REVIEW: Endothelin Receptor Antagonists for Pulmonary Arterial Hypertension: An Overview

The last decade has seen major advances in the pharmacotherapy of pulmonary arterial hypertension (PAH). One of these advances has been the discovery of endothelin receptor antagonists (ERAs). ERAs are a class of potent vasodilators and antimitotic substances, which could specifically dilate and remodel pulmonary arterial system, and have been proposed as an alternative to traditional therapies for PAH. Current available evidence suggests that ERAs improve exercise capacity, functional status, pulmonary hemodynamics, and delay the time to clinical worsening for patients with PAH. This review attempts to provide an overview of the pharmacology, therapeutic benefits, and safety profile of ERAs in patients with PAH.     

Drug Insight: endothelin-receptor antagonists for pulmonary arterial hypertension in systemic rheumatic diseases

Rapid advances in the understanding of endothelin as a naturally occurring peptide with developmental and regulatory roles in normal physiology, along with a number of deleterious effects under pathologic conditions (including vasoconstriction, fibrosis, vascular hypertrophy, and inflammation) have led to the development of endothelin-receptor antagonists (ERAs). Bosentan, an antagonist with dual specificity for the endothelin-receptor subtypes A and B, has been shown to be efficacious and well tolerated in placebo-controlled clinical trials and is now approved in many countries, including the US, Canada, and Europe, for treatment of pulmonary arterial hypertension (PAH), including PAH associated with rheumatic diseases. ERAs with specificity for the endothelin-receptor subtype A, including sitaxsentan and ambrisentan, are currently undergoing investigation. This article reviews PAH associated with systemic rheumatic diseases and describes the role of ERAs in this setting.     

Endothelin receptor antagonist therapy in congenital heart disease with shunt-associated pulmonary arterial hypertension: A qualitative systematic review

BACKGROUND:

Congenital heart disease (CHD) with systemic-to-pulmonary shunting is associated with pulmonary arterial hypertension (PAH). There are similar clinical and pathophysiological features between CHD with shunt-associated PAH and idiopathic PAH. Endothelin-receptor antagonists (ERAs) are oral medications that improve pulmonary hemodynamics, symptoms and functional capacity in many PAH patients. However, the role of ERAs in CHD with shunt-associated PAH is unclear.

METHODS:

MEDLINE, EMBASE and the Cumulative Index of Nursing and Allied Health Literature (CINAHL) databases were searched for articles published from 1966 through September 2006, as well as bibliographies of all retrieved papers. All published English-language studies of adult CHD patients with shunt-associated PAH treated with ERAs were reviewed for clinical, functional and hemodynamic outcomes.

RESULTS:

Ten studies of 174 adult CHD subjects with shunt-associated PAH were identified. Other than one placebo-controlled, randomized clinical trial, all studies were open-label, uncontrolled observational trials. Subjects were treated with the ERA bosentan for a mean (± SD) of 9±7 months. Nine studies reported improved World Health Organization (WHO) modification of the New York Heart Association functional class, with 95 of 164 subjects (58%) improving by at least one functional class. The 6 min walk distance improved in all eight studies in which it was assessed. Bosentan was generally well tolerated; 2.3% of subjects withdrew because of elevated liver enzymes. Two patients with WHO functional class IV PAH died during bosentan therapy.

CONCLUSION:

Treatment of CHD patients with shunt-associated PAH with the ERA bosentan is associated with an improvement in functional class and objectively measured exercise capacity. The consistency of the uncontrolled data and the positive results of a single randomized clinical trial suggest a role for ERA therapy in CHD patients with shunt-associated PAH. Caution is suggested when considering bosentan therapy for CHD patients with WHO functional class IV PAH.     

