Treating pulmonary hypertension in the elderly

ABSTRACT

Introduction

Despite an increasingly older pulmonary hypertension (PH) population, data on PH treatments in these patients are limited because there exist no clinical studies dedicated to geriatric groups. Furthermore, elderly patients with comorbidities have been systematically excluded from clinical trials, limiting the evidence base for drugs approved for pulmonary arterial hypertension (PAH).     

肺动脉高压药物治疗进展

目的:探讨肺动脉高压(pulmonary hypertension,PH)药物治疗的最新进展。方法:查阅国内外公开发表的文献,综述肺动脉高压的药物治疗进展。结果:目前肺动脉高压分为5大类,常见类型20余种。第一大类动脉型肺动脉高压(pulmonary arterial hypertension,PAH)与其他类型肺动脉高压的治疗策略有所不同,目前用于动脉型肺动脉高压治疗的药物主要有5类。结论:目前上市的相关靶向药物主要是针对动脉型肺动脉高压的治疗,这些药物都显示具有改善肺动脉高压患者的运动耐量、症状及血流动力学的作用。     

An update on the diagnosis and treatment of pediatric pulmonary hypertension

ABSTRACT

Introduction

Pulmonary hypertension (PH) is a heterogeneous disease that mainly affects the pulmonary arterioles, leading to significant morbidity and mortality. Pulmonary hypertension in children from birth to adolescence presents important differences from that of adults. The majority of pediatric pulmonary arterial hypertension (PAH) cases are idiopathic or associated with congenital heart disease. However, the management of pediatric PAH mainly depends on the results of evidence-based adult studies and the clinical experiences of pediatric experts.     

Tadalafil for the treatment of pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a progressive occlusive disease affecting the pulmonary vasculature; it carries a poor prognosis. Because right ventricular failure is the key feature of deterioration in PAH patients, vasodilator treatments relieving right ventricular afterload have gained ground in the treatment of this disorder. Phosphodiesterase-5 inhibitors are effective and well tolerated vasodilators that were originally developed for erectile dysfunction. Tadalafil, the first once-daily drug of this class, was approved by the USFDA in May 2009 for the treatment of patients suffering from PAH.

Areas covered: This review outlines the currently available data about tadalafil and its effects in patients with PAH. It also presents evidence from recent clinical trials of tadalafil and discusses potential improvements over existing therapy options and their impact on current treatment strategies.

Expert opinion: Tadalafil is an efficacious drug with a favorable side-effect profile and convenient mode of administration. More studies are needed to analyze its impact on survival and to substantiate its role in an upfront combination treatment strategy.     

Riociguat for pulmonary hypertension

Pulmonary hypertension, an elevation of the mean pulmonary artery pressure ≥25 mmHg, ultimately leads to premature death due to right ventricular dysfunction. Ten treatments from three classes of drugs are licensed for the management of pulmonary arterial hypertension. These treatments have improved exercise capacity but median survival is still poor. Additionally there are no licensed therapies for the other groups of pulmonary hypertension. Riociguat is a novel drug that stimulates soluble guanylate cyclase independently of nitric oxide and in synergy with nitric oxide. This review summarises the available evidence for riociguat in the treatment across all groups of pulmonary hypertension with a focus on pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension.     

Selexipag for the treatment of pulmonary arterial hypertension

Introduction: Targeted pulmonary vasoactive substances are the cornerstone of treatment in pulmonary arterial hypertension (PAH). Approved drugs act on various receptors and molecules within the pulmonary arteries, mainly causing pulmonary vasodilation and potentially reversing remodeling with consequent improvement of right ventricular function. A key role is attributed to the prostacyclin pathway and especially the prostacyclin receptor (IP). Selexipag is a recently developed, non-prostanoid, oral IP receptor agonist for the treatment of PAH which has been approved in countries/regions including the USA and Europe.

Areas covered: We review the discovery and development of drugs targeting IP receptors in PAH and describe preclinical and phase I studies of selexipag. Furthermore, we review important phase II and III selexipag studies and place them into the clinical context of previously approved prostanoids.

