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 antagonism in pulmonary arterial hypertension

The pathobiology of pulmonary arterial hypertension (PAH) reflects a multifactorial process and complex evolution that involves dysfunction of underlying cellular pathways and mediators. Among these, the endothelin system has been shown to be important in the pathogenesis of PAH. Endothelin-1 (ET-1), which is found in high levels in PAH, is a known potent vasoconstrictor with proliferative vascular remodeling properties. Left unchecked, endothelin excess, along with other derangements, may contribute to the development and perpetuation of PAH. There is now substantial evidence from clinical trials and long-term data that monotherapy with an endothelin receptor antagonist (ERA) is a beneficial, therapeutic approach in PAH. Combination therapy of an ERA with a prostanoid or phosphodiesterase-5 inhibitor, two drug classes that have different mechanisms of action, is conceptually appealing, but the evidence for its efficacy and safety are still being investigated. This review provides an overview of endothelin biology and the clinical use of ERAs for the treatment of PAH. The use of ERAs for other forms of pulmonary hypertension will not be reviewed here.     

Congenital heart disease and pulmonary hypertension: pharmacology and feasibility of late surgery

Pulmonary arterial hypertension (PAH) with increased pulmonary vascular resistance (PVR), previously termed pulmonary vascular obstructive disease or pulmonary vascular disease is a frequent complication of congenital heart disease (CHD).While there have been advances in the medical treatments available for classic Eisenmenger syndrome patients who are not suitable for repair, the sub-group of patients with moderate sized congenital systemic to pulmonary shunts and mild to moderately elevated PVR remains challenging. With the development of targeted medical treatments for pulmonary arterial hypertension (PAH), the concept of a combined medical and interventional/surgical approach for patients with PAH associated with CHD (APAH-CHD) has emerged. Careful evaluation and an understanding of the predominant physiologic features will help guide the management of these complex patients and whether late surgical repair is feasible.     

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.     

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.     

Evaluating operability in adults with congenital heart disease and the role of pretreatment with targeted pulmonary arterial hypertension therapy

Pulmonary arterial hypertension (PAH) associated with congenital heart disease remains a major problem despite advances in cardiac surgery. Recently, advanced therapies for PAH have become available and have been effective in reducing pulmonary vascular resistance and symptoms in patients with near-systemic pulmonary arterial pressures, previously thought to have irreversible pulmonary vascular disease. This has led to a new dilemma, namely could intracardiac communications previously considered inoperable due to severe pulmonary vascular disease become amenable to surgery after successful treatment with advanced therapy? We address, hereby, the potential merits and hazards of a "treat-and-repair" approach using advanced therapies in patients with PAH associated with congenital heart disease.     

Pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a term used to classify a variety of conditions that have in common an injury to the pulmonary vasculature that produces elevations in pulmonary arterial pressure. There have been considerable advances in our understanding of the pathogenesis and treatment of PAH over the past decade. The article reviews the classification of diseases associated with PAH, the current understanding of its pathogenesis, and the contemporary approach to therapy.     

Anticoagulation in pulmonary arterial hypertension: a qualitative systematic review.

Thrombotic arteriopathy has been implicated in the pathophysiology of pulmonary arterial hypertension (PAH). However, the role of anticoagulants in the treatment of PAH is uncertain. Through a qualitative systematic review of epidemiological studies, the effectiveness of anticoagulation therapy with warfarin on survival was evaluated in patients with PAH. MEDLINE (1966 to November 2005), EMBASE (1966 to November 2005), bibliographies of included studies and published reviews were searched without language restriction. Epidemiological studies evaluating the effectiveness of warfarin in PAH were included. Studies had to report mortality as an outcome. Seven observational studies evaluating the effectiveness of warfarin comprising 488 patients were identified. Five studies support the effectiveness of anticoagulation therapy, whereas two do not. Data from observational studies suggest that anticoagulation therapy may be an effective intervention in pulmonary arterial hypertension. However, given the methodological limitations and the small number of existing observational studies, a randomised controlled trial is needed in order to definitively address this important clinical issue.     

