Selective pulmonaryangiography by directinjection of thepulmonary arteries

Gold standard for delineating chronic pulmonarythromboembolism to define the location and extent ofdisease. It may be superseded by magnetic resonanceangiography or multislice CT.

Echocardiography Screening tool of choice for PH. Detects cardiac disease(congenital, myocardial, valvular, intracavity clot or tumour,pericardial). Use of contrast may be helpful to identifyshunts

Cardiac magneticresonance

Good examination for imaging the right ventricle. Helpful indelineating congenital heart defects, and the pulmonarycirculation by angiography

Abdominal ultrasound Used for investigation of liver disease and suspected portalhypertension.





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test is that it has not been proven useful as a serial measurementin drug trials.62–64

RECOMMENDATIONS20. The 6MWT is the preferred exercise outcome measure for

use in assessing patients with PH both at baseline andsubsequent visits and should be performed according toAmerican Thoracic Society (ATS) guidelines.

21. A baseline CPET may be useful in selected cases to confirmthat exercise limitation is due to PH and to delineate furtherdisease severity and prognosis.

5.5.3 Lung functionComprehensive dynamic and static lung function testing is ableto detect the presence of coincident obstructive or restrictivelung disease. The classical picture in PAH without coexistentlung disease is normal spirometry and lung volumes, sometimeswith mild restriction, but decreased diffusing capacity. Normallung function does not preclude PH.

RECOMMENDATIONS22. Lung function testing should include the measurement of

spirometry, static and dynamic lung volumes and DLCO.

5.5.4 BiomarkersSeveral biomarkers have been shown to be useful markers ofheart disease. Brain natriuretic peptide (BNP) is released fromventricular myocytes in response to increased wall tension. It isrecognised as a predictor of mortality, disease progression andresponse to therapy in PAH and CTEPH.65–67 ProBNP is theprohormone which is cleaved into active BNP and more stableN-terminal fragment, NT-proBNP. The levels of BNP andproBNP are dependent on age, sex, glomerular filtration rateand obesity.66 68–70

BNP and/or proBNP have been shown to be elevated in IPAH,PAH associated with scleroderma, systemic-to-pulmonaryshunts, and PH with interstitial lung disease, chronic obstruc-tive pulmonary disease (COPD), and CTEPH.66 67 71–75 Baselineand/or serial changes in BNP and NT-proBNP correlate withsurvival and surrogate markers such as pulmonary haemody-namics, functional class and 6MWT distance.65 66 76–78 Data ontroponin are too limited to make any recommendations atpresent.79

RECOMMENDATIONS23. Baseline plasma NT-proBNP is a useful prognostic marker in

PAH patients without significant renal or left ventricularimpairment.

5.5.5 Right heart catheterisationRight heart catheterisation should be undertaken in newpatients after other investigation results have been reviewedin order to determine exactly which measurements are needed(box 4). It is also used to answer specific clinical questionsduring follow-up. Cardiac output should be measured either bythermodilution or the Fick method, the latter only when oxygenconsumption is measured. Exercise haemodynamics may behelpful to evaluate borderline PH and left heart disease.

A vasoreactivity study is undertaken to determine suitabilityfor high dose calcium antagonist therapy in those groups ofpatients who are known to benefit from such therapy. Thesestudies are performed using inhaled NO (the agent of choice), oran infusion of intravenous epoprostenol or adenosine.2 Apositive response is apparent when the mean PAP falls at least10 mm Hg to ,40 mm Hg with either an increase or no changein cardiac output. A vasoreactivity study is contraindicated inPAH associated with significant venous or capillary involve-ment because of the risk of pulmonary oedema.

RECOMMENDATIONS24. Right heart catheterisation is essential during the initial

investigation of new patients.

Box 3 Other investigations recommended in theassessment of pulmonary hypertension

c Respiratory:– 6 min walk test– arterial blood gases in room air– lung function (including FEV1, FVC, TLC, FRC, RV, TLCO,

DLCO, KCO)– nocturnal oxygen saturation monitoring

c Cardiology:– ECG– echocardiogram– cardiac catheterisation (including right heart

catheterisation with saturations and haemodynamics,and acute pulmonary vasoreactivity study as appropriate)

c Blood investigations include:– routine biochemistry and haematology– thrombophilia screen in CTEPH– thyroid function– autoimmune screen (including anti-centromere antibody,

anti-SCL70 and U1 RNP, phospholipid antibodies)– hepatitis serology– serum angiotensin converting enzyme– HIV

c Urine:– b-HCG (women)

Figure 3 Diagnostic approach to chronic thromboembolic pulmonaryhypertension (CTEPH). CT, computed tomography; MR magneticresonance.





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25. A vasoreactivity study should be performed in patients withIPAH, FPAH, CTD APAH (excluding SSc APAH), andanorexogen-induced APAH. Only responders should betreated with high dose calcium channel blockers.

6. OBJECTIVES AND PRIORITIES FOR TREATMENT

6.1 AnticoagulationVascular thrombotic lesions have been identified with highprevalence at post-mortem in patients with IPAH80 81 and otherforms of PAH.82 Although a relationship between thromboticlesions, age and disease duration83 have been suggested this isnot a universal finding.17 Thrombosis appears uncommon inchildren. Abnormalities in coagulation and fibrinolytic path-ways, and platelet function have also been demonstrated.84–86

Clinical studies are limited. Two retrospective81 87 and one smallnon-randomised prospective study88 have associated anticoagu-lation use with a survival benefit. These studies have beenconducted almost exclusively in patients with IPAH.Randomised controlled trials are needed in patients with PAHassociated with other diseases where the risk benefit ratio ofanticoagulation is not known.

RECOMMENDATIONS26. Anticoagulation with warfarin is recommended in patients

with IPAH and CTEPH in the absence of contraindications.The international normalised ratio (INR) should be main-tained between 2 and 3. For IPAH patients with a higherthan normal bleeding risk an INR of 1.5 to 2.5 is suggested.

27. Anticoagulant therapy is recommended in Ssc APAHalthough this recommendation is purely consensus based.

6.2 Oxygen therapyOxygen administered acutely has been demonstrated to reducePVR in both hypoxic and non-hypoxic patients with PH. Thereare no randomised data available to suggest that long termoxygen therapy (LTOT) is beneficial in PAH. There are datashowing that nocturnal oxygen therapy does not modify thenatural history of advanced Eisenmenger syndrome89 (seesection 6.4.8.3). This does not exclude the possibility of benefitfrom LTOT in other patient groups with PH since it is an

increase in alveolar oxygen which leads to a reduction inpulmonary vascular resistance. Arterial oxygenation is not agood reflection of alveolar oxygenation in Eisenmenger physiol-ogy.

Based on the limited evidence from studies with COPD,90 91

oxygen should be prescribed in accordance with the BTSWorking Group on Home Oxygen Services.92 When arterialoxygen pressure (PaO2) is consistently at or ,8 kPa (breathingroom air) during a period of clinical stability, oxygen should ormay be prescribed for at least 15 h a day (including night time)to achieve a PaO2 of .8 kPa. Where daytime oxygenation issatisfactory, nocturnal oxygenation should be assessed andoxygen prescribed if mean overnight saturations are ,90% toachieve a mean saturation greater than this. There can be norecommendation for oxygen in PAH associated with congenitalheart disease.

Arterial hypoxaemia can contribute to breathlessness onexertion through stimulation of the peripheral chemoreflex. Theprescription of ambulatory oxygen should follow the recom-mendations of the BTS document.92 Consequently, the patientwill qualify for ambulatory oxygen if there is evidence ofsymptomatic benefit and correctible desaturation of .4% to,90% on a 6MWT.

There have been no studies using flight simulation todetermine which patients require oxygen during air travel, butgiven the known physiological effects of hypoxia, it seemscurrently prudent to consider in-flight oxygen for all patientswith significant pulmonary hypertension. A flow rate of2 l/min will raise inspired PO2 to sea level values.

RECOMMENDATIONSExcept with congenital heart disease:28. All patients should have nocturnal oxygen saturation

monitoring at initial assessment and thereafter whenclinically indicated.

29. Oxygen should be administered to maintain daytime andnocturnal PaO2 .8 kPa.

30. Ambulatory oxygen can be considered in those withcorrectable exercise desaturation of .4% to ,90% forsymptomatic benefit.

31. In-flight supplemental oxygen should be considered for allpatients in WHO functional class III and IV or those withresting oxygen saturations ,95%.

6.3 Supportive medical therapyAssisting patients to adapt to the uncertainty associated withchronic, life shortening disease is essential if they are to adjustsuccessfully to the demands of their illness and its treatment.The health care team needs to be highly skilled in managing theburden and impact of this disease, and its complex and intrusivetherapies at both physical and psychological levels.

Patients with PH often feel isolated by their diagnosis93 andmany seek help from support groups for numerous reasonsincluding learning about their illness, sharing coping strategieswith others who have similar health problems, sharing theirexperiences, and gaining emotional support. Encouragingpatients and their family members to be part of support groupscan have positive effects on coping, confidence, outlook andrelationships.94 Nationally the UK pulmonary hypertensionpatient group (The Pulmonary Hypertension Association UK,http://www.pha-uk.com) offers support to patients and theircarers. Patients may also access the NHS Expert PatientsProgramme for people living with long term chronic ill health

Box 4 Measurements typically made at right heartcatheterisation

c Pressure measurements should be made in the followingplaces:

– systemic artery– pulmonary capillary wedge (or left ventricular end-

diastolic pressure if not obtainable)– pulmonary artery– right ventricle– right atrium– (left atrium if entered via a patent foramen ovale or atrial

septal defect)c Blood samples for oximetry should be taken from:

– systemic artery– (left atrium if entered)– pulmonary artery (take 3 saturations and average results)

c Derived variables to be calculated:– cardiac output and index– pulmonary and systemic vascular resistances





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through their local GP surgery or library, and their localpulmonary hypertension support group where this exists.

RECOMMENDATIONS32. Patients with PH should be managed by an experienced

multiprofessional team with the required skill and expertiseto meet the holistic needs of the patient and their carers.These needs include information about the disease and itsprognosis, education and support in managing complexdrug therapies, psychological, social and spiritual support,and access to local support in the community.

33. Patients should be encouraged to join a support group.

6.3.1 Family planningPregnancy is associated with a high risk of maternal death. TheWHO identifies PH as a contraindication to pregnancy andadvises discussing termination in the event of pregnancy.

For contraception progesterone only preparations such asmedroxyprogesterone acetate and etonogestrel are highlyeffective.95 The Mirena coil is also effective but 5% of womenmay have a vasovagal reaction96 which can have potentially fataleffects in the setting of reduced cardiovascular reserve.Sterilisation is rarely used in this population due to theoperative risks and higher failure rate. Bosentan is an enzymeinducer and may reduce the efficacy of hormonal contraceptivepreparations (see section 6.4.7).

Some patients who become pregnant choose to continue theirpregnancies even when they are informed of the high risk.Despite a variety of approaches to its management97–99 themortality remains high. Early treatment with disease-targetedtherapy100 101 may improve the chances of maternal survival.With timely admission to hospital, planned elective delivery102

and incremental regional anaesthesia with close cooperation of aPH multidisciplinary team, a successful outcome for mother andfetus may be possible although maternal mortality remainshigh.103

RECOMMENDATION34. Patients with PH should be counselled regarding the very

high risk of pregnancy (.30% mortality) with clearcontraceptive advice. They should be offered early termina-tion of pregnancy if the pregnancy is unwanted.

35. If a patient becomes pregnant termination of pregnancyshould be discussed. When patients are fully informed andunderstand the risks of proceeding with pregnancy, treat-ment with disease-targeted therapies for PAH represents arealistic option and may improve the chances of maternalsurvival.

6.3.2 Physical activityAdvice regarding physical activity is empirical in PH and basedon consensus opinion. A recent study has demonstrated animprovement in exercise capacity in patients who took part in atraining programme.104

RECOMMENDATIONS36. Patients should be encouraged to be as active as their

symptoms allow. Mild breathlessness is acceptable butpatients should be advised to stop exercising if they becomemoderately or severely breathlessness, or develop exertionaldizziness or chest pain.

6.3.3 Heart failure and arrhythmiasHeart failure gives rise to fluid retention which is improved bydiuretics, although no randomised controlled trials exist on theuse of diuretics in PH.

Digoxin has been shown to improve cardiac output acutely inIPAH,105 although its efficacy is unknown when administeredchronically.

Atrial flutter and other tachyarrhythmias are often poorlytolerated and may present with worsening heart failure orsyncope. Treatment with an appropriate therapy after verifica-tion of the arrhythmia is recommended. Note that b-blockersare poorly tolerated in PH.106

RECOMMENDATIONS37. Diuretics are indicated to reduce fluid retention.38. Digoxin may be beneficial in heart failure and should be

considered in patients in sinus rhythm who remainsymptomatic on medical therapy.

39. Acute arrhythmias require prompt management with theaim of restoring sinus rhythm and preventing recurrence ofthe arrhythmia.

6.3.4 ImmunisationsPatients with PH are prone to infections which are often poorlytolerated because of their reduced cardiovascular reserve.

RECOMMENDATION40. Patients should be offered immunisation against pneumo-

coccal pneumonia and annual immunisation against influ-enza.

6.4 Disease-targeted therapies for PAHThe aim of therapy is to improve survival, symptoms and QoL.On the basis of a series of randomised trials, epoprostenol,iloprost, treprostinil, bosentan, sitaxsentan and sildenafil areavailable as monotherapy in some forms of PAH. These drugsoffer not only improved symptom control, exercise capacity,QoL and haemodynamics, but also the prospect of extendedsurvival. Survival is closely related to WHO functional class andexercise capacity.15 107

6.4.1 Therapeutic classes of drugsOnly therapies that are used in current clinical practice in theUK and Ireland have been considered. Since many reviews ofdrug trials in PAH have been published, we have chosen totabulate those studies published before November 2006. Forbrevity these trials are not discussed further in the text.Tables 4–11 include all randomised trials and those non-randomised trials considered by the consensus meeting to havesignificant impact based on the number of patients in the trial,study design and data collection. They have not been selectedon the basis of a positive or negative result.

Entry criteria into the randomised trials were similar acrossstudies: 6MWT distance .100–150 m and ,450–500 m (exceptSTRIDE-1 study which had no exercise limitations), mean PAP.25 mm Hg, PCWP (15 mm Hg and PVR .240 dynes/s/cm5.

There are no large comparative studies between the drugs andtherefore our recommendations are based upon a consensus ofUK and Irish specialists and the 2004 European Society ofCardiology guidelines.2

Survival has been examined up to 5 years in open labelstudies. In these tables, data are only reported up to 2–3 yearsowing to the small number of patients beyond these time





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edem

a

62 62 36 11 11 6

200

196

58 31 25 216M

WD

MLH

FQ

OL

scor

eC

ompo

site

sym

ptom

scor

eR

AP

mPA

PPV

RI

Sv O

2

CI

Pbo

0 +0.9

+1.4

+0.7

+96

21.

4%2

0.1

Tre

10 20.

1

20.

52

2.3

228

0+2

%+0

.1

Trea

tmen

tef

fect

+16*

ns +1.0

*

21.

9*2

3*2

376*

23.

