Pharmacotherapy Of Pulmonary Arterial Hypertension Research Articles

Iatrogenic esophageal dysmotility as a barrier to transplantation in pulmonary arterial hypertension

Esophageal dysmotility is identified as a contraindication to lung transplantation at some centers due to increased risks of acute rejection, pulmonary infection, and chronic lung allograft dysfunction. Phosphodiesterase-type 5 inhibitors (PDE5i) are a cornerstone pharmacotherapy for pulmonary arterial hypertension (PAH) and are known to exert off-target effects that may impact lung transplant candidacy, including impaired esophageal contractility and decreased lower esophageal sphincter tone. We report two patients with PAH who were initially declined listing for lung transplantation due to iatrogenic esophageal dysmotility induced by PDE5is. Upon discontinuation of PDE5i therapy, these patients experienced significant improvement in esophageal motility within 14 days and met criteria for transplant listing at their centers. Recognizing and mitigating the off-target effects of PDE5i medications is critical for maximizing access to transplant for patients with PAH.

Analysis of the cost-effectiveness of early diagnosis and pharmacotherapy of pulmonary arterial hypertension

Over the past decades, health policy makers have focused on early diagnosis to introduce targeted and innovative treatments. Early diagnosis of pulmonary arterial hypertension (PAH) is associated with improved long-term survival, so screening high-risk groups is a reasonable strategy to improve outcomes in PAH treatment.
 Today, screening is an important part of preventive medicine, with the goal of detecting disease at an early and pre-symptomatic stage.
 All healthcare systems have limited resources and face opportunity costs; this means that any investment in a screening tool will come at the expense of other healthcare services, to the detriment of those patients who would otherwise be treated.
 By recognizing opportunity costs, health systems can require that health interventions be both clinically and cost-effective to be considered for implementation.
 The objective of the paper –to conduct a cost-effectiveness analysis of early diagnosis and pharmacotherapy of pulmonary arterial hypertension.
 Our analysis of the cost-effectiveness of early diagnosis and pharmacotherapy of pulmonary arterial hypertension is based on a cost‒utility model that estimates patient survival, which is significantly improved by reducing the delay in diagnosis of PAH and indicates the prevention of premature death of undiagnosed patients. The analysis of input data was conducted using systematic review, documentary, informational and graphical research methods.
 The results of the study showed that the choice of the target population and the level of diagnostic coverage of this risk group is critical for the cost-effectiveness of the implementation of PAH diagnostic screening. A decrease in these indicators leads to a decrease in the maximum allowable cost of diagnostic screening, and thus to a decrease in its profitability in real medical practice. The introduction of new treatments and the corresponding increase in the utility of PAP detection have the most positive effect on the profitability of the PAP diagnostic screening program.
 This cost-effectiveness analysis is the first attempt to evaluate the economic value of reducing the delay in PAH diagnosis compared to its benefits to the health care system and society as a whole.

Development conceptual of pharmacoeconomic model of technology for early diagnosis and pharmacotherapy of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare, progressive disease with a poor prognosis in the absence of timely diagnosis and appropriate therapy. Despite significant advances in the treatment of PAH, many patients remain undiagnosed years after the onset of the disease. Evaluation of the implementation of early diagnostic technologies for PAH is increasingly being used to develop economic evidence for health care at the early stages of diagnosis. The development of models of early diagnosis technology for LAH is highly relevant and can be used in the development and management of new medical technologies, as well as to reduce the perceived risks during the implementation of screening programs for LAH diagnosis.
 The objective of the paper: Conceptual development of a pharmacoeconomic model of the technology of early diagnosis and pharmacotherapy of PAH.
 Our pharmacoeconomic analysis is based on the «cost–effectiveness» model, which reflects the effectiveness and associated costs of implementing diagnostic screening for early detection of patients with PAH. The analysis of input data of the existing health care system was conducted using systematic review, documentary, informational and graphical research methods.
 The presented pharmacoeconomic model describes not only the structure of the incidence of PAH in the studied risk group or at the level of the entire population, but also takes into account the pharmacoeconomic evaluation of the complex technology of timely medical care for patients with PAH based on diagnostic screening.
 A pharmacoeconomic model of the technology of early diagnosis and pharmacotherapy of pulmonary arterial hypertension was developed, which covered a horizon of 10 years and was conducted from the point of view of the existing health care system, showed that for patients with delayed diagnosis of PAH, the modeling determined the average life expectancy at the level of 4.13 years and 2.08 QALYs.
 It has been determined that a diagnostic screening strategy for PAH would be cost–effective compared to no screening at different thresholds of diagnostic cost. However, other factors such as public awareness and acceptance of the screening programme and availability of human resources should be considered.

