Principal Pharmacist, Sheffield Teaching Hospitals NHS Foundation Trust
Pulmonary arterial hypertension (PAH) is a rare, progressive condition previously associated with few treatment options. This has changed significantly over the last 20 years. Awareness of the condition has improved and there have been considerable advances in the range of effective therapeutic agents. However it remains a potentially life-threatening illness requiring specialist diagnosis, treatment and ongoing management.
PAH is defined as a mean pulmonary artery pressure (mPAP)≥25 mmHg at rest as assessed by right heart catheterization (RHC) with a normal pulmonary capillary wedge pressure (pcwp) to exclude significant left heart dysfunction. This definition is used for selecting patients in all randomised controlled trials (RCTs) and registries of PAH (Task Force, 2009). The fourth ‘World Symposium on Pulmonary Arterial Hypertension’ in 2008 saw the clinical classification of pulmonary hypertension (PH) revised to identify five major groups (see Table 1). This classification is vital as the aetiology of the disease dictates the appropriate treatment course. Patients with chronic thromboembolic pulmonary hypertension (CTEPH) can potentially be cured by surgery (pulmonary endarterectomy) and medical treatments are available for those with PAH.
Presentation and diagnosis
While breathlessness is the most common symptom of PH, patients may also present with fatigue, weakness, chest pain and syncope with various degrees of disease severity (Rich S, 1987). As symptoms are vague and non-specific, patients often have a considerable wait before referral to a PH specialist. Old US registry data showed patients were waiting up to three years from onset of first symptoms to diagnosis (Abenhaim L, 1996). Sadly, a recent survey by the UK patients’ association, the Pulmonary Hypertension Association, showed the average wait in the UK is still 2.5 years (Armstrong, 2010). Diagnosis of PAH is made following a series of non-invasive and invasive investigations. Patients are often referred on the basis of an abnormal transthoracic echocardiogram performed to investigate breathlessness. The PH specialist is likely to conduct further cardiothoracic imaging with a combination of; ventilation/perfusion scanning, high-resolution compued tomography (CT) thorax, CT pulmonary angiogram and cardiac magnetic resonance imaging (MRI) with pulmonary angiogram. Patients’ exercise capacity will also be most commonly measured using the six-minute walk test (6MWT) and in certain circumstances patients will undergo cardiopulmonary exercise testing. To formally confirm the diagnosis of PH it is necessary to perform RHC to confirm a mPAP≥25 mmHg with a pcwp≤15mmHg. Parameters indicating a poor prognosis include right atrial pressure (RAP)>10mmHg, cardiac index<2.1 and mixed venous oxygen saturation<63% (Galiè N, 2009).
Prevalence and epidemiology
Recent European epidemiological studies have estimated the prevalence of PAH to be 15-50 cases per million population (Humbert M, 2006, Peacock AJ, 2007). In the French registry, 39.2% of such patients had idiopathic PAH (IPAH) and 3.9% had a family history of PAH. In the subgroup of APAH (PAH Associated with other conditions), 15.3% had connective tissue diseases (CTDs; mainly systemic sclerosis), 11.3% had congenital heart disease, 10.4% had portal hypertension, 9.5% had anorexigen-associated PAH and 6.2% had human immunodeficiency virus (HIV) infection (Humbert M, 2006).
Pregnancy in PAH is associated with a high maternal mortality rate. Effective contraceptive advice and implementation is therefore essential. Some of the treatments (notably ERAs and warfarin) are teratogenic and can interact with oral contraceptives reducing their efficacy. Extra vigilance is therefore needed when treating PAH in women of childbearing potential.
Treatments and side effects
PAH is a rapidly growing area both in terms of the number of treatments available and patients receiving them. This is just one of the reasons for an ever increasing pharmacist role in this field.
In the UK designated centres, the number of patients on targeted PAH treatments in both clinical practice and clinical trials on 31st March was 638 in 2004, 1,499 in 2007 and almost 3,000 in 2010. Prescription of these targeted therapies is guided by the National Commissioning Policy (see Table 2) which was introduced in 2008. The updated guidance will be out in Spring 2011. ‘Supportive treatments’ commonly prescribed to PAH patients include warfarin, diuretics, digoxin and oxygen. It is by no means certain that patients will need all, or indeed any of these, but after assessment they may be indicated. Most patients are anticoagulated unless there is a clear contra-indication (one exception being those with portal hypertension and varices). Patients with IPAH will have a survival advantage if prescribed warfarin (S. R. Johnson, 2006). Diuretics are frequently prescribed as management for fluid overload and peripheral oedema. Utmost care is needed in balancing potentially high doses of diuretics with electrolyte disturbance. The need for individual patients to be prescribed Long Term Oxygen Therapy (LTOT) is assessed using resting and overnight oximetry studies. Many PAH patients are not hypoxic at rest but may become significantly so on exertion.
