bay-63-2521 and Hypertension--Pulmonary

Effective clinical decision-making in initial treatment selection and switching or escalations of therapy for pulmonary arterial hypertension (PAH) depends on multiple factors including the patient's risk profile. Data from clinical trials suggest that switching from a phosphodiesterase-5 inhibitor (PDE5i) to the soluble guanylate cyclase stimulator riociguat may provide clinical benefit in patients not reaching treatment goals. In this review, we cover the clinical evidence for riociguat combination regimens for patients with PAH and discuss their evolving role in upfront combination therapy and switching from a PDE5i as an alternative to escalating therapy. Specifically, we review current evidence which suggests or provides a hypothesis for 1) the potential use of riociguat plus endothelin receptor antagonist combinations for upfront combination therapy in patients with PAH at intermediate to high risk of 1-year mortality and 2) the benefits of switching to riociguat from a PDE5i in patients who are not achieving treatment goals with PDE5i-based dual combination therapy and at intermediate risk.

Topics: Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines

The comparative efficacy between riociguat and selexipag in patients with pulmonary arterial hypertension (PAH) has never been described in literature. Our aim was to prepare indirect treatment comparison (ITC) to evaluate the cost-effectiveness of riociguat in Czechia.. A systematic literature review identified two relevant trials with comparable endpoints to inform a Bucher ITC of relative and absolute effects. Given the comparable efficacy of riociguat and selexipag, a cost-minimization analysis (CMA) was conducted.. A Bucher ITC provided evidence for the comparable relative efficacy of riociguat defined as the odds of unimproved functional class III 0.761 (95% CI 0.372 to 1.558; p = 0.455) compared to selexipag and a comparable absolute efficacy defined as a difference in the 6-minute walking distance of 10.560 meters (95% CI -10.692 to 31.812; p = 0.330). The CMA identified riociguat as the cost-saving therapy.. Switching to riociguat represents the cost-saving therapy for PAH patients who were inadequately compensated with the PDE5i+ERA therapy. Consequently, riociguat has been introduced to the list of reimbursed medicines in Czechia from October 2021. Based on two global trials, we prepared the first indirect treatment comparison followed with CMA of these therapies that may improve future decision-making for PAH indications.

Topics: Antihypertensive Agents; Costs and Cost Analysis; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive diseases that can lead to right heart failure and death. Right ventricular dysfunction, hypertrophy and maladaptive remodelling are consequences of increased right ventricular (RV) afterload in PAH and CTEPH and are indicative of long-term outcomes. Because RV failure is the main cause of morbidity and mortality in PAH and CTEPH, successful treatments should lead to improvements in RV parameters. Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of PAH and inoperable or persistent/recurrent CTEPH after pulmonary endarterectomy. This review examines the current evidence showing the effect of riociguat on the right ventricle, with particular focus on remodelling, function and structural parameters in preclinical models and patients with PAH or CTEPH.

Topics: Chronic Disease; Familial Primary Pulmonary Hypertension; Heart Ventricles; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pulmonary Embolism; Pyrazoles; Pyrimidines; Soluble Guanylyl Cyclase

Pulmonary hypertension (PH) is a broad term describing the mean pulmonary artery pressure, as measured by right heart catheterization, exceeds 20mmHg. Pulmonary arterial hypertension (PAH) exists when PH is accompanied by a normal wedge pressure and elevated pulmonary vascular resistance. PAH is typified by dysmorphic and dysfunctional pulmonary arterial vasculature. Attempting to restore the functionality of the pulmonary artery is a hallmark of care to the PAH patient. Riociguat is a powerful stimulator of soluble guanylate cyclase and increases blood flow through the pulmonary arteries by dilating vascular smooth muscle cells. This review examines the pharmacology of riociguat, the fundamental clinical trials applying it to PAH patients, practical aspects when selecting its use, and future directions for its utilization.

Topics: Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines; Soluble Guanylyl Cyclase

Pulmonary hypertension (PH), which includes pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), is a progressive condition with significant morbidity and mortality due to right heart failure if left untreated. Riociguat is a soluble guanylate cyclase (sGC) stimulator and is the only treatment approved for both PAH and CTEPH. The objectives of this review are to describe the epidemiology and pathophysiology of PAH and CTEPH; synthesize the pharmacology, efficacy, safety, and utilization of riociguat; and discuss the role of the pharmacist in managing patients with these conditions. Data presented in this review is supported by peer reviewed literature, using PubMed and key words including pulmonary hypertension, pulmonary arterial hypertension, chronic thromboembolic pulmonary hypertension, and riociguat. The review draws on key studies and review articles that discuss the pathophysiology of PAH and CTEPH, as well as articles discussing the safety and efficacy of riociguat. The overall goal in the treatment of PAH and CTEPH is to improve long-term survival. Treatment planning depends on the type of PH, treatment goals, comorbidities, and risk profiles. Pharmacists serve a valuable role as part of the multidisciplinary team in the care of patients with PH, many of whom may have comorbidities that contribute to high costs and resource utilization. Riociguat is a first-in-class medication and the only approved treatment for both PAH and CTEPH. In clinical trials, riociguat has demonstrated favorable efficacy and tolerability. Riociguat is a valuable addition to the armamentarium of options for treating patients with PH.

Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pulmonary Embolism; Pyrazoles; Pyrimidines

Riociguat therapy has been recommended for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH), and it might have therapeutic significance for other types of pulmonary hypertension (PH). Our purpose was to evaluate the specific impact of riociguat on all types of PH.. We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) comparing the safety and efficacy of riociguat treatment for PH through databases of the Cochrane Library, PubMed, Embase, and Web of Science from inception to the present. Duplicate publications, studies with no full text, incomplete information or inability to extract data, animal experiments and reviews, and systematic reviews were excluded. The software RevMan 5.4 was used for data synthesis.. There were 8 RCTs included in our study, involving 1,606 participants. For PAH and CTEPH patients, riociguat treatment extended 6-minute walk distance (6MWD) by 39.84 meters, decreased mean pulmonary arterial pressure (PAP) by 4.20 mmHg, lowered pulmonary vascular resistance (PVR) by 218.76 dynes/sec/cm-5, cut down right atrial pressure (RAP) by 0.9 mmHg, increased cardiac index (CI) by 0.49 L/min/m2, improved cardiac output (CO) by 0.89 L/min, reduced N-terminal pro-type B natriuretic peptide (NT-proBNP) by 436.21 pg/mL, and decreased adverse events and clinical worsening as compared with placebo. For other types of PH including PH due to left heart disease and PH due to lung disease, riociguat was reported as having improved CI by 0.42 L/min/m2 and CO was increased by 0.92 L/min compared with placebo. Other efficacy outcomes and safety outcomes did not attain statistical difference in other types of PH.. For PAH and CTEPH, riociguat treatment is safe and effective, but for other types of PH, it can only improve some hemodynamic parameters.

Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines

Riociguat is a first-in-class soluble guanylate cyclase stimulator, approved for the treatment of adults with pulmonary arterial hypertension (PAH), inoperable chronic thromboembolic pulmonary hypertension (CTEPH), or persistent or recurrent CTEPH after pulmonary endarterectomy. Approval was based on the results of the phase III PATENT-1 (PAH) and CHEST-1 (CTEPH) studies, with significant improvements in the primary endpoint of 6-minute walk distance vs placebo of +36 m and +46 m, respectively, as well as improvements in secondary endpoints such as pulmonary vascular resistance and World Health Organization functional class. Riociguat acts as a stimulator of cyclic guanosine monophosphate synthesis rather than as an inhibitor of cGMP metabolism. As with other approved therapies for PAH, riociguat has antifibrotic, antiproliferative and anti-inflammatory effects, in addition to vasodilatory properties. This has led to further clinical studies in patients who do not achieve a satisfactory clinical response with phosphodiesterase type-5 inhibitors. Riociguat has also been evaluated in patients with World Health Organization group 2 and 3 pulmonary hypertension, and other conditions including diffuse cutaneous systemic sclerosis, Raynaud's phenomenon and cystic fibrosis. This review evaluates the results of the original clinical trials of riociguat for the treatment of PAH and CTEPH, and summarises the body of work that has examined the safety and efficacy of riociguat for the treatment of other types of pulmonary hypertension.

Topics: Adult; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines

Chronic thromboembolic pulmonary hypertension (CTEPH) is classified as Group-4 pulmonary hypertension caused by organized thrombi in pulmonary arteries. Pulmonary endarterectomy (PEA) has been shown to improve the symptoms and prognoses of patients with proximal CTEPH. The soluble guanylate cyclase stimulator (riociguat) is the sole FDA-licensed drug for the treatment of CTEPH, and guidelines recommend its use for patients with inoperable CTEPH or residual or recurrent pulmonary hypertension following PEA. Balloon pulmonary angioplasty (BPA) is a new procedure, but it is a promising alternative to PEA, especially in patients with inoperable CTEPH. This review summarizes the history, indications, procedures and complications of BPA. Finally, we discuss the future perspective of BPA for better management of CTEPH.

Topics: Angiography; Angioplasty, Balloon; Chronic Disease; Endarterectomy; Enzyme Activators; Humans; Hypertension, Pulmonary; Imaging, Three-Dimensional; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines

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.. This review describes the mechanism of action of riociguat, a soluble guanylate cyclase (sGC) stimulator, with a dual mode of action. The most relevant publications are presented regarding the efficacy of riociguat in PAH and CTEPH, and also data regarding its potential effect on other forms of PH.. Riociguat is a first-in-class drug approved for the treatment of PAH as a monotherapy or added to endothelin-receptor antagonists as a sequential combination therapy, and for the treatment of inoperable CTEPH or persistent/recurrent PH after PEA. As it can stimulate sGC independently of NO, it could be beneficial in PAH patients with inadequate response to phosphodiesterase 5 inhibitors (PDE5i). Future studies are needed to evaluate whether drug switching is beneficial in PAH and which baseline markers could guide the optimal initial treatment selection.

Topics: Enzyme Activators; Healthy Volunteers; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines

The present review provides an update on treatment of chronic thromboembolic pulmonary hypertension (CTEPH), a rare form of pulmonary hypertension characterized by precapillary pulmonary hemodynamic parameters with chronic thrombotic occlusion of the pulmonary vasculature.. Pulmonary thromboendarectomy (PTE) remains the recommended treatment for patients with surgically accessible disease. Recent data suggest that patients preoperatively bridged with medical therapy may have improved outcomes but further research is needed. Riociguat improves hemodynamics, right ventricular function, quality of life, and functional capacity and is the drug of choice for patients with inoperable/persistent disease. Recently published data suggest that endothelin receptor blockers and treprostinil may also have a role in medical management of this patient population. A growing body of evidence indicates that in experienced centers balloon pulmonary angioplasty (BPA) may be a well tolerated and effective adjunct to pharmacological treatment for patients with inoperable disease affecting subsegmental vasculature.. Untreated CTEPH carries significant morbidity and mortality. Recent publications provide a wealth of data on safety and efficacy of BPA for inoperable subsegmental disease, but its precise fit in the treatment algorithm, both pharmacological and procedural, requires further investigation. PTE remains the procedure of choice for surgically accessible disease.

Topics: Angioplasty, Balloon; Anticoagulants; Antihypertensive Agents; Chronic Disease; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Epoprostenol; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Vasodilator Agents

Topics: Bosentan; Disease Progression; Endothelin Receptor Antagonists; Enzyme Activators; Humans; Hypertension, Pulmonary; Hypoxia; Idiopathic Pulmonary Fibrosis; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Circulation; Pulmonary Diffusing Capacity; Pulmonary Ventilation; Pyrazoles; Pyrimidines; Sildenafil Citrate; Treatment Failure; Vascular Remodeling; Vasoconstriction

Riociguat treatment might be beneficial for pulmonary arterial hypertension. However, the results of studies to date are controversial. We conducted a systematic review and meta-analysis to explore the influence of riociguat treatment on pulmonary arterial hypertension.. The PubMed, Embase, Web of science, EBSCO, and Cochrane Library databases were systematically searched. Randomized controlled trials (RCTs) assessing the effect of riociguat treatment on pulmonary arterial hypertension were included. Two investigators independently searched articles, extracted data, and assessed the quality of included studies. This meta-analysis was performed using the random effects model.. Seven RCTs were included in the meta-analysis. Compared with a control intervention in pulmonary arterial hypertension, riociguat treatment was able to substantially improve results of the six-minute walking distance (6-MWD; standardized mean difference [SMD] = 0.53; 95% CI = 0.36-0.69; p < 0.00001), EQ-5D score (SMD = 0.35; 95% CI = 0.15-0.54; p = 0.0005), and cardiac index (SMD = 0.94; 95% CI = 0.59-1.29; p < 0.00001). The Living With Pulmonary Hypertension (LPH) score (SMD = -0.33; 95% CI = -0.50--0.17; p < 0.0001) and pulmonary vascular resistance (PVR; SMD = -0.88; 95% CI = -1.05--0.70; p < 0.00001) were significantly reduced after riociguat treatment. There was no increase in adverse events with riociguat treatment compared with the control intervention (RR = 1.04; 95% CI = 0.98-1.09; p = 0.19).. Riociguat treatment for pulmonary arterial hypertension led to a significant increase in the 6‑MWD, EQ-5D score, and cardiac index, as well as a decrease in LPH score and PVR.

Topics: Enzyme Activators; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic

Chronic thromboembolic pulmonary hypertension (CTEPH) is a complication of pulmonary embolism and a major cause of chronic PH leading to right heart failure and death. Lung ventilation/perfusion scintigraphy is the screening test of choice; a normal scan rules out CTEPH. In the case of an abnormal perfusion scan, a high-quality pulmonary angiogram is necessary to confirm and define the pulmonary vascular involvement and prior to making a treatment decision. PH is confirmed with right heart catheterisation, which is also necessary for treatment determination. In addition to chronic anticoagulation therapy, each patient with CTEPH should receive treatment assessment starting with evaluation for pulmonary endarterectomy, which is the guideline recommended treatment. For technically inoperable cases, PH-targeted medical therapy is recommended (currently riociguat based on the CHEST studies), and balloon pulmonary angioplasty should be considered at a centre experienced with this challenging but potentially effective and complementary intervention.

Topics: Angiography; Angioplasty, Balloon; Anticoagulants; Cardiac Catheterization; Chronic Disease; Endarterectomy; Heart Failure; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Tomography, X-Ray Computed

Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by unresolved thrombi in the pulmonary arteries and microvasculopathy in nonoccluded areas. If left untreated, progressive pulmonary hypertension will induce right heart failure and, finally, death. Currently, pulmonary endarterectomy (PEA) remains the only method that has the potential to cure CTEPH. Unfortunately, up to 40% of patients are ineligible for this procedure for various reasons. In recent years, refined balloon pulmonary angioplasty (BPA) has become an alternative option for inoperable CTEPH patients, and it may be another curative treatment in the future, particularly in combination with prior PEA. Nevertheless, 23% of patients still suffer from persistent PH after BPA. Given that CTEPH shares many similarities with idiopathic pulmonary arterial hypertension (PAH), targeted drugs developed for PAH are also attractive options for CTEPH, especially for inoperable or persistent/recurrent CTEPH patients. To date, riociguat, macitentan, and subcutaneous treprostinil are the only drugs proven by randomized control trials to be capable of improving the exercise capacity (6-min walking distance) of CTEPH patients. In this review, we summarize the achievements and unresolved problems of PAH-targeted therapy for CTEPH over the last decade.

Topics: Adult; Aged; Angioplasty, Balloon; Antihypertensive Agents; Chronic Disease; Drug Therapy, Combination; Endarterectomy; Endothelin Receptor Antagonists; Epoprostenol; Female; Heart Failure; Hemodynamics; Humans; Hypertension, Pulmonary; Injections, Subcutaneous; Male; Molecular Targeted Therapy; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Treatment Outcome; Walk Test

Oral riociguat is a soluble guanylate cyclase (sGC) stimulator that targets the nitric oxide (NO)-sGC-cyclic guanosine monophosphate pathway with a dual mode of action: directly by stimulating sGC, and indirectly by increasing the sensitivity of sGC to NO. It is rapidly absorbed, displays almost complete bioavailability (94.3%), and can be taken with or without food and as crushed or whole tablets. Riociguat exposure shows pronounced interindividual (60%) and low intraindividual (30%) variability in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), and is therefore administered using an individual dose-adjustment scheme at treatment initiation. The half-life of riociguat is approximately 12 h in patients and approximately 7 h in healthy individuals. Riociguat and its metabolites are excreted via both renal (33-45%) and biliary routes (48-59%), and dose adjustment should be performed with particular care in patients with moderate hepatic impairment or mild to severe renal impairment (no data exist for patients with severe hepatic impairment). The pharmacodynamic effects of riociguat reflect the action of a vasodilatory agent, and the hemodynamic response to riociguat correlated with riociguat exposure in patients with PAH or CTEPH in phase III population pharmacokinetic/pharmacodynamic analyses. Riociguat has a low risk of clinically relevant drug interactions due to its clearance by multiple cytochrome P450 (CYP) enzymes and its lack of effect on major CYP isoforms and transporter proteins at therapeutic levels. Riociguat has been approved for the treatment of PAH and CTEPH that is inoperable or persistent/recurrent after surgical treatment.

Topics: Administration, Oral; Animals; Drug Interactions; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Soluble Guanylyl Cyclase

The NO/sGC/cGMP signaling cascade plays a pivotal role in regulation of cardiovascular, cardiopulmonary and cardiorenal diseases and impairment of this cascade results in severe pathologies. Therefore, pharmacological interventions, targeting this pathway are promising strategies for treating a variety of diseases. Nitrates, supplementing NO and, PDE5 inhibitors preventing cGMP degradation, are used for angina pectoris treatment and the treatment of pulmonary arterial hypertension (PAH), respectively. More recently, a new class of drugs which directly stimulate the sGC enzyme and trigger NO-independent cGMP production was introduced and termed sGC stimulators. In 2013, the first sGC stimulator, riociguat, was approved for the treatment of PAH and chronic thromboembolic pulmonary hypertension (CTEPH). Since cGMP targets multiple intracellular downstream targets, sGC stimulators have shown - beyond the well characterized vasodilatation - anti-fibrotic, anti-inflammatory and anti-proliferative effects. These additional modes of action might extend the therapeutic potential of this drug class substantially. This review summarizes the NO/sGC/cGMP signaling cascades, the discovery and the mode of action of sGC stimulators. Furthermore, the preclinical evidence and development of riociguat for the treatment of PAH and CTEPH is reviewed. Finally, a summary of the antifibrotic effects of sGC stimulators, especially the most recent finding for skin fibrosis are included which may indicate efficacy in fibrotic diseases like Systemic Sclerosis (SSc).

Topics: Cyclic GMP; Enzyme Activators; Humans; Hypertension, Pulmonary; Nitric Oxide; Pyrazoles; Pyrimidines; Rare Diseases; Scleroderma, Systemic; Soluble Guanylyl Cyclase

Chronic thromboembolic pulmonary hypertension (CTEPH), a rare consequence of an acute pulmonary embolism, is a disease that is underdiagnosed, and surgical pulmonary thromboendarterectomy (PTE) remains the preferred therapy. However, determination of operability is multifactorial and can be challenging. There is growing excitement for the percutaneous treatment of inoperable CTEPH with data from multiple centers around the world showing the clinical feasibility of balloon pulmonary angioplasty. Riociguat remains the only approved medical therapy for CTEPH patients deemed inoperable or with persistent pulmonary hypertension after PTE. We recommend that expert multidisciplinary CTEPH teams be developed at individual institutions. Additionally, optimal and standardized techniques for balloon pulmonary angioplasty need to be developed along with dedicated interventional equipment and appropriate training standards. In the meantime, the percutaneous revascularization option is appropriate for patients deemed inoperable in combination with targeted medical therapy, or those who have failed to benefit from surgery.

Topics: Chronic Disease; Clinical Trials as Topic; Endarterectomy; Enzyme Activators; Fibrinolytic Agents; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines

Current research is aimed at studying the fundamental therapeutic targets and discovering new drugs acting on previously set targets. Until recently, the only therapeutic strategy to influence the molecular pathway of nitric oxide (NO) - soluble guanylate cyclase (sGC) - cyclic guanosine monophosphate (cGMP) was the use of phosphodiesterase type 5 inhibitors (PDE-5 inhibitors), such as sildenafil. In September 2014, the first member of sGC stimulators riociguat was licensed in Russia. In the paper, the results of 5 multicenter studies (CHEST-1 and PATENT-1, CHEST-2 and PATENT-2, RESPITE), which reflect the effectiveness and safety of mono - and combination therapy with riociguat in patients suffer from some forms of pulmonary arterial hypertension, and patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTPH), as well as the possibility of optimizing therapy in patients with PAH using iPDE-5 -> riociguat switching was reviewed. It also provides information on the recently launched international registries EXPERT CTEPH; new REPLACE study was announced.

Topics: Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Russia

Despite advances in treatments and improved survival, patients with pulmonary hypertension still experience poor exercise and functional capacity, which has a significant detrimental impact on their quality of life. The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine 3',5'-monophosphate (cGMP) pathway has been shown to play an important role in cardiovascular physiology, especially in vasodilation and pulmonary vascular tone. The oral sGC stimulator riociguat has a dual mode of action on the NO-sGC-cGMP pathway: direct stimulation of sGC independent of NO and indirect simulation via sensitization of sGC to endogenous NO. Riociguat is now licensed in >50 countries worldwide, including in Europe, the USA, Canada, and Japan. Approval for the treatment of pulmonary arterial hypertension (PAH) was based on Phase III data from the PATENT studies, in which riociguat significantly improved exercise capacity, pulmonary vascular resistance, a range of secondary end points, and hemodynamic parameters in patients with symptomatic PAH. In the Phase III CHEST studies, riociguat consistently improved exercise capacity in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy and is now the only drug to be approved for this indication. Riociguat was well tolerated in long-term studies of PAH and CTEPH. This review describes the role of the NO-sGC-cGMP pathway in the pathophysiology of pulmonary hypertension, and reviews the clinical efficacy and safety of riociguat in patients with PAH and inoperable or persistent/recurrent CTEPH. Based on its demonstrated efficacy and established safety profile, riociguat is a promising treatment option for patients with PAH and CTEPH.

Topics: Animals; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Solubility

Riociguat is a soluble guanylate cyclase stimulator that has been approved for the treatment of pulmonary arterial hypertension and inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension following pulmonary endarterectomy. Riociguat is administered using an 8-week individual dose-adjustment scheme whereby a patient initially receives riociguat 1.0 mg three times daily (tid), and the dose is then increased every 2 weeks in the absence of hypotension, indicated by systolic blood pressure measurements and symptoms, up to a maximum dose of 2.5 mg tid. The established riociguat dose-adjustment scheme allows the dose of riociguat to be individually optimized in terms of tolerability and efficacy. The majority of patients in the phase III clinical trials and their long-term extension phases achieved the maximum riociguat dose, whereas some patients remained on lower doses. There is evidence that these patients may experience benefits at riociguat doses lower than 2.5 mg tid, with improvement in exercise capacity being observed after only 2-4 weeks of treatment in the phase III studies and in the exploratory 1.5 mg-maximum patient group of PATENT-1. This review aims to provide an overview of the rationale behind the riociguat dose-adjustment scheme and examine its application to both clinical trials and real-life clinical practice.

Topics: Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Enzyme Activators; Exercise Tolerance; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Pulmonary Embolism; Pyrazoles; Pyrimidines; Vascular Resistance; Walk Test

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are progressive and debilitating diseases characterized by gradual obstruction of the pulmonary vasculature, leading to elevated pulmonary artery pressure (PAP) and increased pulmonary vascular resistance (PVR). If untreated, they can result in death due to right-sided heart failure. Riociguat is a novel soluble guanylate cyclase (sGC) stimulator that is approved for the treatment of PAH and CTEPH. We describe in detail the role of the nitric oxide-sGC-cyclic guanosine monophosphate (cGMP) signaling pathway in the pathogenesis of PAH and CTEPH and the mode of action of riociguat. We also review the preclinical data associated with the development of riociguat, along with the efficacy and safety data of riociguat from initial clinical trials and pivotal phase III randomized clinical trials in PAH and CTEPH.