4%*

+0.2

*

Infu

sion

syst

emm

alfu

nctio

nco

mm

on(2

4vs

33%

)

Ols

chew

ski

etal

2002

11

4

(AIR

Stu

dy)

PR

OL

Neb

ulis

edilo

pros

tvs

plac

ebo

Dur

atio

n:12

wee

ks

Out

com

es:

1.6M

WD

2.H

aem

odyn

amic

s,co

mpo

site

endp

oint

n=

203

(M66

,F

137)

IPA

H10

2,C

TD37

,an

orex

9,C

TEPH

57

Age

FCIII

:IV6M

WD

RA

PM

PAP

PVR

CO

Pos

t12

wee

ks:

Mea

nfr

eque

ncy

ofin

hala

tion

7.56

/day

Med

ian

inha

led

dose

30m

g/da

y

‘‘Ser

ous

adve

rse

effe

cts

sim

ilar’’

Impr

ovem

ents

mos

tm

arke

din

IPA

Hgr

oup

Com

bine

den

dpo

int

com

pris

ing:

NIm

prov

emen

tin

FCN

.10

%im

prov

emen

tin

6MW

DN

Lack

ofcl

inic

alde

terio

ratio

n

Rig

hthe

art

failu

reS

ynco

pe

Cou

ghH

eada

che

Flus

hing

Hyp

oten

sion

Jaw

pain

Dia

rrho

eaN

ause

aV

ertig

o

Pbo

10%

0 26%

20%

9% 6% 3% 11%

8% 11%

Ilo 4% 5%**

39%

**30

%27

%*

11%

12%

**9% 13

%7%

Sup

p53 59

:43

315

8 54 1041

3.8

Ilo 51 60:4

133

2

9 53 1029

3.8

5de

aths

(4Pb

o,1

Ilo)

Impr

oved

FC6M

WD

Com

bine

den

dpoi

ntEu

roQ

oL

RA

Pm

PAP

PVR

Sv O

2

CO

Pbo

13%

NR

5% +7 +1.4

20.

2+9

62

3%2

0.2

Ilo 24%

NR

17%

21

+0.5

-0.1

29*

21%

+0.1

**

Trea

tmen

tef

fect

+36*

+8**

ns ns 210

3ns +0

.3

Flus

hing

and

jaw

pain

usua

llytr

ansi

ent

Abb

revi

atio

nsfo

rta

bles

4–11

.Tr

ial

desi

gn:

DB

,do

uble

blin

d;E,

exte

nsio

n;N

R,

not

rand

omis

ed;

OL,

open

labe

l;P,

pros

pect

ive;

Pbo,

plac

ebo

cont

rolle

d;pt

,pa

tient

;R

,ra

ndom

ised

;R

e;re

tros

pect

ive.

Trea

tmen

ts:

Bos

(),

bose

ntan

(dai

lydo

se);

Epo

(),

epop

rost

enol

(ng/

kg/m

in);

IVIlo

(),

intr

aven

ous

ilopr

ost

(ng/

kg/m

in);

Neb

Ilo()

,ne

bulis

edilo

pros

t(d

aily

dose

inm

g);

Sild

(),

sild

enaf

il(d

aily

dose

inm

g);

Sita

x()

,si

taxs

enta

n(d

aily

dose

inm

g);

Sup

p,su

ppor

tive;

Trep

,tr

epos

tinil.

Con

ditio

ns:

APA

H,

asso

ciat

edpu

lmon

ary

arte

rial

hype

rten

sion

(con

nect

ive

tissu

edi

seas

e,re

paire

dco

ngen

ital

hear

tdi

seas

e,H

IVin

fect

ion

oran

orex

igen

use)

;A

SD

,at

rial

sept

alde

fect

;C

HD

,co

ngen

ital

hear

tdi

seas

e;C

TD,

conn

ectiv

etis

sue

dise

ase;

CTE

PH,

chro

nic

thro

mbo

embo

licpu

lmon

ary

hype

rten

sion

;IP

AH

,id

iopa

thic

pulm

onar

yar

teria

lhy

pert

ensi

on;

PoPH

,po

rto-

pulm

onar

yhy

pert

ensi

on;

VS

D,

vent

ricul

arse

ptal

defe

ct.

Par

amet

ers:

6MW

D,6

min

wal

kdi

stan

ce(m

etre

s);

AT,

anae

robi

cth

resh

old;

BD

I,B

org

dysp

noea

inde

x;C

Icar

diac

inde

x(l/

min

/m2);

CW

,clin

ical

wor

seni

ng;

F,fe

mal

e;FC

,fun

ctio

nalc

lass

;I/I

I/III/

IVfu

nctio

nalc

lass

esI/I

I/III/

IV;

m,m

ale;

mPA

P,m

ean

pulm

onar

yar

teria

lpre

ssur

e(m

mH

g);

PFI,

pulm

onar

yflo

win

dex

(l/m

in/m

2);

PVR

,pul

mon

ary

vasc

ular

resi

stan

ce(d

yn.s

/cm

5);

PVR

I,pu

lmon

ary

vasc

ular

resi

stan

cein

dex

(dyn

.s/c

m5/m

2);

SvO

2,m

ixed

veno

usox

ygen

satu

ratio

n;Q

oLqu

ality

oflif

e;R

AP,

right

atria

lpre

ssur

e(m

mH

g);S

BP,

syst

olic

(sys

tem

ic)

bloo

dpr

essu

re;

SF-

36,M

edic

alO

utco

mes

Stu

dy36

-item

shor

t-fo

rmhe

alth

surv

ey;S

FI,s

yste

mic

flow

inde

x(l/

min

/m2);

Sp

O2,p

erip

hera

loxy

gen

satu

ratio

ns;T

CW

,tim

eto

clin

ical

wor

seni

ng;T

PR,t

otal

pulm

onar

yre

sist

ance

;{

Trou

ghha

emod

ynam

ics

–m

easu

rem

ents

take

nbe

fore

Ilopr

ost

nebu

lisat

ion;

VE/

VC

O2

vent

ilato

ryef

ficie

ncy;

VO

2m

ax,

max

imal

oxyg

enup

take

onca

rdio

pulm

onar

yex

erci

sete

stin

g(m

l/min

/kg)

;B

NP,

B-t

ype

natr

iure

ticpe

ptid

e.S

tatis

tics:

NS

non-

sign

ifica

nt(p

.0.

05);

NR

data

not

repo

rted

;*p

,0.

01;

**p,

0.05

.M

isce

llane

ous:

HLT

x,he

art–

lung

tran

spla

ntat

ion;

PEA

,pu

lmon

ary

enda

rter

ecto

my;

PT,

patie

nt;

ULN

,up

per

limit

ofno

rmal

.





j.com/


ebruary 2008. Dow

nloaded from


Tabl

e5

Pros

tano

ids:

non-

rand

omis

edst

udie

s

Stu

dych

arac

teri

stic

sP

atie

nts

Out

com

em

easu

res

Sid

eef

fect

sC

omm

ents

Bar

stet

al19

941

17

PN

RO

LD

eno

voep

opro

sten

ol

Long

term

follo

w-u

p(u

pto

69m

onth

s)

n=

18(M

6,F

12)

IPA

H18

Pos

t1

year

:2

deat

hsM

ean

dose

:17

.6ng

/kg/

min

‘‘Min

orco

mpl

icat

ions

com

mon

’’7

non-

fata

lse

psis

2de

aths

due

topu

mp

failu

reC

lott

ing

oflin

e5

Cat

hete

rre

plac

emen

t3

Sur

viva

lin

clud

espa

tient

sw

how

ere

tran

spla

nted

(8/1

8pa

tient

s)

Sur

viva

lst

rong

lyas

soci

ated

with

NYH

Acl

ass

atba

selin

e.A

geFC

II:III

:IV6M

WD

RA

PM

PAP

TPR

SvO

2C

I

Epo

36 1:13

:426

4m11 61 17

6059

%1.

9

6MW

DR

AP

mPA

PTP

RS

vO2

CI

6m

onth

s37

02

42

62

560

+8%

+0.4

12m

onth

s34

82

32

72

640

+5%

+0.6

Long

term

follo

w-u

p(m

ean

dura

tion

Epo

17m

onth

s)4

deat

hs,

8tr

ansp

lant

ed

Sur

viva

l1

year

2ye

ar3

year

NIH

pred

icte

d77

%41

%27

%

Epo

87%

72%

63%

Hig

genb

otta

met

al19

981

13

RN

RO

L

Epop

rost

enol

61Ilo

pros

t13

Sup

port

ive

24N

oth

erap

y48

Dur

atio

n:up

to3

year

s

n=

146

(M54

,F

92)

IPA

H98

;C

TD9;

CTE

PH39

72di

ed22

tran

spla

nted

,2

pulm

onar

yen

dart

erec

tom

yM

edia

nsu

rviv

al69

5da

ys

Pred

icto

rsof

deat

h:S

v O2,

PVR

,FC

IIIor

IV,

supp

ortiv

eth

erap

y

For

patie

nts

with

SvO

2,

60%

,m

edia

nsu

rviv

al:

Pros

tano

idgr

oup:

585

days

Sup

port

ive

grou

p:23

9da

ys

NR

Onl

y9%

ofpa

tient

sw

ithFC

IIw

ere

give

npr

osta

noid

svs

64%

ofFC

IIIor

IVN

odi

ffer

ence

insu

rviv

alw

hen

stra

tifie

dfo

rac

ute

resp

onde

rst

atus

Age

FCI/I

I:III/

IV

RA

PM

PAP

PVR

CI

Sv O

2

Sup

p43 32

:39

8 58 14.6

2.1

63%

Pros

t34 3:

69

12 67 18.7

1.7

57

Roz

enw

eig

etal

1999

12

5

PN

RO

L

IVep

opro

sten

ol(f

aile

dsu

ppor

tive

ther

apy)

inco

ngen

ital

hear

tdi

seas

e

Dur

atio

n:12

mon

ths

n=

20(M

8,F

12)

CH

D20

Pos

t1

year

:1

patie

ntdi

eddu

ring

follo

wup

FCim

prov

edin

14,

unch

ange

din

5M

ean

dose

:82

ng/k

g/m

in

No

chan

gein

mea

nsy

stol

icpr

essu

rew

ithch

roni

cus

eJa

wpa

in8

Ras

h8

Art

hral

gia

6N

ause

a2

Dis

lodg

edca

thet

er7

Loca

llin

ein

fect

ion

4S

epsi

s0

Pum

pm

alfu

nctio

n2

Am

ixed

grou

pof

patie

nts

incl

udin

g11

patie

nts

who

had

unde

rgon

esu

rgic

alre

pair

ofde

fect

s;4

had

had

surg

ery

with

inth

epr

evio

usye

arA

geFC

II:III

:IV6M

WD

RA

PM

PAP

PVR

IS

v O2

CI

Epo

15 3:10

:740

8m

6 77 25 64%

3.5

6MW

DR

AP

MPA

PPV

RI

Sv O

2

CI

Epo

460m

+2 216

212

+6%

+2.4

pV

alue

ns * * * *

Long

term

outc

ome

(16

mon

ths

to5.

5ye

ars)

3tr

ansp

lant

ed,

1de

ath

Con

tinue

d





j.com/


ebruary 2008. Dow

nloaded from


Tabl

e5

Con

tinue

d

Stu

dych

arac

teri

stic

sP

atie

nts

Out

com

em

easu

res

Sid

eef

fect

sC

omm

ents

McL

augh

linet

al19

991

1

PN

RO

L

Epop

rost

enol

for

seco

ndar

ypu

lmon

ary

hype

rten

sion

Dur

atio

n:12

mon

ths

n=

33(M

7;F

26)

CH

D7;

CV

D14

;C

TEPH

3;Po

PH7

Pos

t12

mon

ths:

3pa

tient

sdi

ed1

deat

hdu

eto

pum

pfa

ilure

Sid

e-ef

fect

s‘‘c

omm

on’’:

diar

rhoe

a,ja

wpa

in,

head

ache

s,flu

shin

g7

patie

nts

had

loca

lex

itsi

tein

fect

ions

3pa

tient

sha

dse

psis

Inci

denc

eof

infe

ctio

n:Ex

itsi

te:

0.38

per

patie

ntye

arS

epsi

s:0.

09pe

rpa

tient

year

Wal

kdi

stan

ceno

tre

port

edN

opa

tient

str

ansp

lant

ed

Age

FCIII

:V

RA

PM

PAP

PVR

Sv O

2

CO

Epo

43 13:2

0

13 60 1143

54%

3.9

FCII:

III:IV

RA

PM

PAP

PVR

Sv O

2

CO

Epo

3:16

:1

23

214

256

8+1

0%+2

.4

pva

lue

ns * * * *

Long

term

outc

ome:

6de

aths

with

in18

mon

thpe

riod

Sitb

onet

al20

021

5

PN

RO

LE

Long

term

IVEp

opro

sten

ol

Dur

atio

n:up

to98

mon

ths

n=

178

(M43

,F

135)

IPA

H17

8M

ean

follo

wup

26m

onth

s(r

ange

0.5

to98

)M

ean

dose

Epo

14.4

ng/k

g/m

in

Afte

r1

year

:

Min

orco

mpl

icat

ions

freq

uent

76ep

isod

esof

cath

eter

rela

ted

seps

is(0

.19

even

tspe

rpa

tient

-ye

ar)

4de

aths

due

tose

psis

7pa

tient

sde

velo

ped

seve

repu

lmon

ary

oede

ma,

conf

irmed

asPV

OD

/PC

Hin

3

Maj

ority

ofde

aths

occu

rred

with

in2

year

sof

com

men

cing

ther

apy.

Thos

ew

hoim

prov

edto

FCI

orII

durin

gfir

st3

mon

ths

had

high

est

prob

abili

tyof

surv

ival

Mor

talit

yin

depe

nden

tof

age

orge

nder

.Pr

edic

tors

ofde

ath

atba

selin

e:N

FCIV

atba

selin

eN

6MW

D,

250

mat

base

line

NR

AP

>12

mm

Hg

Nm

PAP

,65

mm

Hg

Age

FCIII

:IV6M

WD

RA

PM

PAP

TPR

Sv O

2

CI

Epo

43 120:

5824

012 67 29

3654 2.

