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National Specialised Commissioning Group
Ref 20/11
Commissioning Policy
Targeted therapies for the treatment of
pulmonary hypertension in adults
September 2011
September 2012 - Targeted therapies for pulmonary hypertension COMMISSSIONING POLICY
In April 2008, the commissioning of pulmonary hypertension (PH) became the direct
responsibility of the 10 Specialised Commissioning Groups (SCGs) in England. These are
supra-regional services. As a consequence, a single national commissioning policy, operating
across England, was developed. This policy was produced, and now revised, by SCG
commissioning and public health representatives in collaboration with consultant staff who
specialise in the care and treatment of patients with pulmonary hypertension. It has drawn on
available evidence of clinical effectiveness, particularly clinical guidelines published in 2009 by
The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European
Society of Cardiology (ESC) and the European Respiratory Society (ERS).i

The policy provides the national commissioning position for disease-targeted medicines in the treatment of pulmonary hypertension in adults. This commissioning policy should be read in conjunction with the national service specification for the pulmonary hypertension service. PULMONARY HYPERTENSION


Pulmonary hypertension (PH) is a rare disorder of the blood vessels in the lung, characterised by raised pressure in the pulmonary artery, which results in a range of symptoms and may be life threatening. PH is defined as an increase in mean pulmonary artery pressure (PAP) of 25mmHg or greater at rest as assessed by right heart catheterisation. A definition of PH on exercise (as a mean PAP >30mm Hg) is not supported by published data. PH can be found in a diverse range of clinical conditions, including connective tissue disease, congenital heart diseases, chronic pulmonary thromboembolism, sickle cell disease, HIV infection, use of an appetite suppressant, and liver disease (Table 1). Pulmonary arterial hypertension (PAH) is a clinical condition characterised by the presence of pre-capillary PH in the absence of other causes of pre-capillary PH such as lung disease, chronic thromboembolism, or other rare causes. If the cause is unknown then it is referred to as idiopathic pulmonary arterial hypertension (IPAH). IPAH can occur sporadically or may be familial. - Targeted therapies for pulmonary hypertension Table 1: Updated clinical classification of pulmonary hypertension (Dana Point, 2008)1

Pulmonary arterial hypertension (PAH)
1.2.2 ALK1, endoglin (with or without hereditary haemorrhagic telangiectasia) 1.5 Persistent pulmonary hypertension of the newborn Pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis
Pulmonary hypertension due to left heart disease
Pulmonary hypertension due to lung diseases and/or hypoxia
3.1 Chronic obstructive pulmonary disease 3.3 Other pulmonary diseases with mixed restrictive and obstructive pattern Chronic thromboembolic pulmonary hypertension
PH with unclear and/or multifactorial mechanisms
5.1 Haematological disorders: myeloproliferative disorders, splenectomy. 5.2 Systemic disorders: sarcoidosis, pulmonary Langerhans cell histiocytosis, lymphangioleiomyomatosis, neurofibromatosis, vasculitis 5.3 Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid disorders 5.4 Others: tumoural obstruction, fibrosing mediastinitis, chronic renal failure on dialysis ALK-1 = activin receptor-like kinase 1 gene; APAH = associated pulmonary arterial hypertension; BMPR2 = bone morphogenetic protein receptor, type 2; HIV = human immunodeficiency virus; PAH = pulmonary arterial hypertension. - Targeted therapies for pulmonary hypertension Signs and Symptoms

The symptoms of PH are non-specific and include breathlessness, fatigue, weakness, angina, syncope, and abdominal distension. Symptoms at rest are reported only in patients with very advanced disease. Many of these symptoms are shared with other common diseases and the signs of pulmonary hypertension are difficult to elicit. The delay between onset of symptoms and diagnosis can be as long as two years. Incidence and Prevalence

