bay-63-2521 and Pulmonary-Arterial-Hypertension

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

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

Pulmonary arterial hypertension (PAH) is a severe clinical condition that significantly affects patients' quality of life and survival. Since the emergence of prostanoids 45 years ago, different drugs acting on vasoconstriction/vasodilation mechanisms have been developed for the treatment of PAH. Current evidence shows that better results occur when combined therapy is initiated up-front with periodic and systematized evaluations for escalation and switching. Among these strategies, riociguat has a relevant role, supported by the results of several clinical studies. This document issues recommendations by a panel of experts who analysed and discussed the indications and limitations for riociguat in PAH in different institutions of the Mexican health system.

Topics: Humans; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines; Quality of Life

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

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

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

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

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

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

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

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

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

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

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

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

Pulmonary veno-occlusive disease (PVOD) is a rare condition with poor prognosis, and lung transplantation is recommended as the only curative therapy. The role of pulmonary arterial hypertension targeted therapy in PVOD remains controversial, and long-term effects of targeted therapy have been rarely reported. This study aims to retrospectively evaluate the role of targeted therapy in PVOD patients and the long-term outcome.. PVOD patients with good responses to targeted therapies were analyzed, and data pre- and post- targeted therapies were compared. An overview of the effects of targeted therapies on PVOD patients was also conducted.. Five genetically or histologically confirmed PVOD patients received targeted therapies and showed good responses. Their mean pulmonary arterial pressure by right heart catheterization was 62.0 ± 11.7 mmHg. Two receiving monotherapy got stabilized, and three receiving sequential combination therapy got improved, cardiac function and exercise capacity significantly improved after treatments. No pulmonary edema occurred. The mean time from the first targeted therapy to the last follow up was 39.3 months, and the longest was 9 years. A systematic review regarding the effects of targeted therapies on PVOD patients indicated majorities of patients got hemodynamics or 6-min walk distance improved, and 26.7% patients developed pulmonary edema. The interval from targeted drugs use to death ranged from 71 min to over 4 years.. Cautious use of targeted therapy could safely and effectively improve or stabilize hemodynamics and exercise capacity of some patients without any complications. PVOD patients could live longer than expected.

Topics: Acetamides; Adult; Anticoagulants; Antihypertensive Agents; Cardiac Catheterization; Disease Progression; Diuretics; Drug Therapy, Combination; Echocardiography, Doppler; Endothelin Receptor Antagonists; Enzyme Activators; Exercise Tolerance; Female; Humans; Male; Natriuretic Peptide, Brain; Peptide Fragments; Phosphodiesterase 5 Inhibitors; Prostaglandins; Pulmonary Arterial Hypertension; Pulmonary Diffusing Capacity; Pulmonary Edema; Pulmonary Veno-Occlusive Disease; Pyrazines; Pyrazoles; Pyrimidines; Retrospective Studies; Walk Test

Current treatment of pulmonary arterial hypertension (PAH) targets three signalling pathways: the nitric oxide (NO) pathway, the endothelin pathway and the prostacyclin pathway. Riociguat is a soluble guanylate cyclase stimulator, acting via the NO pathway in a new way: unlike other common drugs targeting this pathway (eg tadalafil and sildenafil), riociguat acts independently of endogenous NO. This MiniReview focuses on PAH treatment with riociguat and on its advantages and disadvantages compared with other drugs targeting the NO pathway. In the PATENT-1 trial (NCT00810693), riociguat improved significantly the 6-minute walking distance in patients suffering from PAH, with a mean difference (MD) of 36 m compared with a placebo group. The results are comparable to those found for its competitors tadalafil (MD of 33 m) and sildenafil (MD of 50 m) in the PHIRST-1 trial (NCT00125918) and the SUPER-1 trial (NCT00644605). No obvious advantages were found regarding pharmacokinetic features and adverse events. In the RESPITE study (NCT02007629), patients with PAH with insufficient response to treatment with tadalafil or sildenafil were switched to riociguat. These results indicate that riociguat might be superior regarding efficacy to PDE-5 inhibitors in a patient group, where endogenous NO production might be insufficient. This finding was further examined in the REPLACE study (NCT02891850). Moreover, riociguat has shown promising anti-proliferative, anti-inflammatory and anti-fibrotic effects in animal models. Further investigations are needed to determine whether this applies also to human beings. Taken together, riociguat induces vasodilation of the pulmonary arteries and leads to an improvement in the ability to carry out physical activity.

