Riociguat In Patients Research Articles

Validation of REVEAL Risk Score Calculator 2.0 in Patients with PAH in the Phase III PATENT Study

The REVEAL risk score (RRS) predicts 1-year survival in patients with pulmonary arterial hypertension (PAH). RRS was shown previously to improve with riociguat in the Phase III PATENT-1 study in patients with PAH and predicted survival and clinical worsening-free survival (CWFS) in the long-term extension PATENT-2. RRS 2.0, an updated RRS, was developed based on modified point values, cut-offs, and variables. This post hoc analysis aimed to validate RRS 2.0 in the PATENT database (a population not derived from REVEAL), as done previously, and assess if the tool discriminates outcomes in a carefully selected and followed patient population. RRS 2.0 was calculated for patients receiving riociguat up to 2.5 mg tid or placebo (pbo) at PATENT-1 baseline (BL) and Week 12, and PATENT-2 Week 12. Only patients enrolled in PATENT-2 were included in the analysis. Patients were stratified by RRS 2.0 into low (≤7), average/moderately high (8-9), and high/very high (≥10) risk strata at BL and Week 12. Relationship between RRS 2.0 and survival and CWFS in PATENT-2 was examined by Kaplan-Meier and Cox proportional hazards analyses. At BL, mean±SD RRS 2.0 was 6.5±2.6 in riociguat patients (n=231) and 6.4±2.2 in pbo patients (n=109). Risk status at BL was low in 213 patients (63%), average/moderately high in 87 (26%), and high/very high in 40 (12%). At PATENT-1 Week 12, patients receiving riociguat had improved RRS 2.0 by a least squares mean difference of -0.95 vs. pbo (95% CI -1.35 to -0.55; p<0.0001); risk status improved in 57% of patients with riociguat and 42% of patients with pbo (p<0.0001). At PATENT-2 Week 12, RRS 2.0 had improved to 5.1±2.7 (n=224) and 5.6±2.7 (n=107) in riociguat and former pbo patients, respectively. In PATENT-2 (median [range] treatment duration: 139 [0-244] weeks), Cox proportional hazards analyses showed that RRS 2.0 at PATENT-1 BL and Week 12 were significantly associated with survival and CWFS (p<0.0001). Kaplan-Meier analyses showed significant differences in survival and CWFS between patients in the three risk strata at PATENT-1 BL and Week 12 (p<0.0001). Riociguat improved RRS 2.0 and risk strata in PATENT-1. RRS 2.0 predicted survival and CWFS over two years in PATENT-2, making RRS 2.0 a useful tool to predict outcomes in patients with PAH. Further assessment of the discriminatory power of RRS 2.0 vs. the original RRS will be done.

Validation of REVEAL Risk Score Calculator 2.0 in Patients with CTEPH in the Phase III CHEST Study

The REVEAL risk score (RRS) predicts 1-year survival in patients with pulmonary arterial hypertension; it also improved with riociguat in patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) in the Phase III CHEST-1 study, and predicted survival and clinical worsening-free survival (CWFS) in the long-term extension CHEST-2. RRS 2.0, an updated RRS, was developed based on modified point values, cut-offs, and variables. This post hoc analysis aimed to validate RRS 2.0 in the CHEST database (a population not derived from REVEAL), as done previously, and assess if the tool discriminates outcomes in a carefully selected and followed patient population. RRS 2.0 was calculated for patients receiving riociguat up to 2.5 mg tid or placebo (pbo) at CHEST-1 baseline (BL) and Week 16, and CHEST-2 Week 12. Only patients enrolled in CHEST-2 were included. Patients were stratified by RRS 2.0 into low (≤7), average/moderately high (8-9), and high/very high (≥10) risk strata at BL and Week 16. Relationship between RRS 2.0 and survival and CWFS in CHEST-2 was examined by Kaplan-Meier and Cox proportional hazards analyses. At baseline, mean±SD RRS 2.0 was 7.1±2.7 in riociguat patients (n=155) and 6.9±2.6 in pbo patients (n=82). Risk status at BL was low in 131 patients (55%), average/moderately high in 59 (25%), and high/very high in 47 (20%). At CHEST-1 Week 16, riociguat improved RRS 2.0 by a least squares mean difference of -1.48 vs. pbo (95% CI -1.97 to -0.99; p<0.0001); risk status improved in 70% with riociguat and 39% with pbo patients (p<0.0001). At CHEST-2 Week 12, RRS 2.0 improved to 5.5±3.1 (n=152) and 6.1±3.1 (n=79) in riociguat and former pbo patients, respectively. In CHEST-2 (median [range] treatment duration 116 [2-232] weeks), Cox proportional hazards analyses showed RRS 2.0 at CHEST-1 BL and Week 16 was significantly associated with survival and CWFS (p<0.0001). Kaplan-Meier analyses showed significant differences in survival and CWFS between patients in the three risk strata at CHEST-1 BL and Week 16 (p<0.0001). Riociguat improved RRS 2.0 and risk strata in CHEST-1. RRS 2.0 predicted survival and CWFS over two years in CHEST-2. Thus, RRS 2.0 may be a useful tool to predict outcomes in patients with CTEPH. Further assessment of the discriminatory power of RRS 2.0 vs. the original RRS will be done.