Scientific substantiation of the concept of pharmacoeconomic analysis of technologies for early diagnosis and pharmacotherapy of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) is a rare, progressive disorder characterized by high blood pressure (hypertension) in the arteries of the lungs (pulmonary artery) for no apparent reason.
 Because symptoms are nonspecific and physical signs may be subtle, the disease is often diagnosed at late stages. Over the past few decades, significant progress has been made in the field of pulmonary arterial hypertension. Technological progress allows to diagnose the disease in the early stages, as well as to better assess the severity of the disease.
 Today, screening studies are becoming increasingly important to establish a clinical diagnosis and minimize lost opportunities without timely diagnosis, especially in patients with idiopathic PAH.
 Therefore, the issue of early diagnosis of patients with suspected PAH and confirmation of the diagnosis is a very important and urgent issue today.
 The objective of the paper: to study the methods of implementation of technologies for early diagnosis and pharmacotherapy of pulmonary arterial hypertension and conceptual presentation of the results of their implementation.
 The work used available scientific sources of information on the results of the implementation of diagnostic screening for early detection of PAH and pharmacotherapy in the world. The analysis of input data was carried out using systematic, documentary, informational and graphical research methods.
 The result of the analysis of information materials showed that over the past two decades, significant progress has been made in the treatment of PAH and more than doubled the survival rate of patients.
 It has been found that diagnostic screening is a relatively unique medical technology in relation to other medical interventions and can be defined as the systematic use of diagnostic technologies in individuals at risk to detect the disease before the onset of symptoms.
 The study proposes a systematic concept of economic evaluation of the diagnostic screening program for PAH to determine its optimal design.
 At the same time, this concept embodies the complex effect of the introduction of technologies for early diagnosis and pharmacotherapy of PAH, which is expressed in the positive dynamics of clinical indicators, reduced mortality and improved quality of life.
 It should be noted that a number of new tools and approaches for diagnostic screening give hope that advances in the diagnosis of PAH will also affect the effectiveness of medical care.

Opportunities and challenges of pharmacotherapy for pulmonary arterial hypertension in children.

Pediatric pulmonary hypertension (PAH) is a rare disease that carries a poor prognosis if left untreated. Although there are published guidelines for the treatment of children with pulmonary hypertension, due to the limited number of robust pediatric clinical trials, recommendations are often based on limited data or clinical experience. Furthermore, many practical aspects of care, particularly for the pediatric patient, are learned through experience and best navigated with a multidisciplinary team. While newer PAH therapies have been approved for adults, there is still limited but expanding experience in pediatrics. This new information will help improve the targets of goal-oriented therapy. Lastly, this review highlights practical aspects in the use of the different therapies available for the treatment of pediatric pulmonary hypertension.

Pharmacotherapy for pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a condition associated with substantial morbidity and mortality. Over the last 25 years there has been a significant evolution in the therapies to treat PAH. These therapies are effective for patients with group I PAH and group IV PH [chronic thromboembolic pulmonary hypertension (CTEPH)]. PAH is characterized by an imbalance of nitric oxide, prostacyclin and endothelin levels, and current pharmacotherapy involves these three pathways. Earlier clinical trials involving PAH-specific therapies evaluated improvements in 6-minute walk time as a primary improvement whereas contemporary trials have been larger and focused on morbidity and mortality reductions. While there may be a role for monotherapy in disease management, most patients should be considered for dual or triple therapy.

Efficacy and Safety of the Use of Pulmonary Arterial Hypertension Pharmacotherapy in Patients with Pulmonary Hypertension Secondary to Left Heart Disease: A Systematic Review.