Medical therapies for pulmonary arterial hypertension

Pulmonary Arterial hypertension (PAH) is a chronic and progressive disease characterized by an increase in pulmonary vascular resistance due to severe remodeling of the small pulmonary arteries. In PAH, the endothelial cells fail to maintain their homeostatic balance, with the consequent impaired production of vasodilators and over-expression of vasoconstrictors and proliferators. Current treatment of PAH is based on the discovery of three main pathways of endothelial dysfunction (prostacyclin, nitric oxide and endothelin-1), and includes drugs such as prostacyclin analogs, phosphodiesterase-5 inhibitors and endothelin receptor antagonists (ERAs). Recently approved drugs that act through these classic pathways include riociguat (cyclic GMP stimulator) and macitentan (a tissue specific dual ERA). However, several new drugs and new pathways are under study. New targeted therapies include tyrosine kinase inhibitors, Rho kinase inhibitors and serotonin receptor blockers. There are now ten drugs approved for the treatment of PAH that, alone or in combination, have changed the natural history of this disease. The new drugs will allow us to further modified the patients’ life expectancy and move towards a cure.     

Pulmonale Hypertonie

Pulmonary hypertension (PH) is a devastating disease that, if untreated, is characterized by a poor prognosis. According to the current classification (Venice, 2003), pulmonary arterial hypertension (PAH) is distinguished from other forms of PH. Recent advances in drug therapy have led to a dramatic improvement in medical care, particularly in patients with PAH. Hence, early establishment of the diagnosis and a precise classification appear increasingly important. This review provides an overview on the definition, classification, pathophysiology, and clinical presentation of various forms of PH. Furthermore, it summarizes the recommended diagnostic work-up and current treatment options, particularly for PAH, with special emphasis on prostanoids, endothelin receptor antagonists (ERAs), and phosphopdiesterase type 5 (PDE5) inhibitors such as sildenafil. Finally, novel developments are discussed which currently represent an exciting field of basic and clinical research.     

Hemodynamic Stability After Transitioning Between Endothelin Receptor Antagonists in Patients With Pulmonary Arterial Hypertension

Background

Maintenance of a favourable hemodynamic profile is central to therapeutic success in pulmonary arterial hypertension (PAH). There is little information about the safety of transitioning patients between oral therapies for PAH. Endothelin receptor antagonists (ERAs) have been a therapeutic mainstay in PAH, providing benefit to many patients. Three ERAs, bosentan, sitaxsentan, and ambrisentan have been approved for clinical use. Sitaxsentan was voluntarily withdrawn from the market in late 2010 resulting in the need to quickly transition a large number of stable patients.

Methods

We transitioned 30 clinically stable patients to either ambrisentan or bosentan. Patients underwent a right heart catheterization, measurement of serum N-terminal pro-brain natriuretic peptide (NT-proBNP), and assessment of functional class before changing ERA and again 4 months later. We present a retrospective analysis of those data.

Results

Of the 30 patients transitioned (15 to ambrisentan, 15 to bosentan), 23 had complete hemodynamic data. No significant change was observed in the groups in right atrial, mean pulmonary artery, and pulmonary artery wedge pressures, or in cardiac output, pulmonary vascular resistance, or NT-proBNP levels. There was no change in World Health Organization functional class. Four ambrisentan and 2 bosentan-treated patients reported fluid retention, and 3 bosentan-treated patients had elevation of hepatic transaminases. Two of the patients had a right atrial pressure increase of ≥5 mm Hg, and 4 had pulmonary artery wedge pressure increase of ≥5 mm Hg.

Conclusions

Transitioning between ERAs in stable PAH patients does not result in hemodynamic or clinical deterioration during the first 4 months posttransition. A minority of patients have developed increased cardiac filling pressures.     

Update on Endothelin Receptor Antagonists in Hypertension

Purpose of Review

To review the most recent data on the development of endothelin receptor antagonists (ERAs) for the treatment of hypertension and the management of diabetic nephropathy

Recent Findings

Recent reviews and meta-analyses of experimental and clinical data obtained with ERAs confirmed that endothelin receptor blockade is associated with significant decreases in blood pressure in essential hypertension but also in resistant hypertension. In addition, in patients with diabetic nephropathy, ERAs induce significant 30–40% decreases in albuminuria when administered on top of blockers of the renin-angiotensin system. Yet, the benefits of ERAs have often been limited by their tolerability profile, essentially fluid retention and the development of edema and liver toxicity. Hence, several programs have been interrupted. Today, only one ERA, aprocitentan, is still under development for the treatment of resistant hypertension. Regarding the place of ERAs in the management of diabetic nephropathy, the results of the SONAR trial with atrasentan are eagerly awaited but the recent interruption of this trial because of insufficient events is worrisome, as one might not obtain all the expected information for this major trial.

