Pulmonary arterial hypertension is a progressive disease, characterised by abnormally high blood pressure in the blood vessels which supply the lungs. Patients with PAH are clinically defined as those with mean pulmonary arterial pressure > 25 mm Hg at rest or > 30 mm Hg during exercise1 with a normal pulmonary capillary wedge pressure (PCWP). PAH is a rare and incurable condition that often lies undetected until it reaches the most severe stages. As the disease takes control of the lungs and cripples the heart, patients become unable to perform even routine daily tasks without severe shortness of breath (dyspnoea), fatigue and fainting. If left untreated pulmonary arterial hypertension leads to premature death and therefore early detection is critical.

The estimated annual incidence of primary pulmonary hypertension is one to two cases per year, and that of pulmonary arterial hypertension related to scleroderma is about eight cases per million individuals per year. Approximately 100,000 people in Europe and the United States are affected with PAH.

Whilst it is a rare condition, the outlook for untreated patients is bleak. The life-threatening illness most often occurs in young women and if left untreated between 45 and 60 percent of patients with PAH will die within two years of diagnosis.

Endothelin, a neurohormone synthesised in the endothelium (the lining of the blood vessels) has been implicated in the development of PAH, as endothelin levels have been found to be elevated in the blood and tissue levels of patients with PAH. Endothelin acts through two receptor types, ETA and ETB, ETA is believed to play a role in constriction of smooth muscle cells, whilst ETB is involved in the development of thickened walls (fibrosis), cell proliferation, an enlargement of cells (hypertrophy) and cellular remodelling.

PAH results from the combination of restricted blood flow from the lungs due to the constriction of the smooth muscle cells in the pulmonary vascular system and changes in the underlying structure of the blood vessels. Over time, the right ventricle of the heart is unable to sustain adequate blood flow without incurring damage and the patient develops heart failure.

Types of Pulmonary Arterial Hypertension

PAH can occur in isolation (primary pulmonary hypertension - PPH) or related to other diseases which affect the body as a whole, such as connective tissue disease which includes systemic sclerosis (scleroderma) and systemic lupus erythematosus.

PPH may occur in isolation without any apparent cause or it may be inherited; it is estimated that at least 10% of cases are genetic.

Some people with existing conditions may be at an increased risk of developing PAH, such as those with:

Connective tissue diseases
Systemic sclerosis (scleroderma)
Systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis and other connective tissue diseases
Congenital Heart Disease
Patients with a familial history of primary pulmonary hypertension
HIV-positive patients

In addition to other diseases, exposure to specific toxins can also cause PAH. These include:

Use of appetite-suppressant drugs such as fenfluramine or dexfenfluramine
Use of cocaine, methamphetamine or other street drugs
Exposure to toxins in contaminated food or the environment

Often the first sign of PAH is dyspnoea, especially on exertion. Other symptoms may include:

Fatigue
Dizziness
Fainting (near syncope)

Many of these symptoms are non-specific, and are therefore unlikely to be attributed to PAH at an initial consultation. Whilst early diagnosis of PAH is critical to improving the prognosis and survival of the patient, recognition of PAH is often delayed until symptoms begin to have a serious impact on the patient’s daily life. At this point, a patient may be referred to a specialist for their particular symptoms, usually a cardiologist, rheumatologist or respiratory physician for further investigation. The majority of patients wait for two to three years between experiencing their first symptoms and receiving a diagnosis of PAH and a significant number of patients may wait for up to five years.

PAH is diagnosed by a process of elimination to exclude or identify reasons for the pulmonary hypertension.

While early diagnosis is optimal with PAH, it is rarely the case. Diagnosis is often made at more advanced stages when symptoms such as shortness of breath, dizziness, fainting and extreme fatigue become pronounced.

PAH can be suspected based on symptoms and heart sounds. Valuable tests to identify and characterise PAH and exclude other reasons for breathlessness include:

Echocardiography with Doppler
Chest radiography
High Resolution Computerised Tomography (HRCT) scan of chest
Pulmonary function tests

Right heart catheterisation - entails the introduction of special catheters into the arteries and veins of the arms and legs through which their tips are manipulated into the right-side of the heart. This provides data on blood flow and pressures within the cardiopulmonary vasculature.