Targeted treatments for PAH
In addition to supportive treatments, it is necessary to reduce the high pressures by dilating vessels in the pulmonary vasculature. This can be achieved selectively via ERAs and phosphodiesterase type 5 inhibitors (PDE-5I) (although these may also act elsewhere) and non-selectively through calcium channel blockers (CCBs) or prostacyclin analogues.
Until ten years ago, treatment of PAH was by continuous infusions of prostacyclin or the prostacyclin analogue, iloprost. Around this time a clinical trial enrolled patients to receive another prostaglandin, treprostinil, via a continuous sub-cutaneous infusion. Treprostinil has been licensed across Europe but withdrawn from the UK and Ireland. However, the advents of oral therapies in the form of first Endothelin Receptor Antagonists (ERA) and subsequently the PDE-5Is have transformed the treatment arena. Three ERAs (bosentan, sitaxentan and ambrisentan), one PDE-5I (sildenafil) and two prostaglandins (iloprost and prostacyclin) have been given EMA approval for the treatment of PAH, although recently sitaxentan has been withdrawn from use.
Calcium channel blockers
Rich and colleagues (Rich S, 1992) reported that a proportion of IPAH patients may respond well to CCB. This group could be identified by vasoreactivity testing at the time of RHC. Responders had a dramatic improvement in survival compared with non-responders. Diltiazem at mean doses of 720mg daily and nifedipine 170mg were studied. More recent work suggests that only around 5% of patients with IPAH will enjoy a sustained benefit from CCBs. These are likely to be patients with less severe disease (WHO class I or II) with near normal PVR and PAP after the vasoreactivity test (Olivier Sitbon, 2005). Patients demonstrating an inadequate response to CCBs should be treated with additional PAH therapy (Task Force, 2009).
Endothelin receptor antagonists
Bosentan was the first oral treatment for PAH (and the only one licensed for paediatric use in children over the age of two) and has been shown to be effective in IPAH & PAH associated with connective tissue disease (Lewis J. Rubin, 2002), congenital heart disease (Nazzareno Galiè, 2006) in large RCTs and HIV through a smaller prospective study (Olivier Sitbon, 2004).
Bosentan is a dual Endothelin (ET) receptor antagonist, which exerts its action by blocking both ET A and B receptors. This results in vasodilatation and anti-proliferative action through inhibition of ET-1. It is prescribed at a dose of 62.5mg bd for one month then 125mg bd thereafter.
Sitaxentan was the first selective ET-A receptor antagonist. This pharmacological difference never manifested itself in terms of clinical efficacy advantage over bosentan. Just before going to print, Sitaxentan was withdrawn from the market as a consequence of the risk of life-threatening liver reactions.
Ambrisentan is the newest ERA, another selective ET-A receptor that is prescribed at 5–10mg daily. Ambrisentan has the lowest incidence of LFT abnormality of the ERAs. The major advantage of ambrisentan over the other ERAs is the lack of significant drug-drug interactions. This is of particular benefit to those patients prescribed warfarin whose INR may be hard to control with the other ERAs. While concomitant use of bosentan with warfarin is not contraindicated, it is recommended that intensified monitoring of INR is carried out during the treatment initiation and up-titration period. Ambrisentan is also not known to have singnifcant interactions with hormonal contraception and hence might of be of interest for women of child bearing potential.
Monthly LFT monitoring remains mandatory for patients prescribed any one of the three ERA’s. Post-marketing surveillance data has yielded important data for bosentan and sitaxsentan, with ambrisentan data keenly awaited.
Phosphodiesterase type 5 inhibitors
Sildenafil (as Viagra) has been prescribed in PAH since 2003, however it did not receive its’ UK license until 2005. The SUPER-1 licensing study findings brought about the approval of Revatio® 20mg tds. Interestingly the extension study used doses of 40mg and 80mg tds (which are not currently licensed for PAH), and although higher doses did not affect the primary outcome (exercise capacity), a dose-dependant response in terms of haemodynamicsm was noted.
