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.     

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.     

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.     

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.     

临床药师对低体质量慢性血栓栓塞性肺动脉高压患者应用利伐沙班的药学监护及文献复习

目的:探讨低体质量慢性血栓栓塞性肺动脉高压患者服用利伐沙班后凝血异常的原因及剂量选择。方法:临床药师深入临床,对1例低体质量慢性血栓栓塞性肺动脉高压患者实施药学监护。临床药师计算机检索各数据库,结合相关文献,分析患者出现凝血异常的原因,评定患者使用利伐沙班的剂量,提出个体化给药建议。结果与结论:极端体质量患者使用常规剂量的利伐沙班,凝血酶原时间变化有一定的意义,必要时进行血药浓度监测是最佳选择。     

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.     

Riociguat

肺高压是一种进行性、致死性疾病,其特征是肺动脉压升高,导致血管重构、右心肥大和心衰.研究表明,肺高压与内源性血管扩张剂NO的产生受损有关.Riociguat是首个新一类可溶性鸟苷酸环化酶(sGC)激动剂,它直接刺激sGC,增强其对低水平NO的敏感度.目前应用本品对肺动脉高压(PAH)患者进行Ⅲ期临床、对慢性血栓栓塞性肺...     

Inhaled Iloprost for Chronic Thromboembolic Pulmonary Hypertension (CTEPH) During Pregnancy: A Case Report

Chronic thromboembolic pulmonary hypertension (CTEPH) is a subset of pulmonary hypertension caused by acute and recurrent pulmonary emboli. Pulmonary thromboendarterectomy is the treatment of choice, but 10–50% of patients are ineligible for this procedure. We describe the case of a 25‐year‐old, morbidly obese (228‐kg, body mass index 83.5 kg/m²) pregnant woman (G₃P₂) who presented at 24 weeks’ gestation; bilateral pulmonary angiography revealed filling defects and confirmed the diagnosis of CTEPH. The patient was evaluated and deemed to present too high of a risk for pulmonary thromboendarterectomy, so a multidisciplinary team initiated medical therapy. Sildenafil 20 mg orally 3 times/day was started at week 24 of gestation, and inhaled iloprost was added at 26 weeks and titrated to 5 µg inhaled every 2 hrs in order to optimize hemodynamic status prior to a cesarean section delivery scheduled to be performed 6 weeks later. At 32 weeks of gestation, the patient's pulmonary arterial systolic pressure was 77 mm Hg, right atrial pressure was 15 mm Hg, and pulmonary capillary wedge pressure of 16 mm Hg, and a healthy 1741‐g male infant was delivered by cesarean section. The patient was transferred back to the medical intensive care unit in stable condition and discharged home 9 days following the procedure. Pharmacotherapeutic strategies for patients with CTEPH who become pregnant are limited to phosphodiesterase type 5 inhibitors and prostacyclin analog therapies due to the teratogenicity of the other drug classes used to treat the disorder (endothelin receptor antagonists and soluble guanylate cyclase stimulators). To our knowledge, this is the first case report of inhaled iloprost use in addition to oral sildenafil to improve patient symptomatology and hemodynamics during the peripartum period of a young pregnant patient with inoperable CTEPH. This drug therapy was used safely, with no noted adverse effects to the newborn or to the patient.     

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.     

Calcium Channel Blockers and Pulmonary Hypertension

Abstract: In vascular smooth muscle from the pulmonary circulation, potassium evoked contractions are abolished in calcium-free medium and by calcium channel blockers (CCB). Noradrenaline, histamine, and serotonin induced contractions are partly resistant. Pulmonary arterial hypertension may occur both as a primary disorder and secondary to cardiac and pulmonary diseases; in both types there may be a component of pulmonary arterial vasoconstriction. In animal models, hypoxic pulmonary hypertension is counteracted by CCBs, nifedipine being particular effective. In patients with this disorder, CCBs also seem able to lower pulmonary arterial pressure and vascular resistance, but no controlled trials documenting their clinical efficacy have been performed. This is valid also for primary pulmonary hypertension, where some of the CCBs may have clinical value.     

