bay-63-2521 and Chronic-Disease

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), 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 novel soluble guanylate cyclase stimulator, and has been widely used for the treatment of pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension (CTEPH). Some studies found that riociguat had better effects on CTEPH and proved to be safe, but the results were not utterly consistent. Therefore, the purpose of this study was to comprehensively evaluate the efficacy and safety of riociguat in the treatment of CTEPH.. Randomized controlled trials on riociguat for the treatment of CTEPH were searched through such electronic databases as PubMed, Embase, Cochrane Library, Web of Science, China national knowledge internet, and Wanfang. The outcomes included exercise capacity, pulmonary hemodynamics, and side effects. The fixed-effects or random-effects models were used to analyze the pooled data, and heterogeneity was assessed by the I2 test.. Four studies involving 520 patients were included in this meta-analysis. Compared with the placebo group, riociguat significantly improved the hemodynamic indexes and increased 6-min walking distance (P < .0001, standardized mean difference (SMD) = -0.24, 95%CI -0.35 to -0.12; P < .00001, SMD = 0.52, 95%CI 0.33 to 0.71), and decreased the Borg dyspnea score (P = .002, SMD = -0.31, 95%CI -0.51 to -0.12). In addition, riociguat could also significantly reduce the living with pulmonary hypertension scores and increase the EQ-5D scores (P = .01, SMD=-0.23, 95%CI -0.42 to -0.05; P < .00001, SMD = 0.47, 95%CI 0.27 to 0.66), but there was no significant difference in the change level of N-terminal pro-hormone B-type natriuretic peptide in patients with riociguat (P = .20, SMD = -0.24, 95%CI -0.61 to -0.13). The common adverse events of riociguat were dyspepsia and peripheral edema, and no other serious adverse reactions were observed.. We confirmed that riociguat had better therapeutic effects in improving the hemodynamic parameters and exercise capacity in patients with CTEPH without inducing serious adverse events. This will provide a reasonable medication regimen for the treatment of CTEPH.

Topics: Adult; Aged; Case-Control Studies; China; Chronic Disease; Data Management; Enzyme Activators; Exercise Tolerance; Female; Hemodynamics; Humans; Male; Middle Aged; Placebos; Pulmonary Arterial Hypertension; Pulmonary Embolism; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Safety; Soluble Guanylyl Cyclase; Treatment Outcome

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Transition to pulmonary arterial hypertension (PAH)-specific drugs is considered in patients with PAH and chronic thromboembolic pulmonary hypertension who do not respond to combination therapy or who experience side effects to the combination drugs. Riociguat directly stimulates soluble guanylate cyclase independently of nitric oxide. Therefore, transition from a phosphodiesterase type 5 inhibitor (PDE5i), which requires nitric oxide to exert its effects, to riociguat might be effective. The length of time of washout periods for transition is important because haemodynamic instability sometimes occurs during these periods or during transition with no washout period.. We investigated the feasibility of transitioning from a PDE5i to riociguat without washout periods by monitoring haemodynamics under right heart catheterisation in six patients with PAH and one with chronic thromboembolic pulmonary hypertension who had already received dual- or triple-combination therapy.. Reasons for transition were headache caused by a PDE5i in three patients, and an inadequate response to combination therapy in four. Transition was successful in all patients, with no haemodynamic instability observed. Pulmonary vascular resistance (from 797 ± 241 to 518 ± 230 dyne/s/cm. Transition from a PDE5i to riociguat without a washout period is safe. This transition may be a viable option for patients with headaches caused by a PDE5i, or who have an inadequate response to combination therapy that includes a PDE5i.

Topics: Adult; Aged; Cardiac Catheterization; Chronic Disease; Cohort Studies; Female; Hemodynamics; Humans; Male; Middle Aged; Monitoring, Physiologic; Phosphodiesterase 5 Inhibitors; Pilot Projects; Pulmonary Arterial Hypertension; Pulmonary Embolism; Pyrazoles; Pyrimidines; Transitional Care

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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: 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

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

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: 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