Summary

Blockade of endothelin receptor have a high potential in the treatment of hypertension and the prevention of the progression of renal diseases such as diabetic nephropathy. Today, the number of clinical programs investigating the potential benefits of ERAs is limited and more data must be obtained to define the real place of ERAs in these indications.

     

Bosentan for the treatment of adult pulmonary hypertension

Pulmonary hypertension is a severe progressive disease with a marked morbidity and a high mortality attributed to right heart failure. Bosentan, a dual endothelin receptor antagonist, is an effective and well-tolerated oral therapy for the management of pulmonary arterial hypertension (PAH; WHO group 1 pulmonary hypertension). Bosentan improves cardiopulmonary hemodynamics, exercise capacity, WHO functional class and quality of life, as well as delaying time to clinical worsening in patients with PAH. This article reviews the role of endothelin-1 in the pathogenesis and progression of PAH, the diagnosis of PAH and the pharmacology of bosentan, and summarizes the current available evidence for the safety and efficacy of bosentan for the treatment of PAH as a monotherapy and combination therapy, as well as its role in the management of other forms of pulmonary hypertension.     

Therapie der pulmonalen Hypertonie

Prostanoids and endothelin receptor antagonists (ERA) currently possess the largest practical value for therapy of pulmonary hypertension. In future, phosphodiesterase inhibitors will likely gain importance. Among the ERA, bosentan was approved by the European Medical Agencies (EMEA) and in America (FDA). Bosentan is currently the only approved oral medication and normally represents the therapy of first choice in pulmonary arterial hypertension (PAH). The first approved prostanoid, epoprostenol, is currently the first choice only for decompensated right heart failure in PAH. Alternatively, subcutaneous treprostinil can be applied. It has a longer half-life and is less risky and expensive compared to epoprostenol but did not receive EMEA approval. Beraprost, an oral prostanoid, was not approved by either the EMEA or FDA. Inhaled iloprost combines the features of a prostanoid with pulmonary and intrapulmonary selectivity and was approved by the EMEA and in Australia. Alternatively, iloprost is being used as a continuous intravenous infusion, which has been approved in New Zealand. The phosphodiesterase-5 inhibitor sildenafil was significantly effective in small randomized controlled trials (RCTs). The results of a large RCT will soon be available.     

Compelling Evidence of Long-Term Outcomes in Pulmonary Arterial Hypertension? : A Clinical Perspective

Pulmonary arterial hypertension (PAH) is a rare and progressive disease of the pulmonary arterial circulation that is characterized by a progressive rise in pulmonary vascular resistance, eventually leading to right-heart failure and death. There are currently 3 classes of drugs approved for the treatment of PAH: prostacyclin analogues, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors. All of these therapies have been approved for use on the basis of relatively small, short-term studies, yet it is common for each to be administered (alone or in combination) over the lifetime of a patient with PAH. Very few prospective, well-controlled PAH studies have examined long-term clinical outcomes associated with current medical therapy. Therefore, data that support the long-term therapeutic benefits of these long-term PAH therapies are limited and derived primarily from uncontrolled, observational studies. In this perspective, the authors review the published research to assess the strengths and weaknesses of the data that support the long-term clinical benefit of current PAH therapies. The authors conclude that current medical therapies approved for the treatment of PAH can provide sustained benefits in hemodynamic function and exercise capacity. The cumulative evidence, in the form of meta-analysis and registry data, suggest that patients are living longer compared with untreated patients; the reasons are likely multifactorial. Although definitive evidence will require randomized and properly controlled long-term trials, the current evidence supports the long-term use of these drugs for the treatment of patients with PAH.     