Pulmonary hypertension (PH) is often caused by left heart disease (LHD) such as heart failure (HF) or valvular heart disease. Historically, few randomized controlled trials have evaluated the off-label use of medications for treating pulmonary arterial hypertension (PAH) in patients with PH-LHD. However, multiple randomized controlled trials have been published over the last decade that investigated their use in patients with PH-LHD. In addition, recent updates in the classification and definitions of PH have led to an improved recognition of PH-LHD phenotypes, notably combined post-capillary and pre-capillary PH and isolated post-capillary PH. In this systematic review, we show that PAH medications should not be recommended in two distinct HF populations: patients with HF without definitive PH diagnosis and patients with isolated post-capillary PH due to HF. In addition, the use of bosentan or macitentan is not recommended in patients with combined post-capillary and pre-capillary PH due to HF, but sildenafil may be considered to improve pulmonary hemodynamics and exercise capacity in patients with combined post-capillary and pre-capillary PH due to HF. Riociguat 2mg 3 times daily may also be considered to improve pulmonary hemodynamics in patients with combined post-capillary and pre-capillary PH due to heart failure with reduced ejection fraction but not heart failure with preserved ejection fraction. The postoperative use of sildenafil in the setting of PH after valvular heart disease intervention was evaluated. Limited clinical data and safety concern warrants caution with the postoperative use of sildenafil in patients with PH due to valvular heart disease. Despite recent advances in the understanding of PAH medications for patients with PH-LHD, uncertainty remains about their utility in distinct subgroups. Nonetheless, PAH pharmacotherapy should generally be avoided for most patients with PH-LHD.

Pulmonary Arterial Hypertension Medical Management of the Adult Patient with Congenital Heart Disease

Congenital heart disease (CHD)-associated pulmonary arterial hypertension (PAH) includes a heterogeneous patient population that can be characterized by the underlying cardiac malformation. CHD-associated PAH has an estimated prevalence of 5–10% in adult patients, with an increasing number of patients surviving to adulthood because of advances in the surgical management and the development of pulmonary arterial hypertension (PAH)-targeted pharmacotherapy. Although limited data exist, targeted PAH pharmacotherapy has proven to be beneficial in patients with CHD-associated PAH, with observed improvement in functional class, increase in exercise capacity, and improvement in quality of life and cardiopulmonary hemodynamics. Additionally, there has been increasing interest in the “treat-to-close” strategy. PAH-targeted pharmacotherapy may be used to optimize cardiopulmonary hemodynamics so as to improve patients’ operability in repairing the cardiac defect. Although there have been significant advances in the management of this disease state in the past 2 decades, mortality remains high, and ongoing clinical trials are needed to better understand the treat-to-close strategy.

Epidemiology and treatment of pulmonary arterial hypertension.

In the past 2 decades, major changes have occurred in the epidemiological and treatment landscape of pulmonary arterial hypertension (PAH). Previously regarded as a disease of the young and middle-aged, contemporary registries from the Western world have demonstrated an increase in the age of patients with PAH, many of whom are elderly with multiple comorbidities. Another important observation is the improvement in survival of patients with PAH in the modern treatment era compared with historical cohorts, before the availability of advanced therapy. The management of PAH has also become more complex, and numerous drugs are now approved that target the endothelin 1, nitric oxide, and prostacyclin pathways. Combining drugs from different classes is now considered the standard of care and has been demonstrated to improve outcomes. Furthermore, the current treatment paradigm is the early use of combination therapy, often at the time of diagnosis, particularly in patients with severe disease. This Review provides a comprehensive update on the epidemiology and pharmacotherapy of PAH.

Eisenmenger syndrome: current perspectives

Eisenmenger syndrome: current perspectives Heba Nashat,1–3 Aleksander Kempny,1–3 Colm McCabe,1 Laura C Price,1–3 Carl Harries,1 Rafael Alonso-Gonzalez,1–3 Michael A Gatzoulis,1–3 Stephen J Wort,1–3 Konstantinos Dimopoulos1–3 1Adult Congenital Heart Centre and National Centre for Pulmonary Hypertension, Royal Brompton Hospital, 2National Heart and Lung Institute (NHLI), Imperial College, 3National Institute for Health Research (NIHR) Cardiovascular Biomedical Research Unit, Royal Brompton Hospital and National Heart and Lung Institute, Imperial College, London, UK Abstract: Eisenmenger syndrome (ES) is the most severe form of pulmonary arterial hypertension (PAH) related to congenital heart disease (CHD). It results from a cardiac defect allowing significant systemic-to-pulmonary (left-to-right) shunting, which triggers the development of pulmonary vascular disease (PVD) if the defect is not repaired in a timely fashion. Once severe PVD has developed, the defect cannot be repaired. With advances in pediatric cardiology and surgery, the prevalence of ES is steadily falling in developed countries; nonetheless, there will always be patients who are unsuitable for repair at the time of diagnosis, or emigrating from countries with less advanced healthcare, who will develop ES. ES is a multisystem disorder causing chronic hypoxemia and reduced cardiac output resulting in significant morbidity and mortality. While lung (plus defect repair) or combined heart and lung transplantation is thought be the definitive treatment for ES, transplant organs are a limited resource and long-term results are still suboptimal. PAH pharmacotherapy was, until quite recently, largely directed at symptomatic relief and had no impact on morbidity and mortality. Targeted PAH therapies have recently been proven to be beneficial in various forms of PAH in terms of functional status, progression of disease, and prognosis. Data on the effect of PAH therapies in the ES cohort remain limited, but available studies demonstrate evidence of improvement in symptoms, exercise capacity, and some evidence of survival benefit. ES patients should be followed in specialized centers, by means of an interdisciplinary approach by clinicians experienced in PAH and CHD. However, local physicians working in cardiology, respiratory medicine, primary care, and emergency services are likely to encounter ES patients and need to be aware of the main issues and pitfalls in their care. The authors present an overview of the management of ES, focusing on the most common issues and complications. Keywords: Eisenmenger syndrome, pulmonary arterial hypertension, congenital heart disease, cyanosis, pulmonary arterial hypertension therapies, hyperviscosity, thrombosis, bleeding, pregnancy, Down syndrome