Registries in Scotland and France have described the epidemiology of PAH.2, 3 The lowest estimates of the prevalence of PAH and IPAH are 15 cases and 5.9 cases/million adult population, respectively. The lowest estimate of PAH incidence is 2.4 cases/million adult population/year. Recent data from Scotland and other countries have confirmed that PAH prevalence is in the range 15–50 subjects per million population in Europe.3 In the French registry, 39.2% of patients had IPAH and 3.9% had family history of PAH. In the subgroup of APAH, 15.3% had connective tissue diseases (CTDs; mainly systemic sclerosis), 11.3% had CHD, 10.4% had portal hypertension, 9.5% had anorexigen-associated PAH and 6.2% had human immunodeficiency virus (HIV) infection.2 All designated treatment centres are required to register patients and submit data to the National Audit of Pulmonary Hypertension (NAPH) as a condition of funding. This database will provide more accurate and detailed information on the prevalence and incidence of PH in England from 2011/12. Diagnosis

IPAH is a diagnosis of exclusion. Admission is usually necessary in order to carry out a series of investigations regarding cause, baseline evaluation of pulmonary haemodynamics and function and responsiveness to potential therapy. Assessments of disease severity and prognosis are also undertaken. The diagnostic evaluation of PAH includes the following: 12-lead electrocardiogram, chest radiograph, echocardiogram, cardiopulmonary exercise testing (6 minutes walk or shuttle test), ventilation perfusion lung scan, high resolution CT scan, CT pulmonary angiogram and pulmonary function tests and in selected cases MRI and pulmonary angiography. Liver function and thyroid function studies, collagen vascular screen, and HIV antibody are useful in determining whether PAH is associated with systemic disorders. Diagnosis is made at the time of right heart catheterisation (although in very sick unstable patients this may be dangerous and treatment may be commenced in the absence of catheter data if other indicators are consistent with severe disease). It is performed primarily to confirm the diagnosis of PAH and as an indicator of disease severity. Cardiopulmonary haemodynamic measurement and vasoreactivity testing is performed to help guide therapy in selected patients, and decide on the appropriateness of calcium antagonist therapy. - Targeted therapies for pulmonary hypertension Functional class

Assessment of WHO Functional Class (FC) is an important predictor of survival, despite
large inter-observer variation in its measurement.1Table 2 describes the characteristics
of the four classes.
In untreated patients with IPAH or heritable PAH, historical data suggests a median
survival of 6 months in patients in WHO-FC IV, 2.5 years for those in WHO-FC III, and 6
years for WHO-FC I and II.1
It is expected that defining a patient‟s functional class will be a multidisciplinary team decision. Table 2: Functional classification of PH1
Patients with pulmonary hypertension but without resulting limitation of physical activity. Ordinary physical activity does not cause undue dyspnoea or fatigue, chest pain, or near syncope. Patients with pulmonary hypertension resulting in slight limitation of physical activity. They are comfortable at rest. Ordinary physical activity causes undue dyspnoea or fatigue, chest pain, or near syncope. Class III
Patients with pulmonary hypertension resulting in marked limitation of physical activity. They are comfortable at rest. Less than ordinary activity causes undue dyspnoea, fatigue, and chest pain or near syncope. Patients with pulmonary hypertension with inability to carry out any physical activity without symptoms. These patients manifest signs of right heart failure. Dyspnoea and/or fatigue may be present even at rest. Discomfort is increased by any physical activity. TREATMENT CENTRES