B-Type Natriuretic Peptide and the Right Heart

B-type natriuretic Peptide (BNP) is elevated in conditions with ventricular volume and pressure overload. The physiological, diagnostic and therapeutic role of BNP in right ventricular (RV) dysfunction and pulmonary arterial hypertension (PAH) are reviewed in this article. BNP levels can be used to differentiate between breathless patients with a respiratory disease and those with PAH. BNP has been shown to correlate with mean pulmonary arterial pressure and pulmonary vascular resistance in patients with PAH, whether primary or secondary. BNP is also a predictor of mortality in patients with primary pulmonary hypertension. These are important clinical implications in that a non-invasive blood test may be used to identify patients who require more invasive procedures (such as cardiac catheterization). There is increasing evidence that BNP or NT-proBNP measurements may also be used to guide therapy (e.g. pulmonary vasorelaxants) in PAH. Enhancement of the natriuretic peptide pathway has been shown to reduce cardiac hypertrophy and PAH and hence, there may be therapeutic potential via recombinant BNP or neutral endopeptidase inhibitors in RV dysfunction and PAH.     

Differences in hemodynamic and oxygenation responses to three different phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension: a randomized prospective study

OBJECTIVES: We sought to compare the short-term impact of three different phosphodiesterase-5 (PDE5) inhibitors on pulmonary and systemic hemodynamics and gas exchange parameters in patients with pulmonary arterial hypertension (PAH). BACKGROUND: The PDE5 inhibitor sildenafil has been reported to cause pulmonary vasodilation in patients with PAH. Vardenafil and tadalafil are new PDE5 inhibitors, recently being approved for the treatment of erectile dysfunction. METHODS: Sixty consecutive PAH patients (New York Heart Association functional class II to IV) who underwent right heart catheterization received short-term nitric oxide (NO) inhalation and were subsequently assigned to oral intake of 50 mg sildenafil (n = 19), 10 mg (n = 7) or 20 mg (n = 9) vardenafil, or 20 mg (n = 9), 40 mg (n = 8), or 60 mg (n = 8) tadalafil. Hemodynamics and changes in oxygenation were assessed over a subsequent 120-min observation period. RESULTS: All three PDE5 inhibitors caused significant pulmonary vasorelaxation, with maximum effects being obtained after 40 to 45 min (vardenafil), 60 min (sildenafil), and 75 to 90 min (tadalafil). Sildenafil and tadalafil, but not vardenafil, caused a significant reduction in the pulmonary to systemic vascular resistance ratio. Significant improvement in arterial oxygenation (equally to NO inhalation) was only noted with sildenafil. CONCLUSIONS: In PAH patients, the three PDE5 inhibitors differ markedly in their kinetics of pulmonary vasorelaxation (most rapid effect by vardenafil), their selectivity for the pulmonary circulation (sildenafil and tadalafil, but not vardenafil), and their impact on arterial oxygenation (improvement with sildenafil only). Careful evaluation of each new PDE5 inhibitor, when being considered for PAH treatment, has to be undertaken, despite common classification as PDE5 inhibitors.     

Changing the prognosis of pulmonary arterial hypertension: impact of medical therapy

Pulmonary arterial hypertension (PAH) is a progressive arteriopathy of the pulmonary circulation that can affect a wide group of patients. Presentation and natural history of PAH are intimately linked to progressive right ventricular failure. Historically, survival in PAH has been poor, especially for patients with PAH associated with progressive systemic sclerosis and human immunodeficiency virus. Oral, subcutaneous, and intravenous therapies that have emerged during the last decade can improve symptoms and hemodynamics. This review explores the impact of these therapies on prognosis in PAH, which ultimately rests on the ability to reverse the pulmonary arteriopathy and preserve right ventricular function.     

Pulmonary hypertension in patients with hematological disorders following splenectomy

Prevalence of pulmonary arterial hypertension (PAH) was studied by Echocardiography and Doppler in 43 splenectomised patients with various disorders 1–20 years after splenectomy. PAH was detected only in thalassemia major, intermedia, hereditary sphereocytosis and myelofibrosis groups comprising a total of 21 patients. Six patients out of 21 was found to have PAH with mean pulmonary arterial pressure of 46.28 ± 28.17 mmHg. Twenty one controls having similar duration and type of disease also were assessed for PAH in this case control study 3/21 had PAH in this control group. The difference in number of patients showing pulmonary hypertension between case and control was not statistically significant (chi-square test p = 0.29-though the difference in pulmonary arterial pressure between case and control were significantly different (t-test p<0.0029) with control group showing a mean pulmonary arterial pressure of 25 ± 19 mmHg. Platelet count in the splenectomised group was significantly higher (p = 0.0029) than the controls. Pulmonary thromboembolism was equally high in the PAH patients with and without splenectomy. Patients undergoing splenectomy due to trauma, immune thrombocytopenia, sideroblastic anemia, extra hepatic portal hypertension, autoimmune hemolytic anemia did not show PAH after splenectomy even years after the procedure PAH following splenectomy is common after certain disorders and control patients with these diseases have tendency to develop PAH even without splenectomy. Pulmonary thromboembolism may be an important pathophysiological mechanism leading to this condition. Patients having hemolytic anemia and myelofibrosis should have regular evaluation of pulmonary arterial pressure whether he/she has been splenectomised or not. This is particularly important as availability of phosphodiesterase inhibitors like sildenafil allows one to manage these cases.     