Topics: Chronic Disease; Cyclic GMP; Humans; Hypertension, Pulmonary; Nitric Oxide; Pulmonary Embolism; Pyrazoles; Pyrimidines; Signal Transduction; Treatment Outcome; Walk Test

Pulmonary hypertension (PH) is a chronic cardiopulmonary disorder that if left untreated, progresses rapidly and is ultimately fatal. The World Health Organization (WHO) has classified PH into 5 distinct groups according to pathophysiology, hemodynamic characteristics, and clinical presentation. Dysfunction in the nitric oxide (NO) pathway plays a key role in the pulmonary hypertension disease process, including in WHO Groups 2 and 3 PH. PH is associated with endothelial dysfunction, impaired synthesis of NO, and insufficient stimulation of the NO-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) pathway, which reduces cGMP production. cGMP regulates vascular tone, cellular proliferation, inflammation, and fibrosis and its depletion can lead to a variety of abnormalities, including pulmonary vasoconstriction, impaired vascular remodeling, and in situ thrombosis. This review will examine a novel class of drugs called sGC stimulators which directly stimulate sGC independently of NO, leading to increased production of cGMP.

Topics: Clinical Trials as Topic; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Pyrazoles; Pyrimidines; Soluble Guanylyl Cyclase; Vascular Remodeling

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by vasculopathy, inflammation and fibrosis. These three main disease-determining pathways are the target of the currently available treatments used to possibly modify the progression of disease-related manifestations, although this synergy has not been fully applied on SSc joint, skin or lung involvement yet. Areas covered: we describe the current status of SSc treatment/therapy performing a literature search in MEDLINE/Pubmed and Thomson Reuter's Web of Science for articles published until March 2016. Moreover, ongoing registered clinical trials (RCTs) on SSc were searched through clinicaltrials.gov website. Expert commentary: presently, promising drugs are under evaluation to target the different pathogenic pathways of systemic sclerosis: Tocilizumab and Abatacept for skin and lung fibrosis; Riociguat and Selexipag are approved for pulmonary arterial hypertension but promising anti-fibrotic effects are now being studied. Finally, several anti-fibrotic molecules are currently involved in RCTs, such as Nintedanib, IVA-337, Terguride.

Topics: Abatacept; Acetamides; Antibodies, Monoclonal, Humanized; Biological Products; Clinical Trials as Topic; Fibrinolytic Agents; Fibrosis; Humans; Hypertension, Pulmonary; Indoles; Inflammation; Joints; Lisuride; Lung; PubMed; Pyrazines; Pyrazoles; Pyrimidines; Scleroderma, Systemic; Skin

The aim was to update the 2009 European League against Rheumatism (EULAR) recommendations for the treatment of systemic sclerosis (SSc), with attention to new therapeutic questions. Update of the previous treatment recommendations was performed according to EULAR standard operating procedures. The task force consisted of 32 SSc clinical experts from Europe and the USA, 2 patients nominated by the pan-European patient association for SSc (Federation of European Scleroderma Associations (FESCA)), a clinical epidemiologist and 2 research fellows. All centres from the EULAR Scleroderma Trials and Research group were invited to submit and select clinical questions concerning SSc treatment using a Delphi approach. Accordingly, 46 clinical questions addressing 26 different interventions were selected for systematic literature review. The new recommendations were based on the available evidence and developed in a consensus meeting with clinical experts and patients. The procedure resulted in 16 recommendations being developed (instead of 14 in 2009) that address treatment of several SSc-related organ complications: Raynaud's phenomenon (RP), digital ulcers (DUs), pulmonary arterial hypertension (PAH), skin and lung disease, scleroderma renal crisis and gastrointestinal involvement. Compared with the 2009 recommendations, the 2016 recommendations include phosphodiesterase type 5 (PDE-5) inhibitors for the treatment of SSc-related RP and DUs, riociguat, new aspects for endothelin receptor antagonists, prostacyclin analogues and PDE-5 inhibitors for SSc-related PAH. New recommendations regarding the use of fluoxetine for SSc-related RP and haematopoietic stem cell transplantation for selected patients with rapidly progressive SSc were also added. In addition, several comments regarding other treatments addressed in clinical questions and suggestions for the SSc research agenda were formulated. These updated data-derived and consensus-derived recommendations will help rheumatologists to manage patients with SSc in an evidence-based way. These recommendations also give directions for future clinical research in SSc.

Topics: Angiotensin-Converting Enzyme Inhibitors; Delphi Technique; Endothelin Receptor Antagonists; Europe; Fingers; Fluoxetine; Gastrointestinal Diseases; Glucocorticoids; Hematopoietic Stem Cell Transplantation; Humans; Hypertension, Pulmonary; Kidney Diseases; Lung Diseases; Phosphodiesterase 5 Inhibitors; Prostaglandins I; Pyrazoles; Pyrimidines; Raynaud Disease; Rheumatology; Scleroderma, Systemic; Selective Serotonin Reuptake Inhibitors; Ulcer

Until recently, three classes of medical therapy were available for the treatment of pulmonary arterial hypertension (PAH)--prostanoids, endothelin receptor antagonists and phosphodiesterase type 5 (PDE5) inhibitors. With the approval of the soluble guanylate cyclase stimulator riociguat, an additional drug class has become available targeting a distinct molecular target in the same pathway as PDE5 inhibitors. Treatment recommendations currently include the use of all four drug classes to treat PAH, but there is a lack of comparative data for these therapies. Therefore, an understanding of the mechanistic differences between these agents is critical when making treatment decisions. Combination therapy is often used to treat PAH and it is therefore important that physicians understand how the modes of action of these drugs may interact to work as complementary partners, or potentially with unwanted consequences. Furthermore, different patient phenotypes mean that patients respond differently to treatment; while a certain monotherapy may be adequate for some patients, for others it will be important to consider alternating or combining compounds with different molecular targets. This review describes how the four currently approved drug classes target the complex pathobiology of PAH and will consider the distinct target molecules of each drug class, their modes of action, and review the pivotal clinical trial data supporting their use. It will also discuss the rationale for combining drugs (or not) from the different classes, and review the clinical data from studies on combination therapy.

Topics: Antihypertensive Agents; Drug Interactions; Drug Therapy, Combination; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Phosphodiesterase Inhibitors; Prostaglandins; Pyrazoles; Pyrimidines

Pulmonary artery hypertension (PAH) refers to several subgroups of disease in which the mean pulmonary artery pressure (mPAP) is elevated to more than 25 mm Hg, pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg, and an elevated pulmonary vascular resistance (PVR) > 3 Wood units as confirmed by right heart catheterization. The prevalence and geographic distribution of PAH vary depending on the type and etiology of the disease. Despite enormous efforts in the research and development of therapeutic agents in the last twenty years, the disease remains relatively incurable and the overall prognosis remains guarded. Median survival for an untreated patient is 2.8 years. In the last three decades, there have been dramatic advances in understanding the molecular mechanisms and signaling pathways involved in the disease, resulting in emerging new treatment strategies. In the following pages, we will review currently approved treatments for PAH, as well as a new generation of investigational drugs.

Topics: Calcium Channel Blockers; Dichloroacetic Acid; Drug Therapy, Combination; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Protein Kinase Inhibitors; Pulmonary Artery; Pyrazoles; Pyrimidines; Receptors, Epoprostenol; Registries; rho-Associated Kinases; Soluble Guanylyl Cyclase

Pulmonary hypertension is a condition of complex aetiology that culminates in right heart failure and early death. Soluble guanylate cyclase (sGC) stimulators are a promising class of agents that have recently gained approval for use.. To evaluate the efficacy of sGC stimulators in pulmonary hypertension.. We searched CENTRAL (Cochrane Central Register of Controlled Trials), MEDLINE, EMBASE and the reference lists of articles. Searches are current as of 12 February 2016.. We selected randomised controlled trials (RCTs) involving participants with pulmonary hypertension of all ages, severities and durations of treatment.. AW, MS and RW independently selected studies, assessed evidence quality and extracted data. This process was overseen by RT and SG. All included studies were sponsored by the drug manufacturer.. Five trials involving 962 participants are included in this review. All trials were of relatively short duration (< 16 weeks). Due to the heterogenous aetiology of pulmonary hypertension in participants, results are best considered according to each pulmonary hypertension subtype.Pooled analysis shows a mean difference (MD) increase in six-minute walking distance (6MWD) of 30.13 metres (95% CI 5.29 to 54.96; participants = 659; studies = 3). On subgroup analysis, for pulmonary arterial hypertension (PAH) there was no effect noted (6MWD; MD 11.91 metres, 95% CI -44.92 to 68.75; participants = 398; studies = 2), and in chronic thromboembolic pulmonary hypertension (CTEPH) sGC stimulators improved 6MWD by an MD of 45 metres (95% CI 23.87 to 66.13; participants = 261; studies = 1). Data for left heart disease-associated PH was not available for pooling. Importantly, when participants receiving phosphodiesterase inhibitors were excluded, sGC stimulators increased 6MWD by a MD of 36 metres in PAH. The second primary outcome, mortality, showed no change on pooled analysis against placebo (Peto odds ratio (OR) 0.57, 95% CI 0.18 to 1.80).Pooled secondary outcomes include an increase in World Health Organization (WHO) functional class (OR 1.53, 95% CI 0.87 to 2.72; participants = 858; studies = 4), no effect on clinical worsening (OR 0.45, 95% CI 0.17 to 1.14; participants = 842; studies = 3), and a reduction in mean pulmonary artery pressure (MD -2.77 mmHg, 95% CI -4.96 to -0.58; participants = 744; studies = 5). There was no significant difference in serious adverse events on pooled analysis (OR 1.12, 95% CI 0.66 to 1.90; participants = 818; studies = 5) or when analysed at PAH (MD -3.50, 95% CI -5.54 to -1.46; participants = 344; studies = 1), left heart disease associated subgroups (OR 1.56, 95% CI 0.78 to 3.13; participants = 159; studies = 2) or CTEPH subgroups (OR 1.29, 95% CI 0.65 to 2.56; participants = 261; studies = 1).It is important to consider the results for PAH in the context of a person who is not also receiving a phosphodiesterase-V inhibitor, a contra-indication to sGC stimulator use. It should also be noted that CTEPH results are applicable to inoperable or recurrent CTEPH only.Evidence was rated according to the GRADE scoring system. One outcome was considered high quality, two were moderate, and eight were of low or very low quality, meaning that for many of the outcomes the true effect could differ substantially from our estimate. There were. sGC stimulators improve pulmonary artery pressures in people with PAH (who are treatment naive or receiving a prostanoid or endothelin antagonist) or those with recurrent or inoperable CTEPH. In these settings this can be achieved without notable complication. However, sGC stimulators should not be taken by people also receiving phosphodiestase-V inhibitors or nitrates due to the risks of hypotension, and there is currently no evidence supporting their use in pulmonary hypertension associated with left heart disease. There is no evidence supporting their use in children. These conclusions are based on data with limitations, including unavailable data from two of the trials.

Topics: Adult; Female; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Male; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Time Factors; Walking

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but life-threatening condition resulting from unresolved thromboembolic obstructions. Pulmonary endarterectomy surgery is currently the standard of treatment, as it is potentially curative; however, not all cases are amenable to surgical intervention due to distal distribution of the organized thromboembolic material or the presence of comorbidities. Up to one-third of patients have persistent or recurrent pulmonary hypertension after pulmonary endarterectomy. In addition to the occlusive organized thromboembolic material, there is a small-vessel vasculopathy in nonoccluded parts of the pulmonary circulation that is histologically similar to that described in pulmonary arterial hypertension. This observation has led to frequent off-license use of approved pulmonary arterial hypertension therapies in CTEPH. Small uncontrolled trials have investigated prostacyclin analogs, endothelin receptor antagonists, and phosphodiesterase type 5 inhibitors in CTEPH with mixed results. A phase III study of the endothelin receptor antagonist bosentan met only one of its two coprimary end points. The first large randomized controlled trial showing a positive treatment effect was the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase Stimulator Trial (CHEST). This study led to the licensing of riociguat for use in inoperable or persistent recurrent CTEPH. Rigorous randomized controlled trials of medical therapy for CTEPH are needed, and several are underway or planned. In the future, outcomes research may be facilitated by identification of novel end points specific to CTEPH.

Topics: Bosentan; Chronic Disease; Comorbidity; Endarterectomy; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Recurrence; Secondary Prevention; Sulfonamides

Pulmonary arterial hypertension (PAH) is a rare disease with a poor prognosis if not treated. Pharmacological treatment options for PAH have increased significantly over the past 10 years, with availability of intravenous, oral and inhaled drugs targeting the nitric oxide, endothelin and prostacyclin pathways. Treatment with these therapies in specialised pulmonary hypertension centres has resulted in reductions in patient symptoms, disease progression and mortality, and improved exercise capacity. Recognition of chronic thromboembolic pulmonary hypertension is important, as this cause of pulmonary hypertension may be amenable to surgical treatment. Several new oral drugs, including macitentan, riociguat and selexipag, some of which have novel modes of action, and the use of combinations of PAH drugs have recently been shown to be beneficial in treating PAH and are likely to change treatment for this condition in the future.

Topics: Acetamides; Antihypertensive Agents; Australia; Drug Therapy, Combination; Humans; Hypertension, Pulmonary; Pyrazines; Pyrazoles; Pyrimidines; Sulfonamides; World Health Organization

The development of pulmonary hypertension (PH) has multifactorial underlying pathophysiological causes and can be classified into five groups. While three different classes of therapeutic drugs are licensed for the treatment of pulmonary arterial hypertension (PAH, WHO group 1), specific medical therapies are lacking for other forms of PH, such as PH due to left heart disease. In 2013 riociguat, a first-in class soluble guanylate cyclase stimulator, has also become available for the treatment of PAH. Riociguat was further introduced as the first approved pharmacotherapy for the treatment of patients with chronic thromboembolic PH (WHO group 4, CTEPH). Despite these advances in therapeutic options for patients with PH, none of these agents have been approved for the treatment of PH due to left heart disease. Areas covered: We aim to give an overview of the pathophysiology of PH, pharmacodynamics and pharmacokinetic properties, safety and efficacy of riociguat, including adverse events, contraindications and drug interactions. Expert opinion: Considering the increasingly broad indications for riociguat in patients with PH, substantial knowledge of data and properties on safety and efficacy of riociguat are becoming more and more important for physicians prescribing riociguat to PH patients.

Topics: Animals; Drug Interactions; Heart Diseases; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Soluble Guanylyl Cyclase

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition distinguished by elevated pressure of pulmonary arteries and increased vascular resistance. The management of patients with PAH and CTEPH has advanced rapidly over last decade but despite the progress in the treatment, the survival of suffering patients remain unsatisfactory and there is no cure for the diseases. However, surgery is not a first choice for patients. Furthermore, some patients who undergo surgery have persistent pulmonary hypertension (HTN) as a side effect after surgery. Therefore, the search for an "ideal" therapy still goes on and it lead to the approval of riociguat as a potential agent for the treatment. It acts directly on soluble guanylate cyclase, exciting the enzyme, and elevating sensitivity to lower levels of NO. Riociguat, therefore, has potential as a novel therapy for PAH and CTEPH. This review is focused on various aspects of the recently approved "riociguat" including its efficacy and safety profiles with the clinical data highlighting its importance in the present scenario.

Topics: Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Hypertension, Pulmonary; Pulmonary Wedge Pressure; Pyrazoles; Pyrimidines

Nitric oxide (NO) activates soluble guanylate cyclase (sGC) by binding its prosthetic heme group, thereby catalyzing cyclic guanosine monophosphate (cGMP) synthesis. cGMP causes vasodilation and may inhibit smooth muscle cell proliferation and platelet aggregation. The NO-sGC-cGMP pathway is disordered in pulmonary arterial hypertension (PAH), a syndrome in which pulmonary vascular obstruction, inflammation, thrombosis, and constriction ultimately lead to death from right heart failure. Expression of sGC is increased in PAH but its function is reduced by decreased NO bioavailability, sGC oxidation and the related loss of sGC's heme group. Two classes of sGC modulators offer promise in PAH. sGC stimulators (e.g., riociguat) require heme-containing sGC to catalyze cGMP production, whereas sGC activators (e.g., cinaciguat) activate heme-free sGC. Riociguat is approved for PAH and yields functional and hemodynamic benefits similar to other therapies. Its main serious adverse effect is dose-dependent hypotension. Riociguat is also approved for inoperable chronic thromboembolic pulmonary hypertension.

Topics: Animals; Benzoates; Chronic Disease; Cyclic GMP; Drug Design; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Nitric Oxide; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Thromboembolism

Riociguat is the first clinically available soluble Guanylate-cyclase stimulator (sGC) and representative of a completely new class of drugs. Riociguat is approved for pulmonary arterial hypertension (PAH) and non-operable or recurrent/persistent chronic thromboembolic pulmonary hypertension (CTEPH). Moreover, Riociguat is currently under investigation for a wider spectrum of diseases. This article focusses on its mode of action and clinical trial data. Finally, based on these data, the status of approval, as well as the costs a proposal is given how Riociguat can be integrated in the current treatment of PAH and CTEPH.

Topics: Antihypertensive Agents; Chronic Disease; Fibrinolytic Agents; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Treatment Outcome

Chronic thromboembolic pulmonary hypertension (CTEPH) is an insidious, progressive disease with a poor prognosis. The treatment of choice is pulmonary thromboendarterectomy, although not all patients benefit from surgery at a specialized center. Riociguat, an oral soluble guanylate cyclase (sGC) stimulator is the first pharmacotherapeutic agent that has been shown to improve exercise capacity and hemodynamics in a large multicenter, double-blind, randomized placebo-controlled trial for the treatment of patients with inoperable or persistent CTEPH. Riociguat stimulates sGC directly in a nitric oxide (NO)-independent manner, thereby increasing the sensitivity of sGC to NO, and also in synergy with NO, leading to increased production of cyclic guanosine monophosphate, an intracellular messenger involved in regulating vascular tone, smooth muscle cell proliferation, fibrosis and inflammation. This review will summarize the pharmacodynamics, pharmacokinetics as well as safety and efficacy data of riociguat in inoperable or persistent CTEPH.

Topics: Animals; Chronic Disease; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Nitric Oxide; Pyrazoles; Pyrimidines; Thromboembolism

Riociguat is the first approved medication from the novel class of soluble guanylate cyclase (sGC) stimulators and the only agent approved for treating both chronic thromboembolic hypertension (CTEPH) and pulmonary arterial hypertension (PAH). The novel mechanism of riociguat lies in its ability to restore the homeostatic and therapeutic effects of nitric oxide that are diminished as a result of phenotypic alterations associated with pulmonary hypertension (PH). Improvements in 6-minute walk distance (6MWD) in patients with PAH during the phase 3 PATENT-1 trial were comparable to other oral agents approved for the treatment of PAH. Improvements in 6MWD in patients with CTEPH during the phase 3 CHEST-1 trial were greater than those previously observed with other oral PAH-directed therapies. Hypotension is the dose-limiting adverse effect of riociguat and dose titration is performed gradually according to systolic blood pressure. Riociguat was tolerated at maximal doses by most patients during PATENT-1 and CHEST-1 and was well tolerated during long-term extension studies. Key factors to consider with riociguat are a patient's systolic blood pressure, drug interactions mediated by CYP1A1, CYP3A4, and P-glycoprotein, cost, and teratogenicity requiring enrollment in a Risk Evaluation and Mitigation Strategy program. Recently published guidelines recommend riociguat monotherapy as an option for treatment-naïve patients with World Health Organization Functional Class (WHO FC) II or III symptoms or as add-on therapy for patients with persistent WHO FC III or IV symptoms being treated with an ERA or inhaled prostanoid. Postmarketing experience and ongoing clinical investigations will further define the safety and role of riociguat in patients with PAH and other types of PH.

Topics: Clinical Trials, Phase III as Topic; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

Many targeted therapies have been approved for pulmonary arterial hypertension (PAH), most of which are in oral forms. However, the effects of these drugs on lifesaving are unclear. Our objective was to evaluate the effects of oral treatments on clinical outcomes especially all-cause mortality in patients with PAH.. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for relevant articles up to April 2014. Randomized, double-blind, parallel-group clinical trials that compared oral agents with placebo were selected. Data for populations, interventions, and outcomes were extracted independently by 2 investigators, and disagreements were resolved by consensus. Quality assessment was performed using the Cochrane risk-of-bias tool.. Twenty-one randomized, controlled, clinical trials involving 5105 patients were identified in the primary analysis. The overall estimated odds ratio (OR) of combined clinical worsening (CCW) events between active treatment groups and control groups was 0.55 (95% CI 0.47-0.64, P < .001). However, the effect of oral treatments on reducing all-cause mortality was not statistically significant (OR 0.82, 95% CI 0.61-1.10, P = .192), which was consistent for approved drugs (OR 0.84, 95% CI 0.61-1.18, P = .316) and drugs that were not approved (OR 0.72, 95% CI 0.36-1.44, P = .352). In the sensitivity analysis, a significant reduction was achieved in CCW events (P < .001) but not in all-cause mortality (P = .057).. This pooled analysis shows the benefits of oral treatments on CCW events in patients with PAH. However, these drugs seem to exhibit less favorable effects on life expectancy in the short-term follow-up, suggesting further evaluation is required.

Topics: Administration, Oral; Antihypertensive Agents; Benzamides; Endothelin Receptor Antagonists; Exercise Test; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Phosphodiesterase 5 Inhibitors; Piperazines; Prostaglandins; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Pyrimidines; Treatment Outcome; Vasodilator Agents

Nitric oxide (NO) is a critical signaling molecule in the pulmonary vasculature. NO activates soluble guanylate cyclase (sGC) resulting in the synthesis of cyclic guanosine monophosphate (cGMP) - a key mediator of pulmonary artery vasodilatation that may also inhibit smooth muscle proliferation and platelet aggregation. Pulmonary hypertension, a serious, progressive and often fatal disease is characterized by NO-sGC-sGMP pathway dysregulation. Riociguat is a member of a novel therapeutic class known as soluble guanylate stimulators. Riociguat has a dual mode of action, acting in synergy with endogenous NO and also directly stimulating sGC independently of NO availability. Phase 3 randomized control trials have demonstrated that riociguat improves clinical, physiologic and hemodynamic parameters in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. In this review we will discuss the pharmacologic properties of riociguat and its appropriate implementation into clinical practice.

Topics: Antihypertensive Agents; Clinical Trials as Topic; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Lung; Nitric Oxide; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

The development of therapeutic concepts in pulmonary hypertension (PH) is intimately linked with the unraveling of pathogenetic sequelae. This perspective highlights advances in our understanding of the regulation of vasomotion and vascular remodeling that have led to "reverse-remodeling" and regenerative strategies as novel treatment concepts. Progress has been made in understanding redox-dependent signaling; inflammatory sequelae; and transcription factor, ion channel, and metabolic abnormalities, as well as growth factor-dependent hyperproliferation that underlies PH. We are, however, far from understanding the molecular pathways that differentially drive the various vascular phenotypes (intimal thickening, media hypertrophy, adventitial thickening, plexiform lesions, vascular pruning) in this disease. Antiproliferative strategies, transcription factor-based therapies, inflammation/immune cell-focused approaches, and epigenetic modulation-based therapies are all novel treatment concepts for PH. The proangiogenic potential of genetically engineered mesenchymal stem cells and endothelial progenitor cells has been explored as a regenerative strategy. The progress that has been made in identifying important cellular and molecular mechanisms and applying this knowledge to novel therapies is largely restricted to group 1 PH. However, understanding the molecular sequelae underlying PH in groups 2 through 5 PH is also urgently needed.

Topics: Angiogenesis Inhibitors; Antihypertensive Agents; Epigenesis, Genetic; Familial Primary Pulmonary Hypertension; Histone Deacetylase Inhibitors; Humans; Hypertension, Pulmonary; Protein Kinase Inhibitors; Pulmonary Artery; Pyrazoles; Pyrimidines; Sulfonamides; Vasodilation; Vasodilator Agents

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.

Topics: Animals; Clinical Trials as Topic; Drug Evaluation, Preclinical; Guanylate Cyclase; Hemodynamics; Humans; Hypertension, Pulmonary; Nitric Oxide; Pyrazoles; Pyrimidines; Treatment Outcome; Vasodilator Agents

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but debilitating and life-threatening complication of acute pulmonary embolism. CTEPH results from persistent obstruction of pulmonary arteries and progressive vascular remodelling. Not all patients presenting with CTEPH have a history of clinically overt pulmonary embolism. The diagnostic work-up to detect or rule out CTEPH should include ventilation-perfusion scintigraphy, which has high sensitivity and a negative predictive value of nearly 100%. CT angiography usually reveals typical features of CTEPH, including mosaic perfusion, part or complete occlusion of pulmonary arteries, and intraluminal bands and webs. Patients with suspected CTEPH should be referred to a specialist centre for right-heart catheterisation and pulmonary angiography. Surgical pulmonary endarterectomy remains the treatment of choice for CTEPH and is associated with excellent long-term results and a high probability of cure. For patients with inoperable CTEPH, various medical and interventional therapies are being developed.