Brief Review of Pharmacotherapy for Pulmonary Arterial Hypertension

Brief Review of Pharmacotherapy for Pulmonary Arterial Hypertension

Physicochemical Properties of Bosentan and Selected PDE-5 Inhibitors in the Design of Drugs for Rare Diseases

The study provides the physicochemical characteristic of bosentan (BOS) in comparison to tadalafil (TA) and sildenafil citrate (SIL). Despite some reports dealing with thermal characteristic of SIL and TA, physicochemical properties of BOS have not been investigated so far. Recent clinical reports have indicated that the combination of bosentan and PDE-5 inhibitor can improve the effectiveness of pharmacotherapy of pulmonary arterial hypertension (PAH). However, in order to design personalized medicines for therapy of chronic rare diseases, detailed information on the thermal behaviour and solubility of each drug is indispensable. Thus, XRD, DSC and TGA-QMS analyses were applied to compare the properties of the drugs, their thermal stability as well as to identify the products of thermal degradation. The dehydration of BOS started at 70°C and was followed by the chemical degradation with the onset at 290°C. The highest thermal stability was stated for TA, which decomposed at ca. 320°C, whereas the lowest onset of the thermal decomposition process was stated for SIL, i.e. 190°C. The products of the drug decomposition were identified. FT-FIR was applied to study intra- and intermolecular interactions between the drug molecules. FT-MIR and Raman spectroscopy were used to examine the chemical structure of the drugs. Chemoinformatic tools were used to predict the polar surface area, pKa, or logP of the drugs. Their results were in line with solubility and dissolution studies.

Pharmacologic Therapy for Pulmonary Arterial Hypertension in Adults: CHEST Guideline and Expert Panel Report

Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding pharmacologic therapy for adult patients with PAH as informed by available evidence. This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus. Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded. Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH.

A New START for Sildenafil in Pediatric Pulmonary Hypertension

Pharmacotherapy for pulmonary arterial hypertension (PAH) has evolved dramatically over the past decade. One of the agents at the vanguard of this evolution was sildenafil, which was reported in 2005 to improve exercise capacity, functional status, and hemodynamics in a large randomized controlled trial (RCT) of adults with PAH (SUPER-1) 1 , and has since become a therapeutic mainstay 2 . Based in part on the promising early findings of SUPER-1, sildenafil was studied in treatment-naive children and adolescents as part of the first ever RCT for pediatric PAH, STARTS-1, which randomized patients to placebo or 1 of 3 dose-ranges of sildenafil 3 . After the 16-week evaluation, patients were allowed to remain on therapy in the extension trial, STARTS-2, which continued sildenafil in treated patients and randomized those in the placebo arm to one of the sildenafil doses. STARTS-1 enrolled 234 patients over 4.5 years at 32 centers, the vast majority of whom continued in STARTS-2.

Practical Considerations for the Pharmacotherapy of Pulmonary Arterial Hypertension