0

26de

aths

,13

tran

spla

nted

FCI:I

I:III:

IV

RA

PM

PAP

TPR

Sv O

2

CI

Sur

viva

l1

year

2ye

ar3

year

Epo

5:77

:42:

6

0 28

298

4+8

%+0

.6N

IHpr

edic

ted

76%

60%

47%

pV

alue

ns * * * * Epo

85%

70%

63%

McL

augh

linet

al20

021

07

PN

RO

LLo

ngte

rmIV

epop

rost

enol

Dur

atio

n:up

to12

2m

onth

s

n=

162

(M:F

1:3)

IPA

H16

2M

ean

follo

wup

36m

onth

s(m

edia

n31

,ra

nge

1to

122)

Mea

ndo

seEp

o52

ng/k

g/m

inA

fter

18m

onth

s:

Min

orsi

de-e

ffec

tsno

tre

port

ed

119

loca

lin

fect

ions

atex

itsi

te(0

.24

per

pers

on-y

ear)

70ep

isod

esof

seps

is(0

.14

per

pers

onye

ar)

4de

aths

due

tose

psis

72ep

isod

esre

quiri

ngca

thet

erre

plac

emen

t1

deat

hdu

eto

inte

rrup

tion

ofEp

o

No

rela

tions

hip

betw

een

dose

and

surv

ival

note

dTh

ose

patie

nts

who

rem

aine

dFC

IIIor

IVat

18m

onth

sat

wor

stsu

rviv

alIm

prov

edha

emod

ynam

ics

also

pred

icte

dlo

ngte

rmsu

rviv

alPr

edic

tors

ofde

ath

atba

selin

e:N

Bas

elin

eex

erci

setim

eN

Lack

ofva

sodi

lato

rre

spon

seN

FCIV

atba

selin

eN

RA

P

Age

FCIII

:IVEx

erci

setim

eR

AP

MPA

PPV

RS

v O2

CI

Epo

42 91:7

119

2s

14 61 1400

53%

1.8

FCim

prov

edEx

erci

setim

eR

AP

MPA

PPV

RS

v O2

CI

Sur

viva

l1

year

2ye

ar3

year

Epo

79%

+215

23

28

252

0+8

%+0

.6N

IHpr

edic

ted

59%

46%

35%

pV

alue

* * * * * * Epo

88%

76%

63%

Con

tinue

d





j.com/


ebruary 2008. Dow

nloaded from


Tabl

e5

Con

tinue

d

Stu

dych

arac

teri

stic

sP

atie

nts

Out

com

em

easu

res

Sid

eef

fect

sC

omm

ents

Taps

onet

al20

051

26

PN

RO

L

IVtr

epro

stin

il

Dur

atio

n:12

wee

ks

n=

16(F

16)

IPA

H8,

CTD

6,C

HD

2Po

st12

wks

1pa

tient

died

,1

unav

aila

ble

for

follo

w-u

pM

ean

dose

Tre

41ng

/kg/

min

No

serio

usad

vers

eef

fect

sat

trib

utab

leto

Tre

Extr

emity

pain

11(s

ever

e1)

Jaw

pain

11D

iarr

hoea

8H

eada

che

7N

ause

a/vo

miti

ng7

Flus

hing

3

Age

FCIII

:IV

6MW

D

RA

PM

PAP

PVR

CI

Tre

45 14:2

307

12 58 2320

1.7

FCI:I

I:III:

IVR

AP

MPA

PPV

RC

I

Epo

1:4:

9:0

21

24

275

2+0

.5

pV

alue

ns * * *

Lang

etal

2006

12

1

PN

RO

LE

Long

term

SC

Trep

rost

inil

Dur

atio

nup

to57

mon

ths

n=

122

(M34

,F

88)

IPA

H50

,C

TD10

,C

HD

23,

PoPH

3,H

IV3,

CTE

PH23

,O

ther

10M

ean

follo

wup

26m

onth

s(r

ange

3to

57)

31de

aths

,5

tran

spla

nted

82%

site

pain

Onl

y6

patie

nts

(4.9

%)

with

drew

due

topa

inC

ompl

icat

ion

rate

0.23

per

patie

nt-y

ear:

NC

ellu

litis

8%N

Abs

cess

es13

%N

Ble

edin

g7%

No

clea

rdi

ffer

ence

insu

rviv

albe

twee

ntr

eatm

ent

grou

ps,

incl

udin

gC

TEPH

Sur

viva

lsi

mila

rto

that

ofIV

epop

rost

enol

stud

ies,

and

supe

rior

toN

IHpr

edic

tion

Low

with

draw

alra

tedu

eto

site

pain

Dos

e(n

g/kg

/min

)6M

WD

Mea

nFC

12m

onth

s26 40

9*

24m

onth

s32 44

4*2.

5

Age

FCII:

III:IV

Mea

nFC

6MW

D

RA

PM

PAP

PVR

CI

Tre

49 8:81

:33

3.2

305

10 60 1228

2.1

22pa

tient

sre

ceiv

edco

mbi

natio

nth

erap

yaf

ter

1ye

ar

Sur

viva

l1

year

3ye

ar

All

caus

e89

%71

%

Bar

stet

al20

061

18

PN

RO

LLo

ngte

rmS

Ctr

epro

stin

ilD

urat

ion

upto

4ye

ars

n=

860

IPA

H41

2,C

TD16

6,C

HD

177,

HIV

13,

PoPH

43,

CTE

PH49

Of

860

revi

ewed

:M

ean

time

sinc

edi

agno

sis

42m

onth

s50

6pr

emat

urel

ydi

scon

tinue

d13

6pa

tient

sdi

ed,

11tr

ansp

lant

ed11

7de

terio

rate

dre

quiri

ngal

tern

ativ

eth

erap

y

199

(23%

)w

ithdr

ewdu

eto

adve

rse

effe

cts

Site

pain

792

(92%

)B

leed

ing/

brui

sing

170

(20%

)S

itein

fect

ion

35(4

%)

538

(63%

)re

mai

ned

onTr

eat

1ye

ar,

mea

ndo

se26

ng/k

g/m

in

Stu

dypo

pula

tion

take

nfr

omex

tens

ion

ofR

CT

and

deno

vopa

tient

s

No

diff

eren

cein

surv

ival

note

dbe

twee

nsu

b-gr

oups

Pred

icto

rsof

surv

ival

:Fu

nctio

nal

clas

sS

v O2

PVR

Sur

viva

l1

year

2ye

ar3

year

Tre

87%

78%

71%

Age

FCII:

III:IV

Tre

46 128:

654:

78

Of

332

IPA

Hpa

tient

s:

332

IPA

Hpa

tient

san

alys

ed(m

ale

74,

fem

ale

258)

Mea

ntim

esi

nce

diag

nosi

s28

mon

ths

Sur

viva

l1

year

2ye

ar3

year

NIH

pred

icte

d69

%56

%46

%

Tre

91%

82%

76%

Age

FCII:

III:IV

RA

PM

PAP

CI

Tre

45 128:

654:

7810 59 2.

2

Con

tinue

d





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ebruary 2008. Dow

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Tabl

e5

Con

tinue

d

Stu

dych

arac

teri

stic

sP

atie

nts

Out

com

em

easu

res

Sid

eef

fect

sC

omm

ents

Ols

chew

ski

etal

2000

12

3

PN

RO

LN

ebul

ised

ilopr

ost

Dur

atio

n:3

mon

ths

n=

19(M

5,F

14)

IPA

H12

,C

TD3,

CTE

PH2,

ILD

2

Post

3m

onth

sM

ean

dose

120m

g/da

y4

patie

nts

died

4re

mai

ned

bed

boun

d

2pa

tient

sha

ddo

sere

duct

ions

due

tona

usea

Cou

ghco

mm

onN

ause

a,oe

dem

a,th

orac

icpa

in,

head

ache

,ja

wpa

intr

ansi

ent

Oth

ers:

tong

uese

nsiti

vity

,gu

msw

ellin

g,re

tros

tern

albu

rnin

g

Sev

ere

popu

latio

nat

base

line

(9/

19be

dbo

und

orsy

ncop

alat

rest

)

Age

FCIII

:IV6M

WD

RA

PM

PAP

PVR

CI

Neb

Ilo39 4:

1579 15 66 18

541.

6

6MW

DFC

III:IV

RA

Pm

PAP

PVR

CI

Sv O

2

Neb

Ilo36

25:

42

5.5

27.

52

295

+0.2

+4.5

%

pV

alue

** ** ** ** ** **

7re

mai

ned

onIlo

long

term

(mea

ndu

ratio

n53

6da

ys)

Hoe

per

etal

2000

12

0

PN

RO

LN

ebul

ised

ilopr

ost

Dur

atio

n:1

year

n=

24(M

9,F

15)

IPA

H24

Pos

t12

mon

ths:

Cou

ghco

mm

ondu

ring

first

few

days

oftr

eatm

ent

Lung

func

tion

stab

le5

flush

ing,

head

ache

orja

wac

heN

odi

scon

tinua

tions

No

sym

ptom

atic

hypo

tens

ion

Exer

cise

capa

city

fluct

uate

din

rela

tion

totim

ing

ofdo

se

Pers

istin

gsh

ort

term

vaso

dila

tion

post

dose

note

dth

roug

hout

Thos

ew

ithgr

eate

stsh

ort

term

resu

ltha

dm

ost

mar

ked

long

term

impr

ovem

ent

inPV

RA

geFC

III:IV

6MW

DR

AP

MPA

PPV

RS

v O2

CO

Neb

Ilo38 20

:427

88 59 12

0562

%3.

8

6MW

DR

AP

mPA

PPV

RS

v O2

CO

3m

onth

s35

3**

23*

*2

6**

220

4**

+3%

**+0

.2

12m

onth

s36

3**

23*

*2

6**

228

0**

+5%

**+0

.6**

Opi

tzet

al20

051

24

PN

RO

LLo

ngte

rmne

bulis

edilo

pros

tD

urat

ion:

upto

5ye

ars

n=

76(M

22,

F54

)IP

AH

76A

fter

3m

onth

s:5

died

Med

ian

dose

100m

g/da

y

NR

Pred

icto

rsof

even

t-fr

eesu

rviv

alat

base

line:

NS

vO2

NR

AP

NC

IN

PVR

NPe

akV

O2

NEx

erci

sedu

ratio

n

Age

FCII:

III:IV

Peak

VO

2

RA

PM

PAP

PVR

Sv O

2

CI

Neb

Ilo43 18

:51:

711

.28 61 16

3958

%1.

8

FC RA

Pm

PAP

PVR

Sv O

2

CI

Neb

IloN

R +1 +1 +130

23

21

pV

alue

ns ns ns ** **

Aft

er1

year

:32

patie

nts

rem

aine

don

ilopr

ost

mon

othe

rapy

9de

aths

,2

tran

spla

nted

33re

quire

dal

tern

ativ

eth

erap

y

Sur

viva

l1

year

2ye

ar3

year

NIH

expe

cted

68%

55%

46%

Ilo 79%

70%

59%





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ebruary 2008. Dow

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Tabl

e6

Phos

phod

iest

eras

ety

pe5

inhi

bito

rs:

rand

omis

edst

udie

s

Stu

dych

arac

teri

stic

sP

atie

nts

Out

com

em

easu

res

Sid

eef

fect

sC

omm

ents

Wilk

ins

etal

2005

12

8(S

ERA

PH)

PR

DB

Ora

lsi

lden

afil

(50

mg

thre

etim

esda

ily)

vsbo

sent

an(1

25m

gtw

ice

daily

)

Dur

atio

n16

wee

ks

Out

com

es:

1.R

Vm

ass

onM

RI

2.6M

WD

,B

OR

G,

QO

L,B

NP,

Echo

mar

kers

n=

26(m

ale

5,fe

mal

e21

)IP

AH

22,

CTD

3P

ost

16w

eeks

:O

nede

ath

inS

ilgr

oup

No

with

draw

als

3pa

tient

son

bose

ntan

had

adm

issi

ons

toho

spita

l,2

with

fluid

rete

ntio

nN

obl

ood

test

ing

abno

rmal

ities

note

d.

Kans

asC

ardi

omyo

path

yQ

oLas

sess

men

tus

ed

Bos

Sil

Bos

Sil

Trea

tmen

tef

fect

Age

4144

RV

mas

s2

32

8.8

ns

FCI:I

I:III:

IV0:

0:14

:00:

0:12

:06M

WD

+59

+75

ns

BO

RG

scor

e+0

.22

1.5

ns

6MW

D30

429

0B

NP

fmol

/ml

26

219

ns

PAS

P91

96Q

oLS

core

+27

+6+2

2*

RA

volu

me

8783

RA

vol

+42

4ns

RV

mas

s(g

)13

416

0D

EI2

0.22

20.

01ns

CI

2.2

2.4

TEI

inde

x2

0.02

20.

11ns

CI

+0.3

+0.3

ns

Gal

ieet

al20

051

27

(SU

PER

1)

PR

DB

(E)

Ora

lsi

lden

afil

(ran

dom

ised

to20

mg,

40m

gor

80m

gth

ree

times

daily

)vs

plac

ebo

Dur

atio

n:12

wee

ks

Long

term

OL

exte

nsio

n(s

ilden

afil

80m

gth

ree

times

daily

only

)

Out

com

es:

1.6M

WD

2.H

aem

odyn

amic

s,FC

,tim

eto

clin

ical

wor

seni

ng,

requ

irem

ent

for

othe

rth

erap

y

n=

278

(mal

e69

,fe

mal

e20

9)IP

AH

175,

CTD

84,

CH

D18

Post

12w

eeks

:4

deat

hs,

9w

ithdr

awal

sN

odi

ffer

ence

note

dbe

twee

nsu

b-gr

oups

No

sign

ifica

ntdi

ffer

ence

in6M

WD

betw

een

dose

s,bu

tsi

gnifi

cant

diff

eren

cein

impr

ovem

ent

inFC

and

haem

odyn

amic

s

All

exte

nsio

nst

udy

data

base

don

80m

gth

ree

times

daily

dose

1ye

arsu

rviv

alda

tain

clud

es15

with

draw

npa

tient

s

Pbo

Sil

Age

Pbo

Sil

Pbo

Sil

20S

il40

Sil

80H

eada

che

39%

45%

FC49

516M

WD

+45*

+46*

+50*

Flus

hing

4%12

%

I:II:I

II:I

V1:

32:3

4:3

0:75

:126

:6Im

prov

edFC

7%28

%*

36%

*42

%*

Dys

peps

ia7%

12%

6MW

D34

434

4C

linic

alw

orse

ning

73

25

Bac

kpa

in11

%11

%

RA

P9

9O

ther

ther

apy

10

12

Dia

rrho

ea6%

10%

MPA

P56

52R

AP

+0.3

20.

82

1.1

21.

0M

yalg

ia6%

9%

PVR

1051

925

mPA

P+0

.62

2.1*

*2

2.6*

24.

7*Ep

ista

xis

1%7%

CI

2.2

2.4

PVR

+49

212

2*2

143*

226

1*In

som

nia

1%6%

CI

0+0

.21

+0.2

4**

+0.3

7*V

isua

ldi

stur

banc

e0%

5%

Exte

nsio

nst

udy

(med

ian

follo

wup

589

days

)n

=25

94

deat

hs,

15w

ithdr

awal

sat

1ye

ar8

rece

ived

addi

tiona

lth

erap

yM

ean

chan

gein

6MW

D51

mat

1ye

arO

vera

ll1

year

surv

ival

96%

Vis

ual

dist

urba

nce

dose

depe

ndan

t,no

tre

port

edat

20m

gdo

se

Onl

y2

serio

usev

ents

cons

ider

edat

trib

utab

leto

sild

enaf

il:N

1Le

fthe

art

dysf

unct

ion

N1

Post

ural

hypo

tens

ion





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points. Some survival studies compare observed survival againstNIH predicted survival.14 It is not clear whether this formula canaccurately predict the current natural history of IPAH and itsresults should be interpreted with caution.