Topics: Animals; Disease Models, Animal; Drug Substitution; Endothelins; Enzyme Activators; Epoprostenol; Guanylate Cyclase; Humans; Nitric Oxide; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pulmonary Artery; Pyrazoles; Pyrimidines; Randomized Controlled Trials as Topic; Signal Transduction; Treatment Outcome; Vasodilation

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

Topics: Bosentan; Endothelin Receptor Antagonists; Heart Diseases; Hemodynamics; Humans; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines; Sildenafil Citrate; Sulfonamides

Risk assessment is essential in pulmonary arterial hypertension (PAH) management. We investigated the effect of riociguat on REVEAL Lite 2 score, an abridged version of the REVEAL risk score, and its association with long-term outcomes in PATENT.. PATENT-1 was a randomized, double-blind study of riociguat vs placebo in patients with PAH. In the PATENT-2 open-label extension, all patients received riociguat up to 2.5 mg three times daily (n = 396). REVEAL Lite 2 scores were calculated at baseline, PATENT-1 Week 12, and PATENT-2 Week 12, with patients stratified as low- (1-5), intermediate- (6-7), or high-risk (≥8). Kaplan-Meier and Cox proportional hazards analyses assessed association of riociguat with survival and clinical worsening-free survival (CWFS).. REVEAL Lite 2 score improved with riociguat 2.5 mg at PATENT-1 Week 12 (least-squares mean difference vs placebo: -0.8; p = 0.0004). More patients receiving riociguat 2.5 mg stabilized or improved risk stratum at PATENT-1 Week 12 vs placebo (p = 0.0005) and achieved low-risk status. REVEAL Lite 2 score at baseline and PATENT-1 Week 12 were associated with survival and CWFS (all p < 0.0001), as was change in score from baseline to Week 12 (p = 0.0002 and p < 0.0001, respectively). Survival and CWFS differed between risk strata at baseline (p < 0.0001) and PATENT-1 Week 12 (p < 0.0001).. This analysis confirms the risk-reduction benefits of riociguat in patients with PAH and further contributes to the validation of REVEAL Lite 2 in facilitating PAH risk assessment.

Topics: Double-Blind Method; Humans; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines; Risk Factors; Treatment Outcome