Topics: Angioplasty, Balloon; Bosentan; Chronic Disease; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Piperazines; Pulmonary Embolism; Purines; Pyrazoles; Pyrimidines; Sildenafil Citrate; Sulfonamides; Thromboembolism

Topics: Diagnosis, Differential; Diagnostic Imaging; Diagnostic Tests, Routine; Dyspnea; Endothelin Receptor Antagonists; General Practice; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Prostaglandins; Pyrazoles; Pyrimidines

Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are serious and often fatal diseases. The pathophysiology of both diseases is complex and in part is attributed to alterations in the nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate pathway. Riociguat, a novel sGC stimulator, acts on this pathway through a dual mechanism of action by directly stimulating sGC in a NO-independent manner and also increasing the sensitivity of sGC to NO. Based on benefits from clinical trials for both PAH and CTEPH, riociguat was approved by Health Canada and the US Food and Drug Administration as the first medical therapy for patients with CTEPH who are deemed inoperable or have residual/recurrent PH after pulmonary endarterectomy (PEA), and as a novel treatment option for patients with PAH. This article reviews the key findings from the phase III trials for riociguat that led to these approvals and the implications this has for the treatment of patients with PAH and CTEPH.

Topics: Animals; Chronic Disease; Clinical Trials, Phase III as Topic; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines

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.. 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.. 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.

Topics: Chronic Disease; Clinical Trials as Topic; Enzyme Activators; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

The pharmacology, pharmacokinetics, clinical efficacy, safety, and role in therapy for riociguat are reviewed.. Riociguat is the first member of a new class of medications, soluble guanylate cyclase stimulators. Riociguat is indicated for patients with resistant or recurrent chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy who have World Health Organization (WHO) functional class IV pulmonary arterial hypertension (PAH) and in patients with inoperable CTEPH, regardless of WHO functional class, to improve exercise capacity and WHO functional class. Riociguat is indicated in patients with WHO functional class II PAH to improve exercise capacity, improve functional class, and delay clinical worsening. The mechanism of action of riociguat is within the nitric oxide pathway in the pulmonary vasculature. Clinical trials have demonstrated improvements in exercise capacity as measured by the six-minute walk distance test and in pulmonary arterial hemodynamics as measured by invasive pulmonary monitoring. Riociguat must be administered three times daily and requires dosage adjustments. Riociguat is a pregnancy category X drug and interacts with numerous medications. The two most serious adverse effects related to riociguat are hypotension and bleeding. Riociguat's role in the therapy of both PAH and CTEPH will be determined as more clinical experience and data are collected. Riociguat will likely cost approximately $90,000 annually.. Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of CTEPH and PAH. It can be considered first-line therapy for the treatment of CTEPH and should be considered as an alternative to phosphodiesterase type-5 inhibitors in patients with PAH.

Topics: Chronic Disease; Female; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pregnancy; Pulmonary Embolism; Pyrazoles; Pyrimidines; Thromboembolism

Riociguat (Adempas(®)), a soluble guanylate cyclase stimulator, is a new, first-in-class drug approved for the treatment of patients with chronic thromboembolic pulmonary hypertension (CTEPH) [inoperable or persistent/recurrent following surgery] or pulmonary arterial hypertension (PAH). It has been designated an orphan medicine by the European Medicines Agency and the US FDA. This article reviews the available pharmacological properties of oral riociguat and its clinical efficacy and tolerability in adults with CTEPH or PAH. Riociguat is effective and well tolerated in patients with inoperable CTEPH or persistent/recurrent CTEPH following pulmonary endarterectomy, and in patients with PAH. It has a positive result on exercise capacity and pulmonary haemodynamics, and improves WHO functional class. Most adverse events can be attributed to the vasodilatory mechanism of riociguat; however, there is a potential for serious bleeding and fetal harm, and riociguat use is contraindicated in pregnant patients. Pulmonary endarterectomy remains the first treatment of choice for CTEPH, as it is potentially curative. Head-to-head trials comparing riociguat with the approved phosphodiesterase type 5 inhibitors in patients with PAH would be of value for the placement of riociguat in the management of this disease. Riociguat is a promising addition to the treatment options for patients with CTEPH or PAH.

Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Thromboembolism

Topics: Adult; Antihypertensive Agents; Combined Modality Therapy; Cooperative Behavior; Drug Approval; Drug Therapy, Combination; Endothelin Receptor Antagonists; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Interdisciplinary Communication; Molecular Targeted Therapy; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Survival Rate; Treatment Outcome

Chronic thromboembolic pulmonary hypertension (CTEPH) results from inadequate recanalization of the pulmonary circulation after pulmonary thromboembolism. Its 2-year prevalence is 1-4% . If untreated, patients with CTEPH have a mean life expectancy of less than three years. Fortunately, a number of effective treatments are now available.. This review is based on a selective search of PubMed for pertinent articles published from 1980 to 2014.. The gold-standard test for the exclusion of CTEPH is perfusion scintigraphy: the predictive value of a negative test is nearly 100% . On the other hand, confirmation of a positive diagnosis for treatment planning requires right-heart catheterization and pulmonary angiography. The treatment of first choice for CTEPH is surgical pulmonary endarterectomy (PEA), with which about 70% of patients can be cured. The perioperative mortality of this procedure in experienced centers is now 2-4% . Thirty to 50% of all patients with CTEPH are considered inoperable; for these patients, and for patients with persistent pulmonary hypertension after PEA, the drug riociguat was introduced in Germany in 2014 (the first drug specifically introduced for the treatment of CTEPH). There is also a new interventional treatment option for inoperable patients-pulmonary balloon angioplasty, which is currently being performed in a small number of centers.. The timely diagnosis of CTEPH, followed by referral to a specialized center, is now more important than ever, because treatment options are now available for nearly all of the forms in which this disease can manifest itself.

Topics: Angioplasty, Balloon; Diagnosis, Differential; Endarterectomy; Evidence-Based Medicine; Humans; Hypertension, Pulmonary; Perfusion Imaging; Pulmonary Embolism; Pyrazoles; Pyrimidines; Treatment Outcome; Vasodilator Agents

Chronic thromboembolic pulmonary hypertension (CTEPH) is a form of pulmonary hypertension caused by non-resolving thromboembolisms of the pulmonary arteries. In Japan, in contrast to Western countries, CTEPH is more prevalent in women. A Japanese multicenter study reported that a form of CTEPH unrelated to deep vein thrombosis is associated with HLA-B⁎5201, suggesting that this form of CTEPH may be associated with vasculopathy. CTEPH can be cured by pulmonary endarterectomy, provided that the thrombi are surgically accessible; thus, early diagnosis is important, and all patients with exertional dyspnea should be evaluated for pulmonary hypertension. Ventilation/perfusion scans provide an excellent non-invasive means to distinguish CTEPH from pulmonary arterial hypertension. Similarly, computed tomographic pulmonary angiograms allow for the detection of thrombi and evaluation of pulmonary hemodynamics in a minimally invasive manner. Importantly, the absence of subpleural perfusion on pulmonary angiograms can suggest the presence of small vessel disease. Small vessel disease might be involved in the pathogenesis of CTEPH, and its detection is essential in preventing operative death. Although no modern therapies for pulmonary arterial hypertension have been approved for treatment of CTEPH, a recent randomized control trial of riociguat in patients with CTEPH demonstrated that riociguat significantly improved 6-min walking distance. Further investigations into treatments that target endothelial dysfunction and hyperproliferative CTEPH cells are needed. Recently, balloon pulmonary angioplasty has emerged as a promising treatment modality in Japan. A specialized medical team, including at least one expert surgeon, should make decisions regarding patients' candidacy for pulmonary endarterectomy and/or balloon pulmonary angioplasty.

Topics: Angioplasty, Balloon; Chronic Disease; Diagnosis, Differential; Endarterectomy; HLA-B Antigens; Hypertension, Pulmonary; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Tomography, X-Ray Computed

Chronic thromboembolic pulmonary hypertension (CTEPH) is a life-threatening condition that historically has a poor outcome with supportive medical treatment. Pulmonary endarterectomy (PEA) is the treatment of choice and offers the only chance of cure. A significant proportion of patients is either not suitable due to the distal distribution of the disease or has persistent pulmonary hypertension (PH) after PEA. Despite the lack of licensed therapies for CTEPH, the similarities in pathobiology of pulmonary arterial hypertension (PAH) and CTEPH has led to the compassionate use of PAH therapies in CTEPH patients. This article reviews the pathobiology of CTEPH and summaries the available evidence for the use of PAH-targeted drugs in CTEPH.

Topics: Antihypertensive Agents; Bosentan; Chronic Disease; Compassionate Use Trials; Endarterectomy; Humans; Hypertension, Pulmonary; Piperazines; Pulmonary Embolism; Purines; Pyrazoles; Pyrimidines; Sildenafil Citrate; Sulfonamides; Sulfones; Treatment Outcome

Soluble guanylate cyclase (sGC) is a key enzyme in the nitric oxide (NO) signalling pathway. On binding of NO to its prosthetic haem group, sGC catalyses the synthesis of the second messenger cyclic guanosine monophosphate (cGMP), which promotes vasodilation and inhibits smooth muscle proliferation, leukocyte recruitment, platelet aggregation and vascular remodelling through a number of downstream mechanisms. The central role of the NO-sGC-cGMP pathway in regulating pulmonary vascular tone is demonstrated by the dysregulation of NO production, sGC activity and cGMP degradation in pulmonary hypertension (PH). The sGC stimulators are novel pharmacological agents that directly stimulate sGC, both independently of NO and in synergy with NO. Optimisation of the first sGC stimulator, YC-1, led to the development of the more potent and more specific sGC stimulators, BAY 41-2272, BAY 41-8543 and riociguat (BAY 63-2521). Other sGC stimulators include CFM-1571, BAY 60-4552, vericiguat (BAY 1021189), the acrylamide analogue A-350619 and the aminopyrimidine analogues. BAY 41-2272, BAY 41-8543 and riociguat induced marked dose-dependent reductions in mean pulmonary arterial pressure and vascular resistance with a concomitant increase in cardiac output, and they also reversed vascular remodelling and right heart hypertrophy in several experimental models of PH. Riociguat is the first sGC stimulator that has entered clinical development. Clinical trials have shown that it significantly improves pulmonary vascular haemodynamics and increases exercise ability in patients with pulmonary arterial hypertension (PAH), chronic thromboembolic PH and PH associated with interstitial lung disease. Furthermore, riociguat reduces mean pulmonary arterial pressure in patients with PH associated with chronic obstructive pulmonary disease and improves cardiac index and pulmonary vascular resistance in patients with PH associated with left ventricular systolic dysfunction. These promising results suggest that sGC stimulators may constitute a valuable new therapy for PH. Other trials of riociguat are in progress, including a study of the haemodynamic effects and safety of riociguat in patients with PH associated with left ventricular diastolic dysfunction, and long-term extensions of the phase 3 trials investigating the efficacy and safety of riociguat in patients with PAH and chronic thromboembolic PH. Finally, sGC stimulators may also have potential therapeutic applications in other dis

Topics: Animals; Clinical Trials as Topic; Cyclic GMP; Guanylate Cyclase; Heterocyclic Compounds, 2-Ring; Humans; Hypertension, Pulmonary; Morpholines; Nitric Oxide; Pyrazoles; Pyridines; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

Available targeted therapies for pulmonary arterial hypertension are capable only of slowing progression of the disease and a cure remains elusive. However with the improved understanding of the pulmonary vascular remodeling that characterizes the disease, there is optimism that the disconnect between preclinical and clinical studies may be bridged with some of the newer therapies that are now at different stages of clinical evaluation. This article examines the evidence behind these new candidate treatments that may become part of the arsenal available for clinicians managing this devastating disease.

Topics: Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Receptors, Epoprostenol; Sulfonamides

Topics: Animals; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Clinical Trials, Phase III as Topic; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Thromboembolism; Ventricular Dysfunction, Left

It is well established that the endothelin, nitric oxide and prostacyclin pathways play an important role in the development of pulmonary arterial hypertension (PAH). Indeed, the therapeutic options currently available for the management of PAH all act on one of these mechanistic pathways. However, this is an exciting time for both clinicians and scientists, as increased understanding of the mechanisms involved in the pathogenesis and progression of PAH has resulted in the development of a number of novel therapeutic options. This article highlights how the introduction of new compounds such as macitentan, riociguat and selexipag, which act on the endothelin, nitric oxide and prostacyclin pathways, respectively, have the potential to further improve the prognosis for patients with PAH.

Topics: Acetamides; Animals; Antihypertensive Agents; Benzamides; Clinical Trials as Topic; Drugs, Investigational; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Epoprostenol; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Lisuride; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Piperazines; Protein Kinase Inhibitors; Pyrazines; Pyrazoles; Pyrimidines; Serotonin Antagonists; Sulfonamides

This review summarizes the role of soluble guanylate cyclase (sGC)-cyclic guanosine 3', 5'-monophosphate pathways in heart failure and several new drugs that modify guanylate cyclase. The sGC activators and stimulators as modulators of sGC are promising drugs in the therapy for decompensated heart failure and pulmonary hypertension. Cinaciguat is a nitric oxide (NO)-independent direct activator of sGC, which also may be effective under oxidative stress conditions resulting in oxidized or heme-free sGC refractory to organic nitrates. Riociguat is an NO-independent direct stimulator of sGC with beneficial effects in patients with decompensated heart failure and pulmonary hypertension. The sGC modulators play an important role in patients with heart failure and pulmonary hypertension.

Topics: Benzoates; Cardiovascular Agents; Guanylate Cyclase; Heart Failure; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Signal Transduction

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

Topics: Animals; Antihypertensive Agents; Clinical Trials as Topic; Drug Evaluation, Preclinical; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Models, Cardiovascular; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

Pulmonary hypertension (PH) encompasses a group of diseases associated with progressively increasing pulmonary vascular resistance, right heart failure and premature death. Riociguat is a novel, first-in-class oral drug that directly stimulates soluble guanylate cyclase, both independently of the endogenous vasodilator nitric oxide (NO) and in synergy with NO. Single oral doses of riociguat were well tolerated in a Phase I study of healthy volunteers. They had a favorable safety profile, and improved pulmonary hemodynamics and cardiac index to a greater extent than inhaled NO in a proof-of-concept study in patients with moderate-to-severe PH. In a 12-week Phase II trial in patients with chronic thromboembolic PH or pulmonary arterial hypertension, pulmonary hemodynamics and exercise capacity improved following individual dose titration with oral riociguat, which was generally well tolerated. Further trials in PH have been initiated.

Topics: Administration, Oral; Endothelium, Vascular; Exercise Tolerance; Guanylate Cyclase; Half-Life; Hemodynamics; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Vascular Resistance

Although pulmonary endarterectomy remains the treatment of choice for patients with chronic thromboembolic pulmonary hypertension (CTEPH), not all patients will benefit from or receive this highly specialised surgery. Patients whose CTEPH is deemed inoperable by an experienced centre and patients with persistent pulmonary hypertension after surgery are candidates for trial of pulmonary arterial hypertension (PAH) specific pharmacotherapies. However, the currently available PAH specific pharmacotherapies have not demonstrated a clear benefit in either of these patient groups. Accordingly, PAH therapies remain off-label for use in CTEPH. Riociguat (BAY 63-2521) is a stimulator of soluble guanylate cyclase, and may represent a novel agent in the treatment of select patients with CTEPH. Pre-clinical and human phase II studies with riociguat have reported promising results, and a multinational, randomised, controlled, double-blinded phase III study is currently underway to investigate the effect of riociguat in patients with inoperable CTEPH and those with persistent or recurrent pulmonary hypertension following pulmonary endarterectomy.

Topics: Chronic Disease; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pulmonary Circulation; Pulmonary Embolism; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

Pulmonary arterial hypertension (PAH) is a severe, progressive and often fatal disease for which only a limited number of drugs have proven to be of clinical benefit. One of the therapeutic approaches for this disease is the induction of pulmonary vasodilation via stimulation of the nitric oxide (NO)-mediated pathway. Abnormalities in the NO/soluble guanylate cyclase (sGC) axis and enhanced PDE5 activity render currently available drugs ineffective in many patients with PAH. Bayer AG is developing riociguat, an oral sGC stimulator, for the potential treatment of patients with PAH. Treatment with riociguat abrogated the severity of pulmonary hypertension in rodent models of the disease. Published data from phase I and II clinical trials demonstrated that riociguat was well tolerated, with single doses significantly decreasing pulmonary arterial pressure and increasing cardiac output and physical-exercise tolerance in patients with PAH. A decrease in systemic arterial diastolic pressure was the only significant side effect reported. Ongoing phase II and III trials for riociguat have been designed to address the long-term safety and clinical effectiveness of the drug in different types of pulmonary hypertension. Should the results of these trials demonstrate that riociguat is superior to current therapies, such as cyclic AMP-dependent drugs and endothelin receptor antagonists, the drug could become the preferred pharmacological treatment for patients with PAH.

Topics: Animals; Antihypertensive Agents; Chemistry, Pharmaceutical; Clinical Trials as Topic; Diastole; Dose-Response Relationship, Drug; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Male; Molecular Structure; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Receptors, Cytoplasmic and Nuclear; Recombinant Proteins; Soluble Guanylyl Cyclase; Structure-Activity Relationship; Tablets; Treatment Outcome; Vasodilator Agents

The prognosis for patients with pulmonary hypertension remains poor despite recent treatment advances, and there is a need for therapies with new modes of action. Nitric oxide (NO) is an endogenous vasodilator, the levels of which are regulated throughout the lung to ensure preferential perfusion of well-ventilated regions. Drugs that act in synergy with endogenous NO would therefore promote pulmonary vasodilation while maintaining optimal gas exchange. Riociguat is an oral stimulator of the NO receptor soluble guanylate cyclase. It synergises with NO and has demonstrated vasodilatory and antiremodelling properties in preclinical studies. Riociguat has been shown to have a favourable safety profile in healthy volunteers and in patients with pulmonary hypertension. Pharmacokinetic analyses have revealed substantial interindividual variation, suggesting that individual dose titration will be required. In a proof-of-concept study of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension, riociguat improved cardiopulmonary haemodynamics from baseline. It also caused systemic vasodilation, which was well tolerated but should be monitored in future studies. Dose titration of riociguat should promote pulmonary vasodilation while maintaining control of systemic effects, and has been investigated in a phase-II study of patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Preliminary results indicate that phase-III trials are warranted.

Topics: Enzyme Activation; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Vasodilator Agents

Balloon pulmonary angioplasty (BPA) and medical therapy, such as soluble guanylate cyclase stimulators, are recommended treatments for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are ineligible for pulmonary endarterectomy (PEA). However, monotherapy with BPA or medical therapy cannot always eliminate symptoms such as exertional dyspnoea. Thus, this study aims to clarify the efficacy of continuous treatment with riociguat in inoperable CTEPH patients with normalised haemodynamics after BPA.. This is a double-blind, multicentre, randomised, placebo-controlled trial. Participants with CTEPH who are ineligible for PEA will receive riociguat followed by BPA. Subsequently, participants will be randomised (1:1) into either riociguat continuing or discontinuing groups and will be observed for 16 weeks after randomisation. The primary endpoint will be the change in peak cardiac index (CI) during the cardiopulmonary exercise test. In the primary analysis, the least square mean differences and 95% CIs for the change in peak CI at 16 weeks between the groups will be estimated by a linear mixed-effects model with baseline value as a covariate, treatment group as a fixed effect and study institution as a random effect.. National Hospital Organisation Review Board for Clinical Trials (Nagoya) and each participating institution approved this study and its protocols. Written informed consent will be obtained from all participants. The results will be disseminated at medical conferences and in journal publications.. Japan Registry of Clinical Trials: jRCT no. 041200052.. gov by National Library of Medicine Registry ID: NCT04600492.. NCT04600492.

Topics: Angioplasty, Balloon; Chronic Disease; Humans; Hypertension, Pulmonary; Multicenter Studies as Topic; Pulmonary Embolism; Randomized Controlled Trials as Topic

Initial combination therapy with an endothelin receptor antagonist (ERA) and riociguat in pulmonary arterial hypertension (PAH) has limited supporting data.. We performed a prospective, single-arm, open-label trial of riociguat, and ambrisentan for incident PAH patients in functional class III. The primary endpoint was pulmonary vascular resistance (PVR) at 4-months.. Twenty patients (59 ± 13 years old, 85% female) enrolled and 1 died before their 4-month follow-up. Fifteen patients completed a 4-month and 13 completed the 12-month follow-up. At 4-months PVR decreased 54% with an absolute change of -5.8 Wood units (95% CI -4.0; -7.5, p < 0.001). Other hemodynamic variables and risk scores also improved. Six patients discontinued riociguat and 8 discontinued ambrisentan, with 5 (25%) discontinuing both.. These results do not support the routine use of riociguat plus ambrisentan in initial regimens. Future studies are needed to compare this strategy with phosphodiesterase-5 inhibitors and an ERA with respect to tolerability and long-term outcomes.

Topics: Aged; Antihypertensive Agents; Endothelin Receptor Antagonists; Familial Primary Pulmonary Hypertension; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phenylpropionates; Prospective Studies; Pulmonary Arterial Hypertension; Pyrazoles; Pyridazines; Pyrimidines; Treatment Outcome

Treatment options for patients with chronic thromboembolic pulmonary hypertension ineligible for pulmonary endarterectomy (inoperable CTEPH) include balloon pulmonary angioplasty (BPA) and riociguat. However, these two treatment options have not been compared prospectively. We aimed to compare the safety and efficacy of BPA and riociguat in patients with inoperable CTEPH.. This open-label, randomised controlled trial was conducted at four high-volume CTEPH centres in Japan. Patients aged 20-80 years with inoperable CTEPH (mean pulmonary arterial pressure ≥25 to <60 mm Hg and pulmonary artery wedge pressure ≤15 mm Hg) and WHO functional class II or III were randomly assigned (1:1) to BPA or riociguat via a computer program located at the registration centre using a minimisation method with biased-coin assignment. In the BPA group, the aim was for BPA to be completed within 4 months of the initial date of the first procedure. BPA was repeated until mean pulmonary arterial pressure decreased to less than 25 mm Hg. The frequency of BPA procedures depended on the difficulty and number of the lesions. In the riociguat group, 1·0 mg riociguat was administered orally thrice daily. When the systolic blood pressure was maintained at 95 mm Hg or higher, the dose was increased by 0·5 mg every 2 weeks up to a maximum of 2·5 mg thrice daily; dose adjustment was completed within 4 months of the date of the first dose. The primary endpoint was change in mean pulmonary arterial pressure from baseline to 12 months, measured in the full analysis set (patients who were enrolled and randomly assigned to one of the study treatments, and had at least one assessment after randomisation). BPA-related complications and indices related to clinical worsening were recorded throughout the study period. Adverse events were recorded throughout the study period and evaluated in the safety analysis set (patients who were enrolled and randomely assigned to one of the study treatments, and had received part of or all the study treatments). This trial is registered in the Japan Registry of Clinical Trials (jRCT; jRCTs031180239) and is completed.. Between Jan 8, 2016, and Oct 31, 2019, 61 patients with inoperable CTEPH were enrolled and randomly assigned to BPA (n=32) or riociguat (n=29). Patients in the BPA group underwent an average of 4·7 (SD 1·6) BPA procedures. In the riociguat group, the mean maintenance dose was 7·0 (SD 1·0) mg/day at 12 months. At 12 months, mean pulmonary arterial pressure had improved by -16·3 (SE 1·6) mm Hg in the BPA group and -7·0 (1·5) mm Hg in the riociguat group (group difference -9·3 mm Hg [95% CI -12·7 to -5·9]; p<0·0001). A case of clinical worsening of pulmonary hypertension occurred in the riociguat group, whereas none occurred in the BPA group. The most common adverse event was haemosputum, haemoptysis, or pulmonary haemorrhage, affecting 14 patients (44%) in the BPA group and one (4%) in the riociguat group. In 147 BPA procedures done in 31 patients, BPA-related complications were observed in 17 procedures (12%) in eight patients (26%).. Compared with riociguat, BPA was associated with a greater improvement in mean pulmonary arterial pressure in patients with inoperable CTEPH at 12 months, although procedure-related complications were reported. These findings support BPA as a reasonable option for inoperable CTEPH in centres with experienced BPA operators, with attention to procedure-related complications.. Bayer Yakuhin.. For the Japanese translation of the abstract see Supplementary Materials section.