Expert opinion: Oral selexipag offers a promising therapeutic option within the class of available drugs targeting IP receptors. However, its role as first-line therapy based on its efficacy/side-effect profile in current studies is questionable. Most likely, selexipag will be used in combination with other PAH-specific oral drugs. The potential of selexipag to replace or postpone the use of inhaled or parenteral prostanoids needs to be investigated in future trials.     

Treatment of pulmonary hypertension with riociguat: a review of current evidence and future perspectives

ABSTRACT

Introduction

Pulmonary arterial hypertension (PAH) is still a chronic disorder characterized by high morbidity and mortality. Chronic thromboembolic pulmonary hypertension (CTEPH) is another form of pulmonary hypertension (PH) for which pulmonary endarterectomy (PEA) is the treatment of choice. However, not all patients are operable, while PH is often recurrent or persistent. Thus, for both disorders novel treatment options are urgently needed.     

Riociguat for the treatment of pulmonary hypertension

Introduction: Pulmonary hypertension (PH) is a severe condition with a poor prognosis despite recent treatment advances. Therapies with new mechanisms of action are needed.

Areas covered: This review will help readers understand the mechanism of action of the soluble guanylate cyclase (sGC) stimulator riociguat (BAY 63-2521) and will provide a comprehensive summary regarding efficacy and safety of this drug in the management of PH. The most relevant publications up to December 2010 were used as sources for this review.

Expert opinion: Cyclic guanosine monophosphate (cGMP) is an important mediator of the preferential perfusion of well-ventilated regions throughout the lung. Drugs that increase cGMP levels could promote pulmonary vasorelaxation while maintaining optimal gas exchange. cGMP is generated by sGC, which can be stimulated by nitric oxide (NO). Riociguat stimulates sGC independently of NO and increases the sensitivity of sGC to NO, resulting in increased cGMP levels. Results to date suggest rapid, potent and prolonged efficacy and good tolerability in different types of PH. Phase III clinical trials are evaluating the long-term safety and clinical effectiveness of riociguat in pulmonary arterial hypertension (PAH) and chronic thromboembolic PH. Riociguat has the potential to become an important drug for the treatment of patients with PH.     

Tetrandrine prevents monocrotaline-induced pulmonary hypertension in rats

In this study, the effects of chronic administration of tetrandrine (TET) on monocrotaline (MCT) induced pulmonary hypertension were investigated. The results showed that MCT induced marked pulmonary hypertension and right ventricular hypertrophy; TET 50 mg kg⁻¹ and 100 mg kg⁻¹ significantly decreased pulmonary artery pressure (Ppa, from 5.2 ± 0.48 kPa to 4.35 ± 0.69 kPa, P < 0.05 and to 3.79 ± 0.84 kPa, P < 0.05, respectively) without marked influence on systemic arterial pressure (Psa). TET restored right ventricular hypertrophy (right ventricular index significantly decreased from 0.41 to 0.37 and 0.32, respectively). Histological findings showed that TET restored MCT-induced lung tissues and vascular lesion and pulmonary arteries media hypertrophy. We conclude that chronic administration of TET does have selective effects on pulmonary hypertension produced by MCT. Drug Dev. Res. 39:158–160. © 1997 Wiley-Liss, Inc.     

Treprostinil therapy for pulmonary artery hypertension

Pulmonary artery hypertension is a life-threatening disease characterised by a pulmonary vasculopathy and progressive right ventricular failure. Major advances were made with the development of continuous intravenous epoprostenol (Flolan?) as a treatment modality. Nevertheless, it is far from ideal as treatment for this disease. Subcutaneous treprostinil has been FDA approved for the treatment of New York Heart Association Functional Class II – IV pulmonary artery hypertension. It is a longer acting subcutaneous prostacyclin analogue that offers an additional mode of therapy for this disease. A discussion of the pharmacology of this prostacyclin analogue as compared to its related compounds, the clinical studies which led to its approval, a review of some additional basic studies and the practical use of this drug in the treatment modalities for precapillary pulmonary artery hypertension in 2002 in light of other available therapies is discussed.     