Six centres are designated by the National Commissioning Group to provide pulmonary
hypertension services for adults. The centres offer investigation and treatment of patients
with idiopathic pulmonary hypertension, pulmonary hypertension complicating other
diseases and assessment of response to treatment. The centres and staff also provide
support for patients and their families.
Importantly, only the designated centres are able to initiate treatment with a disease-
targeted medicine under this policy
. In some circumstances, explicit and formalised
shared-care agreements may be made by the designated centres with other specialist
centres to prescribe disease-targeted therapies. However, non-specialist clinicians and
General Practitioners should not be asked to routinely prescribe these medicines since they
are not able to submit information to the national database.
Where a patient is started on a disease-targeted therapy, their GP should be informed and
alerted to any potential for unwanted effects, including interactions with other medicines.
A service specification including standards for the delivery of care was agreed by the
National Commissioning Group (NCG) and each centre is measured against these
standards. - Targeted therapies for pulmonary hypertension Cambridge
NB: Great Ormond Street Hospital is designated to provide pulmonary hypertension
services for children. This service is funded centrally by the National Commissioning Group.
Each centre has an agreed action plan to enable them to move towards meeting all the standards. There are discussions in progress to support the development of shared care arrangements with appropriate local clinical services. There are also discussions taking place about links with the designated services for grown up congenital heart disease. COMMISSIONING OF TREATMENT

Included patient populations

Treatment with disease-targeted medicines, as described in section 5.3, will be routinely
commissioned for adults, assessed as in WHO-FC III or IV, in one of the following clinical
classifications (Table 1):
Inoperable chronic thromboembolic pulmonary hypertension (CTEPH) [NB This includes patients with potentially operable disease who refuse surgery or who are waiting for acceptance for surgery]
Treatment will also be routinely commissioned for patients with chronic renal failure on
dialysis or sarcoidosis associated with pulmonary hypertension, and for women who are
pregnant (see 5.4.5), who fall within one of the allowed classes described above.

Excluded patient populations

Treatment with disease-targeted medicines will not be routinely commissioned for patients
in the following groups unless described otherwise above:
WHO-FC I or II: clinicians support the use of disease-targeted therapies in patients in WHO Functional Class II. However, commissioners believe that further work is needed to assess the clinical and financial impact of their inclusion. Estimating the number of such patients is difficult since many will be managed within other clinical services and not known to PH centres. - Targeted therapies for pulmonary hypertension A further review of the evidence-base for targeted therapies in the
management of patients in functional class II will be submitted to the
National Commissioners Forum by November 2011 for consideration for
Patients in clinical classifications 2 and 3: the use of targeted therapies for patients in these classifications is not recommended until robust data are available. PH with unclear or multifactorial mechanisms (clinical classification group 5): there is no robust evidence to support treatment with targeted therapies in these patient groups. NB: treatment for patients with chronic renal impairment on dialysis and those with sarcoidosis is routinely commissioned as discussed in 5.1. Approved medicines

Three types of medicine may be used under this policy. However, due to differences
between some products within each class, particularly in price, they are commissioned by
individual product rather than by type, unless stated otherwise.
Doses above those specified (e.g. bosentan 250mg twice daily) will not be routinely
Commissioners with work with provider organisations to develop service specifications for
the managed supply of targeted therapies and a standard approach to pricing.
1) Phosphodiesterase type 5 inhibitors (PDE5I)
i) As Viagra tablets (unlicensed indication): for dose escalation 25-100mg three ii) As Revatio tablets: for use only at licensed dose of 20mg three times daily b) Tadalafil (oral) tablets: for use only at licensed dose of 40mg once daily
2) Endothelin receptor antagonists (ERA) (NB commissioned by type)

a) Bosentan (oral) tablets: 62.5mg – 125mg twice daily b) Ambrisentan (oral) tablets: 5-10mg once daily
3) Prostanoids
a) Epoprostenol (intravenous): dose titrated to response b) Iloprost (nebulised): 5micrograms up to 9-times daily c) Iloprost (intravenous, unlicensed product): dose titrated to response NB Treprostinil will not be routinely commissioned for new patients but funding will
continue for patients already established under the terms of the national policy.
Treprostinil is a prostanoid that may be administered by sub-cutaneous or intravenous
routes (unlicensed product). While it may have a role in the sub-cutaneous treatment of
very small numbers of seriously ill patients with PH who are not suitable for nebulised or
intravenous administration of a prostanoid, commissioners believe that, at around 3-4
times the price of equivalent alternatives, its new pricing structure cannot be justified. - Targeted therapies for pulmonary hypertension Table 3: Approximate treatment costs at recommended doses