Topics: Angioplasty, Balloon; Chronic Disease; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Treatment Outcome

Riociguat is effective in delaying the time to clinical worsening (TCW) in patients with groups 1 and 4 pulmonary hypertension.. Is riociguat more effective than placebo in prolonging TCW in sarcoidosis-associated pulmonary hypertension (SAPH)?. This was a double-blind placebo-controlled trial. Patients with SAPH confirmed by right heart catheterization were randomized 1:1 to riociguat or placebo. Patients underwent 6-min walk distance (6MWD) and spirometry testing every 8 weeks. The primary end point was TCW, which was defined by the time to the first of the following: (1) all-cause mortality, (2) need for hospitalization because of worsening cardiopulmonary status attributable to progression of disease, (3) > 50 m decrease in the 6MWD test, or (4) worsening of World Health Organization functional class.. A total of 16 patients were randomized to riociguat (n = 8) or placebo (n = 8). No difference was found in pulmonary artery mean, pulmonary vascular resistance, initial 6MWD, or FVC between the two groups. Five of eight patients who received placebo met TCW criteria, whereas none of the patients who received riociguat experienced a qualifying event. By log-rank analysis, patients who received riociguat were in the study for a significantly longer period (χ. Over the 1 year of the study, riociguat was effective in preventing clinical worsening and improving exercise capacity in patients with SAPH.. ClinicalTrials.gov; No.: NCT02625558; URL: www.clinicaltrials.gov.

Topics: Aged; Disease Progression; Double-Blind Method; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Quality of Life; Sarcoidosis; Spirometry; Walk Test

Management of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remains a clinical challenge. Currently, riociguat, a soluble guanylate-cyclase stimulator is recommended by international guidelines. More recently, balloon pulmonary angioplasty (BPA) develops as an alternative treatment for inoperable CTEPH.. This study is a single-center randomized controlled trial. Subjects with inoperable CTEPH are randomized into either a BPA combined with riociguat or riociguat monotherapy group (2:1) and observed for 12 months after initiation of treatment. The primary endpoint is the change in pulmonary vascular resistance from baseline to 12 months after initiation of treatment. The secondary endpoints include 6-min walk distance (6MWD), WHO-FC, NT-proBNP, SF-36, and other hemodynamic parameters. Safety endpoints are analyzed too.. This study aims to compare the efficacy and safety of BPA combined with riociguat and riociguat monotherapy for inoperable CTEPH.. Chinese Clinical Trial Registry ChiCTR2000032403 . Registered on 27 April 2020.

Topics: Angioplasty, Balloon; Chronic Disease; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic

Riociguat in Patients with Symptomatic Pulmonary Hypertension associated with Idiopathic Interstitial Pneumonias (RISE-IIP), a randomized, controlled, phase 2b trial of riociguat for pulmonary hypertension associated with idiopathic interstitial pneumonia, was terminated early due to increased mortality in riociguat-treated patients. Baseline characteristics of enrolled patients demonstrated a low diffusing capacity of the lung for carbon monoxide (DL. Available baseline/pre-baseline high-resolution computed tomography scans were reviewed centrally by 2 radiologists. The extent of emphysema and fibrosis was retrospectively scored and combined to provide the total CPFE score.. Data were available for 65/147 patients (44%), including 15/27 fatal cases (56%). Of these, 41/65 patients (63%) had CPFE. Mortality was higher in patients with CPFE (12/41; 29%) than those without (3/24; 13%). Fourteen patients with CPFE had emphysema > fibrosis (4 died). No relationship was observed between CPFE score, survival status, and treatment assignment. A low DL. High parenchymal lung disease burden and the presence of more emphysema than fibrosis might have predisposed patients with pulmonary hypertension associated with idiopathic interstitial pneumonia to poor outcomes in RISE-IIP. Future studies of therapy for group 3 pulmonary hypertension should include centrally adjudicated imaging for morphologic phenotyping and disease burden evaluation during screening.

Topics: Aged; Dose-Response Relationship, Drug; Female; Forced Expiratory Volume; Humans; Hypertension, Pulmonary; Idiopathic Interstitial Pneumonias; Lung; Male; Prognosis; Pulmonary Wedge Pressure; Pyrazoles; Pyrimidines; Retrospective Studies; Tomography, X-Ray Computed; Vital Capacity

In the Phase III PATENT-1 (NCT00810693) and CHEST-1 (NCT00855465) studies, riociguat demonstrated efficacy vs placebo in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Clinical effects were maintained at 2 years in the long-term extension studies PATENT-2 (NCT00863681) and CHEST-2 (NCT00910429).. This post hoc analysis of hemodynamic data from PATENT-1 and CHEST-1 assessed whether riociguat improved right ventricular (RV) function parameters including stroke volume index (SVI), stroke volume, RV work index, and cardiac efficiency. REVEAL Risk Score (RRS) was calculated for patients stratified by SVI and right atrial pressure (RAP) at baseline and follow-up. The association between RV function parameters and SVI and RAP stratification with long-term outcomes was assessed.. In PATENT-1 (n = 341) and CHEST-1 (n = 238), riociguat improved RV function parameters vs placebo (p < 0.05). At follow-up, there were significant differences in RRS between patients with favorable and unfavorable SVI and RAP, irrespective of treatment arm (p < 0.0001). Multiple RV function parameters at baseline and follow-up were associated with survival and clinical worsening-free survival (CWFS) in PATENT-2 (n = 396; p < 0.05) and CHEST-2 (n = 237). In PATENT-2, favorable SVI and RAP at follow-up only was associated with survival and CWFS (p < 0.05), while in CHEST-2, favorable SVI and RAP at baseline and follow-up were associated with survival and CWFS (p < 0.05).. This post hoc analysis of PATENT and CHEST suggests that riociguat improves RV function in patients with PAH and CTEPH.

Topics: Adult; Atrial Pressure; Enzyme Activators; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyrimidines; Stroke Volume; Treatment Outcome; Ventricular Function, Right

Management of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remains a clinical challenge. Currently, medical treatment involving pulmonary vasodilators (such as soluble guanylate-cyclase stimulators) is recommended, primarily for ameliorating symptoms. More recently, balloon pulmonary angioplasty (BPA) has been developed as alternative treatment for inoperable CTEPH. This study aimed to compare the efficacy and safety of BPA and riociguat (a soluble guanylate-cyclase stimulator) as treatments for inoperable CTEPH.. This study is a multicentre randomised controlled trial. Subjects with inoperable CTEPH were randomised (1:1) into either a BPA or riociguat group, and observed for 12 months after initiation of treatment. The primary endpoint will be the change in mean pulmonary arterial pressure from baseline to 12 months after initiation of treatment. For primary analysis, we will estimate the least square means difference and 95% CI for the change of pulmonary arterial pressure between the groups at 12 months using the analysis of covariance adjusted for allocation factors.. This study and its protocols were approved by the institutional review board of Keio University School of Medicine and each participating institution. Written informed consent was obtained from all participants. Results will be disseminated at medical conferences and in journal publications.. University Hospital Medical Information Network Clinical Trial Registry (UMIN000019549); Pre-results.

Topics: Adult; Angioplasty, Balloon; Antihypertensive Agents; Combined Modality Therapy; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyrimidines; Quality of Life; Treatment Outcome

Pulmonary artery denervation (PADN) procedure has not been applied to patients with residual chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy (PEA).. This study sought to assess the safety and efficacy of PADN using remote magnetic navigation in patients with residual CTEPH after PEA.. Fifty patients with residual CTEPH despite medical therapy at least 6 months after PEA, who had mean pulmonary artery pressure ≥25 mm Hg or pulmonary vascular resistance (PVR) > 400 dyn‧s‧cm. PADN in patients with residual CTEPH resulted in substantial reduction of PVR at 12 months of follow-up, accompanied by improved 6-min walk test.

Topics: Cardiac Catheterization; Denervation; Endarterectomy; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Artery; Pulmonary Embolism; Pulmonary Wedge Pressure; Pyrazoles; Pyrimidines; Surgery, Computer-Assisted; Treatment Outcome; Vascular Resistance; Walk Test

Idiopathic interstitial pneumonias are often complicated by pulmonary hypertension, increasing morbidity and mortality. There are no approved treatments for pulmonary hypertension associated with idiopathic interstitial pneumonia (PH-IIP). We aimed to evaluate the efficacy and safety of riociguat in patients with PH-IIP.. RISE-IIP was a double-blind, randomised, placebo-controlled study done at 65 pulmonary hypertension and interstitial lung disease centres in 19 countries to evaluate the efficacy and safety of riociguat in patients with PH-IIP. Eligible patients were adults (aged 18-80 years) diagnosed with idiopathic interstitial pneumonia (as per American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association guidelines), forced vital capacity (FVC) of at least 45%, 6MWD of 150-450 m, WHO functional classes II-IV, precapillary pulmonary hypertension confirmed by right heart catheterisation, systolic blood pressure of at least 95 mm Hg, and no signs or symptoms of hypotension. Patients were randomly allocated (1:1) using an interactive voice and web response system to riociguat (0·5-2·5 mg three times daily) or placebo for 26 weeks (main study), after which they could enter an open-label extension in which all patients received riociguat. The primary endpoint was change in 6-min walking distance (6MWD) in the intention-to-treat population. Prespecified safety variables included adverse events and serious adverse events, laboratory parameters, and adverse events of special interest (haemoptysis and symptomatic hypotension), assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, number NCT02138825.. Between June 4, 2014, and May 5, 2016, we enrolled 229 participants. After the exclusion of 82 participants, 147 were randomly allocated to treatment (73 to riociguat, 74 to placebo). The study was terminated early (median treatment duration 157 days [range 6-203]) at the request of the data monitoring committee owing to increased serious adverse events (main study: 27 [37%] of 73 participants in the riociguat group vs 17 [23%] of 74 in the placebo group) and mortality in patients receiving riociguat, and the absence of efficacy signals in the riociguat group. 11 patients died in the main study (eight in the riociguat group, three in the placebo group), and nine died in the extension phase (one in the riociguat group, eight in the former placebo group; all received riociguat). In the main study, the most common adverse events were peripheral oedema (16 [22%] of 73 in the riociguat group vs seven [9%] of 74 in the placebo group) and diarrhoea (11 [15%] vs seven [9%]). The most common serious adverse events were worsening of interstitial lung disease (main study: six [8%] of 73 in the riociguat group vs five [7%] of 74 in the placebo group) and pneumonia (four [5%] vs one [1%]). Riociguat did not improve 6MWD versus placebo at 26 weeks (least-squares mean difference 21 m; 95% CI -9 to 52).. In patients with PH-IIP, riociguat was associated with increased serious adverse events and mortality, and an unfavourable risk-benefit profile. Riociguat should not be used in patients with PH-IIP.. Bayer AG and Merck & Co.

Topics: Aged; Double-Blind Method; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Idiopathic Interstitial Pneumonias; Male; Pyrazoles; Pyrimidines; Treatment Outcome

Current pulmonary hypertension treatment guidelines recommend use of a risk stratification model encompassing a range of parameters, allowing patients to be categorised as low, intermediate or high risk. Three abbreviated versions of this risk stratification model were previously evaluated in patients with pulmonary arterial hypertension (PAH) in the French, Swedish and COMPERA registries. Our objective was to investigate the three abbreviated risk stratification methods for patients with mostly prevalent PAH and chronic thromboembolic pulmonary hypertension (CTEPH), in patients from the PATENT-1/2 and CHEST-1/2 studies of riociguat.. Risk was assessed at baseline and at follow-up in PATENT-1 and CHEST-1. Survival and clinical worsening-free survival were assessed in patients in each risk group/strata.. With all three methods, riociguat improved risk group/strata in patients with PAH after 12 weeks. The French non-invasive and Swedish/COMPERA methods discriminated prognosis for survival and clinical worsening-free survival at both baseline and follow-up. Furthermore, patients achieving one or more low-risk criteria or a low-risk stratum at follow-up had a significantly reduced risk of death and clinical worsening compared with patients achieving no low-risk criteria or an intermediate-risk stratum. Similar results were obtained in patients with inoperable or persistent/recurrent CTEPH.. This analysis confirms and extends the results of the registry analyses, supporting the value of goal-oriented treatment in PAH. Further assessment of these methods in patients with CTEPH is warranted.

Topics: Adult; Aged; Chronic Disease; Europe; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines; Registries; Risk Assessment; Risk Factors; Survival Analysis; Thromboembolism

The REVEAL risk score (RRS) was developed to predict survival in patients with pulmonary arterial hypertension (PAH), based on multiple patient characteristics. Herein we calculated RRS for patients in the randomized CHEST-1 study and open-label CHEST-2 extension study of riociguat in inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). We investigated the effect of riociguat vs placebo on RRS in the CHEST-1 study, and the relationship between RRS and long-term outcomes in the CHEST-2 study.. RRS was calculated post hoc for baseline and Week 16 of CHEST-1 and Week 12 of CHEST-2, based on 9 evaluable elements. Patients were grouped into risk strata by RRS. Relationships between RRS and both survival and clinical worsening-free survival were examined by Kaplan-Meier and Cox proportional hazards analyses.. Overall, 237 patients completed CHEST-1 and entered CHEST-2. In CHEST-1, riociguat significantly improved RRS (p < 0.0001) and risk stratum (p < 0.001) vs placebo from baseline to Week 16. RRS at baseline, and at Week 16, and change in RRS during CHEST-1 were significantly associated with survival (hazard ratios for a 1-point reduction in RRS: 0.702, 0.692, and 0.682, respectively) and clinical worsening-free survival (hazard ratios: 0.697, 0.719, and 0.754, respectively) over 2 years in CHEST-2.. Riociguat improved RRS in patients with inoperable and persistent/recurrent CTEPH. RRS at baseline and Week 16, and change in RRS from baseline, predicted survival and clinical worsening-free survival. This analysis of RRS in patients with inoperable or persistent/recurrent CTEPH suggests utility for the RRS in indications beyond PAH.

Topics: Chronic Disease; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Risk Assessment; Survival Rate; Thromboembolism

Riociguat is a soluble guanylate cyclase stimulator approved for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTPEH). The objective of this study was to evaluate right heart size and function assessed by echocardiography during long term treatment with riociguat.. Patients who started riociguat treatment (1.0-2.5 mg tid) within the trials phase II, PATENT, PATENTplus, EAS, CHEST and continued treatment for 3-12 months were included in this study. Echocardiography was analysed off-line at baseline, after 3, 6 and 12 months by investigators who were blinded to clinical data. Last and baseline observation carried forward method (LOCF, BOCF) were performed as sensitivity analysis.. Seventy-one patients (45% PAH, 55% CTEPH; 53.5% female; 60 ± 13 years, mean pulmonary arterial pressure 46 ± 10 mmHg, mean PVR 700 ± 282dynes·sec·cm-5) were included. After 6 months, RA and RV area, RV thickness tricuspid regurgitation velocity showed a significant reduction. After 12 months, patients receiving riociguat therapy showed a significant reduction in right atrial (- 2.6 ± 4.4 cm2, 95% CI -3.84, - 1.33; p < 0.001, n = 49) and right ventricular (RV) area (- 3.5 ± 5.2 cm2, 95% CI -5.1, - 1.9; p < 0.001; n = 44), RV thickness (- 0.76 ± 2.2 mm, 95% CI -1.55, 0.03; n = 32), and a significant increase in TAPSE (2.95 ± 4.78 mm, 95% CI 1.52, 4.39; n = 45) and RV fractional area change (8.12 ± 8.87 mm, 95% CI 4.61, 11.62; n = 27). Both LOCF and BOCF showed similar results but lower effect sizes.. Patients under long-term treatment with riociguat show significantly reduced right heart size and improved RV function in PAH and CTEPH. Further controlled prospective studies are needed to confirm these results.

Topics: Aged; Chronic Disease; Double-Blind Method; Enzyme Activators; Female; Heart Ventricles; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Ventricular Function, Right

Riociguat was well tolerated and improved exercise and functional capacity in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH) in a 12-week Phase II trial. We present final data from the long-term extension phase of this study.. During this multicenter, open-label, uncontrolled long-term extension study, riociguat dose could be changed at the physician's discretion (range 0.5-2.5 mg three times daily). The primary outcome was long-term safety and tolerability of riociguat; secondary outcomes included 6-minute walking distance, World Health Organization functional class, survival, and clinical worsening-free survival.. Sixty-eight patients (inoperable CTEPH, n = 41; PAH, n = 27) entered the long-term extension. Median treatment duration at the final data cut-off was 77 months. The most common adverse events were nasopharyngitis (57%) and peripheral edema (37%). Three patients (4%) experienced serious adverse events of hemoptysis: two moderate, one severe, none fatal or considered drug-related. At Month 48, 6-minute walking distance increased from baseline by 69 ± 105 m, and World Health Organization functional class improved/stabilized/worsened versus baseline in 50/45/5% of patients. Three-year survival and clinical worsening-free survival were 91% and 49%, respectively (with patients censored if they withdrew without experiencing an event). Starting a new PAH treatment was the most frequent clinical worsening event.. Improvements in exercise and functional capacity were maintained at 4 years in patients remaining on treatment, with no new safety signals identified. These data support riociguat as a long-term treatment option for PAH and inoperable CTEPH.. ClinicalTrials.gov.. NCT00454558.

Topics: Adult; Aged; Antihypertensive Agents; Disease-Free Survival; Enzyme Activators; Exercise; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyrimidines; Soluble Guanylyl Cyclase; Treatment Outcome; Walk Test

Following positive results from the Phase III CHEST-1 study in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), the Phase IIIb CTEPH early access study (EAS) was designed to assess the safety and tolerability of riociguat in real-world clinical practice, as well as to provide patients with early access to riociguat before launch. Riociguat is approved for the treatment of inoperable and persistent/recurrent CTEPH.. We performed an open-label, uncontrolled, single-arm, early access study in which 300 adult patients with inoperable or persistent/recurrent CTEPH received riociguat adjusted from 1 mg three times daily (tid) to a maximum of 2.5 mg tid. Patients switching from unsatisfactory prior pulmonary arterial hypertension (PAH)-targeted therapy (n = 84) underwent a washout period of at least 3 days before initiating riociguat. The primary aim was to assess the safety and tolerability of riociguat, with World Health Organization functional class and 6-min walking distance (6MWD) as exploratory efficacy endpoints.. In total, 262 patients (87%) completed study treatment and entered the safety follow-up (median treatment duration 47 weeks). Adverse events were reported in 273 patients (91%). The most frequently reported serious adverse events were syncope (6%), right ventricular failure (3%), and pneumonia (2%). There were five deaths, none of which was considered related to study medication. The safety and tolerability of riociguat was similar in patients switched from other PAH-targeted therapies and those who were treatment naïve. In patients with data available, mean ± standard deviation 6MWD had increased by 33 ± 42 m at Week 12 with no clinically relevant differences between the switched and treatment-naïve subgroups.. Riociguat was well tolerated in patients with CTEPH who were treatment naïve, and in those who were switched from other PAH-targeted therapies. No new safety signals were observed.. ClinicalTrials.org NCT01784562 . Registered February 4, 2013.

Topics: Aged; Antihypertensive Agents; Chronic Disease; Drug Administration Schedule; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Syncope; Thromboembolism; Treatment Outcome

The 12-week, phase III Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT)-1 study investigated riociguat in patients with pulmonary arterial hypertension (PAH). Here, we present a prospectively planned analysis of the safety and efficacy of riociguat in the subgroup of patients with PAH associated with connective tissue disease (PAH-CTD).. Patients with PAH-CTD were further classified post hoc as having PAH associated with systemic sclerosis or PAH-other defined CTD. In PATENT-1, patients received riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo. Efficacy endpoints included change from baseline in 6-minute walking distance (6MWD; primary endpoint), haemodynamics and WHO functional class (WHO FC). In the long-term extension PATENT-2, patients received riociguat (maximum 2.5 mg three times daily); the primary endpoint was safety and tolerability.. In patients with PAH-CTD, riociguat increased mean 6MWD, WHO FC, pulmonary vascular resistance and cardiac index. Improvements in 6MWD and WHO FC persisted at 2 years. Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%). Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population.. Riociguat was well tolerated and associated with positive trends in 6MWD and other endpoints that were sustained at 2 years in patients with PAH-CTD.. PATENT-1 (NCT00810693), PATENT-2 (NCT00863681).

Topics: Adult; Aged; Antihypertensive Agents; Connective Tissue Diseases; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Scleroderma, Systemic; Treatment Outcome; Vascular Resistance; Walk Test

RISE-SSc is a randomized, double-blind, placebo-controlled phase 2 study investigating the efficacy and safety of riociguat in patients with diffuse cutaneous systemic sclerosis (dcSSc). Based on positive results from riociguat trials in patients with pulmonary hypertension and chronic thromboembolic pulmonary hypertension in combination with the known antiproliferative and antifibrotic effects seen in animal models, patients with SSc may benefit from treatment with riociguat. Patients with SSc meeting the ACR/EULAR systemic sclerosis classification criteria with diffuse cutaneous SSc (dcSSc) subset per LeRoy criteria, and a disease duration of less than or equal to 18 months will be randomized to placebo or riociguat 0.5 mg (up-titrated to a maximum dose of 2.5 mg TID over 10 weeks) and maintained on therapy for a total of 52 weeks. During the first 10 weeks of the long-term extension phase, placebo subjects will be up-titrated on riociguat, and all patients will be followed for up to 6 years. The primary endpoint of change in modified Rodnan skin score (mRSS) from baseline will be assessed at 52 weeks, as will be secondary endpoints such as mRSS progression and regression rates, patient quality of life, digital ulcer burden, and change in forced vital capacity and carbon monoxide diffusing capacity. This review will further define the clinical rationale for the use of riociguat in the treatment of SSc and provide details on study protocol, design, and outcome reporting.. Clinicaltrials.gov identifier: NCT02283762.

Topics: Carbon Monoxide; Dose-Response Relationship, Drug; Double-Blind Method; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Pulmonary Diffusing Capacity; Pulmonary Embolism; Pyrazoles; Pyrimidines; Quality of Life; Scleroderma, Diffuse; Scleroderma, Systemic; Skin; Skin Diseases; Soluble Guanylyl Cyclase; Treatment Outcome; Vital Capacity

Patients with pulmonary arterial hypertension (PAH) who do not have an adequate response to therapy with phosphodiesterase-5 inhibitors (PDE-5i) may have insufficient synthesis of cyclic guanosine monophosphate (cGMP). These patients may respond to a direct soluble guanylate cyclase (sGC) stimulator such as riociguat. RESPITE (NCT02007629) was an open-label, multicenter, uncontrolled, single-arm phase 3b study of riociguat in patients with PAH who demonstrated an insufficient response to treatment with PDE-5i. Insufficient response was defined as World Health Organization functional class (WHO FC) III despite PDE-5i therapy for at least 90 days; 6-min walk distance (6MWD) of 165-440 m, and right-heart catheterization showing mean pulmonary artery pressure >30 mmHg, cardiac index <3.0 L/min/m

Topics: Adolescent; Adult; Aged; Endothelin Receptor Antagonists; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Nitric Oxide; Outcome Assessment, Health Care; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyrimidines; Quality of Life; Sildenafil Citrate; Soluble Guanylyl Cyclase; Young Adult

In clinical trials of treatments for pulmonary arterial hypertension (PAH), objective measures, such as 6-min walk distance (6MWD) are limited in their ability to characterize the impact of PAH therapy from a patient's perspective. Few clinical studies have evaluated the primary effects of pharmacologic treatment on patient-reported outcomes, such as symptoms, health-related quality of life (HRQoL), and productivity. MOTION (NCT02191137) is a prospective, multicenter, single-arm, open-label, phase 4 trial designed to assess whether riociguat monotherapy will improve patient-reported outcomes in patients with PAH in the United States who are not currently on treatment. Following a screening period of up to 14 days, eligible subjects will receive riociguat (0.5-2.5 mg TID) during a 10-week titration phase and a 14-week maintenance phase. The primary endpoint is change from baseline in the Living with Pulmonary Hypertension (LPH) questionnaire, a disease-specific HRQoL measure, after 24 weeks of riociguat treatment. The Short Form-12 Health Survey (SF-12) and the Work Limitations Questionnaire 8 (WLQ-8) will also be utilized to assess patient-reported outcomes. Other variables include change from baseline in World Health Organization functional class, 6MWD, and modified Borg Dyspnea Index. In addition, accelerator band activity will be validated against the 6MWD test. Safety will also be assessed. The MOTION trial will provide information on the effect of riociguat on patient-reported outcomes in PAH patients in the United States who are not currently on active treatment through the use of disease-specific and generic HRQoL measures (LPH and SF-12) and a measure of worker productivity (WLQ-8).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Patient Reported Outcome Measures; Prospective Studies; Pyrazoles; Pyrimidines; Quality of Life; Research Design; Soluble Guanylyl Cyclase; Treatment Outcome; United States; Young Adult

Detailed hemodynamic data from the phase III PATENT-1 study of riociguat in patients with pulmonary arterial hypertension (PAH) were investigated.. Patients with PAH who were treatment naïve or pre-treated with endothelin receptor antagonists or non-intravenous prostanoids were randomly assigned to riociguat up to 2.5 mg 3 times a day or placebo. Hemodynamic parameters were assessed at baseline and week 12.. Riociguat significantly decreased pulmonary vascular resistance in treatment-naïve (n = 221; least squares [LS] mean difference -266 dyne∙sec∙cm. Riociguat significantly improved hemodynamic parameters in pre-treated and treatment-naïve patients with PAH.