6.4.2 Calcium channel blockersHigh dose calcium channel blockers are beneficial in a subset(,10%) of patients with IPAH, FPAH and anorexigen APAH whodemonstrate a positive vasoreactivity response at right heartcatheterisation and have improved 5 year survival.88 108–110 In thesepatients treatment is started with slowly titrated high dosecalcium channel blockers (for example, up to 240 mg/day ofnifedipine or up to 900 mg/day of diltiazem). If there is noimprovement after 1 month or patients are unable to achieveWHO class I or II with associated improvement in haemody-namics over 3 months, then patients should be treated as non-responders. Only 54% of those who respond acutely will maintaina sustained response to calcium channel blockers.110 Patients whohave not undergone a vasoreactivity study or those with a negativestudy should not be started on these agents.111

RECOMMENDATIONS41. Patients with IPAH, FPAH and anorexigen APAH and a

positive vasoreactivity response should be treated with highdoses of calcium channel blockers. Since only half willrespond chronically, it is important to ascertain normal-isation or near-normalisation of PAP at follow-up.

42. If patients taking high dose calcium channel blockersdemonstrate no clinical improvement after 1 month or areunable to achieve functional class I or II with associatedimprovement in haemodynamics over 3 months, then theyshould be treated as non-responders.

6.4.3 ProstanoidsProstanoids are analogues of prostacyclin and include epopros-tenol, iloprost and treprostinil. They must be given by infusion

or aerosolised for inhalation. Dosing requires balancing symp-tom control with side effects (including headache, flushing,nausea, vomiting, loose bowel motions, jaw pain and limb pain)and needs to be managed on an individual basis. There is noprescribed upper limit to dose. In most patients the doserequires progressive uptitration over time. There is a risk of localand systemic sepsis in patients on infusions. Patients must beable to manage an infusion or frequent inhaled treatment athome.

It is not possible to draw firm conclusions about the relativeefficacy of different prostanoids. The choice of therapy isdetermined by patient and physician choice which in turn isaffected by differences in the half-life of the drugs, side effectprofile, complexity of the delivery system, patient acceptabilityand the patient’s home circumstances. In some patients non-licensed therapies are preferred for these reasons.

The results of randomised trials11 110 112–116 are shown in table 4and non-randomised trials15 107 117–126 in table 5. Their use isdescribed in fig 4.

6.4.4.Phosphodiesterase 5 inhibitorsPDE 5 inhibitors are the newest class of disease-targeted therapyin PAH and there is less long term experience than prostanoidsor endothelin receptor antagonists (ERAs). Only sildenafil isavailable for use in PAH. While sildenafil has been licensed foruse at 20 mg three times daily, longer term survival data hasbeen collected at 80 mg three times daily.

The results of randomised trials127 128 are shown in table 6 andnon-randomised trials129 130 in table 7.

6.4.5 Endothelin antagonistsBosentan, an ETA and ETB receptor blocker, and sitaxsentan, aselective ETA receptor blocker, are available in the UK.

Patients taking ERAs require monthly liver function tests tomonitor transaminases which may rise and progress to liverfailure unless the dose is reduced or the drug discontinued.

Table 7 Phosphodiesterase type 5 inhibitors: non-randomised studies

Sastry et al 2004130

P R DB

Oral sildenafil (weightbased regimen 25 –100 mg three timesdaily) vs placebo

Cross over designDuration: 12 weeks

n = 22 (male 10, female 12)IPAH 22

Post 12 weeks (6 week cross over period)1 death, 1 withdrawal

Backache, headache, constipationand numbness reported morefrequentlyAge 16–55

FC II:III 18:4 Sil P Value

Exercise time 440 s Exercise time 686 s *

QoL score QoL score

Dyspnoea 22 Dyspnoea +4 *

Fatigue 20 Fatigue +2 **

Emotional 34 Emotional +3 ns

PASP 105 PASP 27 ns

CO 2.8 CO +0.7 *

Mikhail et al 2004129

P NR OL

Sildenafil

50 mg three timesdaily

Duration: 3 months

n = 10 (male 2, female 8)IPAH 7, CTD 1, toxins, 1, CTEPH 1

After 3 months:1 withdrawal

1 withdrawal due to blurred vision

‘‘No other serious acute or chronicadverse effects observed’’

Sil p Value

Sil 6MWD 395 *

Age 35 FC I:II:III 1:7:1

FC II:III 5:5 VO2max 15.1 ns

6MWD 283 RAP +1 ns

VO2max 14.8 mPAP 25 **

RAP 5 PVR 2120 *

MPAP 56 SvO2 +4 **

PVR 880 CO +0.3 ns

SvO2 65 Improvement also noted in PA accel time on echo

CO 4.7





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ebruary 2008. Dow

nloaded from


Tabl

e8

Endo

thel

inre

cept

oran

tago

nist

s:ra

ndom

ised

tria

ls

Stu

dyP

atie

nts

Out

com

em

easu

res

Sid

eef

fect

sC

omm

ents

Cha

nnic

ket

al20

011

32

RD

BPC

Pbo

vsB

os(2

50)

inPA

H

Dur

atio

n12

wee

ks

Out

com

es:

1.6M

WD

2.H

aem

odyn

amic

s,B

DI,

FC,

TCW

n=

32(M

4,F

28)

(IPA

H27

,C

TD5)

Pbo

Bos

pV

alue

Elev

ated

tran

sam

inas

es:

Bos

2(t

rans

ient

requ

iring

noch

ange

inth

erap

y)Pb

oB

osII/

III/IV

1/8/

2NS

10/1

1/0*

n11

216M

WD

349N

S43

0**

**

Age

4752

RA

P+4

.92

1.3

*

II/III

/IV0/

11/0

0/21

/0m

PAP

+5.1

21.

6**

6MW

D35

536

0PV

R+1

912

223

*

RA

P9.

99.

7C

I2

0.5

+0.5

*

mPA

P56

54p

valu

esvs

base

line

insa

me

colu

mn

pva

lues

Bos

vsPb

o(4

thco

lum

n)B

DI

1.6

(95%

CI

0.0

to3.

1)lo

wer

inB

oscf

.Pbo

Tim

eto

clin

ical

wor

seni

ngB

os.

Pbo*

PVR

942

896

CI

2.5

2.4

Rub

inet

al20

021

35

BR

EATH

E-1

RD

BPC

Pbo

vsB

os(2

50)

vsB

os(5

00)

inPA

HD

urat

ion

16w

eeks

Out

com

es:

1.6M

WD

2.B

DI,

FC,

TCW

n=

213

(M45

,F

168)

IPA

H15

0,C

TD63

.Im

prov

emen

tin

FC:

Wor

seni

ngof

pulm

onar

yhy

pert

ensi

on—

Pbo

19%

;B

os(c

ombi

ned)

8%A

bnor

mal

hepa

ticfu

nctio

n—

Pbo

3%;

Bos

(com

bine

d)9%

Sub

grou

pan

alys

isof

6MW

D:

IPA

H:

Pbo

vsB

os(c

ombi

ned)

+51

(NS

)S

Sc:

Pbo

vsB

os(c

ombi

ned)

+43

(NS

)

Pbo

Bos

Bos

Pbo

Bos

Bos

Dos

e–

250

500

Dos

e–

250

500

n69

7470

Imp

toII

28%

38%

NS

34%

NS

Age

4750

47Im

pto

I0%

3%N

S1%

NS

III/I

V65

/468

/662

/8O

vera

ll30

%42

%N

S

6MW

D33

432

633

3Pb

oB

osB

os

RA

P8.

99.

79.

9D

ose

–25

050

0

mPA

P53

5357

6MW

D32

635

3*37

9*

PVR

880

884

1167

BD

I+0

.32

0.1N

S2

0.6*

*

CI

2.4

2.5

2.2

Tim

eto

clin

ical

wor

seni

ngB

os.

Pbo*

Bar

stet

al20

046

3

STR

IDE-

1

RD

BPC

Pbo

vsS

itax(

100)

vsS

itax(

300)

inPA

H

Dur

atio

n:

12w

eeks

Out

com

es:

10%

ofpr

edic

ted

VO

2m

ax2.

6MW

D,

FC,

VO

2an

dV

E/V

c O2

atA

T,S

F36,

TCW

,ha

emod

ynam

ics

n=

178

(M37

,F

141)

IPA

H94

,C

TD42

,C

HD

42Pb

oS

itax

Sita

xN

odi

ffer

ence

sbe

twee

ngr

oups

inth

eto

tal

num

ber

ofad

vers

eev

ents

.In

cide

nce

ofse

rious

adve

rse

even

ts:

Pbo

15%

;S

itax(

100)

5%;

Sita

x(30

0)16

%).

One

deat

hdu

eto

wor

seni

ngPA

Hin

Sita

x(30

0).

Mos

tfr

eque

ntly

repo

rted

clin

ical

adve

rse

even

tsw

ithS

itax

wer

ehe

adac

he,

perip

hera

loe

dem

a,na

usea

,na

sal

cong

estio

n,an

ddi

zzin

ess.

Sig

nific

ant

inte

ract

ion

with

war

farin

led

tosi

gnifi

cant

rises

inIN

R.

Elev

ated

tran

sam

inas

es(.

36U

LN):

Pbo

3%S

itax(

100)

0%S

itax(

300)

10%

(NS

)

Whe

nda

taco

mbi

ned

with

open

labe

lex

tens

ion

stud

y,Ka

plan

–Mei

eres

timat

efo

rel

evat

edtr

ansa

min

ases

(.3x

ULN

)at

9m

onth

s8%

for

Sita

x(10

0)an

d32

%fo

rS

itax(

300)

.A

sm

ilder

pts

and

pts

with

CH

Din

clud

edin

this

stud

yun

like

BR

EATH

E-1,

post

hoc

anal

ysis

exam

ined

end

poin

tsw

hen

only

pts

with

IPA

Han

dC

TDw

ithba

selin

e6M

W,

450

inFC

III/IV

incl

uded

.6M

Wim

prov

emen

tfo

rS

itax(

com

bine

d)in

crea

sed

from

+34

to+6

5̀

Dos

e–

100

300

Pbo

Sita

xS

itax

Impr

oved

FC15

%29

%**

30%

**

Dos

e–

100

300

Wor

sene

dFC

7%0%

NS

2%N

S

n60

5563

6MW

400

416*

407*

Age

4845

44R

AP

+10N

S2

1*

II/III

/IV22

/36/

216

/39/

021

/42/

0m

PAP

02

3*2

5*

6MW

D41

339

438

7PV

R+4

92

221*

219

4*

RA

P8

79

CI

0.0

+0.3

**+0

.4*

mPA

P52

5454

%pr

edV

O2m

ax2

0.1

20.

4+3

.0N

S

PVR

911

1026

946

*,**

pvs

Pbo

CI

2.4

2.3

2.3

Tim

eto

clin

ical

wor

seni

ngS

F-36

,V

O2

and

VE/

VC

O2

atA

T:

%pr

edV

O2m

ax48

4545

No

sign

ifica

ntdi

ffer

ence

sbe

twee

ngr

oups

Con

tinue

d





j.com/


ebruary 2008. Dow

nloaded from


Tabl

e8

Con

tinue

d

Stu

dyP

atie

nts

Out

com

em

easu

res

Sid

eef

fect

sC

omm

ents

Gal

ieet

al20

061

34

BR

EATH

E-5

RD

BPC

Pbo

vsB

os(2

50)

inC

HD

(age

d.12

)

Dur

atio

n:16

wee

ks

Out

com

es:

1.S

p O2,

PVR

I2.

Hae

mod

ynam

ics,

6MW

D,

FC

n=

54(M

21,

F33

)A

SD

13,

VS

D36

,A

SD

+VS

D5

Pbo

Bos

pV

alue

Mea

nsy

stem

icar

teria

lpr

essu

rero

seby

2.5

inPb

ogr

oup

and

fell

by3.

8m

mH

gin

Bos

grou

p(d

iffer

ence

6.3

mm

Hg,

p=

0.02

8).

Pbo

/Bos

(%)

Perip

hera

loe

dem

a6/

19H

eada

che

12/1

4Pa

lpita

tions

0/11

Che

stpa

in0/

8(S

ever

ein

tens

ity18

/8)

Dis

cont

inua

tions

12/5

incl

udin

g1

epis

ode

ofel

evat

edtr

ansa

min

ases

inB

osgr

oup

Dro

pin

syst

emic

arte

rial

pres

sure

inB

osgr

oup

was

wel

lto

lera

ted

with

only

one

epis

ode

ofva

sova

gal

sync

ope

afte

rfir

stdo

seof

Bos

afte

r12

hof

bed

rest

.

II/III

/IV2/

14/1

NS

13/2

3/1N

S

Pbo

Bos

6MW

D35

637

5*

n17

37R

AP

+0.4

+0.3

NS

Age

4437

LAP

+0.5

+0.4

NS

II/III

/IV0/

17/0

0/37

/0m

PAP

+0.5

25

**

Sp O

284

82PV

RI

+155

231

7N

S

6MW

D36

633

2S

VR

I+3

792

373

NS

RA

P5

6.1

PFI

+0.0

+0.1

**

LAP

6.5

8.1

SFI

20.

2+0

.9N

S

mPA

P72

78p

valu

esfo

rFC

vsba

selin

e

PVR

I28

7034

25S

p O2

Pbo

corr

ecte

def

fect

ofB

os+1

.0%

SV

RI

3658

3244

PFI

2.0

1.9

SFI

2.1

2.7

Den

ton

etal

2006

13

3

RD

BPC

with

OL

E

PAH

CTD

pts

from

exte

nsio

nst

udie

sfr

omC

hann

ick

etal

13

2an

dB

REA

THE-

113

5(B

os(2

50an

d50

0))

Dur

atio

n:2

year

s

Initi

altr

eatm

ent

inPC

tria

lB

osPb

oA

ten

dof

PCtr

ial

Add

ition

ofEp

o1

Dis

cont

inua

tions

23D

eath

5El

evat

edtr

ansa

min

ases

7W

orse

ning

PAH

4W

ithdr

awal

ofco

nsen

t2

Hep

atiti

s2

Ana

emia

1Pn

eum

onia

1R

aise

dbi

lirub

in1

Pts

with

sign

ifica

ntin

ters

titia

llu

ngdi

seas

e(f

orce

dvi

tal

capa

city

,70

%pr

edic

ted)

wer

eex

clud

ed.

n44

22B

osPb

op

Val

ue

M/F

6/38

5/17

III/IV

NR

NR

Age

5850

6MW

D33

235

8N

S

III/IV

42/2

21/1

Even

t-fr

eesu

rviv

alat

16w

eeks

:B

os90

vsPb

o86

%M

ean

dura

tion

offo

llow

-up

1.8

year

s.D

ose

NR

Of

66pt

s,64

ente

red

into

OL

Est

udy

40re

mai

ned

onB

osm

onot

hera

pyat

1.8

year

s.In

this

grou

p,FC

had

impr

oved

in25

%an

d6M

WD

incr

ease

dfr

om35

2to

367

1ye

arsu

rviv

al86

%2

year

surv

ival

73%

SS

c37

15

SLE

53

Ove

rlap

syn

13

Unc

lass

ified

11

6MW

D31

236

1

RA

P8

8

mPA

P47

45

CI

2.4

2.5

PVR

809

722

Bar

stet

al20

061

31

STR

IDE-

2

RD

BPC

Pbo

vsS

itax(

50)

vsS

itax(

100)

vsB

os(2

50)

open

-labe

l

Dur

atio

n:18

wee

ks

Out

com

es:

1.6M

WD

2.FC

,B

DI,

TCW

n=

245

(M55

,F

190)

IPA

H14

4,C

TD74

,C

HD

26Im

prov

emen

tin

FC:

Adv

erse

even

ts–

nodi

ffer

ence

sbe

twee

ngr

oups

.N

asal

cong

estio

n,fa

tigue

and

inso

mni

are

port

edm

ore

freq

uent

lyin

Sita

xgr

oups

(NS

).D

isco

ntin

uatio

ns:

Pbo

10%

Sita

x(50

)7%

Sita

x(10

0)3%

Bos

10%

(NS

)El

evat

edtr

ansa

min

ases

(.36

ULN

):Pb

o6%

Sita

x(50

)5%

Sita

x(10

0)3%

Bos

11%

(NS

)

Div

idin

gth

est

udy

popu

latio

nin

tofo

urgr

oups

may

have

redu

ced

the

pow

erto

dete

ctdi

ffer

ence

sbe

twee

ntr

eatm

ent

and

plac

ebo

rela

ting

totim

eto

clin

ical

wor

seni

ng.