WHO Group 1 pulmonary arterial hypertension: Current and investigative therapies

Major advances have been made in the treatment of World Health Organization Group 1 pulmonary arterial hypertension (PAH). Since the mid-1990s, nine medications have become available in the United States to target three key pathophysiologic derangements in PAH – the prostacyclin, endothelin, and nitric oxide pathways. As a group, these agents have led to improvements in functional capacity, symptoms, hemodynamics, and survival. Most patients with mild to moderate PAH are started on orally active agents such as endothelin receptor antagonists or phosphodiesterase inhibitors. Patients with more severe disease, particularly those with evidence of right heart failure, should be treated with continuous prostacyclin infusion or a combination of a prostacyclin and oral therapy. Each medication has unique properties and clinical considerations, and the selection of an appropriate therapy must be tailored to the individual patient. None of the currently available WHO Group 1 PAH therapies are curative, however, and it is the hope that new therapies in development may halt or reverse disease progression. This review will discuss the major therapeutic classes of presently available medications and their role in managing the patient with PAH. We will also review data supporting the use of combination therapy, adjuvant background therapy, and new agents currently under investigation.     

Pulmonale Hypertonie und rheumatische Erkrankungen

After idiopathic pulmonary arterial hypertension (IPAH), connective tissue disease (CTD)-associated PAH represents the largest subgroup within the PAH group of diseases. Systemic sclerosis (SSc) and mixed connective tissue diseases are at the highest risk of PAH; however, systemic lupus erythematosus (SLE), dermatomyositis, Sjögren’s syndrome, antisynthetase syndrome and rheumatoid arthritis also show an increased risk for PAH. The pulmonary symptoms and treatment are similar to those for IPAH. For SSc a yearly echocardiographic screening for PAH is recommended. In the other CTDs this diagnostic measure is recommended only if signs and symptoms of PAH occur, particularly dyspnea on exertion, fatigue or fainting/syncope. An early therapy with targeted PAH medication is recommended, as the prognosis of CTD-associated PAH is much worse compared to IPAH. A CTD-associated pulmonary veno-occlusive disease (PVOD) must be considered as a differential diagnosis, because this disease is particularly prone to treatment-associated side effects. Approved for targeted collagen-associated PAH are endothelin receptor antagonists (ERA), phosphodiesterase 5 inhibitors (PDE5i), IP receptor agonists (IPA) and stimulators of soluble guanylate cyclase (sGCS). When combined with immunosuppressants and because of the special properties of the underlying diseases, targeted PAH medications are associated with higher risks of severe side effects compared to IPAH patients.     

Therapie der pulmonalarteriellen Hypertonie

Current international guidelines on the treatment of pulmonary arterial hypertension (PAH) are compiled by the European Society of Cardiology and the American College of Chest Physicians. The classification of pulmonary hypertension and guidelines on diagnosis and therapy were last adopted at the 4th World Congress of PAH in Dana Point (California) in the year 2008. Based on these guidelines this article presents an overview of the current therapy recommendations for patients with PAH corresponding to group 1 of the diagnostic WHO classification of pulmonary hypertension. Here it is recommended that diagnostic and therapy should be carried out in an expert centre. The therapy forms for PAH can be classified into basic therapy (e. g. oral anticoagulants, diuretics and oxygen therapy) and specific therapy (e. g. phosphodiesterase-5 inhibitors, endothelin receptor antagonists and prostanoids). Finally, some new substances will be presented which have already progressed relatively far in the clinical development.     