Topics: Administration, Oral; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Endothelin Receptor Antagonists; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Internationality; Male; Maximum Tolerated Dose; Prospective Studies; Prostaglandins; Pyrazoles; Pyrimidines; Reference Values; Severity of Illness Index; Treatment Outcome; Vascular Resistance

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, debilitating, and life-threatening disease. We investigated associations between markers of disease severity and long-term outcomes in patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) who were receiving the soluble guanylate cyclase stimulator riociguat. We also present safety and efficacy from the final data cutoff of CHEST-2, where most patients had received riociguat for at least 2 years.. Eligible patients from the CHEST-1 study entered the CHEST-2 open-label extension study, in which all patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times per day. The primary endpoint was safety and tolerability. We did exploratory assessments of associations between markers of disease severity (6-min walking distance [6MWD], N-terminal prohormone of brain natriuretic peptide [NT-proBNP] concentration, and WHO functional class) at baseline and follow-up with overall survival and clinical worsening-free survival. We used Kaplan-Meier and Cox proportional hazards analyses. CHEST-2 is registered at ClinicalTrials.gov, number NCT00910429.. 237 patients entered CHEST-2. At 2 years, overall survival was 93% (95% CI 89-96) and clinical worsening-free survival was 82% (77-87). A significant association with overall survival was seen for 6MWD and NT-proBNP concentration at baseline (p=0·0199 and p=0·0183, respectively) and at follow-up (p=0·0385 and p=0·0068, respectively). Change from baseline in 6MWD was also significantly associated with survival (p=0·0047). WHO functional class at baseline and follow-up showed no significant association with overall survival but was associated with clinical worsening-free survival. Riociguat was well tolerated by most patients and no new safety signals were identified. Serious adverse events were seen in 129 (54%) of 237 patients, and 14 (6%) discontinued riociguat therapy because of adverse events.. Riociguat may be used long term in patients with CTEPH. 6MWD and NT-proBNP concentration are good prognostic markers.. Bayer Pharma AG.

Topics: Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Chronic Disease; Double-Blind Method; Drug Administration Schedule; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Pulmonary Embolism; Pyrazoles; Pyrimidines; Time; Treatment Outcome; Young Adult

Pulmonary arterial hypertension is a chronic disease associated with poor long-term outcomes. Identifying predictors of long-term outcome in pulmonary arterial hypertension is important to assess disease severity and guide treatment. We investigate associations between efficacy parameters and long-term outcomes in patients with pulmonary arterial hypertension receiving riociguat in the PATENT-2 study. We also present safety and efficacy data from the final data cutoff of PATENT-2, where most patients had received at least 2 years of riociguat treatment.. Eligible patients from the PATENT-1 study entered the PATENT-2 open-label extension, which will continue until all patients transition to the commercial drug. All patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times a day. The primary endpoint was safety and tolerability, assessed with recording adverse events, serious adverse events, discontinuations, and deaths; exploratory assessments included 6-min walking distance (6MWD), WHO functional class, N-terminal prohormone of brain natriuretic peptide (NT-proBNP)concentrations, Borg dyspnoea score, health-related quality of life (EQ-5D score), survival, and clinical worsening-free survival. Association between efficacy parameters and long-term outcomes was assessed using Kaplan-Meier analyses and a Cox proportional-hazards regression model. PATENT-2 is registered at ClinicalTrials.gov, number NCT00863681.. 396 patients entered PATENT-2, of whom 197 patients were receiving riociguat monotherapy and 199 were receiving riociguat in combination with endothelin receptor antagonists or prostanoids, or both. A significant association was noted between 6MWD, NT-proBNP concentration, and WHO functional class and overall survival at baseline (p=0·0006, 0·0225, and 0·0191, respectively), and at follow-up (p=0·021, 0·0056, and 0·0048, respectively). Riociguat was well tolerated in PATENT-2. Serious adverse events were recorded in 238 (60%) of the total population, and 45 (11%) patients discontinued treatment because of an adverse event. Improvements in 6MWD, WHO functional class, and NT-proBNP concentrations were maintained after 2 years of treatment.. These results support the long-term use of riociguat in patients with pulmonary arterial hypertension, and emphasise the prognostic value of 6MWD, WHO functional class, and NT-proBNP concentrations.. Bayer Pharma AG.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antihypertensive Agents; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Endothelin Receptor Antagonists; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Prostaglandins; Pulmonary Artery; Pyrazoles; Pyrimidines; Quality of Life; Time; Treatment Outcome; Young Adult

The presence of pulmonary hypertension (PH) severely aggravates the clinical course of heart failure with preserved ejection fraction (HFPEF) resulting in substantial morbidity and mortality. So far, neither established heart failure therapies nor pulmonary vasodilators have proven to be effective for this condition. Riociguat (Adempas®, BAY 63-2521), a stimulator of soluble guanylate cyclase, is a novel pulmonary and systemic vasodilator that has been approved for the treatment of precapillary forms of PH. With regard to postcapillary PH, the DILATE-1 study was a multicenter, double-blind, randomized, placebo-controlled single-dose study in subjects with PH associated with HFPEF. Although there was no significant change in the primary outcome measure, peak decrease in mean pulmonary artery pressure with riociguat versus placebo, riociguat significantly increased stroke volume without changing heart rate, pulmonary artery wedge pressure, transpulmonary pressure gradient or pulmonary vascular resistance. The present study is designed to test the efficacy of long-term treatment with riociguat in patients with PH associated with HFPEF.. The DYNAMIC study is a randomized, double-blind, placebo-controlled, parallel-group, multicenter clinical phase IIb trial evaluating the efficacy, safety and kinetics of riociguat in PH-HFPEF patients. The drug will be given over 26 weeks to evaluate the effects of riociguat versus placebo. The primary efficacy variable will be the change from baseline in cardiac output at rest, measured by right heart catheter after 26 weeks of study drug treatment. Additional efficacy variables will be changes from baseline in further hemodynamic parameters, changes in left and right atrial area, right ventricular volume, as well as right ventricular ejection fraction measured by cardiac magnetic resonance imaging, and changes from baseline in World Health Organization (WHO) class and N‑terminal prohormone B‑type natriuretic peptide (NT-proBNP). The trial was registered on 25 August 2014 (EudraCT Number: 2014-003055-60; www.clinicaltrialsregister.eu ).

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Double-Blind Method; Female; Germany; Humans; Hypertension; Hypertension, Pulmonary; Male; Metabolic Clearance Rate; Middle Aged; Placebo Effect; Pyrazoles; Pyrimidines; Research Design; Stroke Volume; Vasodilator Agents; Young Adult

Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, riociguat showed a favourable benefit-risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from CHEST-1 received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of riociguat; exploratory efficacy end-points included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC). Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±sd 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236). Long-term riociguat had a favourable benefit-risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year.

Topics: Aged; Antihypertensive Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Exercise Test; Female; Follow-Up Studies; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Respiratory Function Tests; Risk; Thromboembolism; Time Factors; Walking

Riociguat is a soluble, guanylate cyclase stimulator, approved for pulmonary arterial hypertension. In the 12-week PATENT-1 study, riociguat was well tolerated and improved several clinically relevant end-points in patients with pulmonary arterial hypertension who were treatment naïve or had been pretreated with endothelin-receptor antagonists or prostanoids. The PATENT-2 open-label extension evaluated the long-term safety and efficacy of riociguat. Eligible patients from the PATENT-1 study received riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was to assess the safety and tolerability of riociguat; exploratory efficacy assessments included 6-min walking distance and World Health Organization (WHO) functional class. Overall, 396 patients entered the PATENT-2 study and 324 (82%) were ongoing at this interim analysis (March 2013). The safety profile of riociguat in PATENT-2 was similar to that observed in PATENT-1, with cases of haemoptysis and pulmonary haemorrhage also being observed in PATENT-2. Improvements in the patients', 6-min walking distance and WHO functional class observed in PATENT-1 persisted for up to 1 year in PATENT-2. In the observed population at the 1-year time point, mean±sd 6-min walking distance had changed by 51±74 m and WHO functional class had improved in 33%, stabilised in 61% and worsened in 6% of the patients versus the PATENT-1 baseline. Long-term riociguat was well tolerated in patients with pulmonary arterial hypertension, and led to sustained improvements in exercise capacity and functional capacity for up to 1 year.

Topics: Adult; Aged; Antihypertensive Agents; Double-Blind Method; Endothelin Receptor Antagonists; Exercise Test; Female; Follow-Up Studies; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Kaplan-Meier Estimate; Male; Middle Aged; Patient Safety; Prostaglandins; Pyrazoles; Pyrimidines; Quality of Life; Time Factors; Treatment Outcome

PATENT PLUS evaluated the safety and efficacy of riociguat in combination with sildenafil in pulmonary arterial hypertension patients. Patients receiving sildenafil (20 mg three times daily) were randomised to placebo or riociguat (up to 2.5 mg three times daily) for 12 weeks. The primary outcome was maximum change in supine systolic blood pressure (SBP) from baseline within 4 h of dosing. Secondary objectives comprised additional blood pressure, heart rate and exploratory efficacy variables, and safety. Patients could enter a long-term extension (LTE), where all patients received riociguat plus sildenafil. There was no difference in maximum change in supine SBP from baseline within 4 h between the riociguat (n=12) (mean±sd baseline: -20.2±15.3 mmHg; week 12: -20.7±18.0 mmHg) and placebo groups (n=6) (-7.6±3.9 and -20.2±12.9 mmHg, respectively). Changes in standing SBP and supine or standing diastolic blood pressure were also not different. Combination therapy showed no favourable effects on exploratory clinical parameters, including haemodynamics and exercise capacity. In the LTE, there were high rates of discontinuation due to hypotension and three (18%) deaths (not considered study drug-related by the investigator). There were potentially unfavourable safety signals with sildenafil plus riociguat and no evidence of a positive benefit/risk ratio. Concomitant use of riociguat with phosphodiesterase-5 inhibitors is therefore contraindicated.

Topics: Aged; Antihypertensive Agents; Diastole; Double-Blind Method; Europe; Exercise; Female; Follow-Up Studies; Guanylate Cyclase; Heart Rate; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Patient Safety; Phosphodiesterase 5 Inhibitors; Pyrazoles; Pyrimidines; Sildenafil Citrate; Systole

In PATENT-1, riociguat significantly improved 6-minute walking distance (6MWD) and a range of secondary end-points in patients with pulmonary arterial hypertension (PAH). We investigated whether riociguat increased the proportion of patients achieving clinically relevant responder thresholds compared with placebo during PATENT-1.. In PATENT-1, a randomized, double-blind study, treatment-naïve patients or patients on background PAH-targeted therapy with symptomatic PAH received 12 weeks of treatment with placebo, riociguat up to 2.5 mg 3 times daily, or riociguat up to 1.5 mg 3 times daily. Increases in 6MWD ≥40 m, 6MWD ≥380 m, cardiac index ≥2.5 liter/min/m(2), mixed venous oxygen saturation ≥65%, World Health Organization functional class I/II, N-terminal pro-brain natriuretic peptide <1,800 pg/ml, and right atrial pressure <8 mm Hg were chosen as threshold criteria of a positive response.. Riociguat increased the proportion of treatment-naïve patients and patients on background PAH-targeted therapy with 6MWD ≥380 m at Week 12 (+21% and +15%, respectively), whereas there was a small reduction in 6MWD in placebo-treated patients for both sub-groups. Riociguat also increased the proportion of treatment-naïve patients and patients on background PAH-targeted therapy achieving World Health Organization functional class I/II (+12% and +19%, respectively) and cardiac index ≥2.5 liter/min/m(2) (+30% and +33%, respectively) at Week 12, whereas there was little change in the respective placebo groups.. Compared with placebo, riociguat increased the proportion of treatment-naïve patients and patients on background PAH-targeted therapy who fulfilled criteria defining a positive response to therapy.

Topics: Dose-Response Relationship, Drug; Double-Blind Method; Exercise Test; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Treatment Outcome; Ventricular Function, Right; Ventricular Pressure; Walking

In the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase - Stimulator Trial 1 (CHEST-1) study, riociguat improved 6-minute walking distance (6MWD) vs placebo in patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. In this study, the proportion of patients who achieved responder thresholds that correlate with improved outcome in patients with pulmonary arterial hypertension was determined at baseline and at the end of CHEST-1.. Patients received placebo or riociguat individually adjusted up to 2.5 mg 3 times a day for 16 weeks. Response criteria were defined as follows: 6MWD increase ≥40 m, 6MWD ≥380 m, cardiac index ≥2.5 liters/min/m(2), pulmonary vascular resistance <500 dyn∙sec∙cm(-5), mixed venous oxygen saturation ≥65%, World Health Organization functional class I/II, N-terminal pro-brain natriuretic peptide <1,800 pg/ml, and right atrial pressure <8 mm Hg.. Riociguat increased the proportion of patients with 6MWD ≥380 m, World Health Organization functional class I/II, and pulmonary vascular resistance <500 dyn∙sec∙cm(-5) from 37%, 34%, and 25% at baseline to 58%, 57%, and 50% at Week 16, whereas there was little change in placebo-treated patients (6MWD ≥380 m, 43% vs 44%; World Health Organization functional class I/II, 29% vs 38%; pulmonary vascular resistance <500 dyn∙sec∙cm(-5), 27% vs 26%). Similar changes were observed for thresholds for cardiac index, mixed venous oxygen saturation, N-terminal pro-brain natriuretic peptide, and right atrial pressure.. In this exploratory analysis, riociguat increased the proportion of patients with inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy achieving criteria defining a positive response to therapy.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Double-Blind Method; Female; Follow-Up Studies; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Retrospective Studies; Time Factors; Treatment Outcome; Vascular Resistance; Ventricular Function, Right; Ventricular Pressure; Young Adult

The Pulmonary Arterial hyperTENsion sGC-stimulator Trial-1 (PATENT-1) was a randomised, double-blind, placebo-controlled phase III trial evaluating riociguat in patients with pulmonary arterial hypertension (PAH). PATENT-2 was an open-label long-term extension to PATENT-1. Here, we explore the efficacy and safety of riociguat in the subgroup of patients with persistent/recurrent PAH after correction of congenital heart disease (PAH-CHD) from the PATENT studies.. In PATENT-1, patients received riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo for 12 weeks; efficacy assessments included change from baseline to study end in 6-min walking distance (6MWD; primary), pulmonary vascular resistance (PVR), N-terminal of the prohormone of brain natriuretic peptide (NT-proBNP), WHO functional class (WHO FC) and time to clinical worsening. In PATENT-2, eligible patients from PATENT-1 received long-term riociguat (maximum 2.5 mg three times daily); the primary assessment was safety and tolerability. All PAH-CHD patients had a corrected cardiac defect.. In PATENT-1, riociguat increased mean±SD 6MWD from baseline to week 12 by 39±60 m in patients with PAH-CHD versus 0±42 m for placebo. Riociguat also improved several secondary variables versus placebo, including PVR (-250±410 vs -66±632 dyn·s/cm(5)), NT-proBNP (-164±317 vs -46±697 pg/mL) and WHO FC (21%/79%/0% vs 8%/83%/8% improved/stabilised/worsened). One patient experienced clinical worsening (riociguat 1.5 mg group). Riociguat was well tolerated. In PATENT-2, riociguat showed sustained efficacy and tolerability in patients with PAH-CHD at 2 years.. Riociguat was well tolerated in patients with PAH-CHD and improved clinical outcomes including 6MWD, PVR, WHO FC and NT-proBNP.. The clinical trials numbers are NCT00810693 for PATENT-1 and NCT00863681 for PATENT-2.

Topics: Adult; Antihypertensive Agents; Dose-Response Relationship, Drug; Double-Blind Method; Drug Administration Schedule; Female; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Male; Pyrazoles; Pyrimidines; Treatment Outcome

Deficient nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate signaling results from endothelial dysfunction and may underlie impaired cardiac relaxation in patients with heart failure with preserved left ventricular ejection fraction (HFpEF) and pulmonary hypertension (PH). The acute hemodynamic effects of riociguat, a novel soluble guanylate cyclase stimulator, were characterized in patients with PH and HFpEF.. Clinically stable patients receiving standard HF therapy with a left ventricular ejection fraction > 50%, mean pulmonary artery pressure (mPAP) ≥ 25 mm Hg, and pulmonary arterial wedge pressure (PAWP) > 15 mm Hg at rest were randomized to single oral doses of placebo or riociguat (0.5, 1, or 2 mg). The primary efficacy variable was the peak decrease in mPAP from baseline up to 6 h. Secondary outcomes included hemodynamic and echocardiographic parameters, safety, and pharmacokinetics.. There was no significant change in peak decrease in mPAP with riociguat 2 mg (n = 10) vs placebo (n = 11, P = .6). However, riociguat 2 mg significantly increased stroke volume (+9 mL [95% CI, 0.4-17]; P = .04) and decreased systolic BP (-12 mm Hg [95% CI, -22 to -1]; P = .03) and right ventricular end-diastolic area (-5.6 cm2 [95% CI, -11 to -0.3]; P = .04), without significantly changing heart rate, PAWP, transpulmonary pressure gradient, or pulmonary vascular resistance. Riociguat was well tolerated.. In patients with HFpEF and PH, riociguat was well tolerated, had no significant effect on mPAP, and improved exploratory hemodynamic and echocardiographic parameters.. ClinicalTrials.gov; No.: NCT01172756; URL: www.clinicaltrials.gov.

Topics: Administration, Oral; Aged; Aged, 80 and over; Dose-Response Relationship, Drug; Double-Blind Method; Echocardiography; Female; Follow-Up Studies; Heart Failure, Diastolic; Heart Ventricles; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Retrospective Studies; Treatment Outcome

Pulmonary hypertension caused by systolic left ventricular dysfunction is associated with significant morbidity and mortality; however, no treatment is approved for this indication. We hypothesized that riociguat, a novel soluble guanylate cyclase stimulator, would have beneficial hemodynamic effects in patients with pulmonary hypertension caused by systolic left ventricular dysfunction.. Overall, 201 patients with heart failure resulting from pulmonary hypertension caused by systolic left ventricular dysfunction were randomized to double-blind treatment with oral placebo or riociguat (0.5, 1, or 2 mg 3 times daily) for 16 weeks in 4 parallel arms. The primary outcome was the placebo-corrected change from baseline at week 16 in mean pulmonary artery pressure. Although the decrease in mean pulmonary artery pressure in the riociguat 2 mg group (-6.1±1.3 mm Hg; P<0.0001 versus baseline) was not significantly different from placebo (P=0.10), cardiac index (0.4 L·min(-1)·m(-2); 95% confidence interval, 0.2-0.5; P=0.0001) and stroke volume index (5.2 mL·m(-2); 95% confidence interval, 2.0-8.4; P=0.0018) were significantly increased without changes in heart rate or systemic blood pressure compared with placebo. Both pulmonary (-46.6 dynes·s(-1)·cm(-5); 95% confidence interval, -89.4 to -3.8; P=0.03) and systemic vascular resistance (-239.3 dynes·s(-1)·cm(-5); 95% confidence interval, -363.4 to -115.3; P=0.0002) were significantly reduced with riociguat 2 mg. Riociguat reduced the Minnesota Living With Heart Failure score (P=0.0002). Discontinuation of treatment was similar between treatment groups.. Although the primary end point of the study was not met, riociguat was well tolerated in patients with pulmonary hypertension caused by systolic left ventricular dysfunction and improved cardiac index and pulmonary and systemic vascular resistance.. URL: http://www.clinicaltrials.gov. Unique identifier: NCT01065454.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pyrazoles; Pyrimidines; Ventricular Dysfunction, Left

Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension.. In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety.. By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn·sec·cm(-5) in the riociguat group and increased by 23 dyn·sec·cm(-5) in the placebo group (least-squares mean difference, -246 dyn·sec·cm(-5); 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P=0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group).. Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.)

Topics: Aged; Chronic Disease; Double-Blind Method; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Least-Squares Analysis; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyrimidines; Vascular Resistance; Walking

Riociguat, a soluble guanylate cyclase stimulator, has been shown in a phase 2 trial to be beneficial in the treatment of pulmonary arterial hypertension.. In this phase 3, double-blind study, we randomly assigned 443 patients with symptomatic pulmonary arterial hypertension to receive placebo, riociguat in individually adjusted doses of up to 2.5 mg three times daily (2.5 mg-maximum group), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (1.5 mg-maximum group). The 1.5 mg-maximum group was included for exploratory purposes, and the data from that group were analyzed descriptively. Patients who were receiving no other treatment for pulmonary arterial hypertension and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary end point was the change from baseline to the end of week 12 in the distance walked in 6 minutes. Secondary end points included the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnea scale, quality-of-life variables, and safety.. By week 12, the 6-minute walk distance had increased by a mean of 30 m in the 2.5 mg-maximum group and had decreased by a mean of 6 m in the placebo group (least-squares mean difference, 36 m; 95% confidence interval, 20 to 52; P<0.001). Prespecified subgroup analyses showed that riociguat improved the 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids. There were significant improvements in pulmonary vascular resistance (P<0.001), NT-proBNP levels (P<0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnea score (P=0.002). The most common serious adverse event in the placebo group and the 2.5 mg-maximum group was syncope (4% and 1%, respectively).. Riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension. (Funded by Bayer HealthCare; PATENT-1 and PATENT-2 ClinicalTrials.gov numbers, NCT00810693 and NCT00863681, respectively.).