Ope

n-la

bel

Bos

arm

mak

esan

yco

mpa

rison

sw

ithth

isgr

oup

prob

lem

atic

Pbo

Sita

xS

itax

Bos

Pbo

Sita

xS

itax

Bos

Dos

e–

5010

025

0

Dos

e–

5010

025

010

%N

R13

%N

RN

R

n62

6261

60Im

prov

emen

tor

noch

ange

inFC

:

Age

5357

5549

85%

NR

98%

**N

R

II/III

/IV23

/35/

421

/38/

326

/34/

122

/37/

1W

orse

ning

FC(p

valu

esN

R):

6MW

D32

132

836

033

713

%13

%2%

9%

mPA

P49

4845

50p

vsPb

oTi

me

tocl

inic

alw

orse

ning

and

BD

I:N

osi

gnifi

cant

diff

eren

ces

betw

een

grou

psPV

R88

080

080

088

0

CI

2.4

2.7

2.4

2.4





j.com/


ebruary 2008. Dow

nloaded from


Tabl

e9

Endo

thel

inre

cept

oran

tago

nist

s:no

n-ra

ndom

ised

tria

ls

Stu

dyP

atie

nts

Out

com

em

easu

res

Sid

eef

fect

sC

omm

ents

Bar

stet

al20

031

36

BR

EATH

E-3

PO

LB

os(d

ose

rang

ing)

inPA

Hin

paed

iatr

icpt

sD

urat

ion:

12w

eeks

Wei

ght

(kg)

n M/F

Age

II/III

IPA

HC

HD

Epo

10–2

07 4/

36 7/

03 4 4

20–4

06 2/

410 5/

14 2 3

.40

6 3/3

14 3/3

3 3 3

Hae

mod

ynam

ics

inpt

s.

8ye

ars

(n=

17)

Min

or:

Flus

hing

4El

evat

edtr

ansa

min

ases

3Pe

riphe

ral

oede

ma

3A

naem

ia0

Maj

or:

Tach

ycar

dia,

hypo

tens

ion,

dizz

ines

s—1

Mar

ked

elev

atio

nin

tran

sam

inas

es—

1(in

asso

ciat

ion

with

scle

rosi

ngch

olan

gitis

)

Targ

etdo

seby

wee

k5:

10–2

0kg

:31.

25tw

ice

daily

20–4

0kg

:62

.5tw

ice

daily

.40

kg:

125

twic

eda

ilyPh

arm

acok

inet

ics

sim

ilar

toad

ults

CI

mPA

PPV

RS

VR

Bas

elin

e4.

060 12

0916

74

12w

eeks

4.5

52**

910*

*12

48**

No

sign

ifica

ntch

ange

sin

6MW

Dor

VO

2m

axFi

vech

ildre

nim

prov

edby

one

FCan

don

ede

terio

rate

d

Lang

lebe

net

al20

041

42

PO

LE

Sita

x(10

0)in

PAH

—co

ntin

uatio

nof

STR

IDE-

1D

urat

ion:

1ye

ar

nM

/FA

geII/

III/IV

IPA

HC

TDC

HD

6MW

Dm

PAP

CO

PVR

112/

948

(n=

10)

1/9/

0(n

=10

)3 3 4 38

6(n

=10

)44

(n=

10)

4.3

(n=

10)

742

(n=

10)

1pt

died

inth

est

udy

and

has

not

been

incl

uded

inth

eda

ta.

Adv

erse

effe

cts

attr

ibut

able

toS

itax:

head

ache

,pe

riphe

ral

oede

ma,

nasa

lco

nges

tion,

naus

ea.

No

elev

ated

tran

sam

inas

es

II/III

/IV6M

WD

mPA

PC

OPV

R

10/0

/0*

436*

*+1

NS

+1.1

*2

157*

*

Arm

ofS

TRID

E-1:

Pbo

4;10

0m

g3;

300

mg

3

Sitb

onet

al20

041

40

PO

LB

os(2

50)

inH

IVPA

HD

urat

ion

12w

eeks

nM

/FA

geI/I

I/III/

IV6M

WD

RA

Pm

PAP

CI

PVR

BD

IEQ

-5D

VA

SEQ

-5D

SF-

36

16 9/7

39 0/15

/133

311 52 2.

678

13.

444 0.

373.

8

I/II/I

II/IV

6MW

DR

AP

mPA

PC

IPV

RB

DI

EQ-5

DV

AS

EQ-5

DS

F-36

12w

eeks

3/10

/342

4*8 2

11*

+0.8

*2

339*

1.5*

*63

*0.

63**

1.8*

Mos

tco

mm

onad

vers

eev

ents

:Pe

riphe

ral

oede

ma

5H

eada

che

3M

uscl

ecr

amps

2Fl

uid

rete

ntio

n2

Vom

iting

2Tr

ansa

min

ases

.36

ULN

2(1

redu

ced

dose

).1

PAH

rela

ted

adm

issi

on

No

impa

cton

CD

4co

unt

orvi

ral

load

.N

ocl

ear

inte

ract

ion

with

antir

etro

vira

lth

erap

y

McL

augh

linet

al20

051

38

PO

LE

IPA

Hpa

tient

sfr

omex

tens

ion

stud

ies

ofB

REA

THE-

125

and

Cha

nnic

ket

al.2

4(s

eepr

evio

usta

ble)

(Bos

(250

and

500)

)D

urat

ion:

3ye

ars

n M/F

(5)

I/II(

%)

III/IV

(%)

Age

6MW

DR

AP

mPA

PC

IPV

RB

os(6

2.5)

1%

Stu

dygr

oup

169

21/7

91/

882

/946 34

510 57 2.

410

32B

os(1

25)

11.3

%

NIH

regi

stry

187

0/29

71 36 NR

10 60 2.3

NR

Mea

nfo

llow

-up

2.1

year

sO

bser

vatio

npe

riod

for

adve

rse

even

tsw

as78

wee

ks.

Inci

denc

eof

elev

ated

tran

sam

inas

es.

36U

LNw

as14

.9%

,5-

86U

LN3.

0%,

.86

ULN

4.2%

.

Doe

sno

tin

clud

ept

sin

who

mpr

osta

noid

ther

apy

was

star

ted

durin

gPC

stud

y(w

how

ere

with

draw

nfr

omth

est

udy)

.N

oPb

oor

hist

oric

alm

atch

edco

ntro

lgro

up.P

atie

nts

wer

ede

rived

from

PCst

udie

s,pe

rhap

sno

tre

flect

ing

norm

alIP

AH

popu

latio

n

1ye

arsu

rviv

al2

year

surv

ival

Stu

dygr

oup

96%

*89

%*

NIH

regi

stry

69%

57%

20de

aths

(incl

udin

gon

ept

lost

tofo

llow

-up)

;3

lung

tran

spla

nts.

39pt

sre

ceiv

edal

tern

ativ

eth

erap

y(in

clud

ing

1pt

lost

tofo

llow

-up

and

3pt

sfo

rw

hom

trea

tmen

tw

asun

know

n).

Rem

aini

ngon

Bos

mon

othe

rapy

:1

year

85%

;2

year

s70

%6M

WD

NR

Bos

(250

)77

.4%

Bos

(500

)10

.1%

Con

tinue

d





j.com/


ebruary 2008. Dow

nloaded from


Tabl

e9

Con

tinue

d

Stu

dyP

atie

nts

Out

com

em

easu

res

Sid

eef

fect

sC

omm

ents

Hug

hes

etal

2006

13

7

Re

Bos

(250

)in

inop

erab

leC

TEPH

Dur

atio

n:1

year

Out

com

es:

1.6M

WD

,FC

2.H

aem

odyn

amic

s

nM

/FA

gePr

evio

usPE

AII/

III/IV

6MW

Dm

PAP

CI

TPR

47 20/2

760 13 10

/32/

529

151 2.

111

22

Impr

ovem

ent

inFC

6MW

D(n

=45

)m

PAP

(n=

28)

CI

(n=

28)

TPR

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j.com/


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The results of randomised trials63 131–135 are shown in table 8and non-randomised trials136–143 in table 9.

6.4.6 Combination therapyThe results of randomised trials144–146 are shown in table 10 andnon-randomised trials147–150 in table 11.

The optimal management for those patients who exhibitclinical deterioration despite targeted monotherapy remains amatter of debate.9 In the event of worsening functional statusand haemodynamics, the approach of combining differentagents to augment the clinical response has a strong rationaleand has already been widely adopted by clinicians in mostcentres in Europe and the USA.150

6.4.6.1 Rationale for combination therapyThe use of combinations of drugs acting on distinctly differentpathways involved in the disease in order to maximise clinicalgain for patients with pulmonary hypertension is an emergingconcept3 151 which has gained acceptance in published guide-lines.2 6 The rationale can be summarised:

1. Multiple pathways involvedThe notion that a unifying molecular mechanism might becritical to the development of PAH seems improbable given thatthere are numerous distinct clinical syndromes, environmentalfactors and genetic abnormalities which predispose to thedisorder.152 Furthermore, a number of defects have beendemonstrated in distinct pathways that have proved amenableto targeted therapies in clinical trials (that is, NO, prostacyclinand endothelin pathways). Consequently, it is unlikely thatemploying treatments that act on a single pathway will beconsistently successful. A broad based approach targetingmultiple pathways is more likely to be effective.153

2. The precedent for combination therapy in medicineCombination therapy is often necessary in order to optimallycontrol systemic hypertension, while in a variety of otherdiseases such as cardiac failure, cancer and HIV infection,combination therapy has become standard care supported bythe highest levels of evidence. The potential for targetingmultiple pathways at the time of initial diagnosis for patientswith advanced disease makes intuitive sense. A treatmentalgorithm that includes combinations of individually successfuldrugs has merit even in the absence as yet of robust supportfrom the medical literature.

3. The lack of a durable response to monotherapyMany patients will have a suboptimal response or developtolerance to an initial therapeutic regimen.15 107 114 116 127 131

Follow-up beyond the first 3 months of oral therapy shows aproportion of patients deteriorate. A well-recognised drawbackof long term epoprostenol therapy is tachyphylaxis154 andrepeated dose escalation is frequently hindered by the onset ofdisabling side effects at high doses. The lack of durable responsedoes not indicate that monotherapy is failing to have a clinicallyimportant effect in slowing disease progression. Indeed with-drawal of the original disease-targeted therapy after addition ofa second therapy may result in acute clinical deterioration evenin stable patients.155 There are no formal trials of, or testedprotocols for, withdrawing the original therapy. Reluctance ofclinicians to withdraw the original therapy comes from theprecarious clinical state of patients who are failing monotherapyas well as evidence that prostacyclin withdrawal results inTa

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clinical deterioration which cannot be rescued by restartingtherapy.

4. Synergies between agentsBy exploiting molecular interrelationships between individualtherapeutic targets, it may be possible to improve overalltreatment efficacy and minimise risk of toxicity by usingreduced dosages of individual agents. PDE inhibitors areresponsible for limiting the adenylate cyclase regulated actionsof epoprostenol.156 The addition of PDE inhibitors may augmentand/or prolong the vasodilatory effects of prostanoids through‘‘crosstalk’’ between the cyclic adenosine monophosphate(cAMP) and cyclic guanosine monophosphate (cGMP) path-ways. The addition of sildenafil in patients refractory toepoprostenol is associated with enhanced levels of cAMP, an

effect mediated via inhibition of PDE-3 by cGMP.157 This effectin turn causes upregulation of NO production and furtherincreases in cGMP concentrations. Sildenafil, when added toaerosolised iloprost, causes a greater reduction in PVR thaneither drug alone.147 158 Co-treatment with sildenafil andberaprost may also result in greater increases in plasmaconcentrations of cAMP and cGMP than with either drugalone.159 Bosentan and sildenafil have synergistic effects onhaemodynamics and mortality in animal models.160 Sinceendothelin suppresses NO production,110 161 ERAs upregulateNO production and synergise sildenafil.147 162

6.4.6.2 Clinical evidence for use of combination therapyTo date there have been relatively few prospective trialsconducted to appraise the merits of combining drugs withdifferent modes of action for the treatment of PAH. Manyauthors have reported successful outcomes with this approachin animal models of PH as well as in observational series andnon-randomised studies. Most of the studies currently availableare of a retrospective or observational nature, describingexperiences with small numbers of heterogeneous patients(often from a single centre) without matched controlscharacterised. Investigators have mostly chosen to investigateIPAH, CTD APAH or anorexigen induced APAH, limiting theapplicability of results to other categories of PH. A number ofwell-designed studies are now underway (Appendix 1) thatshould help clarify the potential benefits of a variety of differentcombination strategies in the next 1–3 years.

A comprehensive listing of published studies is included inthis manuscript (tables 4–11). There are only four possiblecombinations of currently available agents: ERAs and prosta-noids, ERAs and PDE 5 inhibitors, PDE 5 inhibitors andprostanoids, or all three drug types together. Because there arefour types of prostanoids and two ERAs the combinations canbecome complex within these four groups.

6.4.6.3 Approaches to combination therapyGiven the limited amount of conclusive data pertaining tocombination treatment, published guidelines have so far madeno specific recommendation to guide clinicians on the next stepto improve the status of their patients who fail monotherapy.

The most commonly applied combination therapy approachto date has involved the addition of a second drug wherepatients deteriorate (or fail to sufficiently improve) despiteoptimal doses of an initial therapy. The algorithms in figs 4 and5 indicate commonly used clinical criteria for consideringcombination therapy. These criteria were chosen because theyindicate a particularly poor prognosis and can be documented.

For patients who present in WHO functional class III themost common combination is the addition of a second oralagent (sildenafil to an ERA or an ERA to sildenafil). In the UKthis accounts for 65% of combination therapy prescriptions. Insmall studies this approach has been shown to be effective inimproving functional class, 6MWT distance and peak oxygenconsumption.149 163 164

The addition of a parenteral prostanoid to the original oraltherapy increases the complexity of administering treatment. Itis indicated in the event of rapid deterioration, especially whenexpected survival time is limited. The combination of aprostanoid plus sildenafil accounts for 23% of combinationtherapy prescriptions in the UK and confers added clinicalbenefits to monotherapy compared with either class of drugsalone.147 148 158 165

Figure 4 Algorithm for the management of idiopathic, familial andanorexogen-induced pulmonary arterial hypertension. The prefixes 1stand 2nd indicate preferred and alternative drugs based on the quality andthe weight of evidence assessed by the Consensus Meeting. APAH,associated pulmonary arterial hypertension; FPAH, familial pulmonaryarterial hypertension; IPAH, idiopathic pulmonary arterial hypertension;WHO, World Health Organization.