Medical therapies for chronic thromboembolic pulmonary hypertension: an evolving treatment paradigm

Pulmonary endarterectomy (PEA) is recommended as the treatment of choice for eligible patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, only a proportion of patients fulfill the criteria for surgical intervention. In addition, operated patients with CTEPH may experience a gradual hemodynamic and symptomatic decline related to a secondary hypertensive arteriopathy in the small precapillary pulmonary vessels. It has also been questioned what can be done to reduce risks from PEA surgery to improve outcome in "high risk" patients with CTEPH with substantial impairment of pulmonary hemodynamics before surgery. Such patients may benefit from preoperative reduction of pulmonary vascular resistance by means of medical therapy. Conventional medical treatments, such as anticoagulation, diuretics, digitalis, and chronic oxygen therapy, show low efficacy in the treatment of CTEPH as they do not affect underlying disease processes. Over the last decade, several novel therapies have been developed for pulmonary arterial hypertension (PAH), including prostacyclin analogs (epoprostenol, beraprost, iloprost), endothelin receptor antagonists (bosentan, sitaxsentan, ambrisentan), and phosphodiesterase-5 inhibitors (sildenafil). Evidence of efficacy in PAH, coupled with studies showing histopathologic similarities between CTEPH and PAH, provides a rationale to extend the use of some of these medications to the treatment of CTEPH. However, direct evidence from clinical trials in CTEPH is limited to date. This article reviews evidence supporting, and issues surrounding, the possible use of novel PAH medications in CTEPH.     

A new era in the management of pulmonary arterial hypertension related to scleroderma: endothelin receptor antagonism

Evidence suggests that endothelin may have a fundamental role in scleroderma pathogenesis, including pulmonary arterial hypertension (PAH)--a leading cause of death in patients with scleroderma. Development of a new class of drug, endothelin receptor antagonists, heralds an improved outlook for patients with scleroderma and related diseases. Heightened vigilance towards early detection of PAH in scleroderma and a multidisciplinary approach to diagnosis and treatment may improve clinical outcomes for these patients.     

Pulmonary arterial hypertension: therapeutic algorithm.

The numerous controlled clinical trials performed recently in pulmonary arterial hypertension (PAH) can allow us to abandon a clinical-based treatment strategy and adopt an evidence-based therapy. The treatment algorithm is restricted to patients in NYHA class III or IV. The different treatments have been evaluated mainly in sporadic, idiopathic PAH and in PAH associated with scleroderma or to anorexigen use. Extrapolation of these recommendations to other PAH subgroups should be done with caution. High doses of calcium channel blockers are indicated only in the minority of patients who are responders to acute vasoreactivity testing. Patients in NYHA class III should be considered candidates for treatment with either an endothelin receptor antagonist, a prostanoid or a type 5 phosphodiesterase inhibitor. Continuous intravenous administration of epoprostenol is proposed as rescue treatment in NYHA class IV patients. Combination therapy can be attempted in selected cases. Balloon atrial septostomy and/or lung transplantation are indicated for refractory patients or when medical treatments are unavailable.     

Pulmonary hypertension

Pulmonary arterial hypertension (PAH) must be classified into primary pulmonary hypertension and PAH related to other diseases such as collagen vascular diseases, HIV infection or portal hypertension. PAH must also be differentiated from other entities, in particular pulmonary hypertension secondary to thromboembolic diseases, requiring specific approaches. All PAH results in similar histological remodelling of pulmonary arteries, with thickening of the intima, proliferation of the media and plexogenic lesions. Today the physiopathology of these lesions is much better understood and has resulted in new therapies involving substances such as prostacyclins, endothelin receptor antagonists or phosphodiesterase inhibitors, aimed not only at dilating arteries but also at preventing their remodelling. Thromboendarterectomy, septostomy and transplantation remain the only option where medical treatment has failed.     

Advances in diagnosis and treatment in patients with pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a progressive disease marked by vasoconstriction and vascular remodeling within pulmonary arteries leading to right heart failure and death. Significant advances in understanding the pathobiology of the disease have identified three key pathways involved in progression of this disease, which are the endothelin pathway, the prostacyclin pathway, and the nitric oxide/cyclic guanosine monophosphate pathway. Echocardiogram is the best screening tool to obtain an estimation of the pulmonary artery systolic pressure but right heart catheterization remains the standard by which the diagnosis is made. There are currently six FDA approved therapies for PAH. The mechanistic rationale, evidence behind their use and side effect considerations in utilizing these therapies in PAH patients will be the focus of this review. © 2008 Wiley‐Liss, Inc.