Current understanding of the role of bosentan in inoperable chronic thromboembolic pulmonary hypertension

Chronic thromboembolic pulmonary hypertension may occur in the context of incomplete lysis of acute pulmonary emboli, resulting in the obstruction of pulmonary blood flow, as well as progressive right ventricular dysfunction and failure. The treatment of choice for this condition is surgical removal of the obstructing material. However, in many patients, surgery is not possible due to either an unfavourable distribution of the disease, the development of a concurrent small vessel pulmonary arteriopathy, or the presence of significant comorbid conditions. There is increasing evidence that the medical therapies that are used in other forms of pulmonary hypertension may also be effective in inoperable chronic thromboembolic pulmonary hypertension. This article examines the rationale for the use of the oral dual endothelin receptor antagonist bosentan in this life-threatening condition.     

氯沙坦治疗肺动脉高压的初步探讨

目的：探讨氯沙坦在治疗肺动脉高压中的作用，以评价其对慢性肺源性心脏病（肺心病）的疗效。方法：60例慢性阻塞性肺疾病同时伴有肺动脉高压病人分成两组，均给予常规吸氧、抗感染、祛痰、平喘等治疗。治疗组加服氯沙坦，50mg/次，每日一次。疗程2周。治疗前和2周时测定肺动脉压。结果：两组治疗后肺动脉压均有显著下降（P＜0．01）；治疗组肺动脉压的下降与对照组比较有极显著的差异（P＜0．001），动脉血氧分压的上升与对照组比较有明显差异（P＜0．05）。结论：慢性阻塞性肺疾病急性加重期病人通过常规吸氧、抗感染、祛痰、平喘等治疗可使肺动脉压降低，加用氯沙坦可使肺动脉压下降更为明显，并使动脉血氧分压上升，提示氯沙坦可用于肺心病的治疗。     

伊洛前列素治疗肺动脉高压的疗效

目的：观察吸入伊洛前列素治疗重症肺动脉高压的效果。方法：采用病例分析和文献复习方法。3例重症肺动脉高压女性患者,其中2例为特发性肺动脉高压,1例为系统性红斑狼疮合并肺动脉高压。3例患者均在常规治疗基础上吸入伊洛前列素10μg,每次吸入约10～15 min,每隔3 h一次,共6次。观察吸入前后体动脉压、心率、6 min步行距离和超声心动图各项指标的变化以及患者的不适反应。结果：3例患者6 min步行距离和肺动脉压力均有明显改善。结论：吸入伊洛前列素可以显著提高重症肺动脉高压患者活动耐力和降低肺动脉压力。     

Emerging therapies for pulmonary arterial hypertension

Pulmonary arterial hypertension is characterised by increased pulmonary vascular resistance due to increased vascular tone and structural remodelling of pulmonary vessels. The therapies that are in use so far have been developed to correct endothelial dysfunction and reduce vasomotor tone. These treatments have a limited effect on the remodelling process and, increasingly, the focus is turning to potent strategies for inhibiting vascular proliferation and promoting vascular apoptosis. Multiple novel targets have been uncovered over the last 5 years and several are now in early clinical trials. At present, it is clear that there is no single treatment for the condition. Although this is the case, studies are investigating the role of combining therapies that are already established.     

Rho-kinase inhibitors show promise in pulmonary hypertension

In pulmonary arterial hypertension, it is necessary to obtain a vasodilation that is selective for the pulmonary circulation. Ras human orthologue (Rho)/Rho-kinase-mediated Ca²⁺ sensitisation plays a central role in mediating the sustained vasoconstriction and increased vasoreactivity in the rat hypoxic model of pulmonary hypertension. Rho-kinase inhibitors (Y-27632 and/or fasudil) have been shown to reduce pulmonary arterial pressure in three rat models of pulmonary hypertension. The first clinical study to report the effects of a Rho-kinase inhibitor in pulmonary hypertension enrolled nine patients with severe pulmonary hypertension. Fasudil hydrochloride 30 mg for 30 min i.v. caused a slight decrease in the mean pulmonary artery pressure and increase in the cardiac index but neither of these responses was significant. However, fasudil caused a significant decrease in pulmonary vascular resistance. Rho-kinase inhibitors may be useful in pulmonary hypertension, and should undergo further development for this indication.     

Prevalence of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the United States

Abstract

Background:

The prevalence of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) in the US is largely unknown. Prior research has estimated PAH prevalence in Europe at ～15–52 per million.     