Following diagnosis, patients are classified according to the World Health Organisation PAH classification system (WHO I-IV):

Class I: Patients with no symptoms, and for whom ordinary physical pain does not cause fatigue, palpitation, dyspnea, or anginal pain

Class II: Patients who are comfortable at rest but who have symptoms* with less-than-ordinary physical activity

Class III: Patients who are comfortable at rest but have symptoms* with less-than-ordinary effort

Class IV: Patients who have symptoms* at rest

*Key symptoms of PAH include fatigue, dizziness and fainting (near syncope)

Specialists use the WHO classification system to predict the life expectancy of a patient with PAH. The longer the disease goes undiagnosed and the higher the WHO functional class, the worse the prognosis for a patient. Patients in Class II and Class III have an average survival rate of 3.5 years, whereas patients whose illness is at the advanced Class IV stage have an average survival rate of just six months.

Early detection and appropriate treatment of PAH may significantly improve patients lives and increase survival, therefore the primary goals of PAH treatment are to improve symptoms, including increasing a patient’s exercise capacity, leading to improved quality of life and a better chance of survival.

The course of PAH is often one of steady deterioration and reduced life expectancy. The significant symptoms and shortened life span have led to ongoing efforts to develop efficacious medical treatments, however, many of the current available therapeutic options are highly complex, require intensive ongoing follow-up, may not be effective for the majority of patients, and may significantly inhibit patients' quality of life. For those patients who do not respond to any of the medical treatments available, a lung or heart-lung transplant may be recommended as a last resort.

Current medications used to treat PAH include:

Anticoagulants
Patients with pulmonary hypertension have a tendency to form small blood clots in their lungs, and anticoagulants, such as warfarin, prevent these blood clots from forming.

Vasodilator therapy:
These therapies cause the blood vessels to widen or vasodilate. The most commonly used drugs are:

Calcium channel blockers (CCBs)
These agents are used to relieve constriction in the pulmonary arteries. While helpful in some cases, these drugs have proven to be ineffective in the majority of PAH patients (only 15% of patients treated show any improvement) and are associated with side-effects, such as fainting. These drugs tend to be ineffective in scleroderma patients with PAH, since they are not usually vasoreactive.

Intravenous prostacyclin therapy
Infusion of prostacyclin (epoprostenol) has been shown in patients with PPH to improve exercise duration, subjective well-being and survival.

Despite its benefits, the treatment involves a complex regime, as epoprostenol is temperature-sensitive and must be infused continuously and chronically. This requires implantation of a permanent central venous catheter, use of an external portable infusion pump, careful training of the patient in preparing the medication daily, and comprehensive follow-up by fully trained medical staff. Patients who receive epoprostenol are among the most severely ill, and the treatment is generally reserved for those with WHO disease classification IV.

Some complications have been associated with prostacyclin including administration difficulties and side-effects, which may include catheter site infections, jaw pain, ankle pain, diahorrea, and flushing.

Endothelin receptor antagonists
The search for more convenient and orally administered treatments has continued, and research has identified the endothelin receptor antagonists (ERAs) as a promising new class of therapy for patients with PAH. ERAs inhibit the damaging effects of endothelin by competitively binding to endothelin receptors. Their unique mechanism of action allows physicians to treat the symptoms of PAH effectively and slow disease progression.

Tracleer (bosentan) is a dual ERA and the only oral treatment licensed for PAH (in patients with WHO functional class III). It has been available in the USA since December 2001 and has since been launched in the UK, Germany, Ireland, Canada and Switzerland.

Tracleer
Tracleer is the first in a new class of agents called endothelin receptor antagonists (ERAs) and the only oral treatment licensed for PAH. It is currently available in the UK, Germany, USA, Canada, Ireland and Switzerland.

Tracleer is indicated for the treatment of primary pulmonary hypertension and pulmonary arterial hypertension (PAH) related to other diseases, such as scleroderma, for patients with WHO functional class III and its efficacy and ease of administration may lead to a substantial improvement in patients’ quality of life.

Mode of Action – Endothelin Receptor Antagonism
Research has established that blood and tissue levels of endothelin, a neurohormone produced in the endothelium (the lining of the blood vessels), are significantly raised in PAH, and this appears to play a critical role in the development of the disease.

Endothelin is an agent, which causes a number of damaging effects, including narrowing of the blood vessels (vasoconstriction), when secreted in excess in the pulmonary vascular system. Endothelin binds to two main types of receptors (ETA and ETB), which are located both in the lining and muscle layers of the blood vessel walls. These receptors act like ‘light switches’ which sit on the outside of cells and when activated they initiate a series of events inside the cell. The binding of endothelin to both types of endothelin receptors has been found to result in a number of damaging effects, which can contribute to the development of cardiopulmonary conditions such as:

Fibrosis (development of thicker tissue walls)
Cell proliferation (an increase in the number of cells)
Hypertrophy (an increase in the size of cells, leading to an increase in the size of the organ)
Remodelling (a process of reshaping or reorganising cells)

In the healthy person, endothelin appears to play a limited role in physiology and under normal conditions endothelin levels are low. Elevated endothelin levels are closely linked to disease severity and prognosis.