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Although evidence suggests that the combination of bosentanand epoprostenol may have limited benefit,145 the addition ofbosentan to treprostinil improved functional class, exercisecapacity and haemodynamics,148 and the addition of inhalediloprost to bosentan monotherapy improved exercise capacity.146

Prescription of a prostanoid plus an ERA accounts for 12% ofcombination therapy prescriptions in the UK.

Given the likelihood of eventual monotherapy failure,another approach is to commence two (or more) treatmentssimultaneously at the time of diagnosis. This approach isoccasionally applied in patients in WHO functional class IVwhere survival without therapy is measured in months asevidenced by exercise capacity and haemodynamics.

While awaiting the results of further clinical trials a consistentapproach to combination therapy is urgently required in view ofthe risk of fatal outcome. The trigger to consider combinationtherapy should be part of a goal-oriented strategy to assist timingof treatment escalation.150 Individuals who demonstrate aninadequate exercise tolerance despite monotherapy for 3–4 months should be considered for additional therapy as outlinedin figs 4 and 5. All patients should be offered a second agent as partof a clinical trial where possible. There are a number of trialsenrolling patients with PAH who are on monotherapy with eitherbosentan or sildenafil (Appendix 1).

RECOMMENDATIONS43. Individuals who demonstrate an inadequate response to

monotherapy (see figs 4 and 5) should be considered for acombination of two or more disease-targeted therapies.

44. Where combination therapy is to be used, patients should beentered into a clinical trial where possible.

45. In the absence of a clinical trial, there is sufficient expertconsensus to proceed with combination therapy while thepatient’s response to treatment is carefully monitored withconsistent measures linked to national audit.

6.4.7 Drug interactions of disease-targeted therapies for PAHThere is the potential for clinically significant drug interactionsfrom combining some therapies (table 12). In addition topharmacokinetic interactions that alter drug concentrations andmay affect efficacy and increase toxicity, pharmacodynamicinteractions in the systemic vasculature may lead to hypoten-sion and systemic side effects such as dizziness.

Bosentan is an inducer of CYP3A4, a hepatic enzyme involvedin the metabolism of many drugs, as well as being a substratefor this enzyme. Co-administration of bosentan and sildenafil (aCYP3A4 substrate) in patients with PAH has been shown toreduce plasma sildenafil levels by 50%.166 Conversely, bosentanlevels are increased by about 50%, presumably by competition

Figure 5 Algorithm for the managementof pulmonary arterial hypertensionassociated with connective tissuedisease. The prefixes 1st and 2nd indicatepreferred and alternative drugs based onthe quality and the weight of evidenceassessed by the Consensus Meeting.APAH, associated pulmonary arterialhypertension; CTD, connective tissuedisease; WHO, World HealthOrganization.





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with sildenafil for metabolism. The net effect of these changeson response of patients to the combination has not beendetermined but the implications are: (1) the possibility ofhepatic toxicity from higher plasma bosentan levels; and (2) lackof effect from low dose sildenafil (that is, 20 mg dose regimen)when given with bosentan. Bosentan has been reported toreduce the level, and so efficacy, of other CYP3A4 substrates,such as simvastatin, oral oestrogens and ciclosporin. In contrast,CYP3A4 inhibitors, such as ketoconazole and ciclosporin,increase bosentan levels; co-administration of bosentan andciclosporine is contraindicated. Bosentan induces CYP2C9 andincreases warfarin metabolism.

Sitaxsentan is an inhibitor of this enzyme and co-prescriptionwith warfarin requires a reduction in warfarin dose to maintaina therapeutic INR. Sitaxentan is a weak inhibitor of CYP3A4/5.It produces an increase in oestrogen levels when given with oraloestrogen contraceptives, and a small but clinically insignificantelevation of sildenafil when given with this drug.

Sitaxentan levels are increased sixfold when given withciclosporin and co-administration of these drugs is contraindicated.

Sildenafil, as discussed above, is a CYP3A4 substrate andlevels are increased by inhibitors of this enzyme, such aserythromycin, ketoconazole and several HIV protease inhibi-tors, such as ritonavir and saquinovir.

6.4.8 Recommendations and strategies for the use of disease-targeted therapies

6.4.8.1 Idiopathic, familial and anorexogen-induced PAHWhile patients in WHO functional classes III and IV wereincluded in early trials, recent trials have seen the inclusion offunctional class II patients. There is no evidence to support thetreatment of functional class I and this has been excluded fromthe algorithm (fig 4).

The benefit of identifying responders to calcium channelblockers has been covered in section 6.4.2. Most patients inWHO functional class III are commenced on oral therapy asfirst line treatment as distinct from functional class IV whereevidence for prostanoids predominates. In some severely illpatients in functional class IV, most pulmonary hypertensionspecialists are unwilling to undertake an acute vasoreactivitystudy and would institute an intravenous epoprostenol infusionimmediately.

RECOMMENDATIONS46. Patients with IPAH, FPAH or anorexigen-induced PAH

should be managed according to the algorithm in fig 4.

6.4.8.2 Connective tissue diseaseData on the treatment of CTD APAH have been acquired fromsubpopulations of larger studies and are more limited thanIPAH. An algorithm for CTD APAH management is shown infig 5.

6.4.8.2.1 Supportive therapyOxygen therapy may alleviate moderate hypoxia. The use ofdiuretics and digoxin may benefit some patients.167

6.4.8.2.2 Calcium channel blockersThe prevalence of a vasodilator response in CTD APAH isreported between 2–5%.168 169 While reductions in PVR arecommon these do not appear to predict outcome in SSc.42 Noneof these studies has reported a clear correlation betweenresponse to calcium channel blocker therapy and vasodilatorresponse in the setting of CTD. Tolerance of high dose calciumchannel blockers is unusual in SSc APAH.42

RECOMMENDATION47. Routine vasodilator testing in patients with SSc APAH is not

mandatory since this does not identify a population whowill benefit from calcium channel blockers.

6.4.8.2.3 ProstanoidsEpoprostenol improves 6MWT distance in patients with severeSSc APAH.112 There are no long term data showing improvedprognosis. There was no improvement in outcome for SScAPAH, half of whom were treated with epoprostenol,170 whencompared to an untreated population171 10 years earlier.

Not all prostanoids appear to be effective in SSc APAH.62 114 172

Although this population were less tolerant of higher doses oftreprostinil (mean 8.4 ng/kg/min after 12 weeks), they exhib-ited haemodynamic benefit (increase of cardiac index by 0.2 l/min/m2 and reduction of indexed PVR by 320 dynes/s/cm5).There was a trend toward 6MWT distance improvement.173

Inhaled iloprost showed little benefit in the CTD APAH

Table 12 Significant drug interactions

PAH drug Mechanism Interacting drug Interaction

Bosentan CYP3A4 inducer Sildenafil Sildenafil levels fall 50%; bosentan levels increase 50%

CYP3A4 substrate Ciclosporin Ciclosporin levels fall 50%; bosentan levels increase 4-fold. Combinationcontraindicated

CYP3A4 substrate Erythromycin Bosentan levels increased

CYP3A4 substrate Ketoconazole, itraconazole Bosentan levels increased

CYP2C9 inducer HMG CoA reductase inhibitors Simvastatin levels reduced 50%; similar effects likely with atorvastatin

CYP2C9 inducer Warfarin Increases warfarin metabolism, may need to adjust warfarin dose

CYP2C9 and CYP3A4 inducers Hormonal contraceptives Hormone levels decreased, contraception unreliable

Sitaxentan CYP2C9 inhibitor Warfarin Inhibits warfarin metabolism, warfarin dose needs to be reduced

? inhibition of OATP transporter Ciclosporin Increases sitaxentan levels 6-fold; combination contraindicated

Sildenafil CYP3A4 substrate Bosentan Sildenafil levels fall 50%; bosentan levels increase 50%

CYP3A4 substrate HMG CoA reductase inhibitors May increase simvastatin/atorvastatin levels through competition for metabolism

CYP3A4 substrate HIV protease inhibitors Ritonavir and saquinovir increase sildenafil levels

CYP3A4 substrate Erythromycin Sildenafil levels increased

CYP3A4 substrate Ketoconazole Sildenafil levels increased

CYP3A4 substrate Cimetidine Sildenafil levels increased

cGMP Nitrates, nicorandil Profound systemic hypotension





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subpopulation.114 More data on SSc APAH are required todetermine the future roles of these agents.

6.4.8.2.4 Endothelin receptor antagonistsEndothelin levels are elevated in the dermis and internal organsof SSc patients174 175 as well as lung tissue.176 The fundamentalrole of endothelin in fibrotic, mitogenic and proliferativeactivity, and vasoconstriction suggests that ERAs may influencethe pathobiological processes underlying CTD APAH.177

In the SSc subgroup of double-blind, placebo-controlled trials,bosentan prevented a decline in functional ability seen withplacebo patients.133 Bosentan improved 6MWT distance,delayed the time to clinical worsening and reduced dyspnoea.The 1 year survival at 81% was the best reported survival dataat the time. In a single centre historical control registry,bosentan therapy was associated with a marked improvementin survival when compared to previously available therapy.141

The safety of this therapy has now been demonstrated in theTRAX registry which includes nearly 1500 patients with CTDAPAH with an average follow up of 9 months.178

Post hoc analysis of sitaxsentan trials found 119 patients withCTD (63 SSc, 22 MCTD, 25 systemic lupus erythematosus(SLE)) APAH, 58 of whom received placebo, 61 were treatedwith sitaxsentan 100 mg once daily, and small numbers whoreceived either 50 mg or 300 mg.179 For those taking the 100 mgdose, the net improvement in 6MWT distance was 38 m,similar to the improvement seen in IPAH (p = 0.042).

6.4.8.2.5 Phosphodiesterase inhibitionThe SUPER-1 trial127 shows a similar magnitude of benefit withsildenafil to IPAH in the subgroup with CTD APAH.180 In thistrial 84 patients had CTD APAH (including 38 SSc, 12 CREST(calcinosis, Raynaud’s phenomenon, oesophageal dysmotility,

sclerodactyly, and telangiectasia), 19 SLE and 8 MCTD), ofwhom 32 were in WHO functional class II, 51 class III and 1class IV. The 6MWT distance decreased by 13 m in the placebogroup, but increased by 42 m, 36 m and 15 m in the 20, 40 and80 mg three times daily groups, respectively. There are no longterm follow data for the CTD subgroup.

RECOMMENDATION48. ERAs should be first line therapy for patients with CTD

APAH until long term data for other treatment modalitiesshow that they have a comparable effect on survival.

6.4.8.2.6 Combination therapyThere are no data on combination therapy in the CTD PAHpopulation. Only 10% of these patients achieve WHOfunctional class II, mean PAP ,35 mm Hg and NT-proBNP,400 pmol/ml.78 Most have some response, but with a first yearmortality of 20%, and 70% remaining in functional class III orIV, the natural history of the condition has not been sufficientlyaltered to deliver a satisfactory outcome. Current consensus-based clinical practice is illustrated in fig 5 and whencombination therapy is used, sildenafil is added to bosentan orsitaxsentan. The next step is to either add inhaled iloprost or toswitch to intravenous prostanoids.

6.4.8.2.7 TransplantationTransplantation should be considered but is frequently notoffered to patients with systemic conditions. While the resultsof transplantation in a very carefully selected group of patientswith connective tissue disease is the same as for the populationwith interstitial lung disease alone, many potential candidatesmay not be suitable because of their associated comorbiditiessuch as severe oesophageal dysfunction.

Figure 6 Algorithm for the management of adults with classical Eisenmenger syndrome. CT, computed tomography; CXR, chest x ray; ECG,electrocardiogram; Echo, echocardiography; GUCH, grown-up congenital heart disease; 6MWT, 6 min walking test.





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RECOMMENDATION49. Video-fluoroscopic assessment of swallowing should be

undertaken as part of the assessment of transplantation inSSc APAH.

6.4.8.3 Adults with classical Eisenmenger syndromeEisenmenger syndrome is defined as severe PAH associated witha large and non-restrictive intra- or extra-cardiac shunt whichwith time leads to reversal of flow and cyanosis. Althoughannual mortality rates for Eisenmenger patients are relativelylow compared to other forms of PAH, median survival isreduced by at least 20 years and is worse in patients withcomplex cardiac anatomy.38 181 182 A more favourable clinicalcourse than IPAH can be anticipated in Eisenmenger patientsdue to (a) a naturally occurring right-to-left shunt (sustainingsystemic cardiac output, albeit at the expense of cyanosis) and (b)right ventricular remodelling occurring over a long time. Despitethe varied and often complex underlying cardiac anatomy andphysiology, pulmonary vascular histological changes are remark-ably similar to other forms of PAH, and most patients aresymptomatic primarily with breathlessness.183 184

Secondary erythrocytosis is universal in patients withEisenmenger syndrome. Haemoglobin concentration is inverselyrelated to oxygen saturation only in iron-replete patients.182

Furthermore, iron deficiency closely correlates with venesection,often performed for ‘‘symptoms of hyperviscosity’’ or ahaematocrit .65%, although many of these symptoms are alsocommon in patients with iron deficiency. Patients with lowerhaematocrit have a lower exercise capacity and phlebotomyitself is associated with a higher and not lower incidence ofcerebrovascular accidents.185 It is not justified to recommendroutine phlebotomy in these patients. Iron deficiency should bepromptly identified and corrected and an ‘‘upper limit’’ ofhaematocrit or haemoglobin should not be set.185

Many patients are anticoagulated with warfarin or givenantiplatelet therapy to treat or prevent intravascular thrombosiswhich is common in these patients.186 Similarly, some patientsare treated with LTOT at night on an individual basis, despiteconflicting evidence as to a clinical benefit.89 NO, prostanoidsand transplantation have been shown to be effective inimproving functional class, but they are invasive and associatedwith problems of optimal timing and patient selection.125 187 188

Bosentan has been studied in a randomised double blindplacebo controlled study (BREATHE-5) and significantlyimproved haemodynamics and exercise capacity withoutadversely affecting systemic arterial oxygen saturation inWHO functional class III patients.134 Improvements in exercisecapacity were maintained mid to long term in an open-labelextension study.189 Figure 6 shows an algorithm for themanagement of patients with Eisenmenger syndrome.

RECOMMENDATIONSIn grown-up congenital heart disease:50. Patients with Eisenmenger syndrome have a multi-organ

disease and should be managed at least in part in a grown-up congenital heart disease (GUCH) centre.

51. Each GUCH centre should have formal links to a designatedpulmonary hypertension centre.

52. Iron deficiency should be corrected. Venesection should notbe used routinely.

53. No specific recommendations can be given for general use ofanticoagulation, antiplatelet or oxygen therapy, although allof them may be used on an ad hoc basis. INR monitoring

requires specialist expertise and where anticoagulation isused haematology advice should be sought.