Topics: Adult; Aged; Double-Blind Method; Drug Administration Schedule; Drug Therapy, Combination; Endothelin Receptor Antagonists; Exercise Tolerance; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Prostaglandins; Pyrazoles; Pyrimidines; Quality of Life; Vascular Resistance; Walking

We assessed the safety, tolerability and preliminary efficacy of riociguat, a soluble guanylate cyclase stimulator, in patients with pulmonary hypertension associated with interstitial lung disease (PH-ILD). In this open-label, uncontrolled pilot trial, patients received oral riociguat (1.0-2.5 mg three times daily) for 12 weeks (n=22), followed by an ongoing long-term extension (interim analysis at 12 months) in those eligible (n=15). Primary end-points were safety and tolerability. Secondary end-points included haemodynamic changes and 6-min walk distance (6MWD). Overall, 104 adverse events were reported, of which 25 were serious; eight of the latter were considered drug-related. After 12 weeks of therapy, mean cardiac output increased (4.4 ± 1.5 L · min(-1) to 5.5 ± 1.8 L · min(-1)), pulmonary vascular resistance (PVR) decreased (648 ± 207 dyn · s(-1) · cm(-5) to 528 ± 181 dyn · s(-1) · cm(-5)) and mean pulmonary artery pressure (mPAP) remained unchanged compared with baseline. Arterial oxygen saturation decreased but mixed-venous oxygen saturation slightly increased. The 6MWD increased from 325 ± 96 m at baseline to 351 ± 111 m after 12 weeks. Riociguat was well tolerated by most patients and improved cardiac output and PVR, but not mPAP. Further studies are necessary to evaluate the safety and efficacy of riociguat in patients with PH-ILD.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Female; Guanylate Cyclase; Hemodynamics; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Middle Aged; Oxygen; Pilot Projects; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase; Treatment Outcome

Pulmonary hypertension (PH) due to systolic left ventricular dysfunction (PH-sLVD) frequently complicates heart failure (HF), and greatly worsens the prognosis of patients with sLVD, but as yet has no approved treatment. The LEPHT study aims to characterize the haemodynamic profile, safety, tolerability, and pharmacokinetic profile of riociguat (BAY 63-2521), an oral stimulator of soluble guanylate cyclase, in patients with PH-sLVD.. This 16-week, phase IIb, randomized, placebo-controlled, double-blind study enrols patients with PH-sLVD, defined as left ventricular ejection fraction (LVEF) ≤40% and mean pulmonary arterial pressure (PAP(mean)) ≥25 mmHg at rest. Patients using optimized HF medication will receive placebo or riociguat 0.5 mg, 1 mg, or up to 2 mg three times daily. The dose will be titrated for 8 weeks, based on systolic blood pressure and well-being, followed by 8 weeks of treatment at a stable dose. The primary efficacy variable is PAP(mean), while secondary efficacy endpoints include LVEF, exercise capacity, quality of life, and other haemodynamic and echocardiographic measurements. Safety and pharmacokinetics will also be assessed. After the 16-week study, patients will have the opportunity to be treated with riociguat in a long-term extension phase.. The LEPHT study will provide valuable information on the haemodynamic, echocardiographic, and preliminary clinical effects of riociguat in patients with PH-sLVD. Trial registration NCT01065454.

Topics: Dose-Response Relationship, Drug; Double-Blind Method; Exercise Tolerance; Guanylate Cyclase; Heart Failure, Systolic; Hemodynamics; Humans; Hypertension, Pulmonary; Prognosis; Pyrazoles; Pyrimidines; Quality of Life; Research Design; Stroke Volume; Treatment Outcome; Ventricular Dysfunction, Left; Ventricular Function, Left

We assessed the therapeutic potential of riociguat, a novel soluble guanylate cyclase stimulator, in adults with chronic thromboembolic pulmonary hypertension (CTEPH; n = 42) or pulmonary arterial hypertension (PAH; n = 33) in World Health Organization (WHO) functional class II/III. In this 12-week, multicentre, open-label, uncontrolled phase II study, patients received oral riociguat 1.0-2.5 mg t.i.d. titrated according to systemic systolic blood pressure (SBP). Primary end-points were safety and tolerability; pharmacodynamic changes were secondary end-points. Riociguat was generally well tolerated. Asymptomatic hypotension (SBP <90 mmHg) occurred in 11 patients, but blood pressure normalised without dose alteration in nine and after dose reduction in two. Median 6-min walking distance increased in patients with CTEPH (55.0 m from baseline (390 m); p<0.0001) and PAH (57.0 m from baseline (337 m); p<0.0001); patients in functional class II or III and bosentan pre-treated patients showed similar improvements. Pulmonary vascular resistance was significantly reduced by 215 dyn·s·cm(-5) from baseline (709 dyn·s·cm(-5); p<0.0001). 42 (56%) patients were considered to have experienced drug-related adverse events (AEs; 96% mild or moderate). Dyspepsia, headache and hypotension were the most frequent AEs. Study discontinuation because of AEs was 4%. These preliminary data show that riociguat has a favourable safety profile and improves exercise capacity, symptoms and pulmonary haemodynamics in CTEPH and PAH. Randomised controlled trials are underway.

Topics: Administration, Oral; Aged; Antihypertensive Agents; Exercise; Female; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Male; Middle Aged; Prospective Studies; Pyrazoles; Pyrimidines; Thromboembolism; Treatment Outcome

The combination of riociguat and interventional balloon pulmonary angioplasty (BPA) is currently used to treat patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). The aim of the present study was to evaluate the impact of this combination therapy on the prognosis of inoperable CTEPH patients by comparing the long-term survival rates of patients undergoing combination therapy with riociguat and BPA with those of inoperable patients from the first international CTEPH registry who did not receive specific treatment.. Between March 2014 and August 2019, 138 technically inoperable patients were included in the present prospective, observational cohort study when they were treated with riociguat and BPA at a single CTEPH referral center. Long-term survival of this cohort was compared using propensity score matching with that of inoperable patients recruited between 2007 and 2009 in the first international CTEPH registry. Kaplan-Meier methods were used to evaluate differences in outcomes.. Whereas the survival rate in the historical group was 84.6% in the first year, 76.6% in the second, 68.5% in the third, and 58.5% in the fifth year after diagnosis, implementation of riociguat/BPA led to survival rates of 100%, 96.7%, 92.9%, and 90% in the respective follow-up periods. In a comparison of 83 well-matched pairs from the 2 cohorts, survival was markedly better in the group treated with riociguat and BPA than in the historical cohort (HR = 0.145, 95% CI 0.05, 0.421).. The combination of riociguat and BPA for the treatment of inoperable CTEPH is associated with excellent 5-year survival rates.

Topics: Angioplasty, Balloon; Chronic Disease; Humans; Hypertension, Pulmonary; Prognosis; Prospective Studies; Pulmonary Artery; Pulmonary Embolism

The effects of riociguat, an oral-soluble guanylate-cyclase stimulator, were studied in 10 infants with chronic pulmonary arterial hypertension. Respiratory status (n = 8/10), right heart dilation (n = 7/10), function (n = 9/10), and chronic pulmonary arterial hypertension (n = 8/10) improved. Median decrement in systolic (12 [4, 14]), diastolic (14 [7, 20]), and mean arterial (14 [10, 17]) pressures were noted; no critical hypotension or hypoxemia occurred.

Topics: Familial Primary Pulmonary Hypertension; Feasibility Studies; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Infant; Pulmonary Arterial Hypertension

Riociguat is the first approved treatment for inoperable and persistent/recurrent post-surgery chronic thromboembolic pulmonary hypertension (CTEPH). The RetrospectIve Adempas® stuDy (RiAD) aimed to describe the real-world utilization of riociguat in France.. In this retrospective multicentric study in patients initiating riociguat, dosing regimen, co-treatments and clinical characteristics were collected over a 2-year follow-up period.. A total of 173 patients (mean age, 71.4 years; female, 63.0%; NYHA II-III, 80.3%) were included from January 2015 to December 2016 in 18 centers. All patients were diagnosed with CTEPH (75.7% inoperable and 20.8% with persistent/recurrent pulmonary hypertension [pH] after surgery) with mean (SD) right atrial pressure 7.6 (4.2) mmHg, mean pulmonary artery pressure 43.0 (11.4) mmHg and mean cardiac output 4.1 (1.1) L/min. Before riociguat initiation, 32.4% of patients previously received at least one pH-specific therapy. At initiation, 93.1% of patients were receiving anticoagulants and 83.2% were not receiving pH-specific co-treatments. Riociguat was initiated at 1 mg three times daily (t.i.d.) in 85.5% of patients and 82.1% were receiving 2.5 mg dose t.i.d. at 24 months. The maximal daily dose of 7.5 mg was never exceeded. At 24 months, the estimated rate of patients still taking riociguat was 78.8% with an estimated mean (SD) time on treatment of 20.1 (0.5) months per patient. No new safety signals were recorded.. The results of this real-world study show that riociguat is used in France in accordance with its therapeutic indication in patients with inoperable or persistent/recurrent post-operative CTEPH and confirm its long-term safety.

Topics: Aged; Chronic Disease; Female; France; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Retrospective Studies

Topics: Angioplasty; Angioplasty, Balloon; Chronic Disease; Humans; Hypertension, Pulmonary; Lung; Prognosis; Pulmonary Artery; Pulmonary Embolism

Use of endothelin receptor antagonists (ERAs) and riociguat, approved for treatment of pulmonary hypertension (PH), is contraindicated during pregnancy due to reported teratogenicity in animals. We aimed to investigate prescribing of these drugs in girls/women of childbearing age and to explore - as a secondary aim - the occurrence of pregnancies exposed to these drugs. Using the German Pharmacoepidemiological Research Database (GePaRD, claims data from 20% of the German population) we conducted cross-sectional analyses to determine prescribing prevalence of ERAs and riociguat between 2004 and 2019 and to characterize users and prescribing patterns. In a cohort analysis, we assessed the occurrence of pregnancies exposed to these drugs in the critical time window. Overall, we identified 407 women with ≥ 1 dispensation of bosentan between 2004 and 2019; the respective number was 73 for ambrisentan, 182 for macitentan, 31 for sitaxentan, and 63 for riociguat. In nearly all years, more than 50% of the girls/women were ≤ 40 years. Age-standardized prevalence was highest for bosentan (0.04/1000) in 2012 and 2013, followed by macitentan (0.03/1000) in 2018 and 2019. We observed 10 exposed pregnancies: 5 to bosentan, 3 to ambrisentan, and 2 to macitentan. The increased prevalence of macitentan and riociguat from 2014 onwards might reflect changes in PH treatment. Even though PH is a rare disease and pregnancy should be avoided in women with PH, particularly if they use ERAs, we identified pregnancies exposed to ERAs. Multi-database studies will be needed to assess the risk of these drugs on the unborn child.

Topics: Animals; Bosentan; Cross-Sectional Studies; Endothelin Receptor Antagonists; Female; Hypertension, Pulmonary

There remains a lack of prognosis models for patients with chronic thromboembolic pulmonary hypertension (CTEPH). This study aims to develop a nomogram predicting 3-, 5-, and 7-year survival in patients with CTEPH and verify the prognostic model. Patients with CTEPH diagnosed in Fuwai Hospital were enrolled consecutively between May 2013 and May 2019. Among them, 70% were randomly split into a training set and the other 30% as a validation set for external validation. Cox proportional hazards model was used to identify the potential survival-related factors which were candidate variables for the establishment of nomogram and the final model was internally validated by the bootstrap method. A total of 350 patients were included in the final analysis and the median follow-up period of the whole cohort was 51.2 months. Multivariate analysis of Cox proportional hazards regression showed body mass index, mean right atrial pressure, N-terminal pro-brain natriuretic peptide (per 500 ng/ml increase in concentration), presence of anemia, and main treatment choice were the independent risk factors of mortality. The nomogram demonstrated good discrimination with the corrected C-index of 0.82 in the training set, and the C-index of 0.80 (95% CI: 0.70 to 0.91) in the external validation set. The calibration plots also showed a good agreement between predicted and actual survival in both training and validation sets. In conclusion, we developed an easy-to-use nomogram with good apparent performance using 5 readily available variables, which may help physicians to identify CTEPH patients at high risk for poor prognosis and implement medical interventions.

Topics: Adult; Aged; Anemia; Angioplasty, Balloon; Antihypertensive Agents; Atrial Pressure; Body Mass Index; Chronic Disease; Clinical Decision Rules; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Epoprostenol; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Mortality; Multivariate Analysis; Natriuretic Peptide, Brain; Nomograms; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Prognosis; Proportional Hazards Models; Pulmonary Artery; Pulmonary Embolism; Pulmonary Wedge Pressure; Pyrazoles; Pyrimidines; Reproducibility of Results; Survival Rate

Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines

Topics: Heart Failure; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Stroke Volume

Pulmonary hypertension (PH) is a severe and often rapidly progressive disease with fatal outcome. Endothelial dysfunction in PH is associated with decreased nitric oxide production. After reviewing the mechanisms of action and the evidence base for specific therapy with phosphodiesterase 5 inhibitors (PDE-5) and soluble guanylate cyclase stimulators, a reseach review on switching from PDE-5 to riociguat is conducted. A potential advantage of riociguat is its independence from endogenous nitric oxide and from the other (besides PDE-5) isoenzymes of phosphodiesterases. The favorable efficacy profile of sildenafil has been proven for the main forms of pulmonary arterial hypertension, of riociguat for the main forms of pulmonary arterial hypertension and chronic thromboembolic PH. The clinical efficacy of replacing PDE-5 with riociguat has been demonstrated in uncontrolled trials and in the randomized controlled study REPLACE. The possibility of therapy optimization by switching from IFDE-5 to riociguat is fixed in the Russian (class and level of evidence B-3) and Eurasian (class and level of evidence IIb-B) clinical guidelines, as well as in the materials of the Cologne Expert Consensus. An additional argument for switching is the lower cost as compared to combination therapy in the Russian Federation. According to the Russian and Eurasian guidelines for PH and the Russian instructions for the use of riociguat, the drug should be taken at least 24 hours after sildenafil discontinuation.. Легочная гипертензия (ЛГ) тяжелое и часто быстро прогрессирующее заболевание с фатальным исходом. Эндотелиальная дисфункция при ЛГ сопровождается снижением продукции оксида азота. После рассмотрения механизмов действия и доказательной базы специфической терапии ингибиторами фосфодиэстеразы 5 (иФДЭ-5) и стимуляторами растворимой гуанилатциклазы проводится обзор исследований по переключению с иФДЭ-5 на риоцигуат. Потенциальным преимуществом риоцигуата является независимость от эндогенного оксида азота и других (помимо ФДЭ-5) изоферментов фосфодиэстераз. Благоприятный профиль эффективности силденафила доказан для основных форм легочной артериальной гипертензии, риоцигуата для основных форм легочной артериальной гипертензии и хронической тромбоэмболической ЛГ. Клиническая эффективность замены иФДЭ-5 на риоцигуат показана в неконтролируемых исследованиях и рандомизированном контролируемом исследовании REPLACE. Возможность оптимизации терапии за счет переключения с иФДЭ-5 на риоцигуат закреплена в российских (класс и уровень доказательности B-3) и евразийских (класс и уровень доказательности IIb-B) клинических рекомендациях, а также в материалах Кельнского консенсуса экспертов. Дополнительным аргументом за переключение в условиях Российской Федерации служит меньшая стоимость по сравнению с комбинированной терапией. Согласно российским и евразийским рекомендациям по ЛГ и российской инструкции по применению риоцигуата его прием следует начинать не ранее чем через 24 ч после отмены силденафила.

Topics: Humans; Hypertension, Pulmonary; Isoenzymes; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Phosphoric Diester Hydrolases; Pulmonary Arterial Hypertension; Randomized Controlled Trials as Topic; Sildenafil Citrate; Soluble Guanylyl Cyclase

The primary objective of the registry was to assess the impact of riociguat on clinical parameters and quality of life in patients with chronic thromboembolic pulmonary hypertension (CTEPH) that was inoperable or persistent/recurrent after pulmonary endarterectomy (PEA). In contrast to randomized pivotal trials, this non-interventional registry evaluated the effectiveness and safety of riociguat in a real-world setting.. Retrospective data were collected from patients' charts as recorded in routine clinical practice from the initiation of riociguat therapy up to approximately 5 months and 1 year after this initiation.. In total, 51 patients from a single site were enrolled. After 5 months (mean duration) of riociguat treatment, the following improvements from baseline were observed: change of distance in the 6-minute walking distance (6MWD) (P=0.066); change of score from the quality of life questionnaire (EQ5D-5L) (P=0.020), and overall self-assessment of health status (P=0.001). New York Heart Association (NYHA) class improved in 24.3% of patients. After 11.2 months (mean duration) of riociguat treatment, the following improvements from baseline were observed: change of distance in the 6MWD test (P=0.006), and overall self-assessment of health status (P=0.009). NYHA class improved in 46.4% of patients. Riociguat was well tolerated. In total, 4 patients reported side effects, with hospitalization required in one case and 2 patients who had to discontinue the treatment. Annual survival rate was 89.1%.. Riociguat improves functional NYHA class, distance in the 6MWD test and quality of life in a real-world patient population.

Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Quality of Life; Registries; Retrospective Studies; Treatment Outcome

Riociguat is a soluble guanylate cyclase stimulator that improves hemodynamics in patients with pulmonary hypertension (PH). Accumulating evidence implicates the additional effect of riociguat on the increase in cardiac output. However, its mechanisms have not been fully understood. This study aimed to investigate whether riociguat could ameliorate right ventricular (RV) contraction as well as hemodynamics.. We studied 45 patients with pulmonary arterial hypertension (14) or chronic thromboembolic pulmonary hypertension (31) and evaluated hemodynamics, using right-sided heart catheterization, before and after the administration of riociguat. RV function was assessed by echocardiography, including speckle-tracking echocardiography.. Riociguat significantly improved the WHO functional class and reduced the mean pulmonary arterial pressure and vascular resistance. In addition, the cardiac index increased. RV remodeling was ameliorated after riociguat administration as assessed by the echocardiographic parameters, such as RV diameter and RV area index. RV function, including RV fractional area change and RV global longitudinal strain, also significantly improved, and their improvement was even observed in patients with mild PH after pulmonary endarterectomy or balloon pulmonary angioplasty. Furthermore, covariance analysis revealed that RV global longitudinal strain and RV fractional area change improved after riociguat administration, even with the same mean pulmonary arterial pressure, implicating the improvement of RV contractile function by riociguat, regardless of RV loading.. Riociguat not only improved the hemodynamics of patients with PH but also ameliorated the echocardiographic parameters with RV function. RV strain could detect the subtle improvement in mild PH, and riociguat may have a benefit even after intervention, as assessed by speckle-tracking echocardiography.

Topics: Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Ventricular Dysfunction, Right; Ventricular Function, Right

The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.. EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms.. In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]).. Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.

Topics: Aged; Chronic Disease; Data Analysis; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Multicenter Studies as Topic; Prospective Studies; Pulmonary Embolism; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Recurrence; Registries; Safety; Time Factors; Treatment Outcome

Current pulmonary arterial hypertension (PAH) therapeutic strategies mainly focus on vascular relaxation with less emphasis on vascular remodeling, which results in poor prognosis. Hence, dual pathway regulators with vasodilation effect via soluble guanylate cyclase (sGC) stimulation and vascular remodeling regulation effect by AMP-activated protein kinase (AMPK) inhibition provide more advantages and potentialities. Herein, we designed and synthesized a series of novel pyrazolo[3,4-

Topics: Adenylate Kinase; Animals; Cell Line; Drug Design; Humans; Hypertension, Pulmonary; Pyrazoles; Pyridines; Rats; Structure-Activity Relationship; Vascular Remodeling; Vasodilation

Topics: Endothelial Progenitor Cells; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines

Topics: Academic Medical Centers; Enzyme Activators; Female; Guideline Adherence; Humans; Hypertension, Pulmonary; Male; Pyrazoles; Pyrimidines; Retrospective Studies; Risk Evaluation and Mitigation; Soluble Guanylyl Cyclase

Topics: Bosentan; Humans; Hypertension, Pulmonary; Idiopathic Pulmonary Fibrosis; Insurance Coverage; Japan; Phenylpropionates; Prevalence; Prognosis; Pulmonary Disease, Chronic Obstructive; Pyrazoles; Pyridazines; Pyrimidines; Sildenafil Citrate; Sulfonamides; Treatment Outcome; Universal Health Insurance

Topics: Endothelial Progenitor Cells; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines

Topics: Endothelial Progenitor Cells; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines

RESPITE evaluated patients with pulmonary arterial hypertension and an inadequate response to phosphodiesterase type 5 inhibitors (PDE5i) who switched to riociguat. This post hoc analysis assessed response to this switch in parameters associated with clinical improvement.. RESPITE was a 24-week, uncontrolled pilot study (n = 61). Differences in functional, hemodynamic, and cardiac function parameters, REVEAL risk score (RRS), and biomarkers were compared between responders (free from clinical worsening, World Health Organization functional class I/II, and ≥30 m improvement in 6-min walking distance at Week 24) and non-responders.. Of 51 patients (84%) completing RESPITE, 16 (31%) met the responder endpoint. At baseline, there were significant differences between responders and non-responders in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth/differentiation factor 15 (GDF-15), and RRS, whereas there were no differences in hemodynamics or cardiac function. At Week 24, responders had significant improvements in pulmonary arterial compliance, pulmonary vascular resistance, and mean pulmonary arterial pressure, while non-responders showed no significant change. Cardiac efficiency and stroke volume index significantly improved irrespective of responder status.. NT-proBNP, GDF-15, and RRS were identified as potential predictors of response in patients switching from PDE5i to riociguat. Further prospective controlled studies are needed to confirm the association of these parameters with response.

Topics: Humans; Hypertension, Pulmonary; Phosphodiesterase 5 Inhibitors; Pilot Projects; Pyrazoles; Pyrimidines

Chronic thromboembolic pulmonary hypertension (CTEPH) is a precapillary type of pulmonary hypertension with chronic obstruction of large and medium branches of pulmonary arteries along with secondary alterations in pulmonary microcirculation, which cause progressive increases in pulmonary vascular resistance and pulmonary arterial pressure and ensuing severe right heart dysfunction and heart failure. Pulmonary thromboendarterectomy (PTE) is the treatment of choice for CTEPH; however, this procedure is available not for all patients. Although the surgery performed in the conditions of centers with advanced experience generally shows good results, up to 40% of patients are technically inoperable or PTE is associated with a high risk of complications. At present, riociguat, the only officially approved drug from the class of soluble guanylate cyclase stimulators, is considered as a first-line treatment for inoperable and residual forms of STEPH. Introduction of riociguat to clinical practice can be called a real breakthrough in the treatment of patients with STEPH who cannot undergo PTE or those with relapse or persistent STEPH after the surgery.

Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Soluble Guanylyl Cyclase

Currently, treatment of pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) is focused on three signaling pathways: the NO pathway, the endothelin pathway, and the prostacyclin pathway. Riociguat is the only representative of stimulators of the soluble guanylate cyclase (sGC) class that is approved for the treatment of PAH and inoperable and persistent/recurrent CTEPH. The review presents data from clinical trials showing a positive effect of riociguat on the functional and hemodynamic profile of patients with PAH and CTEPH. In recent years there has been much discussion about the possibility of optimizing therapy by switching to drugs that affect a single pathogenesis target. Thus, sGC stimulants have obvious advantages over phosphodiesterase type 5 (PDE-5) inhibitors, including the ability of riociguat to exert pharmacological effects (due to a NO-independent mechanism of action) even in conditions of reduced NO production. Switching from PDE-5 to riociguat may be safe and appropriate, according to clinical trials presented in the review. In accordance with the guidelines for the diagnosis and treatment of pulmonary hypertension of the Eurasian Association of cardiologists from 2019, this strategy is approved when PDE5 therapy is ineffective in patients with PAH FC III (WHO).. В настоящее время лечение легочной артериальной гипертензии (ЛАГ) и хронической тромбоэмболической легочной гипертензии (ХТЭЛГ) сосредоточено на трех сигнальных путях: путь оксида азота (NO), путь эндотелина и путь простациклина. Риоцигуат является единственным представителем класса стимуляторов растворимой гуанилатциклазы, который одобрен для лечения ЛАГ и неоперабельной и персистирующей/рецидивирующей ХТЭЛГ. В обзоре приведены данные клинических исследований, показывающие положительное влияние риоцигуата на функциональный и гемодинамический профиль пациентов с ЛАГ и ХТЭЛГ. В течение последних лет широко обсуждается вопрос о возможности оптимизации терапии за счет замены препаратов, которые воздействуют на одну мишень патогенеза. Так, у стимуляторов растворимой гуанилатциклазы есть очевидные преимущества перед ингибиторами фосфодиэстеразы типа 5 (ИФДЭ-5), среди которых способность риоцигуата оказывать фармакологические эффекты (за счет NO-независимого механизма действия) даже в условиях сниженной продукции NO. Перевод с ИФДЭ-5 на риоцигуат может быть безопасным и целесообразным, согласно данным исследований, представленных в обзоре. В соответствии с клиническими рекомендациями по диагностике и лечению легочной гипертензии Евразийской ассоциации кардиологов от 2019 г. эта стратегия одобрена при неэффективности терапии ИФДЭ-5 у пациентов с ЛАГ III функционального класса.

Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines; Soluble Guanylyl Cyclase

Pulmonary endothelial damage has a negative impact on the maintenance of normal pulmonary vascular function. Such damage results in delayed thrombus dissolution and vascular remodeling in chronic thromboembolic pulmonary hypertension (CTEPH). Although endothelial progenitor cells (EPCs) may be incorporated into neovasculature during vascular repair, their function in CTEPH remains unclarified, especially under the augmentation of soluble guanylate cyclase (sGC) activity.. We evaluated the effect of EPCs on endothelial function and compared the effect of riociguat, a sGC stimulator, on the number and function of circulating EPCs in two groups of CTEPH patients. The two groups consisted 16 CTEPH patients who were treatment naïve (Naïve group), and 14 CTEPH patients who were being treated with riociguat, a sGC stimulator (Riociguat group). The number of circulating EPCs in the Riociguat group was significantly higher than that in the Naïve group. Gene expression levels associated with angiogenesis were significantly higher in EPCs of the Riociguat group. EPC-stimulated tube formation and migration of human pulmonary microvascular endothelial cell (hPMVEC) in the Riociguat group exceeded that in the Naïve group. The angiogenic ability of hPMVECs stimulated by EPCs in the Riociguat group was enhanced compared to that of the sGC stimulator, BAY 41-2272.. These findings indicate that riociguat may induce EPCs to play a protective role via modulation of endothelial functions associated with CTEPH.. Endothelial dysfunction exacerbates CTEPH. Riociguat enhanced the protective role of EPCs via neovascularization, which prevented vascular remodeling and alleviated CTEPH.

Topics: Aged; Chronic Disease; Coculture Techniques; Endothelial Progenitor Cells; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyrimidines

A series of new pyrazolo[3,4-b]pyridin-3-yl pyrimidine derivatives were synthesized and evaluated for the activation of sGC. Compared with riociguat, compound 13a exhibited equivalent in vitro activity on preconstricted rat thoracic aorta rings and in Rat heart Langendorff preparation. Compound 13a also showed acceptable PK profiles, which might become a promising candidate for the treatment of pulmonary hypertension.

Topics: Animals; Antihypertensive Agents; Dose-Response Relationship, Drug; Hypertension, Pulmonary; Male; Molecular Structure; Pyrazoles; Pyridines; Pyrimidines; Rats; Rats, Sprague-Dawley; Soluble Guanylyl Cyclase; Structure-Activity Relationship

Topics: Humans; Hypertension, Pulmonary; Idiopathic Interstitial Pneumonias; Idiopathic Pulmonary Fibrosis; Pyrazoles; Pyrimidines

Current therapeutic methods for chronic thromboembolic pulmonary hypertension (CTEPH) can improve hemodynamic status and are expected to improve prognoses. However, some patients experience dyspnea during effort and continue supplemental oxygenation despite their hemodynamic status being fully improved. Considering the pathogenesis of CTEPH, the dead space and intrapulmonary shunt are assumed to be responsible for hypoxia in CTEPH, but their contributions are unclear. It is also unclear whether they are improved after treatment. The aim of this study was to investigate the implications of the dead space ratio (DSR) and the intrapulmonary shunt ratio (ISR) for hypoxia in CTEPH and treatment for CTEPH.We retrospectively measured the DSR and ISR of 23 consecutive patients with CTEPH. For 11 of these 23 (10 were treated by balloon pulmonary angioplasty, one with riociguat), we also measured these parameters before and after CTEPH treatments. Overall, the DSR and ISR were abnormally elevated (DSR: 0.63 ± 0.06; ISR: 0.20 ± 0.05). After treatment, mean pulmonary artery pressure was improved (from 40.3 ± 8.1 to 25.5 ± 2.7 mmHg). Although atrial oxygen saturation (SaO

Topics: Adult; Aged; Angioplasty, Balloon; Chronic Disease; Female; Hemodynamics; Hospitals, University; Humans; Hypertension, Pulmonary; Japan; Male; Middle Aged; Oxygen Inhalation Therapy; Prognosis; Pulmonary Circulation; Pulmonary Embolism; Pyrazoles; Pyrimidines; Respiratory Dead Space; Respiratory Function Tests; Retrospective Studies; Risk Assessment; Severity of Illness Index; Statistics, Nonparametric; Survival Rate; Treatment Outcome

Research comparing bosentan and macitentan in chronic thromboembolic pulmonary hypertension (CTEPH) is scarce, although macitentan might have superior pharmacologic properties. We present the first real-world, 2-year follow-up results and compare clinical outcomes of both drugs in CTEPH.. All consecutive, technical inoperable or residual CTEPH patients receiving bosentan or macitentan, diagnosed in our multidisciplinary team between January 2003 and January 2019, were included. We report and compare survival, clinical worsening (CW), adverse events, WHO FC, NT-proBNP and 6-min walking test (6MWT) until 2 years after medication initiation.. In total, 112 patients receiving bosentan or macitentan (58% female, mean age 62 ± 14 years, 68% WHO FC III/IV, 51% bosentan) could be included. Mean treatment duration was 1.9 ± 0.4 years for bosentan and 1.2 ± 0.6 years for macitentan. Two-year survival rate was 91% for bosentan and 80% for macitentan (HR mortality macitentan 1.85 [0.56-6.10], p = 0.31). Two-year CW-free survival was 81% and 58%, respectively (HR CW macitentan 2.16 [0.962-4.87], p = 0.06). Right atrial pressure, cardiac output (for mortality alone) and 6MWT lowest saturation were multivariate predictors at baseline. Overall adverse event rates were comparable and WHO FC, NT-proBNP and 6MWT distance improved similar for both drugs till 2-year follow-up.. CTEPH patients receiving bosentan or macitentan have improved clinical outcomes till 2-year follow-up, without significant differences in outcomes between both therapies.

Topics: Aged; Bosentan; Chronic Disease; Drug Therapy, Combination; Endarterectomy; Endothelin Receptor Antagonists; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Sulfonamides; Survival Rate; Walk Test

Topics: Humans; Hypertension, Pulmonary; Idiopathic Interstitial Pneumonias; Pyrazoles; Pyrimidines

The TASK-1 channel gene (KCNK3) has been identified as a possible disease-causing gene in heritable pulmonary arterial hypertension (PAH). In the present study, we show that novel mutated TASK-1 channels, seen in PAH patients, have a substantially reduced current compared to wild-type TASK-1 channels. These mutated TASK-1 channels are located at the plasma membrane to the same degree as wild-type TASK-1 channels. ONO-RS-082 and alkaline pH 8.4 both activate TASK-1 channels but do not recover current through mutant TASK-1 channels. We show that the guanylate cyclase activator, riociguat, a novel treatment for PAH, enhances current through TASK-1 channels but does not recover current through mutant TASK-1 channels.. Pulmonary arterial hypertension (PAH) affects ∼15-50 people per million. KCNK3, the gene that encodes the two pore domain potassium channel TASK-1 (K2P3.1), has been identified as a possible disease-causing gene in heritable PAH. Recently, two new mutations have been identified in KCNK3 in PAH patients: G106R and L214R. The present study aimed to characterize the functional properties and regulation of wild-type (WT) and mutated TASK-1 channels and determine how these might contribute to PAH and its treatment. Currents through WT and mutated human TASK-1 channels transiently expressed in tsA201 cells were measured using whole-cell patch clamp electrophysiology. Localization of fluorescence-tagged channels was visualized using confocal microscopy and quantified with in-cell and on-cell westerns. G106R or L214R mutated channels were located at the plasma membrane to the same degree as WT channels; however, their current was markedly reduced compared to WT TASK-1 channels. Functional current through these mutated channels could not be restored using activators of WT TASK-1 channels (pH 8.4, ONO-RS-082). The guanylate cyclase activator, riociguat, enhanced current through WT TASK-1 channels; however, similar to the other activators investigated, riociguat did not have any effect on current through mutated TASK-1 channels. Thus, novel mutations in TASK-1 seen in PAH substantially alter the functional properties of these channels. Current through these channels could not be restored by activators of TASK-1 channels. Riociguat enhancement of current through TASK-1 channels could contribute to its therapeutic benefit in the treatment of PAH.

Topics: Action Potentials; Cell Membrane; Enzyme Activators; HEK293 Cells; Humans; Hypertension, Pulmonary; Mutation, Missense; Nerve Tissue Proteins; Potassium Channels, Tandem Pore Domain; Pyrazoles; Pyrimidines

Topics: Hemodynamics; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Sildenafil Citrate

Topics: Hemodynamics; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Sildenafil Citrate

Chronic obstructive pulmonary disease (COPD), which comprises the phenotypes of chronic bronchitis and emphysema, is often associated with pulmonary hypertension (PH). However, currently, no approved therapy exists for PH-COPD. Signalling of the nitric oxide (NO)-cyclic guanosine monophosphate (cGMP) axis plays an important role in PH and COPD.We investigated the treatment effect of riociguat, which promotes the NO-cGMP pathway, in the mouse model of smoke-induced PH and emphysema in a curative approach, and retrospectively analysed the effect of riociguat treatment on PH in single patients with PH-COPD.In mice with established PH and emphysema (after 8 months of cigarette smoke exposure), riociguat treatment for another 3 months fully reversed PH. Moreover, histological hallmarks of emphysema were decreased. Microarray analysis revealed involvement of different signalling pathways,

Topics: Animals; Cyclic GMP; Disease Models, Animal; Humans; Hypertension, Pulmonary; Lung; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Pulmonary Disease, Chronic Obstructive; Pulmonary Emphysema; Pyrazoles; Pyrimidines; Retrospective Studies; Signal Transduction; Soluble Guanylyl Cyclase; Translational Research, Biomedical

The Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL) risk score (RRS) calculator was developed using data derived from the REVEAL registry, and predicts survival in patients with pulmonary arterial hypertension (PAH) based on multiple patient characteristics. Herein we applied the RRS to a pivotal PAH trial database, the 12-week PATENT-1 and open-label PATENT-2 extension studies of riociguat. We examined the effect of riociguat vs placebo on RRS in PATENT-1, and investigated the prognostic implications of change in RRS during PATENT-1 on long-term outcomes in PATENT-2.. RRS was calculated post hoc for baseline and Week 12 of PATENT-1, and Week 12 of PATENT-2. Patients were grouped into risk strata by RRS. Kaplan-Meier estimates were made for survival and clinical worsening-free survival in PATENT-2 to evaluate the relationship between RRS in PATENT-1 and long-term outcomes in PATENT-2.. A total of 396 patients completed PATENT-1 and participated in PATENT-2. In PATENT-1, riociguat significantly improved RRS (p = 0.031) and risk stratum (p = 0.018) between baseline and Week 12 compared with placebo. RRS at baseline, and at PATENT-1 Week 12, and change in RRS during PATENT-1 were significantly associated with survival (hazard ratios for a 1-point reduction in RRS: 0.675, 0.705 and 0.804, respectively) and clinical worsening-free survival (hazard ratios of 0.736, 0.716 and 0.753, respectively) over 2 years in PATENT-2.. RRS at baseline and Week 12, and change in RRS, were significant predictors of both survival and clinical worsening-free survival. These data support the long-term predictive value of the RRS in a controlled study population.

Topics: Aged; Algorithms; Cohort Studies; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Proportional Hazards Models; Pyrazoles; Pyrimidines; Registries; Risk Assessment; Survival Rate; Treatment Outcome

Current treatment with vasodilators for pulmonary hypertension associated with respiratory diseases is limited by their inhibitory effect on hypoxic pulmonary vasoconstriction (HPV) and uncoupling effects on ventilation-perfusion (V'/Q'). Hypoxia is also a well-known modulator of the nitric oxide (NO) pathway, and may therefore differentially affect the responses to phosphodiesterase 5 (PDE5) inhibitors and soluble guanylyl cyclase (sGC) stimulators. So far, the effects of the sGC stimulator riociguat on HPV have been poorly characterized.. Contraction was recorded in pulmonary arteries (PA) in a wire myograph. Anesthetized rats were catheterized to record PA pressure. Ventilation and perfusion were analyzed by micro-CT-SPECT images in rats with pulmonary fibrosis induced by bleomycin.. The PDE5 inhibitor sildenafil and the sGC stimulator riociguat similarly inhibited HPV in vitro and in vivo. Riociguat was more effective as vasodilator in isolated rat and human PA than sildenafil. Riociguat was ≈3-fold more potent under hypoxic conditions and it markedly inhibited HPV in vivo at a dose that barely affected the thromboxane A2 (TXA2) mimetic U46619-induced pressor responses. Pulmonary fibrosis was associated with V'/Q' uncoupling and riociguat did not affect the V'/Q' ratio.. PDE5 inhibitors and sGC stimulators show a different vasodilator profile. Riociguat was highly effective and potentiated by hypoxia in rat and human PA. In vivo, riociguat preferentially inhibited hypoxic than non-hypoxic vasoconstriction. However, it did not worsen V'/Q' coupling in a rat model of pulmonary fibrosis.

Topics: Aged; Animals; Disease Models, Animal; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Hypoxia; In Vitro Techniques; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Pulmonary Fibrosis; Pyrazoles; Pyrimidines; Rats; Rats, Wistar; Sildenafil Citrate; Soluble Guanylyl Cyclase; Vasoconstriction; Vasodilator Agents; Ventilation-Perfusion Ratio

A proportion of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) do not achieve treatment goals or experience side effects on their current therapy. In such cases, switching patients to a new drug while discontinuing the first may be a viable and appropriate treatment option. CAPTURE was designed to investigate how physicians manage the switching of patients to riociguat in real-world clinical practice. Observations from the study were used to assess whether recommendations in the riociguat prescribing information are reflected in clinical practice.. CAPTURE was an international, multicenter, uncontrolled, retrospective chart review that collected data from patients with PAH or inoperable or persistent/recurrent CTEPH who switched to riociguat from another pulmonary hypertension (PH)-targeted medical therapy. The primary objective of the study was to understand the procedure undertaken in real-world clinical practice for patients switching to riociguat.. Of 127 patients screened, 125 were enrolled in CAPTURE. The majority of patients switched from a phosphodiesterase type 5 inhibitor (PDE5i) to riociguat and the most common reason for switching was lack of efficacy. Physicians were already using the recommended treatment-free period when switching patients to riociguat from sildenafil, but a slightly longer period than recommended for tadalafil. In line with the contraindication, the majority of patients did not receive riociguat and PDE5i therapy concomitantly. Physicians also followed the recommended dose-adjustment procedure for riociguat.. Switching to riociguat from another PH-targeted therapy may be feasible in real-world clinical practice in the context of the current recommendations.

Topics: Aged; Aged, 80 and over; Chronic Disease; Drug Substitution; Enzyme Activators; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Tadalafil

Bronchopulmonary dysplasia (BPD) remains the most common and serious chronic lung disease of premature infants. Severe BPD complicated with pulmonary hypertension (PH) increases the mortality of these infants. Riociguat is an allosteric soluble guanylate cyclase stimulator and is approved by the FDA for treating PH in adults. However, it has not been approved for use in neonates due to concern for adverse effects on long bone growth. To address this concern we investigated if administration of riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without side effects on long bone growth in newborn rats. Newborn rats were randomized to normoxia (21% O2) or hyperoxia (85% O2) exposure groups within 24 hours of birth, and received riociguat or placebo by once daily intraperitoneal injections during continuous normoxia or hyperoxia exposure for 9 days. In the hyperoxia control group, radial alveolar count, mean linear intercept and vascular density were significantly decreased, the pathological hallmarks of BPD, and these were accompanied by an increased inflammatory response. There was also significantly elevated vascular muscularization of peripheral pulmonary vessels, right ventricular systolic pressure and right ventricular hypertrophy indicating PH. However, administration of riociguat significantly decreased lung inflammation, improved alveolar and vascular development, and decreased PH during hyperoxia by inducing cGMP production. Additionally, riociguat did not affect long bone growth or structure. These data indicate that riociguat is beneficial in preventing hyperoxia-induced lung injury and PH without affecting long bone growth and structure and hence, suggests riociguat may be a potential novel agent for preventing BPD and PH in neonates.

Topics: Animals; Animals, Newborn; Bone Development; Cell Hypoxia; Cyclic GMP; Female; Humans; Hypertension, Pulmonary; Lung; Lung Injury; Pregnancy; Pulmonary Alveoli; Pyrazoles; Pyrimidines; Rats; Rats, Sprague-Dawley; Vascular Remodeling

This study evaluated the incremental effect of riociguat on pulmonary hemodynamics in patients with inoperative or persistent chronic thromboembolic pulmonary hypertension (CTEPH) treated previously with sildenafil.. The retrospective study included 28 patients diagnosed with CTEPH who were ineligible for surgical treatment due to distal thrombi location or who suffered from persistent CTEPH after pulmonary endarterectomy and who were treated with sildenafil at a dose of 25 mg TID for a minimum of 3 months. Sildenafil was subsequently discontinued, and riociguat therapy was started with gradually increasing doses. Right heart catheterization was performed and WHO functional class (FC) was assessed in each patient at three time points: before starting sildenafil therapy (baseline), before the transition to riociguat, and after 3 to 6 months of therapy with riociguat.. Compared to baseline, the use of sildenafil and riociguat significantly decreased pulmonary vascular resistance (PVR) (10.47 ± 3.56 vs. 7.81 ± 3.58 Wood units, p < 0.001) and mean pulmonary arterial pressure (PAP) (54.1 ± 11.6 vs. 46.1 ± 13.2 mm Hg; p < 0.001) while increasing cardiac output (CO) (4.31 ± 0.88 vs. 4.85 ± 0.87 L/min; p = 0.007). Switching from sildenafil to riociguat reduced PVR by 14% (p = 0.005) and the mean PAP by 6% (p = 0.03) while increasing CO by 11% (p = 0,002). The number of patients with WHO FC III and IV symptoms decreased from 71,4% to 57,1% (p = 0,02) after the change from sildenafil to riociguat.. Replacing sildenafil with riociguat in patients with inoperable or persistent CTEPH may improve pulmonary hemodynamics and FC.

Topics: Aged; Aged, 80 and over; Chronic Disease; Drug Substitution; Enzyme Activators; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lung; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyrimidines; Retrospective Studies; Sildenafil Citrate; Treatment Outcome; Vasodilator Agents

Riociguat, a soluble guanylate cyclase stimulator, induces pulmonary artery dilatation through blood flow and is effective in treating chronic thromboembolic pulmonary hypertension (CTEPH). There are two types of vasculopathies in CTEPH based upon its location, in other words, proximal or distal to the thrombus-medicated obstruction. Distal vasculopathy is characterized by intrapulmonary shunts due to diminished blood flow. While other therapeutic interventions for CTEPH including pulmonary endarterectomy and balloon pulmonary angioplasty achieve reperfusion to the distal vasculopathy vessels, the effects of riociguat on distal vasculopathy vessels remain undetermined. Herein, we describe a case of a 66-year-old woman who exhibited deterioration of mean pulmonary artery pressure and exercise tolerance after a 4-month treatment with riociguat. She received balloon pulmonary angioplasty prior to riociguat administration. Her lung perfusion scintigraphy and pulmonary angiography findings did not change over the course of treatment. Notably, after the discontinuation of riociguat, her clinical values returned to their levels prior to riociguat administration. Her intrapulmonary shunt ratio followed a similar course as her hemodynamic status. We demonstrate that riociguat can deteriorate hemodynamic status, which may mediate the dilatation of intrapulmonary shunts. We should perform close monitoring of symptoms and hemodynamic status after riociguat administration, especially in patients in whom the reperfused DVs occurred due to invasive treatment.

Topics: Aged; Angiography; Angioplasty, Balloon; Chronic Disease; Enzyme Activators; Exercise Tolerance; Female; Hemodynamics; Humans; Hypertension, Pulmonary; Lung; Patient Outcome Assessment; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Radionuclide Imaging; Thromboembolism

Topics: Heart Ventricles; Humans; Hypertension, Pulmonary; Prospective Studies; Pyrazoles; Pyrimidines; Ventricular Remodeling

Topics: Disease Models, Animal; Hypertension, Pulmonary; Pulmonary Artery; Pyrazoles; Pyrimidines; Sildenafil Citrate; Ventricular Function, Right

Riociguat, the first approved drug for patients with chronic thromboembolic pulmonary hypertension (CTEPH), is a soluble guanylate cyclase (sGC) Stimulator. It directly stimulates sGC independently of nitric oxide (NO) and increases sGC sensitivity for NO. The safety and efficacy of transitioning from a phosphodiesterase 5 inhibitor (PDE5i) to riociguat is unknown.. Twenty-three patients were prospectively enrolled: 8 symptomatic patients with inadequate clinical responses to PDE5i were changed to riociguat (transitioned group); 15 started riociguat anew (new or add-on group). We analyzed the change from baseline to 6-12 months of riociguat treatment for the 6-minute walk distance (6MWD), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), cardiac index (CI), partial pressure of oxygen in arterial blood (PaO2), brain natriuretic peptide (BNP), World Health Organization (WHO) functional class, safety and adverse events. The mPAP, BNP and WHO functional class significantly improved in total. In the transitioned group, BNP significantly decreased by -116.5±188.6pg/ml (P=0.0156). The 6MWD, mPAP, PVR, CI, and PaO2 improved but not significantly. The baseline condition was significantly more severe in the transitioned than in the new or add-on group. No patients discontinued riociguat. Relatively rapid transitioning from PDE5i to riociguat was safe under careful observation.. Transitioning to riociguat may be safe and effective in CTEPH patients with inadequate clinical responses to PDE5i.

Topics: Aged; Arterial Pressure; Chronic Disease; Drug Substitution; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; Oxygen Consumption; Partial Pressure; Phosphodiesterase 5 Inhibitors; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Time Factors; Vascular Resistance; Walk Test

Chronic thromboembolic pulmonary hypertension (CTEPH) is currently underdiagnosis and consequently undertreatment in the clinical practice. A deficient in diagnostic modality and treatment availability especially in developing countries makes the CTEPH diagnosis unlikely to confirm. However, high index of clinical suspicion of CTEPH will lead to proper diagnosis and correct treatment  with significant reduction in morbidity and mortality. Left untreated, the mean survival time is 6.8 years and the three year mortality rate may be as high as 90 %. The pathophysiology, diagnosis and treatment of CTEPH are necessary to be shared among internists and primary care physicians, in order to improve the overall outcome of the patients.

Topics: Angioplasty, Balloon; Anticoagulants; Chronic Disease; Diagnostic Imaging; Endarterectomy; Enzyme Activators; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Vascular Remodeling

A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study. Patients in World Health Organization (WHO) functional class (FC) III, with 6-min walking distance (6MWD) 165-440 m, cardiac index <3.0 L·min

Topics: Adolescent; Adult; Aged; Antihypertensive Agents; Endothelin Receptor Antagonists; Europe; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Natriuretic Peptide, Brain; North America; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Prospective Studies; Pyrazoles; Pyrimidines; Severity of Illness Index; Treatment Outcome; Vascular Resistance; Walk Test; World Health Organization; Young Adult

Topics: Cyclic GMP; Drug Therapy, Combination; Endothelins; Enzyme Activators; Humans; Hypertension, Pulmonary; Molecular Targeted Therapy; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Precision Medicine; Pyrazoles; Pyrimidines; Signal Transduction; Sildenafil Citrate; Tadalafil

Advances in the treatment of idiopathic interstitial pneumonia (IIP) represent an urgent, unmet medical need for patients with this category of diffuse parenchymal lung disease. IIPs involve varying combinations of fibrosis and inflammation of unknown cause and may be associated with pulmonary hypertension (PH). When it occurs, PH is associated with higher oxygen needs, greater functional impairment, and increased mortality. However, whether or when PH is a maladaptive versus adaptive phenomenon remains to be determined. Despite their differing prognoses, it does appear that the IIPs may follow a similar course once PH supervenes. Therefore, it may be worthwhile to explore studies of PH medications in IIP as a group rather than as individual entities. Such a broad approach eliminates the need to nuance specific diagnoses and thereby facilitates study recruitment and broadens the applicability of the results.