Oral treprostinil in the treatment of pulmonary arterial hypertension

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease resulting in progressive remodeling of the pulmonary vasculature and eventual right ventricular failure. Despite the development of 13 therapies for PAH since 2000, the use of continuously infused prostanoids retains a special role. Infused medications present unique challenges, and the search for an efficacious oral prostanoid culminated in the FDA approval of oral treprostinil – a first in class oral prostanoid medication approved to treat pulmonary arterial hypertension (PAH).

Areas covered: In this discussion, we review the pharmacologic properties of oral treprostinil, and discuss three original major registration studies that resulted in the approval and widespread use of the drug. We also review several post-approval analyses and transitional studies. We discuss administration issues including side effects, transitioning, cost, and comparative analysis with selexipag.

Expert opinion: Though the prospects of harnessing the benefits of continuously infused prostanoid therapy in a pill form are tantalizing, the gap in efficacy between oral and infused treatment is substantial. Major side effects and exorbitant cost are further barriers to broad uptake. Competition from oral prostaglandin receptor agonist selexipag challenges the commercial success of oral treprostinil. The long-term viability of oral treprostinil rests largely on the outcome of the long-term event-driven study of the molecule added to background approved ERA or PDE5 inhibitor monotherapy.     

先天性心脏病合并肺动脉高压患儿57例临床分析

目的分析先天性心脏病合并肺动脉高压患儿的临床资料,以提高对该病的临床诊治水平。方法 57例患儿均予以吸氧、抗感染以及强心、利尿、扩血管治疗。11例左向右分流型先天性心脏病以及5例复杂型先天性心脏病经内科治疗后肺部感染、心力衰竭难以控制,转我院心外科予以手术。术后8例患儿用前列地尔,6例患儿用西地那非降肺动脉压力。患儿于内科治疗前后、手术后药物治疗前后测肺动脉压力(PAP)、左室射血分数(LVEF)及血浆N端-脑钠肽前体(NT-proBNP)。结果 38例左向右分流型先天性心脏病患儿经内科治疗后PAP、血浆NT-proBNP水平均较治疗前下降(P<0.05),LVEF较治疗前升高(P<0.05)。11例左向右分流型先天性心脏病以及5例复杂型先天性心脏病患儿PAP、血浆NT-proBNP水平均高于前述38例患儿(P<0.05),LVEF低于前述38例患儿(P<0.05)。8例患儿术后予以前列地尔,6例予以西地那非治疗后,PAP、血浆NT-proBNP水平较用药前下降(P<0.05),LVEF较用药前升高(P<0.05)。结论先天性心脏病合并肺动脉高压需早治疗,可改善预后。前列地尔、西地那非在治疗肺动脉高压方面是有效的。     

Novel therapeutics for the treatment of paediatric pulmonary arterial hypertension

The treatment of paediatric pulmonary arterial hypertension is challenging due to the serious nature of the disease, its rapid progression and the limited treatment options available. However, recent advances in the treatment of pulmonary arterial hypertension may offer significant improvements for patients suffering from this condition. Novel treatment options include prostacyclin analogues and endothelin receptor antagonists. A comprehensive review of the newer agents, with an emphasis on the pathobiology/pathophysiology of pulmonary arterial hypertension provides insight into future management of paediatric pulmonary arterial hypertension.     

Pediatric pulmonary arterial hypertension: current and emerging therapeutic options

Introduction: Pulmonary arterial hypertension (PAH) is a rare disease in neonates, infants and children that is associated with significant morbidity and mortality. An adequate understanding of the controlling pathophysiologic mechanisms is lacking and although mortality has decreased as therapeutic options have increased over the past several decades, outcomes remain unacceptable.

Areas covered: This review summarizes the currently available therapies for neonates, infants and children with PAH and describes emerging therapies in the context of what is known about the underlying pathophysiology of the disease.

Expert opinion: All of the currently approved PAH therapies impact one of three endothelial-based pathways: nitric oxide–guanosine-3′-5′cyclic monophosphate, prostacyclin or endothelin-1. The beneficial effects of these agents may relate to their impact on pulmonary vascular tone, and/or their antiproliferative and antithrombotic properties. Fundamental advances in PAH therapy are likely to relate to: i) a better understanding of PAH subpopulations, allowing for therapies to be better tailored to individual patients and pathophysiologic processes; and ii) therapies that promote the regression of advanced structural remodeling.