Transition of Intravenous Treprostinil to Oral Therapy in a Patient with Functional Class IV Chronic Thromboembolic Pulmonary Hypertension

Chronic thromboembolic pulmonary hypertension (CTEPH) occurs when pulmonary emboli fail to resolve with anticoagulation. For patients with inoperable or residual CTEPH, riociguat is currently the only therapy approved by the United States Food and Drug Administration. However, some patients with CTEPH may require therapy beyond riociguat, such as intravenous prostacyclins, which can present significant administration challenges in patients with complex comorbid conditions. We describe a 42‐year‐old man with T12 paraplegia complicated by CTEPH (functional class IV with substantial right ventricular dysfunction) and severe pressure ulcers. In order to facilitate goals of care (hospital discharge to a skilled nursing facility where parenteral prostanoids could not be administered), he underwent rapid transition from intravenous treprostinil to oral selexipag in the form of a cross‐taper over 6 days. The patient required readmission due to worsening symptoms and was transitioned back to intravenous treprostinil; he tolerated conversion to oral treprostinil for approximately 4 months, but it was subsequently discontinued due to nausea and modified goals of care. The patient underwent transition to hospice care 3 months later and eventually died from clinical deterioration. To our knowledge, this is the first report to describe transition from intravenous treprostinil to selexipag as well as conversion from parenteral treprostinil to oral treprostinil in a patient with CTEPH and illustrates the approaches to and potential issues with prostanoid transitions. Additional observations are necessary to better understand the relative roles of selexipag and oral treprostinil regarding comparative efficacy and tolerability.     

利奥西呱治疗肺高血压有效性、安全性及经济性的快速卫生技术评估

目的： 快速评价利奥西呱治疗肺高血压（PH）的有效性、安全性和经济性,为临床治疗方案的选择提供循证参考。方法： 计算机检索主要中英文数据库及各大卫生技术评估网站。研究人员独立筛选文献、提取资料。进行质量评价后,对提取的结果进行分类评价和描述性汇总分析。结果： 共纳入文献12篇,其中HTA报告2篇、系统评价/Meta分析7篇、药物经济学研究4篇。有效性分析显示：对于肺动脉高压（PAH）患者,相比于安慰剂,利奥西呱可显著增加6分钟步行距离（6-MWD）、心脏指数（CI）,降低Borg呼吸困难指数（BDI）、平均肺动脉压（mPAP）、肺动脉阻力（PVR）、临床恶化率、血清氨基末端B型脑利钠肽前体（NT-proBNP）、肺高血压评分（LPH评分）,差异有统计学意义。对于慢性血栓栓塞性肺高血压（CTEPH）患者,相比于安慰剂,利奥西呱可显著延长6-MWD,降低mPAP、PVR、BDI、NT-proBNP,差异有统计学意义。对于左心疾病相关性肺高血压（PH-LHD）患者,相比于安慰剂,利奥西呱仅对PVR、CI有显著影响。安全性分析显示：与安慰剂相比,利奥西呱的严重不良事件无显著增加。经济性分析显示：国外研究表明利奥西呱具有较高的增量成本效用比。结论： 利奥西呱对PAH、CTEPH患者具有良好的有效性和安全性,对PH-LHD的有效性尚需进一步研究。亟需开展其国内药物经济学研究。     

Riociguat for the treatment of pulmonary hypertension

Introduction: Pulmonary arterial hypertension (PAH) is still an incurable disease with high mortality despite recent treatment advances. Chronic thromboembolic pulmonary hypertension (CTEPH) is a specific form of pulmonary hypertension due to thromboembolic occlusion of pulmonary arteries. Although 50 – 60% of the CTEPH patients can be cured via pulmonary endarterectomy (PEA), a significant portion is inoperable. For both diseases, therefore, new treatments are urgently needed.

Areas covered: The review will explain the mechanism of action of the soluble guanylate cyclase stimulator riociguat (BAY 63-2521) and will give an overview regarding the current scientific and clinical data of riociguat in both indications PAH and CTEPH. The most relevant publications up to date were used as sources for this review.

Expert opinion: Riociguat is a novel treatment option in PAH class 1, which, in contrast to phosphodiesterase-5 inhibitors, acts independently of endogenous nitric oxide and has shown efficacy in combination therapy with endothelin-1 receptor antagonists. Riociguat is the first approved drug for non-operable CTEPH and sustained CTEPH after PEA, thus introducing a proven pharmacologic treatment option for this group of patients. Long-term results in the real-life setting are still lacking and are needed to provide evidence for the true amount of progress riociguat adds to the field.     

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.     

Pulmonary hypertension in patients with a history of intravenous drug use

Objective: Pulmonary hypertension may be a consequence of intrinsic elevation in pulmonary vasculature resistance or complicate numerous other conditions affecting the cardiac and respiratory systems. In this review we sought to explore the relationship between pulmonary hypertension and intravenous drug use.