Cost without
Cost with
* Basic NHS price. Discounted price available through „home care‟ provider that ensures supply at price similar price to lowest dose of sildenafil. Approved regimens
Treatment should be initiated and, where appropriate, escalated with the least expensive suitable product. Doses higher than those specified in 5.3 will not be routinely funded. 5.4.1 First line
 Monotherapy with an oral PDE5I will be routinely commissioned as first line  Where a PDE5I is not clinically appropriate, an ERA may be substituted.  The choice of medicine is subject to clinical discretion bearing in mind relative safety, evidence of efficacy, and cost of treatment.  Monotherapy with a prostanoid will be routinely commissioned for patients at WHO FC-IV with clinical classification 1 or 1* (see table 1). 5.4.2 Second-line therapy
 Patients who have failed to respond to a trial of therapy of adequate dose and duration (typically 8-12 weeks treatment), or failed to tolerate one of the oral therapies should be switched to an alternative oral product as monotherapy.  Patients who have initially responded to first-line therapy but then deteriorated despite dose escalation (if appropriate) may be considered for dual therapy (see 5.4.3)  Patients who have had a suboptimal response to first-line therapy (with dose escalation where appropriate) may be considered for dual therapy (see 5.4.3)  A prostanoid will be routinely commissioned for patients with clinical classification 1 and 1* (see table 1) with WHO FC-III who have failed to respond adequately or tolerate dual therapy with an oral PDE5I and an oral ERA. [NB In exceptional cases, where an acutely unwell patient requires in-patient treatment, monotherapy with a prostanoid may be initiated as an alternative to dual therapy].  A prostanoid will not be routinely commissioned for use in patients with - Targeted therapies for pulmonary hypertension 5.4.3 Dual therapy

Dual therapy will only be funded in combinations involving a PDE5I unless there
are exceptional circumstances.
Dual therapy will be commissioned for patients
 with progressive disease who have failed to respond to 1st and 2nd-line  who have initially responded to monotherapy but subsequently deteriorated despite dose escalation (if appropriate).  who have had a suboptimal response to monotherapy (with dose In exceptional cases, where a patient is acutely unwell and hospitalised, the progression to dual therapy may be accelerated. 5.4.4 Triple therapy
Triple therapy will be routinely commissioned only for patients who have been
accepted as suitable for transplant.
5.4.5 Pregnancy
PH in pregnancy is associated with high mortality. Disease-targeted therapies may
used alone, or in combination, according to clinical signs and symptoms at the
discretion of the treating clinician, irrespective of functional class.