Pulmonary hypertension in rheumatic diseases: epidemiology and pathogenesis

The focus of this review is to increase awareness of pulmonary arterial hypertension (PAH) in patients with rheumatic diseases. Epidemiology and pathogenesis of PAH in rheumatic diseases is reviewed, with recommendations for early screening and diagnosis and suggestion of possible role of immunosuppressive therapy in treatment for PAH in rheumatic diseases. A MEDLINE search for articles published between January 1970 and June 2012 was conducted using the following keywords: pulmonary hypertension, scleroderma, systemic sclerosis, pulmonary arterial hypertension, connective tissues disease, systemic lupus erythematosus, mixed connective tissue disease, rheumatoid arthritis, Sjogren’s syndrome, vasculitis, sarcoidosis, inflammatory myopathies, dermatomyositis, ankylosing spondylitis, spondyloarthropathies, diagnosis and treatment. Pathogenesis and disease burden of PAH in rheumatic diseases was highlighted, with emphasis on early consideration and workup of PAH. Screening recommendations and treatment were touched upon. PAH is most commonly seen in systemic sclerosis and may be seen in isolation or in association with interstitial lung disease. Several pathophysiologic processes have been identified including an obliterative vasculopathy, veno-occlusive disease, formation of microthrombi and pulmonary fibrosis. PAH in systemic lupus erythematosus is associated with higher prevalence of antiphospholipid and anticardiolipin antibodies and the presence of Raynaud’s phenomenon. Endothelial proliferation with vascular remodeling, abnormal coagulation with thrombus formation and immune-mediated vasculopathy are the postulated mechanisms. Improvement with immunosuppressive medications has been reported. Pulmonary fibrosis, extrinsic compression of pulmonary arteries and granulomatous vasculitis have been reported in patients with sarcoidosis. Intimal and medial hyperplasia with luminal narrowing has been observed in Sjogren’s syndrome, mixed connective tissue disease and inflammatory myopathies. Pulmonary arterial hypertension (PAH) associated with rheumatic diseases carries a particularly grim prognosis with faster progression of disease and poor response to therapy. Though largely associated with systemic sclerosis, it is being increasingly recognized in other rheumatic diseases. An underlying inflammatory component may explain the poor response to therapy in patients with rheumatic diseases and is a rationale for consideration of immunosuppressive therapy in conjunction with vasodilator therapy in treatment for PAH. Further studies identifying pathogenetic pathways and possible targets of therapy, especially the role of immunomodulatory medications, are warranted.     

Pulmonary hypertension in patients with hematological disorders following splenectomy

Prevalence of pulmonary arterial hypertension (PAH) was studied by echocardiography and Doppler in 43 splenectomized patients with various disorders 1–20 years after splenectomy. Pulmonary arterial hypertension was detected only in thalassemia major, intermedia, hereditary sphereocytosis and myelofibrosis groups comprising a total of 21 patients. Six patients out of 21 was found to have PAH with mean pulmonary arterial pressure of 46.28 ± 28.17 mm of Hg. Twenty-one controls having similar duration and type of disease also were assessed for PAH in this case control study 3/21 had pulmonary arterial hypertension in this control group. The difference in number of patients showing pulmonary hypertension between case and control was not statistically significant (Chi square test P=0.29) though the difference in pulmonary arterial pressure between case and control were significantly different (t test P<0.0029) with control group showing a mean pulmonary arterial pressure of 25 ± 19 mm Hg. Platelet count in the splenectomized group was significantly higher (P=0.0029) than the controls. Pulmonary thromboembolism was equally high in the PAH patients with and without splenectomy. Patients undergoing splenectomy due to trauma, immune thrombocytopenia, sideroblastic anemia, extrahepatic portal hypertension, autoimmune hemolytic anemia did not show PAH after splenectomy even years after the procedure PAH following splenectomy is common after certain disorders and control patients in these diseases have tendency to develop PAH even without splenectomy. Pulmonary thromboembolism may be an important pathophysiological mechanism leading to this condition. Patients having hemolytic anemia and myelofibrosis should have regular evaluation of pulmonary arterial pressure whether he/she has been splenectomized or not. This is particularly important as availability of phosphodiesterase inhibitors such as sildenafil allows one to manage these cases.     