Methods: A narrative review was conducted using PubMed MeSH search with further papers identified using a standard PubMed search with relevant key terms and various synonyms.

Results: HIV infection may be associated with pulmonary hypertension due to indirect consequences of viral infection, venous thromboembolism or its therapies. Anti-retroviral infection may also influence plasma concentrations of commonly used treatments for pulmonary hypertension. Intravenous drug use is acknowledged as an important portal for the acquisition of hepatitis virus C infection, with portopulmonary hypertension a potential complication associated with poor prognosis. Interferon based therapy, used in treatment of chronic hepatitis C infection, may also play a causal role in the development of pulmonary hypertension. More recently, sofosbuvir has been linked to development or exacerbation of pulmonary arterial hypertension. Certain drugs of abuse may cause pulmonary hypertension due to properties that result in direct injury to the pulmonary vasculature. The potential for embolic phenomena, complicating venous thromboembolism, recurrent embolization of particulate matter or because of right-sided endocarditis, resulting in pulmonary hypertension is an important contributing factor in the pathophysiology in this unique cohort.

Conclusions: Eliciting a history of intravenous drug use is important and may be associated with a number of less common etiologies, each with specific diagnostic and therapeutic implications.     

Bosentan

Importance to the field: Pulmonary arterial hypertension (PAH) is a morbid condition with high mortality if left untreated. Bosentan is an effective treatment option for group 1 pulmonary arterial hypertension. Bosentan improves exercise tolerance and functional class and delays the time to clinical worsening in these patients. Investigation is ongoing to determine its efficacy in other groups of pulmonary hypertension.

Areas covered in this review: This review provides a background on endothelin activity in PAH, as a rationale for the use of bosentan in this disease. It also presents evidence from key clinical trials of bosentan and discusses future directions in the study of bosentan to help the clinician better understand the role of bosentan in PAH management.

What the reader will gain: i) An understanding of the rationale for using endothelin receptor antagonists in treating PAH; ii) an understanding of the clinical evidence to support bosentan for the treatment of PAH; and iii) an understanding of how to use bosentan optimally in the treatment of PAH.

Take home message: Bosentan is an effective and safe treatment for patients with PAH. Patients with suspected PAH should be evaluated carefully as the use of bosentan in non-group 1 pulmonary hypertension is still being investigated. Patients on bosentan should be monitored with monthly liver transaminase testing. Coadministration with other drugs should be reviewed carefully as drug–drug interactions may be important.     

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.     

Pulmonary artery sarcoma misdiagnosed as chronic thromboembolic pulmonary hypertension

Pulmonary artery sarcomas are rare neoplasms of the pulmonary artery that are often confused with chronic thromboembolic disease, as both diseases have similar presentations. In patients with presumed chronic thromboembolic pulmonary hypertension, certain clinical and imaging characteristics may suggest the alternative diagnosis of pulmonary artery sarcoma. In this article we present a case of a man initially diagnosed with chronic thromboembolic pulmonary hypertension, but who was later found to have pulmonary artery sarcoma. We review the distinguishing characteristics of the two diseases and discuss possible treatment strategies.     

Iptakalim prevents rat pulmonary hypertension induced by endothelin‐1 through the activation of KATP channel in vivo

Iptakalim has been previously characterized as a novel, selective ATP‐sensitive potassium channel opener. In the present study, to determine whether iptakalim can prevent the pulmonary hypertension induced by endothelin‐1 (ET‐1) through the activation of K_ATP channel in vivo, the effects of iptakalim and glibenclamide (a selective K_ATP channel blocker) on the mean pulmonary pressure (mPAP) induced by ET‐1 were examined in rats. Treatment of the animals with exogenous ET‐1 (via the pulmonary artery at a dose of 1.5 µg/kg) induced a pulmonary hypertension in vivo, whereas the administration of iptakalim (via the pulmonary artery at doses of either 0.5 mg or 1.0 mg/kg) prior to ET‐1 prevented pulmonary hypertension induced by ET‐1 in vivo. The ability of iptakalim to prevent pulmonary hypertension induced by ET‐1 was abolished by glibenclamide (via the femoral artery at a dose of 20 mg/kg) in vivo. These findings provide strong evidence that iptakalim acts as a specific K_ATP channel opener to antagonize the vasoconstrictor effect of ET‐1 in the pulmonary circulation. Thus, iptakalim may be developed as a therapeutic option for the treatment of pulmonary hypertension. Drug Dev Res 69: 89–94, 2008. © 2008 Wiley‐Liss, Inc.