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

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

Riociguat and phosphodiesterase-5 inhibitors (PDE5i), approved for the treatment of pulmonary arterial hypertension (PAH), act on the same pathway via different mechanisms. Riociguat might be an alternative option for patients with PAH who do not respond sufficiently to treatment with PDE5i, but comparisons of the potential benefits of riociguat and PDE5i in these patients are needed. The aim of this trial was to assess the effects of switching to riociguat from PDE5i therapy versus continued PDE5i therapy in patients with PAH at intermediate risk of 1-year mortality.. Riociguat rEplacing PDE5i therapy evaLuated Against Continued PDE5i thErapy (REPLACE) was an open-label, randomised controlled trial in 81 hospital-based pulmonary hypertension centres in 22 countries. The study enrolled patients aged 18-75 years with symptomatic PAH at intermediate risk of 1-year mortality (based on the European Society for Cardiology-European Respiratory Society guideline thresholds for WHO functional class and 6-min walk distance [6MWD]) who were receiving treatment with a PDE5i with or without an endothelin receptor antagonist for at least 6 weeks before randomisation. Patients were excluded if they had been previously treated with riociguat, had used prostacyclin analogues or prostacyclin receptor agonists within 30 days before randomisation, had clinically significant restrictive or obstructive parenchymal lung disease, or had left heart disease. Patients were randomly assigned (1:1) to remain on PDE5i treatment (oral sildenafil [≥60 mg per day] or oral tadalafil [20-40 mg per day]; the PDE5i group) or to switch to oral riociguat (up to 2·5 mg three times per day; the riociguat group), using an interactive voice and web response system, stratified by cause of PAH. The primary endpoint was clinical improvement by week 24, defined as an absence of clinical worsening and prespecified improvements in at least two of three variables (6MWD, WHO functional class, and N-terminal prohormone of brain natriuretic peptide), analysed using last observation carried forward in all randomly assigned patients with observed values at baseline and week 24 who received at least one dose of study medication (the full analysis set). Secondary endpoints included clinical worsening events. The trial has been completed and is registered with ClinicalTrials.gov, NCT02891850.. Between Jan 11, 2017, and July 31, 2019, 293 patients were screened, of which 226 patients were randomly assigned to the riociguat group (n=111) or to the PDE5i group (n=115). 211 patients completed the study and 14 patients discontinued (seven in each group). One patient assigned to the PDE5i group did not receive treatment, so 225 patients were included in the safety analysis, and one further patient in the PDE5i group had missing components of the composite primary endpoint at baseline, so 224 patients were included in the full analysis set. The primary endpoint was met by 45 (41%) of 111 patients in the riociguat group and 23 (20%) of 113 patients in the PDE5i group; odds ratio [OR] 2·78 (95% CI 1·53-5·06; p=0·0007). Clinical worsening events occurred in one (1%) of 111 patients in the riociguat group (hospitalisation due to worsening PAH) and 10 (9%) of 114 patients in the PDE5i group (hospitalisation due to worsening PAH [n=9]; disease progression [n=1]; OR 0·10 [0·01-0·73]; p=0·0047). The most frequently occurring adverse events were hypotension (15 [14%]), headache (14 [13%]), and dyspepsia (10 [9%]) in the riociguat group, and headache (eight [7%]), cough (seven [6%]), and upper respiratory tract infection (seven [6%]) in the PDE5i group. Serious adverse events were reported in eight (7%) of 111 patients in the riociguat group and 19 (17%) of 114 patients in the PDE5i group. During the study, four patients died in the PDE5i group, one of them during the safety follow-up period.. Switching to riociguat from PDE5i treatment, both of which act via the nitric oxide-soluble guanylate cyclase-cyclic guanosine monophosphate pathway, could be a strategic option for treatment escalation in patients with PAH at intermediate risk of 1-year mortality.. Bayer AG, Merck Sharp & Dohme.

Topics: Adult; Aged; Female; Humans; Male; Middle Aged; Phosphodiesterase 5 Inhibitors; Prospective Studies; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines; Young Adult

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

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

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

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

Topics: Cyclic Nucleotide Phosphodiesterases, Type 5; Humans; Phosphodiesterase 5 Inhibitors; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines

Pulmonary hypertension (PH) can develop in different systemic autoimmune rheumatic diseases (SARD), such as systemic scleroderma (SSD), systemic lupus erythematosus, rheumatoid arthritis, and mixed connective tissue disease In most cases, patients with SARD develop WHO group I PH (pulmonary arterial hypertension associated with systemic connective tissue diseases, PAH-SCTD). General prevalence of this pathology reaches 15 cases per million adults. Most cases of PAH-SCTD are induced by SSD. Survival of PAH-SCTD patients is generally lower than survival of patients with other forms of LAH. Treatment of any SARD, including in LAH, implies a complex approach using glucocorticoids, disease-modifying anti-rheumatic drugs (cyclophosphamide, methotrexate, azathioprine, and others), and genetically engineered biologics. Specific targeted therapy is indicated for most patients with PAH-SCTD. The representative of a new class (soluble guanylate cyclase (sGC) stimulators), riociguat, has been approved for the treatment of PAH. This drug has a unique double mechanism of action: (i) sGC sensibilization to endogenous nitric oxide (NO) by stabilizing the NO-sGC bond; and (ii) direct, NO-independent sGC stimulation. For patients with PAH-SCTD, riociguat is the major alternative to phosphodiesterase-5 inhibitors both as monotherapy and combination therapy.

Topics: Adult; Connective Tissue Diseases; Humans; Pulmonary Arterial Hypertension; Pyrazoles; Pyrimidines

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