Epidemiology of Pulmonary Arterial Hypertension

The epidemiology of pulmonary arterial hypertension (PAH) has changed over the last decade. Remarkable advances in understanding the pathobiology and clinical care required in PAH have resulted in improved quality of life and survival. Despite such important progress, the long-term rate of survival is still unacceptable. The epidemiology of PAH could not be easily generalized globally, due to the fact that nearly all of the present data has been gathered from Western, multicenter, prospective registries. There are potentially marked differences in PAH patients from Western and Eastern populations, and from developed and developing countries. Therefore, it is clear that more registry data will be needed to address novel questions emerging with improved knowledge of PAH.     

Pulmonary arterial hypertension: evaluation of the newly diagnosed patient

With a quickly growing range of therapeutic options precise prognostic stratification became particularly important for clinical decision making in patients with pulmonary arterial hypertension (PAH). Assessment of disease-specific functional class remains the simplest method and is a fairly reliable way of assessing severity of PAH, and current guidelines recommend a therapeutic algorithm based on functional class evaluation. Six-minute walk is the most widely used test assessing exercise tolerance both in clinical practice and in clinical trials testing new therapies in PAH. Right heart catheterization with a vasoreactivity test is mandatory to identify a subgroup that has good long-term prognosis when treated with calcium channel blockers alone. Echocardiographic variables of documented prognostic value in PAH are not those directly correlated with pulmonary arterial pressure (PAP). Instead, the presence of pericardial effusion, enlarged right atrium, and elevated Doppler index of right ventricular performance have been the most consistently reported signs of poor prognosis. Low or decreasing brain natriuretic peptide (BNP) suggests a good outcome whereas troponin T leak persisting despite therapy is a poor prognostic sign. Biomarkers seem particularly useful for noninvasive follow-up of patients with PAH, and due to simplicity and low costs may successfully compete with echocardiography.     

Pulmonale Hypertonie

Pulmonary hypertension has dramatically evolved as a new scientific field triggered by the development of targeted pulmonary arterial hypertension (PAH) therapies. Pulmonary hypertension is defined by elevated resting pulmonary arterial pressures but the definition of normal values during exercise is currently not possible. Diagnostic tools include the history, physical examination, electrocardiography (ECG), thoracic X-ray and echocardiography. In scleroderma patients a reduced diffusing capacity of the lungs for carbon monoxide (DLCO) is a marker of PAH. Approved PAH therapies include three prostanoids, two endothelin receptor antagonists and two phosphodiesterase 5 inhibitors. These therapies have substantially improved the prognosis of PAH patients. A novel soluble guanylate cyclase (sGC) stimulator has been submitted for approval. There are increasing numbers of elderly PAH patients who have an adverse prognosis as compared with classical PAH patients. In particular those with simple or combined heart and lung diseases pose a challenge for the future.     

Pulmonary arterial hypertension

Significant advances in the treatment of pulmonary arterial hypertension (PAH) have occurred over the last 10 years, starting with the approval of epoprostenol in 1998. Subsequently, multiple additional medications have received approval, including a subcutaneous prostacyclin, an inhaled prostacyclin, and oral medications in 2 separate classes. Over this same period, the classification of pulmonary hypertension has been revised with changes including the substitution of the term idiopathic for primary PAH and an expanded list of conditions felt to be associated with the development of PAH. Long-term follow-up studies have provided better information on prognosis and expected outcomes with treatment, with particularly valuable data on reassessment of prognosis after treatment with epoprostenol. Combination therapy is more frequently being used, and limited data on novel therapies such as stem cell transplantation have been published. The purpose of this review is to describe the current state of evidence for the diagnosis, prognosis, and treatment of the patient with PAH.