Topics: Cell Proliferation; Clinical Trials as Topic; Enzyme Activators; Extracellular Matrix; Fibroblasts; Humans; Hypertension, Pulmonary; Idiopathic Interstitial Pneumonias; Idiopathic Pulmonary Fibrosis; Lung Diseases, Interstitial; Nitric Oxide; Prognosis; Pyrazoles; Pyrimidines; United States

Presence of pulmonary hypertension (PH) and right ventricular dysfunction worsens prognosis in patients with chronic heart failure (CHF). Preclinical and clinical studies suggest a role for the impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway in both PH and CHF. Hence, we examined the effects of the NO-sGC-cGMP pathway modulation by the PDE5 inhibitor sildenafil or sGC stimulator riociguat on pulmonary hemodynamics and heart function in a murine model of secondary PH induced by transverse aortic constriction.. C57Bl/6N mice were subjected to transverse aortic constriction (TAC) for 6weeks to induce left heart failure and secondary PH and were subsequently treated with either sildenafil (100mg/kg/day) or riociguat (10mg/kg/day) or placebo for 2weeks.. Six weeks after surgery, TAC induced significant left ventricular hypertrophy and dysfunction associated with development of PH. Treatment with riociguat and sildenafil neither reduced left ventricular hypertrophy nor improved its function. However, both sildenafil and riociguat ameliorated PH, reduced pulmonary vascular remodeling and improved right ventricular function.. Thus, modulation of the NO-sGC-cGMP pathway by the PDE5 inhibitor sildenafil or sGC stimulator riociguat exerts direct beneficial effects on pulmonary hemodynamics and right ventricular function in the experimental model of secondary PH due to left heart disease and these drugs may offer a new therapeutic option for therapy of this condition.

Topics: Animals; Cyclic GMP; Disease Models, Animal; Heart Function Tests; Humans; Hypertension, Pulmonary; Hypertrophy, Left Ventricular; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Pyrazoles; Pyrimidines; Signal Transduction; Sildenafil Citrate; Soluble Guanylyl Cyclase; Treatment Outcome

Riociguat is newly approved by the FDA for treatment of patients with groups 1 or 4 pulmonary hypertension. Although several vasodilators are on the market for the treatment of pulmonary hypertension group 1, none have been shown to be invariably effective in the treatment of chronic thromboembolic pulmonary hypertension.

Topics: Chronic Disease; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines

Topics: Adult; Angioplasty, Balloon; Cardiovascular Agents; Chronic Disease; Humans; Hypertension, Pulmonary; Male; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Treatment Outcome; Ventricular Function, Right

In the past 18 months, the U.S. Food and Drug Administration approved macitentan, riociguat, and treprostinil as oral agents for the treatment of pulmonary arterial hypertension (PAH); riociguat also became the first agent approved for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH). These new agents are welcome additional therapeutic options for PAH and CTEPH. However, their use can be complicated by potential drug interactions, adverse effects, dosing complexity, and cost. Macitentan, the newest endothelin receptor antagonist, showed significant benefits in a long-term event-driven trial of morbidity and mortality. Dosed once daily and with minimal liver toxicity, it has potential drug interactions with potent CYP 3A4 inhibitors and inducers, and can decrease hemoglobin levels. Riociguat is approved for PAH and clinically inoperable CTEPH to improve exercise capacity and functional status. Riociguat requires dose titration beginning with 1 mg up to 2.5 mg three times a day, as tolerated, and should be used with caution in patients with underlying risk factors for systemic hypotension. Oral treprostinil, approved to improve exercise capacity in PAH, is associated with gastrointestinal side effects and headaches that are often dose limiting. Doses can begin with 0.125 mg or 0.25 mg twice a day with gradual increases on up to a weekly basis, as tolerated. Thrice daily dosing and administration with a meal can improve tolerance. These newer agents represent advances, but their specific roles in relation to pre-existing therapies are undergoing further evaluation. Therefore, close collaboration with clinicians at centers with therapeutic expertise is highly recommended to optimize patient outcomes.

Topics: Administration, Oral; Antihypertensive Agents; Chronic Disease; Drug Approval; Endothelin Receptor Antagonists; Epoprostenol; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Sulfonamides; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Clinical Trials, Phase III as Topic; Disease Progression; Dyspnea; Endpoint Determination; Exercise Test; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Natriuretic Peptide, Brain; Peptide Fragments; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Vascular Resistance; Walking; World Health Organization

Topics: Algorithms; Animals; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Endothelin Receptor Antagonists; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Indoles; Pulmonary Artery; Pyrazoles; Pyridones; Pyrimidines; Rituximab; Scleroderma, Systemic; Sulfonamides

Topics: Chronic Disease; Drug Design; Humans; Hypertension, Pulmonary; Patient Safety; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Thromboembolism; Treatment Outcome

Riociguat is a soluble guanylate cyclase stimulator approved for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The objective of this study was to evaluate the change of right heart size and function assessed by echocardiography during long-term treatment with riociguat.. We assessed patients who started riociguat treatment (1.0-2.5mg tid) within the trials PATENT, PATENTplus, EAS and CHEST and continued for 3-12 months. Echocardiography, 6-minute walking distance (6MWD) and further clinical parameters were analyzed at baseline, after 3, 6 and 12 months. Right heart catheterization was performed at baseline and after 3 months. For missing data we performed the last and baseline observation carried forward (LOCF, BOCF) method as sensitivity analyses.. Thirty-nine patients (21 PAH, 18 CTEPH, mean pulmonary arterial pressure 43 ± 2 mmHg, PVR 600 ± 43 dyn ∗ s ∗ cm(-5), 56.4% treatment-naïve) were included. Mean right ventricular (RV) area significantly decreased after 3 (-2.1 ± 3.9 cm(2), equals -7.4 ± 15.3%, p = 0.002), 6 (-4.2 ± 3.2 cm(2), equals -16.1 ± 11.5%, p < 0.001) and 12 months (-5.9 ± 4.6 cm(2), equals -22.1 ± 14.2%, p < 0.001) compared to baseline. Right atrial area significantly decreased after 12 months (-3.5 ± 4.1cm(2), equals -16.8 ± 19.2%, p < 0.001) and TAPSE significantly improved after 6 (+ 2 ± 4.7, equals 12 ± 25.8%, p = 0.025) and 12 months (+ 3.6 ± 5.4, equals 21.0 ± 29.6%, p = 0.002). Furthermore, RV wall thickness and 6MWD significantly improved after 3, 6 and 12 months (p < 0.05). Invasive hemodynamics significantly improved after 3 months. Both LOCF and BOCF showed similar significance and lower effect sizes.. Long-term treatment with riociguat significantly reduced right heart size and improved RV function in PAH and CTEPH. Further prospective studies are needed to confirm these results.

Topics: Adult; Aged; Atrial Function, Right; Chronic Disease; Echocardiography; Exercise Test; Female; Guanylate Cyclase; Heart Atria; Heart Ventricles; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyrimidines; Treatment Outcome; Ventricular Function, Right; Walking

Topics: Angioplasty, Balloon; Antihypertensive Agents; Arterial Pressure; Endarterectomy; History, 20th Century; History, 21st Century; Humans; Hypertension, Pulmonary; Pulmonary Artery; Pulmonary Embolism; Pyrazoles; Pyrimidines; Treatment Outcome

to undertake economic evaluation of riociguat in comparison with standard practice of treating patients with inoperable or residual chronic thromboembolic pulmonary hypertension (CTEPH) in Russian healthcare. METHODS. Standard practice was revealed by means of peer interview. It comprised bosentan monotherapy with addition of sildenafil in case of disease progression. Difference in efficacy between riociguat and bosentan was established through the indirect comparison based on the results of randomized controlled trials. Difference in costs of CTEPH treatment with riociguat and standard practice eas estimated in the Markov model that simulated changes in disease functional class (FC). Direct medical costs were considered and included drugs prescriptions, in-patient and out-patient medical care. Probabilistic sensitivity analysis was conducted.. The results of indirect comparison suggest statistically significant higher probability of favorable outcomes in case of treatment with riociguat: improvement by ≥ 1 FC (difference in proportions = 14.8% with 95% confidence interval from 0.1 to 29.5; p = 0.048) and increase of distance in 6-minute walking distance (mean difference = 42.9 m with 95% confidence interval from 10.5 to 75.3; p = 0.009). In base-case scenario difference in costs between riociguat and standard practice was 60,646.15 RUB per 1 patient per year in favor of the former. Riociguat costs were lower in 94.4% of sensitivity analysis cycles. In 72.5% of sensitivity analysis cycles costs difference in favor of riociguat was at least half of that in in base-case. In 47.3% of sensitivity analysis costs difference in favor of riociguat was equal or higher to that in base-case.. The results of modeling suggest that in Russian healthcare treatment of CTEPH with riociguat is characterized by higher efficacy at lower costs.

Topics: Adolescent; Adult; Chronic Disease; Drug Costs; Female; Humans; Hypertension, Pulmonary; Male; Middle Aged; Pulmonary Embolism; Pyrazoles; Pyrimidines; Young Adult

A 51-year-old woman presented with a one-year history of progressive dyspnea, WHO functional class III-IV and exercise-related syncope. Transthoracic echocardiography and computed tomography pulmonary angiography were performed, leading to a diagnosis of pulmonary arterial hypertension. She was referred to our pulmonary hypertension unit, where a complete study was performed, including ventilation/perfusion scan, which was consistent with chronic thromboembolic pulmonary hypertension. Risk factors for this condition were excluded and therapeutic options were evaluated. Imaging studies showed distal pulmonary disease so pulmonary endarterectomy was rejected. Further therapeutic options were evaluated and the patient was subsequently enrolled in an open-label uncontrolled trial with riociguat. After one year of treatment, significant improvement in functional class, 6-minute walk test and NT-proBNP were seen, without significant secondary effects.

Topics: Chronic Disease; Exercise; Female; Humans; Hypertension, Pulmonary; Middle Aged; Pyrazoles; Pyrimidines

When pulmonary hypertension results in marked limitation in activities of daily living (functional class III), the first-choice vasodilator is bosentan, despite its limitations. There is no proven advantage of adding another vasodilator. The adverse effects of vasodilators outweigh their uncertain efficacy in patients with only a slight limitation of physical activity (class II). When surgery is not feasible or when chronic thromboembolic pulmonary hypertension persists despite surgery, there are no vasodilators with a favourable harm-benefit balance. Riociguat (Adempas, Bayer) is a vasodilator that acts by enhancing the synthesis of cyclic guanosine monophosphate (cGMP), a mediator of vasodilation. This mechanism of action is similar to that of sildenafil, which inhibits cGMP catabolism. Riociguat has been authorised in the European Union in adult patients with class II or III pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Riociguat monotherapy has not been compared with another vasodilator in patients with pulmonary arterial hypertension. In a 12-week randomised, double-blind, placebo-controlled trial in 380 patients, riociguat had modest symptomatic efficacy, improving the functional class in 21% of patients (versus 14% in the placebo arm). There was no statistically significant difference in mortality. The symptomatic benefit appeared to be similar in patients who continued to take bosentan and in those who were not taking a vasodilator other than riociguat. In a 16-week, double-blind trial in 261 patients with chronic thromboembolic pulmonary hypertension in whom surgery was not feasible or had failed, riociguat was more effective than placebo on symptoms; there was improvement in functional class in respectively 33% and 15% of patients. There was no statistically significant change in mortality. In these two clinical situations, subgroup analyses showed no benefit of riociguat in patients who had only slight limitation of physical activity (class II). The main adverse effects of riociguat are related to its vasodilatory properties, and include headache, arterial hypotension, dizziness and peripheral oedema. Riociguat can also cause bleeding, including potentially severe pulmonary haemorrhage. More data are needed on its cardiac, renal and osseous adverse effects. Riociguat is subject to pharmacodynamic interactions with many other drugs. In particular, riociguat coadministration with a phosphodiesterase type 5 inhi

Topics: Activities of Daily Living; Adult; Animals; Chronic Disease; Cyclic GMP; Humans; Hypertension, Pulmonary; Motor Activity; Pyrazoles; Pyrimidines; Thromboembolism; Vasodilator Agents

Topics: Antihypertensive Agents; Endothelin Receptor Antagonists; Humans; Hypertension, Pulmonary; Pulmonary Veno-Occlusive Disease; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides; Thromboembolism; Treatment Failure; Vasodilator Agents

Topics: Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

Topics: Antihypertensive Agents; Drug Approval; European Union; Exercise Tolerance; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic

Topics: Benzamides; Biomarkers; Biomedical Research; Clinical Trials as Topic; Endothelin A Receptor Antagonists; Exercise Test; Hospitalization; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Multicenter Studies as Topic; Piperazines; Protein Kinase Inhibitors; Pyrazoles; Pyrimidines; Sulfonamides; Walking

Recent years are the time of dynamic development of pulmonary arterial pressure pharmacotherapy. By introducing the goal oriented therapy the survival in this group of patients has significantly increased. Apart from the pharmacotherapy used according to the ESC guidelines, new attempts of interventional treatment based on denervation of pulmonary artery have also been taken. Constantly, the new clinical trials (tests?) of drugs acting via new metabolic pathways have been conducted. They include for example: soluble guanylate cyclase stimulators, tyrosine kinase inhibitors, serotonin receptors inhibitors, Rhokinase inhibitors, VIP analogues. One of the newmedicines is riociguat, the effectiveness and safety of which have been confirmed in the PATENT and CHEST study. However, the small number and clinical diversity in the group of the PAH patients cause significant difficulties with the extrapolation of the results of trials according to the guidelines of the therapy.

Topics: Antihypertensive Agents; Denervation; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Protein-Tyrosine Kinases; Pulmonary Artery; Pyrazoles; Pyrimidines; rho-Associated Kinases; Serotonin Antagonists; Vasoactive Intestinal Peptide

Topics: Female; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Lung Diseases, Interstitial; Male; Pyrazoles; Pyrimidines

Topics: Cardiovascular Agents; Clinical Trials as Topic; Congresses as Topic; Diagnostic Techniques, Cardiovascular; Disease Management; Epoprostenol; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; Respiratory Function Tests; Sulfonamides; Therapies, Investigational; Ventricular Dysfunction, Right

Topics: Female; Hemodynamics; Humans; Hypertension, Pulmonary; Male; Pyrazoles; Pyrimidines; Ventricular Dysfunction, Left

Topics: Female; Humans; Hypertension, Pulmonary; Male; Pyrazoles; Pyrimidines

Idiopathic pulmonary arterial hypertension (IPAH), formerly called primary pulmonary hypertension, is a rare disease (incidence and prevalence rates of approximately one and six cases per million inhabitants, respectively) with different clinical phenotypes. A group of diverse conditions manifest pulmonary arterial hypertension (PAH) and share similar pathological and/or clinical findings with IPAH. By definition, IPAH is diagnosed only after alternative diagnoses have been ruled out. Extensive investigation is needed to determine if PAH is associated with thyroid diseases, infectious diseases, autoimmune conditions, exposure to certain drugs (particularly anorexigens), certain genetic mutations, and so on. The presence of genetic abnormalities and risk factors (such as specific drug exposures) reinforces the "multiple hit" concept for the development of pulmonary hypertension. Fortunately, within the past two decades, therapeutic options have become available for IPAH, resulting in improved survival and clinical outcomes. At least seven different compounds have been registered for PAH treatment. However, even with aggressive PAH-specific therapy, mortality rates remain high (∼40% at 5 years). Given the high mortality rates, the use of combinations of agents that work by different pathways has been advocated (either as "add-on" therapy or initial "up front" therapy). Further, new therapeutic agents and treatment strategies are on the near horizon, aiming to further improve survival from the remarkable progress already seen.

Topics: Aminorex; Antihypertensive Agents; Appetite Depressants; Bosentan; Dasatinib; Epoprostenol; Familial Primary Pulmonary Hypertension; Fenfluramine; Genetic Predisposition to Disease; Humans; Hypertension, Pulmonary; Iloprost; Phenylpropionates; Piperazines; Protein Kinase Inhibitors; Purines; Pyrazoles; Pyridazines; Pyrimidines; Risk Factors; Sildenafil Citrate; Sulfonamides; Sulfones; Thiazoles; Vasodilator Agents

Topics: Adult; Drug Approval; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pyrazoles; Pyrimidines; United States; United States Food and Drug Administration

Riociguat (Adempas(®)), an oral first-in-class soluble guanylate cyclase (sGC) stimulator, is under global development by Bayer Healthcare Pharmaceuticals Inc. for the treatment of adult patients with inoperable or chronic/persistent chronic thromboembolic pulmonary hypertension (CTEPH) and for the treatment of adult patients with pulmonary arterial hypertension (PAH). The drug directly stimulates sGC in a nitric oxide independent manner, thereby increasing the sensitivity of sGC to nitric oxide, leading to increased cyclic guanosine monophosphate generation (a key signalling molecule involved in regulating vascular tone, proliferation, fibrosis and inflammation). Riociguat is the world's first approved pharmacotherapy for CTEPH, with its first global approval in this indication occurring in Canada. It has subsequently been approved in the USA for the treatment of patients with CTEPH and also received its first global approval in patients with PAH in the USA. It is undergoing regulatory review for these indications in Europe and for use in patients with CTEPH in Japan. This article summarizes the milestones in the development of riociguat, leading to its first global approvals in patients with CTEPH and PAH.

Topics: Adult; Animals; Drug Approval; Familial Primary Pulmonary Hypertension; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Nitric Oxide; Pulmonary Embolism; Pyrazoles; Pyrimidines; Receptors, Cytoplasmic and Nuclear; Soluble Guanylyl Cyclase

Topics: Drug Approval; Enzyme Activation; Familial Primary Pulmonary Hypertension; Germany; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Pulmonary Embolism; Pyrazoles; Pyrimidines; Treatment Outcome; United States; United States Food and Drug Administration

Topics: Antihypertensive Agents; Clinical Trials, Phase III as Topic; Humans; Hypertension, Pulmonary; Multicenter Studies as Topic; Mutation, Missense; Nerve Tissue Proteins; Potassium Channels, Tandem Pore Domain; Pyrazoles; Pyrimidines; Treatment Outcome

Pulmonary hypertension (PH) is a progressive disease that is accompanied by a poor prognosis. Pulmonary vasoconstriction is facilitated through multiple pathways and results in increased pulmonary vascular pressure leading to cell proliferation, vascular remodeling, right ventricular hypertrophy/failure, and ultimately death. Until recently, just six medications were approved -all for one subclass of PH. On October 8, 2013, riociguat (Adempas®) became the first medication approved for multiple etiologies of PH. Preclinical studies have demonstrated safety and efficacy with significant clinical trials supporting its advancement into phase IV trials. Although long-term safety and efficacy and place in therapy remain to be established, riociguat presents as an exciting new option for the treatment of PH and potentially has additional indications in the near future.

Topics: Animals; Chronic Disease; Drug Approval; Familial Primary Pulmonary Hypertension; Humans; Hypertension, Pulmonary; Molecular Targeted Therapy; Pulmonary Embolism; Pyrazoles; Pyrimidines

Topics: Africa South of the Sahara; Antihypertensive Agents; Clinical Trials, Phase III as Topic; Humans; Hypertension, Pulmonary; Patient Selection; Pyrazoles; Pyrimidines

The nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal-transduction pathway is impaired in many cardiovascular diseases, including pulmonary arterial hypertension (PAH). Riociguat (BAY 63-2521) is a stimulator of sGC that works both in synergy with and independently of NO to increase levels of cGMP. The aims of this study were to investigate the role of NO-sGC-cGMP signaling in a model of severe PAH and to evaluate the effects of sGC stimulation by riociguat and PDE5 inhibition by sildenafil on pulmonary hemodynamics and vascular remodeling in severe experimental PAH.. Severe angioproliferative PAH was induced in rats by combined exposure to the vascular endothelial growth factor receptor antagonist SU5416 and hypoxia (SUHx). Twenty-one days thereafter rats were randomized to receive either riociguat (10 mg/kg/day), sildenafil (50 mg/kg/day) or vehicle by oral gavage, for 14 days until the day of the terminal hemodynamic measurements. Administration of riociguat or sildenafil significantly decreased right ventricular systolic pressure (RVSP). Riociguat significantly decreased RV hypertrophy (RVH) (0.55 ± 0.02, p<0.05), increased cardiac output (60.8 ± .8 mL/minute, p<0.05) and decreased total pulmonary resistance (4.03 ± 0.3 mmHg min(-1) ml(-1) 100 g BW, p<0.05), compared with sildenafil and vehicle. Both compounds significantly decreased the RV collagen content and improved RV function, but the effects of riociguat on tricuspid annular plane systolic excursion and RV myocardial performance were significantly better than those of sildenafil (p<0.05). The proportion of occluded arteries was significantly lower in animals receiving riociguat than in those receiving vehicle (p<0.05); furthermore, the neointima/media ratio was significantly lower in those receiving riociguat than in those receiving sildenafil or vehicle (p<0.05).. Riociguat and sildenafil significantly reduced RVSP and RVH, and improved RV function compared with vehicle. Riociguat had a greater effect on hemodynamics and RVH than sildenafil.

Topics: Animals; Apoptosis; Blood Pressure; Blotting, Western; Caspase 3; Cell Proliferation; Cyclic GMP; Guanylate Cyclase; Hemodynamics; Hypertension, Pulmonary; Hypertrophy, Right Ventricular; Hypoxia; Immunohistochemistry; Indoles; Lung; Male; Nitric Oxide Synthase Type III; Phosphodiesterase 5 Inhibitors; Piperazines; Purines; Pyrazoles; Pyrimidines; Pyrroles; Random Allocation; Rats; Rats, Sprague-Dawley; Receptors, Cytoplasmic and Nuclear; Sildenafil Citrate; Soluble Guanylyl Cyclase; Sulfones; Time Factors; Treatment Outcome

Topics: Acetamides; Administration, Oral; Antihypertensive Agents; Benzamides; Drug Therapy, Combination; Early Medical Intervention; Epoprostenol; Humans; Hypertension, Pulmonary; Imatinib Mesylate; Piperazines; Pyrazines; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Sulfonamides

There are several animal models for studying human pulmonary hypertension (PH). An increased flow model in pigs was developed at the University Hospital in Heidelberg in order to simulate congenital heart disease. The high pulmonary blood flow is achieved by installation of a Blalock-Taussig anastomosis. In order to further improve this model by adding a pressure component, the left pulmonary artery is ligated. An acute model, which is used at the Innsbruck Medical University, addresses another disease entity. Human meconium is placed deeply into the trachea of the pigs in order to induce an acute respiratory distress syndrome-like response in the lungs. Animals were randomly assigned to four treatment groups. Inhaled iloprost, due to its pulmonary and intrapulmonary selectivity, was the only substance that significantly reduced intrapulmonary shunt volumes. In humans, PH encompasses multiple disease subtypes. Pulmonary arterial hypertension (PAH) accounts for only 6% of PH cases, however, all existing treatments are indicated only for PAH. This means that for 94% of patients with PH, no specific medication is available. Therefore, huge efforts have been made to better understand the pathophysiology of PH and to detect new signalling pathways that may allow new compounds to be developed that will ultimately improve the prognosis of PAH and non-PAH PH patients. Promising new substances include riociguat, a stimulator of the soluble guanylate cyclase (sGC), as well as cinaciguat, a sGC activator, and an elastase inhibitor. Riociguat (BAY 63-2521) is an oral agent that targets the intact/native form of sGC. It enhances the sensitivity of sGC to low levels of bioavailable nitric oxide (NO) and is also capable of stimulating native sGC independently of NO. Thus, unlike phosphodiesterase-5 inhibitors, the effect of riociguat is not limited by low NO levels. In a multicentre open-label phase II study, riociguat exerted strong and significant effects on pulmonary haemodynamics and exercise capacity in patients with PAH and in patients with chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is currently being evaluated in phase III clinical trials both in PAH and in CTEPH patients. Clinical studies with riociguat in earlier development stages have addressed PH in lung diseases and systolic left ventricular failure. An elastase inhibitor is currently being investigated in phase I clinical trials in patients with PH owing to chronic obstructive pulmona

Topics: Animals; Disease Models, Animal; Heart Defects, Congenital; Humans; Hypertension, Pulmonary; Iloprost; Pyrazoles; Pyrimidines; Vasodilator Agents

Topics: Adult; Antihypertensive Agents; Bone Morphogenetic Protein Receptors, Type II; Child; Chronic Disease; Clinical Trials, Phase III as Topic; Combined Modality Therapy; Diagnosis, Differential; Endothelin Receptor Antagonists; Evidence-Based Medicine; Genetic Predisposition to Disease; Germany; Guanylate Cyclase; Hospitals, Special; Humans; Hypertension, Pulmonary; Oxygen Inhalation Therapy; Patient Care Team; Phosphodiesterase 5 Inhibitors; Phosphodiesterase Inhibitors; Practice Guidelines as Topic; Pyrazoles; Pyrimidines; Rare Diseases; Vasodilator Agents

Topics: Clinical Protocols; Clinical Trials, Phase III as Topic; Enzyme Activators; Guanylate Cyclase; Humans; Hypertension, Pulmonary; Molecular Structure; Pulmonary Embolism; Pyrazoles; Pyrimidines