Responsibility for demonstrating exceptionality rests with the requesting clinician.
Only evidence of clinical need will be taken into consideration. Factors such as gender, ethnicity, age, lifestyle or other social factors such as employment or parenthood will not be considered on grounds of equality. In order to demonstrate exceptionality the patient: Must be significantly different to the population of interest (ie patients with pulmonary hypertension and/or the subpopulation). Be more likely to benefit from this intervention than might be expected than The fact that the treatment might be efficacious for the patient is not, in itself, evidence of exceptionality. Both criteria should be met (efficacy and clinical exceptionality). If a patient‟s clinical condition matches certain indications which might be seen as “accepted” (e.g. the trial inclusion criteria, the licensed indication, anecdotal or routine but un-researched clinical practice etc) but these particular indications fall outside the commissioning policy, the patient is, by definition, not exceptional. - Targeted therapies for pulmonary hypertension Pre-agreed exceptions for dual therapy in combination, not involving a PDE5I, are: 6.1 Dual therapy: as a bridge for a patient switching from one mono-therapy to an alternative mono-therapy (up to a maximum of 12 weeks) 6.2 Dual therapy: for patients who have been listed for the following surgery: Heart-lung transplantation Double Lung transplantation Thrombo-endarterectomy (in patients with chronic thrombo-embolic 6.3 Continuation of existing treatments (including a prostanoid) for patients making the transition from children‟s services to adult services where it would be inappropriate to change treatments only to comply with the commissioning policy. 6.4 Continuation of existing treatments (including a prostanoid) for adult patients (i.e. started prior to the policy being agreed) which are not in accordance with the commissioning policy is permitted until the patient and their clinician consider it appropriate to stop. In those situations where the principle of exceptionality cannot be applied (i.e. in situations where there is no reference group such as funding requests for very rare clinical conditions or complications) then the following will be considered: the nature of the condition, the nature of the treatment, consideration of the biological plausibility that this treatment might work in this clinical situation, clinical guidelines, audit data, advice from specialist reference group, an assessment of value for money and prioritisation against other competing demands. Clinical Trials The commissioners will not pick up the funding of patients exiting clinical trials funded by the pharmaceutical industry, extended access programmes or compassionate funding programmes unless prior arrangements have been made with the lead commissioner (NB until national commissioning arrangements are in place, the lead commissioner will vary between regions). It is seen as the responsibility of those initiating therapy, and manufacturers sponsoring trials, to ensure that there is either an exit strategy or that ongoing treatment is provided. Patients should be fully informed of these arrangements. The commissioners will fund patients once the service development has been agreed. Patient Stopping Criteria The continued use of target therapies will be reviewed on a regular basis. The key factors influencing the cessation of treatment will be:- Clinically relevant side-effects e.g. liver function No other active treatment option available - Targeted therapies for pulmonary hypertension Drug therapies may also be withdrawn “at the end of life”. FUNDING APPROVAL

There will be no requirements to seek commissioner approval prior to the commencement of treatment BUT the release of commissioner funding is dependent on registration of the patient with the National Audit of Pulmonary Hypertension AND provision of the commissioner dataset. The commissioner dataset is as follows: - Projected cost to year end (not yet achieved) Primary diagnosis (i.e. underlying condition) WHO/NYHA Functional Classification at baseline (ie treatment-naïve) MONITORING INFORMATION

Each centre will need to provide each SCG with a monthly monitoring statement covering the following fields: - Notification of changes to drugs and dosage This policy will be reviewed on an annual basis and/or in the light of any new clinical or cost effectiveness evidence. New treatment regimens will not be considered in year unless there is evidence of a sustainable benefit. New drugs coming onto the market may be added to the list in year via the commissioners under the following circumstances: - - Targeted therapies for pulmonary hypertension If they have the same or greater efficacy than current drugs If they have an equivalent or lower cost to current treatment POLICY CHANGE PROTOCOL

The key steps in the policy change protocol are as follows:- All requests for changes to the national policy should be made to the lead SCG Director in writing. The change request should clearly set out the evidence supporting the change, the anticipated benefits, and any financial implications Requests from the clinicians should come via the national clinicians group with the chair of the group writing formally to the lead SCG Directors. The lead SCG Director will obtain a public health/specialist pharmacist review of the clinical and cost effectiveness and the cost implications. The original request and the public health/specialist pharmacy opinion will be considered by the national PH Commissioners Forum. The national PH Commissioners Forum will make a recommendation to SCGDN.

1. The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Guidelines for the diagnosis and treatment of pulmonary hypertension. European Heart Journal (2009) 30, 2493–2537. Availabl 2. Humbert M, Sitbon O, Chaouat A, Bertocchi M, Habib G, Gressin V, Yaici A, Weitzenblum E, Cordier JF, Chabot F, Dromer C, Pison C, Reynaud-Gaubert M, Haloun A, Laurent M, Hachulla E, Simonneau G. Pulmonary arterial hypertension in France: results from a national registry. Am J Respir Crit Care Med 2006;173:1023–1030. 3. Peacock AJ, Murphy NF, McMurray JJV, Caballero L, Stewart S. An epidemiological study of pulmonary arterial hypertension. Eur Respir J 2007;30:104–109. - Targeted therapies for pulmonary hypertension


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