The long term results are not yet published, but smaller studies have shown the higher doses to be safe and effective. Tadalafil is approved for treatment of PAH by the FDA and by the UK. It’s once daily dosing offers potential concordance advantages but clinically the drug is similar to sildenafil. Mild headache, myalgia and flushing were the noteworthy adverse effects reported in the PHIRST study (Nazzareno Galiè, 2009). These mirror the commonly seen side effects of sildenafil.
Prostacyclin (epoprostenol) improves life expectancy, Haemodynamics, 6MWT and quality of life in patients with severe IPAH in World Health Organisation (WHO) class III and IV (Barst R J, 1996). It is the only licensed prostaglandin analogue in the UK given by continuous intravenous infusion. It has been shown to be as effective as transplantation in prolonging life. Intravenous infusions of iloprost are unlicensed in the UK, although remain favoured and prescribed by several specialist centres as a result of the better drug stability.
When reconstituted, the solution remains stable over 24 hours. This allows for once daily changing of the infusion pump. Both prostacyclin and iloprost are given via a central Hickman line. Essential to their safe delivery is comprehensive patient education around line maintenance and aseptic technique to reduce the risk of line infections. Iloprost when given via a nebuliser has a UK license.
Iloprost via the iNeb nebuliser has been shown to be an effective treatment in IPAH (Olschewski H, 2002). Whilst avoiding the possibility of life-threatening line infections, it must be used six to nine times daily due to iloprost’s short duration of action. The most common side effects of iloprost and prostacyclin are headache, flushing, GI upset and jaw pain.
Treprostinil is unlicensed in the UK and Ireland and is no longer available to new patients in those countries. It is, however approved across most EU countries and the US. Whilst avoiding the problems associated with the Hickman line, treprostinil infusions caused site pain reactions in 85% patients (Remodulin® Injection Package Insert). This is the major source of discontinuation due to adverse effects at our centre.
Treating conditions with several agents with different mechanisms of action is a logical approach used in many disease areas.
The evidence for applying this in PAH is somewhat lacking. In the absence of good quality studies, the lack of evidence and high cost makes this approach sometimes hard to justify with limited healthcare resources.
It is hoped that current studies such as COMPASS will demonstrate the advantages of certain combinations. Registry data from France shows results from practice including combination use which can differ considerably from those gained in clinical trials.
A UK wide database has been established, the first outcomes from that are due in the New Year. In our centre, the prescription of combinations accounts for around 30% of patients currently treated, and is slowly rising.
Several new agents are being trialled; from known classes, known mechanisms and altogether new pathways. The vasodilator, riociguat is a soluble guanylate cyclise stimulator which acts via the nitric oxide pathway. Phase III PATENT studies are underway. Imatinib is an anti-proliferative agent already used for chronic myeloid leukaemia and other malignancies. It is hoped that promise shown in small case series and phase II work will be borne out in the ongoing IMPRES trial. Beraprost was the first oral prostaglandin, launched in the 1990s but never became successful in the UK. The treprostinil compound is now being studied as an oral formulation in the FREEDOM study. If proven as safe and effective, these and others offer potential to sufferers of PAH and an exciting challenge to those of us managing the condition.
Medical treatment of PAH has seen an almost unparalleled development over the past 15 years. Twenty-five RCTs have been published as of May 2010 (Galiè N, 2010). This rate of development combined with the complexities of the treatments has generated a huge potential for pharmacists to play a crucial role in caring for patients with PAH. In the UK, a network of pharmacists with an interest in PAH has been set up (National Pulmonary Hypertension Pharmacist group, NPHP) and recently held their annual national meeting. By close communication between the UK specialist centres and major referral units, the NPHP aim to share best practice and improve pharmaceutical care in this rare disease.
Pharmacists are ideally placed to complement medical staff by advising on the appropriate prescription of these complex treatments and overseeing monitoring and concordance. We can be a vital source of information for patients and healthcare professionals.
In summary, PAH is a rare disease requiring specialist diagnosis and treatment as well as ongoing care and support at a high level, particularly for those receiving complex therapies. In travelling such distances to specialist centres, patients should have access to a full Multi-professional team to optimise their care. PAH has seen an almost unique increase in drug treatments in the past 20 years which is set to continue with new agents, pathways and combinations being investigated worldwide. As medication plays such an important role in these patients’ holistic care, there is a significant role for pharmacists to play.
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