Pulmonary arterial hypertension is a devastating disease. Before the 1990s, when pharmacologic treatment was finally approved, only supportive therapy was available, consisting of anticoagulation, digoxin, diuretics, and supplemental oxygen. Calcium channel blocker therapy was also an option, but only a small percentage of patients respond to it. However, starting with epoprostenol in 1996, the number of drugs approved to treat pulmonary arterial hypertension increased. Three distinct classes of drugs were developed based on the pathophysiology of the disease: the prostanoids, endothelin-1 receptor antagonists, and phosphodiesterase type 5 inhibitors. The prostanoids are administered either parenterally or by inhalation to replace the lack of prostacyclin within the pulmonary arterial vasculature. The endothelin-1 receptor antagonists were the first class of oral drugs to be developed, but drug interactions and adverse effects are prominent with this class. The phosphodiesterase type 5 inhibitors increase the second messenger cyclic guanosine monophosphate (GMP) that is induced by nitric oxide stimulation. All of the drugs within these three classes are distinct in and of themselves, and their clinical use requires in-depth knowledge of pulmonary arterial hypertension and its pathophysiology. Because these drugs have different mechanisms of action, combination therapy has shown promise in patients with severe disease, although data are still lacking. This article should serve as a practical guide for clinicians who encounter patients with pulmonary arterial hypertension and the drugs used for the treatment of this devastating disease.

Pharmacotherapy for Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) is a disabling, progressive disease. The past decade has seen an explosion in the available therapies for the management of PAH. Choosing appropriate pharmacotherapy can be a daunting task for the practitioner, as no head-to-head comparisons between drugs have been published. This article aims to assist the practitioner in developing an evidence-based, rational pharmacologic treatment algorithm for the management of patients with PAH. Currently approved pharmacotherapy and the pivotal trials that led to approval for the respective agents are reviewed. Common dilemmas in the treatment of PAH for which strong evidence is lacking are discussed.

Pharmacotherapy for pulmonary arterial hypertension

Although pulmonary arterial hypertension (PAH) is an orphan disease with high mortality and for which there is no cure, current treatment have led to considerable gains in the outcomes of these patients. Oral anticoagulation is proposed for most patients; diuretic treatment and supplemental oxygen are indicated in cases of fluid retention and hypoxemia. High doses of calcium-channel blockers are indicated only in the minority of patients who respond to acute vasoreactivity testing. Nonresponders to acute vaoreactivity testing or who remain in World Health Organization (WHO) functional class III, should be considered candidates for treatment with either an oral phophodiesterase-5 inhibitor or an oral endothelin-receptor antagonist. Continuous intravenous administration of epoprostenol remains the treatment of choice in WHO functional class IV patients. Combination therapy is recommended for patients treated with PAH monotherapy who remain in WHO functional class III. The pharmacologic management of PAH is rapidly evolving as newer therapeutic targets that stabilize or reverse pulmonary vascular disease and as clinical practice pattern shift in favor of earlier diagnosis and aggressive treatment. Questions about preferred first-line therapy and when to institute combination therapies remain. Future drug development targeting other molecular pathways of PAH is essential for definitively improving patient survival. The search for novel treatment continues, with promising new concepts arising from a better understanding of the pathobiology of PAH.

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.

Role of Combination Therapy in the Treatment of Pulmonary Arterial Hypertension

As a result of the multimechanistic pathology of pulmonary arterial hypertension (PAH), combination therapy is emerging as a potential treatment option. Recent guidelines from the American College of Chest Physicians and expert consensus from the American College of Cardiology Foundation and American Heart Association do not definitively support or disapprove of combination pharmacotherapy for the treatment of PAH. Published trials have investigated different combinations including endothelin receptor antagonists with prostanoids, prostanoids with phosphodiesterase inhibitors, and phosphodiesterase inhibitors with endothelin receptor antagonists. Pertinent trials on combination pharmacotherapy for PAH were identified through a MEDLINE search of literature from 1967-2009 in addition to a manual search of references from the articles retrieved. Search results identified 12 trials that evaluated combination therapy for PAH; some included an add-on agent for patients who failed treatment with monotherapy and others were placebo controlled. Even with the published data, the overall consensus is unclear. Well-designed, larger trials with validated end points are needed to further identify when to initiate combination therapy for the treatment of PAH. Meanwhile, perhaps the most appropriate situation for using combination pharmacotherapy may be in the setting of a lack of clinical improvement or deterioration.

Novel approaches to the pharmacotherapy of pulmonary arterial hypertension

Pulmonary arterial hypertension (PAH) has evolved from an untreatable condition to a disease for which several classes of drugs have now been approved, including various prostanoids, endothelin receptor antagonists and phosphodiesterase-5 inhibitors. Because the pathogenesis of pulmonary hypertension is increasingly understood, various new substances are now under clinical investigation, including serotonin antagonists, vasoactive intestinal peptide, stimulators of soluble guanylate cyclase and tyrosine kinase inhibitors. Several of these compounds hold promise for the future therapy of PAH, especially as regression of pulmonary vascular remodeling appears to become a realistic possibility with the combination of established and novel treatments.