54. Patients in WHO functional class III should be consideredfor disease-targeted therapies for which there is evidence ofefficacy and safety supporting the use of oral bosentan.

55. Transplantation should be considered for Eisenmengerpatients remaining in WHO functional class IV.

6.4.8.4 Veno-occlusive disease and pulmonary capillaryhaemangiomatosisThe relationship between IPAH and pulmonary veno-occlusivedisease (PVOD) and pulmonary capillary haemangiomatosis(PCH) is unclear. Given reports of familial occurrences in allthree conditions190–192 and the identification of a BMPR2 receptorgene mutation in a patient with PVOD,193 it has been suggestedthat PVOD and PCH may represent variants of IPAH in whichthe primary lesion affects the venous and capillary regions of thepulmonary vascular bed.2

The presentation of PVOD or PCH is often identical to IPAH,although some clinical features can be used to distinguishbetween them including more pronounced respiratory failure,digital clubbing and bibasal crackles.194 High resolution CT scanof the thorax is the most discriminatory non-invasive test. Thepresence of centrilobular ground glass opacities, septal lines andmediastinal lymphadenopathy are the most predictive featuresfor PVOD or PCH.195 It has also been suggested thatbronchoalveolar lavage showing haemosiderin laden macro-phages can be a useful discriminatory test as it demonstrates theoccult alveolar haemorrhage that occurs in PVOD/PCH.196

Definitive diagnosis requires a surgical lung biopsy197 198 but thiscarries significant mortality.198

The use of disease-targeted therapies for PAH in PVOD andPCH is problematic. There are no controlled trials and therehave been a number of case reports associating the use ofvasodilator agents (principally calcium channel blockers andprostanoids) with worsened or even fatal pulmonaryoedema.191 194 199–202 This is particularly true with PCH.203

Conversely, in PVOD there are case reports where the use ofvasodilator agents has appeared to stabilise the condition.194 204–206

There are no published data on the use of ERAs in PVOD and thereis only one reported case of the use of sildenafil,207 althoughunpublished experience with this agent has been promising. Anti-angiogenic agents such as interferon-a2a and doxycycline havebeen used in a small number of patients with PCH with variablereports of benefit.199 203 208–210

Most patients with PVOD die within 2 years.194 211 Mediansurvival with PCH is 3 years.203 Transplantation has beensuccessful in both PVOD and PCH,203 211 although a recent casereport suggests PVOD may recur after transplantation.212

RECOMMENDATION56. An acute vasoreactivity study should not be performed in

patients with PVOD or PCH, although right heartcatheterisation should be performed.

57. Anticoagulation may be hazardous since haemoptysis maybe troublesome, particularly in PCH.

58. Treatment results with disease-targeted therapy are anecdotal.Given the poor prognosis of the condition and the reports oftemporary stabilisation in some patients, disease-targetedtherapies may be attempted but must be stopped if there isany indication of worsening pulmonary oedema.

59. PCH should not currently be treated with disease-targeteddrugs. Anti-angiogenic agents such as doxycycline may be





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considered in association with laboratory measurement ofangiogenic factors.

60. Consider immediate referral for transplantation at time ofdiagnosis.

61. Atrial septostomy is a treatment option but is oftenprecluded by hypoxaemia.

6.4.8.5 Chronic thromboembolic disease6.4.8.5.1 EpidemiologyCTEPH has emerged as one of the leading causes of severe PH.The incidence and prevalence of CTEPH are unknown.Originally it was thought that 0.1–0.5% of patients whosurvived an episode of acute pulmonary embolism developCTEPH.213 214 More recent studies suggest 3.1% of patients willdevelop symptomatic CTEPH at 1 year and 3.8% by 2 yearspost-pulmonary embolism.50 The natural history of untreatedCTEPH is dismal: ,20% of patients survive 2 years if the meanPAP is .50 mm Hg at the time of presentation.215

6.4.8.5.2 PathophysiologyCTEPH is characterised by intraluminal thrombus organisationand fibrous stenosis or complete obliteration of the pulmonaryartery lumen.10 In the currently accepted model of CTEPH disease,acute pulmonary embolism, whether symptomatic or asympto-matic, serves as the initiating event. Following the embolism,disease progression occurs due to progressive pulmonary vascularremodelling and development of a generalised hypertensivepulmonary arteriopathy216 in those areas of the pulmonaryvasculature that were spared from thromboembolic occlusion.Histopathology shows changes in the pulmonary microvascula-ture in CTEPH appearing similar to those seen in other forms ofsevere, non-thromboembolic PAH.216–218 This model explains whysome CTEPH patients have severe PH out of proportion to thedegree of vascular obstruction documented on pulmonaryangiography. Patients with significant PH of microvascular originbut with little or no visible evidence of thromboembolic segmentalvessel occlusion may not always benefit from PEA surgery.219 220

The mechanism underlying the development of CTEPH is notknown. Two factors are important and should be distinguished:prevention of complete recanalisation of a pulmonary arteryafter pulmonary embolism, and the process of remodelling insmall vessels. The normal pulmonary circulation carries a highfibrinolytic potential, but alteration in the fibrinolytic systemhas not been identified in patients with CTEPH. The onlyfactors that have been linked to CTEPH are anticardiolipinantibodies221 and elevated factor VIII.222 Other risk factorsinclude chronic inflammatory disease, myeloproliferative syn-dromes, ventriculo-atrial shunt and splenectomy.223

6.4.8.5.3 Clinical findingsPatients with CTEPH usually present with symptoms and signs ofchronic PH, complaining of progressive dyspnoea on exertion andfatigue, with signs of right heart dysfunction. Others present aftera single or recurrent episode of pulmonary embolism. Clinicalfindings are similar to other forms of PH with the addition of abruit in the lung periphery in approximately 10% of patients. Thisis highly specific although of low sensitivity.

6.4.8.5.4 Investigation and general managementAs the therapeutic approach to CTEPH is different to PAH, it isimportant to clarify the diagnosis by following the diagnosticalgorithm in fig 3.224 Patients with CTEPH should receive life-long anticoagulation with warfarin in the therapeutic range of

INR between 2–3.225 It is accepted worldwide practice to insertan inferior vena cava (IVC) filter in patients with CTEPHundergoing PEA surgery. There is little evidence to support thismanagement, although there is a risk of thromboembolism inthe early postoperative period until full anticoagulation is re-established. In the UK an IVC filter is inserted in most patientsand there have been no adverse consequences arising from thispolicy to date. In females of reproductive age the IVC filter maybe removed postoperatively to avoid potential problems of IVCfilters in pregnancy.

6.4.8.5.5 Surgical managementThe treatment of choice for symptomatic CTEPH is PEA.219 Thisis the only proven treatment to offer significant symptomaticand prognostic benefit.

To identify those patients who will receive the greatestbenefit from surgery, the disease has been classified into foursubgroups based on the operative findings. Patients withproximal disease (types 1 and 2) have a much better risk:benefit ratio from surgery226 than more distal disease. Thosewith a PVR .1200 dyne/s/cm5 have a higher risk of mortalitywith attempted PEA. In particular, in patients with a PVRdisproportionately higher than the segmental obstructionvisible by imaging, there is less benefit from PEA and a muchhigher risk of mortality. Some may be considered for lungtransplantation instead. Decisions regarding operability in somepatients depend on the combined clinical experience of themultidisciplinary team.

Operative risk is almost totally dependent on CTEPH, andconcomitant procedures (CABG, valve replacement, etc) areperformed as necessary without additional risk. The onlycomorbidity that may influence the decision to operate is severe

Figure 7 Algorithm for the management of patients with chronicthromboembolic pulmonary hypertension (CTEPH). PEA, pulmonaryendarterectomy; PVR, pulmonary vascular resistance.





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parenchymal lung disease, but there are few absolute contra-indications to PEA surgery and all patients should be referred aftercomplete investigation for consideration of surgery. Age is not abarrier to surgery, and results in patients .80 years are good.

6.4.8.5.6 Surgical outcomeOverall the reported operative mortality for the PEA procedureis between 5–15% in experienced centres, but is dependent onthe case mix of patients.

6.4.8.5.7 Medical managementWhile there is no doubt that most patients with CTEPH shouldundergo PEA, it is uncertain how to approach those with non-surgical distribution of the disease and those with residual PHpost-PEA. Disease-targeted therapies for PAH are now beingstudied. Intravenous epoprostenol has been used as a bridgebefore surgery resulting in some haemodynamic stabilisa-tion.227 228 Uncontrolled studies suggest a role for both sildena-fil229 and bosentan.137 A randomised, placebo-controlled trial toestablish safety and efficacy of bosentan is currently in progress.A proposed therapeutic approach to CTEPH is presented infig 7.224 Current UK practice for medical treatment of CTEPH isto adopt the treatment algorithm as in IPAH until new evidencefrom randomised trials is available. Patients with significantpostoperative PH or late recurrence of PH are considered fordisease-targeted therapies.

6.4.8.5.8 Organisation of careIn the UK all patients with suspected CTEPH should be referredinitially to their regional NCG designated PH centre who willthen refer appropriate patients to the NCG designated centrefor PEA surgery at Papworth Hospital.

RECOMMENDATION62. All patients with CTEPH should be assessed for PEA unless

they do not wish to undergo surgery.63. An IVC filter should be inserted preoperatively.64. Patients with distal CTEPH should be managed with

disease-targeted therapies for PAH.

6.5 Patient-centred outcomesCompared with healthy individuals, patients with PH sufferfrom limitations in their physical mobility, energy, emotionalreactions and social isolation. Although measurement ofHRQoL and QoL is important in this patient population, theimpact of PH and its treatments on HRQoL or QoL has nottraditionally been assessed in clinical practice.

In some clinical trials of PAH treatments HRQoL and genericmeasures such as the Short-Form-36, Minnesota, or theEuroQoL were assessed.11 114 116 127 172 230 The content of these isnot disease-specific. A new disease-specific patient reportedoutcome instrument, CAMPHOR, has been developed.94

CAMPHOR correlates well with the most common surrogateend points used for assessing disease progression and is sensitiveto small changes in health and QoL in this patient group.231

RECOMMENDATION65. A QoL assessment such as CAMPHOR should be used in

routine clinical practice.

6.5.1 Follow-up and shared carePatients with PAH require life long follow-up since the drugtreatments are not curative and the disease may break through

drug treatment unpredictably. Routine follow-up shouldinclude a history and physical examination, 6MWT andCAMPHOR questionnaire. Further investigations should beperformed according to the clinical status of the patient andinclude ECG, chest radiography, biomarkers, echocardiography,right heart catheterisation, cardiac magnetic resonance and CT.

Patients who live at a distance from a designated centre willbe admitted to their local hospital in case of emergency. It isimportant that a local physician knows the patient. Dependingon the interest of the physician and local hospital facilitiesshared care may be considered.

RECOMMENDATION66. Patients with PAH, CTEPH and others treated with disease-

targeted therapy should receive life-long follow-up in anNCG designated centre.

67. Patients taking disease-targeted therapy normally require3 monthly hospital outpatient visits.

68. Patients living at a distance from a designated centreshould also be followed up by a local physician.

6.6 Atrial septostomyPatients with IPAH and a patent foramen ovale (PFO) have asurvival advantage over those without a PFO,232 supporting theconcept of atrial septostomy as a treatment for IPAH. Thecreation of an inter-atrial right to left shunt can decompress theright ventricle, increase left ventricular preload and increasecardiac output, improving systemic oxygen transport despitearterial oxygen desaturation.

The precise role of atrial septostomy in the treatment of IPAHremains uncertain, but evidence is suggestive of benefit inpatients who are in WHO functional class IV with right heartfailure refractory to medical therapy or with severe syncopalsymptoms.233–235

The recommended technique is graded balloon dilation atrialseptostomy which produces equivalent improvements inhaemodynamics and symptoms but reduced risk comparedwith the original blade technique.235 236 A baseline mean rightatrial pressure of .20 mm Hg and an oxygen saturation at restof ,80% breathing air indicates a high risk of procedure relatedmortality and in general atrial septostomy should be avoided. InUK practice atrial septostomy is considered only in patientswho are failing medical therapies. This includes patients whoare being considered for or awaiting transplantation.

Evidence suggests improvements in cardiac index followingthe procedure of 15–58% with improvements in 6MWTdistance.235 237

Severe IPAH has been the main indication for atrialseptostomy in adults, although other indications include PAHassociated with surgically corrected congenital heart disease,distal CTEPH, PVOD, PCH and SSc APAH.

The impact of atrial septostomy on long term survival has notbeen established in prospective uncontrolled studies, but reportsdo support improvements in survival within the patientpopulations treated and late deaths are primarily due toprogression of the pulmonary vascular disease which isunaffected by septostomy per se.235

RECOMMENDATIONS69. Atrial septostomy should be regarded as a palliative or

bridging procedure for patients with severe PAH failing onmedical therapy.





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70. Atrial septostomy should be performed by centres withexperience in the procedure of graded balloon dilation atrialseptostomy, the preferred choice of procedure.

71. Patients with advanced PAH whose right atrial pressure is.20 mm Hg and whose oxygen saturation at rest is ,80%are at high risk of dying if the procedure is undertaken.

6.7 TransplantationThe advent of effective medical therapy for severe PAH haspresently reduced the number of patients referred for trans-plantation. The long term outcomes of such patients remainuncertain and it is clear that lung or heart lung transplantationwill remain an important mode of treatment both for patientsfailing medical treatment either following an initial period ofclinical benefit or not. Transplantation guidelines have beenpublished.238 Studies demonstrate up to 25% of patients withIPAH may fail to improve on disease-targeted therapy and theprognosis of those who remain in functional class III or IVremains poor.15 107

6.7.1 Prognostic factors in consideration of transplant listingAetiologyThe prognosis of PAH varies according to its underlyingaetiology. SSc APAH has a worse prognosis than IPAH evenwith prostanoids.112 239 Patients with PAH associated withcongenital left to right shunts have an improved survival andthis has been noted in patients with advanced disease ontransplant waiting lists. PVOD and PCH have the worstprognosis due to the lack of disease specific medical therapy.

Functional studiesIn addition to WHO functional class, exercise testing correlateswith survival in IPAH. A 6MWT distance ,332 m or a peakoxygen consumption ,10.4 ml/min/kg is associated with aworse prognosis.54 59

HaemodynamicsAdverse predictors of poor survival include cardiac index,2 l/min/m2, right atrial pressure .20 mm Hg, a mean PAP.55 mm Hg and a mixed venous oxygen saturation ,63%.1 Itis important to note that the adverse haemodynamic data donot predict a lack of potential response to medical therapy.240

6.7.2 Choice of surgeryFor patients with PAH, choosing the transplant operation is animportant facet of preoperative evaluation. Both heart lung andisolated lung transplantations have been performed forpulmonary vascular disease but heart and lung transplantationshould now be reserved for patients who are not candidates forlung transplantation alone. The threshold of unrecoverable rightventricular dysfunction remains unknown and severe dysfunc-tion has been shown to be reversible after isolated lungtransplantation. While afterload is immediately reduced bylung transplantation, right ventricular dysfunction does notimprove immediately and haemodynamic instability is acommon problem in the early postoperative period.241 Bothsingle lung transplantation (SLT) and bilateral lung transplan-tation (BLT) have been performed for PAH. While recipientsurvival rates have been similar after SLT and BLT for PAH, anycomplication in the allograft following SLT is associated withsevere hypoxaemia and there has been a move towards BLT.The International Society of Heart and Lung Transplantation

(ISHLT) reported that in 2005 BLT was performed in 95% ofisolated lung transplantations for PAH.