Endothelin receptor antagonists have the potential to treat diseases caused by elevated levels of endothelin as they can inhibit the damaging effects of the neurohormone.

Importantly there are two principle endothelin receptors ETA and ETB. The ETA receptor appears to be involved mostly in vaso-constriction, whilst the ETB receptor appears to be involved in the mitogenic abnormalities associated with PAH.

Tracleer is a dual endothelin receptor antagonist with a high affinity for both types of endothelin receptor (ETA and ETB) and consequently blocks the damaging effects of endothelin. In the management of diseases such as PAH, the unique mechanism of endothelin receptor antagonism allows physicians to treat symptoms and may also help to stabilise the underlying disease.

Efficacy
Tracleer is effective in decreasing pulmonary vascular resistance, therefore allowing blood to flow through blood vessels more freely. It is also effective in reducing pulmonary arterial pressure, without significantly reducing overall blood pressure in the body. Overall, these effects lead to an increase in cardiac output (the volume of blood ejected by the heart per minute), which improves exercise capacity and symptoms.

Increased exercise capacity
In two pivotal, placebo controlled studies4,5 Tracleer demonstrated statistically significant improvements in the primary efficacy endpoint of exercise capacity with patients achieving a significantly greater, and clinically meaningful increase, in walking distance compared to placebo.

In BREATHE-1 treatment with Tracleer resulted in a 44-metre improvement in walking distance and the increase was apparent as early as week 4 in one study.5 The improvement was also maintained for up to seven months.

Dyspnoea
Dyspnoea is one of the most debilitating symptoms for people with PAH. Clinical trials have demonstrated Tracleer’s efficacy in decreasing dyspnoea. The improvements in dyspnoea in those patients treated with Tracleer are of particular clinical importance as they were achieved in tandem with an increase in walking distance.

Delay in disease progression
Treatment with Tracleer is also associated with a significant delay in disease progression (the time to clinical worsening); defined as the combined endpoint of death, lung transplantation, hospitalisation for PAH, worsening PAH or initiation of intravenous therapy, compared to placebo (p=0.002). 5

WHO functional class is a scale used by physicians to monitor general clinical status and is helpful in predicting the life expectancy of a patient with PAH. In a recent study, a greater proportion of patients treated with Tracleer showed an improvement in WHO functional class (42.9% moving up from class III to class II), compared with the placebo group in which just 9% of patients moved from class III to II, and 18% demonstrated a worsening in disease (moving from class III to IV). By contrast, no patients in the Tracleer group experienced a worsening in WHO functional class. 5

Overall, study results indicate that Tracleer slows down the need for additional PAH therapy,5 which may lead to a substantial improvement in patients’ quality of life.

Tracleer was also associated with significant improvements in pulmonary pressures, pulmonary vascular resistance, a right atrial pressure and cardiac index, with no associated increase in heart rate.4,5

Safety
Several studies have shown Tracleer to be well tolerated. The recent ENABLE trial,6 involving 1,613 participants with chronic heart failure, confirmed Tracleer’s long-term safety profile in patients treated for up to 30 months.

In PAH studies with Tracleer, approximately 11% of patients receiving the drug experienced abnormal, but reversible liver enzyme elevations. It is therefore important that patients undergo monthly liver monitoring with an additional test two weeks after dose increase. Due to the risk of birth defects, women who are pregnant should not take Tracleer and women of childbearing age are advised to take adequate contraceptive methods while using the treatment.

Other PAH Therapies

Although effective in treating some of the symptoms of PAH, many of the currently available therapeutic options are highly complex and requiring intensive ongoing follow-up, and may not be effective for certain groups of patients.

References:

1. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet. 1998; 352:719-725

2. Rubin LJ. Primary pulmonary hypertension. N Engl J Med. 1997; 336:111-117

3. D’Alonzo GE et al. Survival in patients with primary pulmonary hypertension. Results from a national progressive registry. Ann Intern Med 1991;15:345-9

4. Gaine SP, Rubin LJ. Primary pulmonary hypertension. Lancet 1998; 352:719-725

5. Zaret BL et al. Yale University School of Medicine Heart Book. New York: Hearst Books, 1992. p.178

6. Rich S et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107:216-23