In PAH patients with Eisenmenger syndrome the option ofHLT should be carefully considered, despite the fact both SLTand BLT have been combined with repair of cardiovascularanomalies.242

Patients with Eisenmenger syndrome due to ventricular septaldefects have improved survival with HLT.243 Overall worldwideactivity for HLT has dropped over the years with only 75operations reported to the ISHLT in 2006.

OutcomesActuarial survival following transplantation for PAH has beenwell documented by the Registry of the ISHLT. The overall5 year survival is 45–50%.244 Transplantation for PAH andEisenmenger syndrome has the highest perioperative mortalityamong the major diagnostic categories of patients undergoingtransplantation, and this is explained by the complexity of thesurgery in severe PH.

RECOMMENDATION72. Designated PH centres should establish a clear working

relationship with a UK transplant centre to facilitate thereferral process.

73. Patients should be referred if they fulfil the generalinternational guidelines for transplantation and are func-tional class III or worse.

74. The potential need for transplantation should be discussedwith all patients presenting in WHO functional class III.Patients in WHO functional class IV should be referred onpresentation to a transplant unit if they appear to bepotential candidates.

75. All candidates should be treated with disease-targetedtherapy before undergoing transplantation.Transplantation should be undertaken when treatmentwith such therapy is failing.

76. Those patients who show significant improvementsfollowing medical therapy over the first 3 months andwho in particular move to WHO class II functional statuscan defer further transplant assessment or listing.

6.8 New and future therapiesPAH research is currently thriving, with new drug treatments inclinical trials and several novel targets under active investiga-tion. Interest in correcting endothelial dysfunction andincreased vasomotor tone remains, but there is now greateremphasis on addressing directly the structural changes thataccompany and in some cases precede the development ofincreased PVR. The pleotrophic effects of statins (anti-prolifera-tion, pro-apoptosis, anti-inflammation) together with preclini-cal observations suggest this drug class may be beneficial inPAH, but this remains to be demonstrated. Tyrosine kinaseinhibitors such as imatinib have attracted interest following acase report,245 but the results of formal clinical studies areneeded to establish safety in PAH. Other interesting pharma-cological strategies include inhibition of the serotonin reuptaketransporter, activation of potassium channels, inhibition of Rhokinase, and modification of mitochondrial pyruvate dehydro-genase kinase. Cell based therapy is also under investigation.Endothelial progenitor cells from patients can be expanded inculture and there is interest in using these cells to deliver genetherapy to the pulmonary vascular bed. This is at a very early





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stage and further work needs to be done to establish the mostappropriate cell phenotype to deploy.

PAH is a heterogenous condition and it is unlikely that onetreatment protocol will suit all patients. Advances in ourunderstanding of the genetic basis of FPAH have fuelledspeculation that a specific corrective therapy may emerge forsome patients. For many, effective treatment will lie withcombination therapy. At present, the emerging strategy is tocombine existing treatments (prostanoid, ERA and PDE 5inhibitor) and new treatments will have to find their place inthis hierarchy.

A challenge will be to demonstrate efficacy from noveltherapies in clinical trials. Drugs which impact on vascularstructure will not be expected to show acute effects onpulmonary haemodynamics. 6MWT distance has been widelyused as an end point, although its limitations are widelyappreciated. When looking at combination therapies and whenrecruiting patients with milder symptoms (WHO functionalclass I–II), significant increases in 6MWT distance may not beachieved due to a ceiling effect. It is clear other more sensitivetests will be required.

7. PULMONARY HYPERTENSION IN CHILDREN

7.1 IntroductionPulmonary vascular disease may often progress while the lung isstill developing and children are generally sicker than adults atpresentation. The response to treatment is less predictable inchildren who need close monitoring and rapid escalation oftherapy with any clinical deterioration. In IPAH the meansurvival time without treatment is 10 months.

7.2 Causes of pulmonary hypertension in childhoodThe Venice classification (box 1) includes all the types of PHencountered in childhood. The types of PH currently treatedwith disease-targeted therapy in children are shown in box 5.

7.3 Investigation of the pulmonary hypertensive childIt is mandatory to make an accurate and complete diagnosisbefore instituting treatment. There may be an informativehistory of fetal or neonatal incidents, premature delivery,intrauterine growth retardation, congenital diaphragmatichernia, or chronic lung disease. Initial investigations includean ECG, chest x ray and a transthoracic echocardiogram. A6MWT is performed if the child is able to cooperate. This isfollowed by a CT scan, and where appropriate a ventilationperfusion scan and a sleep study. Older children frequentlyrequire formal exercise testing and lung function tests. Evidencefor CTD is sought. The definitive study is cardiac catheterisa-tion following an established protocol with vasodilator testingusing NO and a high inspired oxygen concentration.

7.4 Medical treatment of pulmonary hypertension in childrenThe treatment algorithm is a modification of the one designedfor use in adults (fig 8) and has been developed from clinicalexperience. Children are sometimes too ill to undergo cardiac

Figure 8 Algorithm for the management of pulmonary hypertension inchildren.

Box 5: Types of pulmonary hypertension treated inchildren

1. Pulmonary arterial hypertension1.1 IPAH1.2 FPAH. (Children can express the same genetic mutations anddeletions as adults with IPAH35)1.3.1 Collagen vascular disease and the vasculitides1.3.2 Postoperative congenital heart disease (not acute post-operative pulmonary hypertension, but that sustained over manyyears) which can behave like IPAH1.3.2 Congenital heart disease which has never been operable,pulmonary vascular resistance having been elevated since birthplus the classical Eisenmenger syndrome1.4.1 Pulmonary veno-occlusive disease1.5 Persistent pulmonary hypertension of the newborn

2. Pulmonary hypertension with left heart disease2.1 Left ventricular disease caused by cardiomyopathies andcongenital left heart anomalies

3. Pulmonary hypertension associated with lung diseases3.2 Interstitial and fibrotic lung disease

4. Thromboembolic disease is rare in childhood





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catheterisation246 and treatment may have to be institutedimmediately.

Only 5% of UK patients have been positive responders tovasoreactivity studies. The majority of children are thereforetreated with disease-targeted therapies. These include intra-venous epoprostenol247 (the only drug for children tested in aplacebo-controlled trial), other prostanoids, bosentan,248 andsildenafil.

Choice of therapy is determined by WHO functional class.The age of the child is important because several drugs used totreat adults are unsuitable for young children: subcutaneoustreprostinil causes site pain which is poorly tolerated; small sickchildren cannot reliably inhale an adequate dose of iloprost at2–3 h intervals. Combination therapy is often necessary.107

Treatment regimens vary because pathogenesis, age and under-standing are variable. Future therapies for children await safetydata from adult studies.

Children with severe PH and intact atrial and ventricular septamay have syncopal attacks which require an atrial septostomy.

7.5 Treatment outcome

7.5.1 Quality of lifeEvery effort is made to ensure that the children have as fulfilleda life as possible and to keep the children out of hospital asmuch as possible. Where possible those of nursery and schoolage go back to school at least for some time. This includes thosereceiving intravenous epoprostenol.

There is currently no disease-specific quality of life assess-ment for children. Therefore the SF10 (QualityMetricIncorporated, Boston, USA) is used. Parents and the olderchildren complete the form at each outpatient visit.

The results show that although physical ability is limited toapproximately 50% of normal, the psychological scores are80–90% of normal at the first and subsequent visits.249 250 Dataare similar for IPAH and APAH. The quality of life score doesnot relate to age, time since diagnosis, PVR, type of therapy(oral, intravenous, subcutaneous, or inhaled) or cause of PH.

7.5.2 SurvivalTreatment with disease-targeted therapies for PAH improvedsurvival in patients with severe pulmonary hypertension whowere in WHO functional class III and IV at Great OrmondStreet Hospital for Children (GOSHC). In children with IPAHthe cumulative survival was 84% and 76% at 1 and 3 years,respectively.249 250 It was slightly better in those with APAH.These figures include children who died either at the onset oftherapy or before therapy could be started.

IPAHSurvival is better in children given combination therapy than inthose given monotherapy.249 250 According to the treatmentalgorithm, severely symptomatic children are given epoproste-nol initially while the less symptomatic children are givenbosentan. Children deteriorating on either therapy have theother drug added to their therapeutic regimen.

APAHThese children have benefited considerably from the medica-tions used to treat patients with IPAH. The worst outcome wasseen in children with postoperative pulmonary hypertension,despite being treated as aggressively as those with IPAH. Earlierrecognition of pulmonary hypertension is essential in these

children. Not surprisingly, the best outcome is seen in thosewith Eisenmenger syndrome.

Benefit of atrial septostomyThis procedure is only carried out on the severely symptomaticchild with syncope, with or without right heart failure. Morethan 30 septostomies have been performed with no mortality.In a published series the mean age of the first 21 children treatedwas 8.4 years and the mean follow-up was 2.5 years.251 Atrialdevices have been inserted in 10 children following which therehas been no further syncope and all experienced a beneficialshift in WHO functional class.

TransplantationMany children eventually fail medical treatment and requiretransplantation.

7.6 Current service provision and education

7.6.1 Organisation of the clinical networkThe pulmonary hypertension team at GOSHC provides expertguidance and help to a network of paediatric cardiology centresat Leeds General Infirmary, Bristol Children’s Hospital,Southampton General Hospital, Freeman Hospital Newcastleupon Tyne, Birmingham Children’s Hospital, Yorkhill HospitalGlasgow and the Royal Hospital for Children, Belfast.

Each of these satellite centres has a paediatric cardiologistwith a special interest in PH. The GOSHC team hold jointclinics with local teams every 2–3 months (except Belfast), andteleclinics are interposed as needed with Belfast and Glasgow.Welsh children are seen in the Bristol clinic, with a paediatriccardiologist from the Heath Hospital Cardiff.

A genetic counselling clinic is held at GOSHC for all UKchildren and their families. Parents frequently demand thattheir other children be screened for evidence of pulmonaryhypertension.

Long term support in the community is essential. This isarranged by the Clinical Nurse Specialists who have establishedwidespread links with paediatric community nurses throughoutthe UK and with several hospices for children.

RECOMMENDATIONS77. The UK Children’s Service will accept referral of and/or be

available to give advice for all children, even on suspicion ofthe diagnosis of PH.

78. All appropriate treatment modalities that are offered toadults should be available to children including intravenousepoprostenol.

79. Close liaison with community health care professionals andschools about the pulmonary hypertensive child is essential.

8. CLINICAL RESEARCH IMPLICATIONSCurrent therapies for PAH slow down disease progression butare not curative. New approaches to treatment will be the onlymeans to benefit patients. As the number of clinical trialsexpands in such a limited patient population there are alreadybecoming too few patients to complete all the studies whichinclude new indications for existing therapies, investigation ofbenefit in diagnostic subgroups, new therapies and combina-tions of therapies. This demand for clinical research can only bemet if the maximum number of patients is entered into trialswhile refining techniques used for assessing therapeuticresponse including imaging and biomarkers.





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RECOMMENDATION80. Wherever possible patients with PH should be offered the

opportunity to participate in clinical trials. This will bemost efficiently achieved through designated centres whichall have national and international collaborations.

Funding: The consensus meeting was sponsored by the patients’ association,PHA-UK. The publication costs of this document have been met by unrestrictededucational grants from Actelion Pharmaceuticals, Encysive Pharmaceuticals,GlaxoSmithKline, LungRx, Pfizer, and Bayer Schering Pharma.

Competing interests: Iain Armstrong has received honoraria for lecturing andtravel grants for conferences from Actelion, Schering and Encysive and is amember of the Nurse Advisory Board for Actelion. Dame Carol Black has been anadvisor to Actelion, Cambridge Antibody Technology, Genzyme, and Merck & Co.Gerry Coghlan has received financial support from Actelion for nurse specialist,audit work, consultancy service, lecturing and support for congress attendance;Lilly-Icos for consultancy service; Pfizer for lecturing; Schering for nurse specialistfinancial support and consultancy services. Paul Corris has been a member ofadvisory boards for Actelion, Encysive and Pfizer and has received honoraria forlecturing from Actelion, Pfizer and Schering. Agnes Crozier is on the NurseAdvisory board for Actelion and has received travel grants for conferences fromPfizer and Actelion. Julia De Soyza has received travel grants from Actelion,Schering and Encysive and is a member of the Nurse Advisory Board for Actelion.Charlie Elliott has received honoraria for lectures from Actelion and travel grantsfrom Actelion and Schering. Sean Gaine has been a member of advisory boardsfor Actelion, GlaxoSmithKline, Encycisive and Pfizer and has received honoraria forlecturing from Actelion, GlaxoSmithKline, Encysive, and Schering. The PH Unit hasreceived contributions to research funds from Pfizer, Schering, Actelion andGlaxoSmithKline. Michael A Gatzoulis has received honoraria for lecturing andadvisory board meetings and unrestricted educational grants from Actelion andPfizer. Simon Gibbs has been a member of advisory boards for Actelion,GlaxoSmithKline, Pfizer and Encysive and has received honoraria for lecturingfrom Actelion, GlaxoSmithKline and Schering. Wendy Gin-Sing is a member of thenurse advisory board for Actelion and has received grants to attend conferencesfrom Actelion, Pfizer, Schering, Encysive, United Therapeutics andGlaxoSmithKline, and honoraria for lecturing from Actelion, Encysive and UnitedTherapeutics. Clive Handler has received travel grants for conferences fromActelion and Encysive. Luke Howard has received travel grants and lecture feesfrom Actelion and GlaxoSmithKline. Sheila G Haworth has received consultingfees from Actelion, and accepting honoraria from Pfizer. The PH unit has receivedsupport for the clinical service from Actelion and GSK. Rodney Hughes hasreceived honoraria for lecturing and travel grants from Actelion, Schering andUnited Therapeutics. Martin Johnson has received travel grants for conferencesfrom Actelion, GlaxoSmithKline and Encysive. David G Kiely is a member ofadvisory boards for Actelion, Pfizer and Encysive Pharmaceuticals and hasreceived honoraria for lecturing from Actelion, Schering, Pfizer and UnitedTherapeutics. Jim Lordan has been a member of an advisory board for Encysiveand has received travel grants and honoraria from Encysive. Nicholas Morrell hasreceived honoraria for educational lectures from Actelion, United Therapeuticsand GlaxoSmithKline, and has received research funding from Actelion andNovartis. Andrew Peacock is on the advisory boards for Actelion, Pfizer, GSK andEncysive, and has received lecture fees from Actelion, Pfizer, GSK and Encysive.Joanna Pepke-Zaba is a member of advisory board for Actelion and Pfizer, andhas received honoraria for lecturing from Actelion and Schering. Karen Sheareshas received travel grants for educational meetings/conferences from Actelion,GlaxoSmithKline and United Therapeutics. Martin Wilkins has receivedcontributions to research funds from Pfizer and Actelion and honoraria from Pfizer,Actelion, GlaxoSmithKline and Encysive. John Wort has received contributions forresearch funds and travel grants from Actelion.

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