Multicentre randomised controlled trial of balloon pulmonary angioplasty and riociguat in patients with chronic thromboembolic pulmonary hypertension: protocol for the MR BPA study

IntroductionManagement of inoperable chronic thromboembolic pulmonary hypertension (CTEPH) remains a clinical challenge. Currently, medical treatment involving pulmonary vasodilators (such as soluble guanylate-cyclase stimulators) is recommended, primarily for ameliorating symptoms. More...

EXPRESS: Switching to riociguat: A potential treatment strategy for the management of CTEPH and PAH.

Currently, five classes of drug are approved for the treatment of pulmonary arterial hypertension (PAH): phosphodiesterase 5 inhibitors (PDE5i); endothelin receptor antagonists; prostacyclin analogs; the IP receptor agonist selexipag; and the soluble guanylate cyclase (sGC) stimulator riociguat. For patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH), riociguat is currently the only approved pharmacotherapy. Despite the development of evidence-based guidelines on appropriate use of specific drugs, in clinical practice patients are often prescribed PAH-targeted therapies off label or at inadequate doses.PDE5i are the most often prescribed class of drugs as initial therapy, either alone or in combination with other drug classes. However, a proportion of patients receiving PAH therapies do not reach or maintain treatment goals. As PDE5i and riociguat target different molecules in the nitric oxide-sGC-cyclic guanosine monophosphate (NO-sGC-cGMP) signaling pathway, for patients with PAH without an initial or sustained response to PDE5i, there is a biological rationale for switching to riociguat. However, robust data from randomized controlled trials on the safety and efficacy of switching are lacking, as is formal guidance for clinicians. Here we review studies of sequential combination therapy, and trial data and case studies that have investigated switching between PAH-approved therapies, particularly from PDE5i to riociguat in patients with PAH with an insufficient response to PDE5i, and in patients with CTEPH who were receiving off-label treatment. These studies summarize the current evidence and practical real-life experience on the concept of switching treatments.

Population pharmacokinetics of riociguat and its metabolite in patients with chronic thromboembolic pulmonary hypertension from routine clinical practice.

Pharmacokinetic data for riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH) have previously been reported from randomized clinical trials, which may not fully reflect the population encountered in routine practice. The aim of the current study was to characterize the pharmacokinetic of riociguat and its metabolite M1 in the patients from routine clinical practice. A population pharmacokinetic model was developed in NONMEM 7.3, based on riociguat and its metabolite plasma concentrations from 49 patients with CTEPH. One sample with riociguat and M1 concentrations was available from each patient obtained at different time points after last dose. Age, bodyweight, sex, smoking status, concomitant medications, kidney and liver function markers were tested as potential covariates of pharmacokinetic of riociguat and its metabolite. Riociguat and M1 disposition was best described with one-compartment models. Apparent volume of distribution (Vd/F) for riociguat and M1 were assumed to be the same. Total bilirubin and creatinine clearance were the most predictive covariates for apparent riociguat metabolic clearance to M1 (CLf,M1/F) and for apparent riociguat clearance through remaining pathways (CLe,r/F), respectively. CLf,M1/F, CLe,r/F, Vd/F of riociguat and M1, and clearance of M1 (CLe,M1/F) for a typical individual with 70 mL/min creatinine clearance and 0.69 mg/dL total bilirubin were 0.665 L/h (relative standard error = 17%)), 0.66 (18%) L/h, 3.63 (15%) L and 1.47 (19%) L/h, respectively. Upon visual identification of six outlying individuals, an absorption lag-time of 2.95 (6%) h was estimated for these patients. In conclusion, the only clinical characteristics related to riociguat exposure in patients with CTEPH from routine clinical practice are total bilirubin and creatinine clearance. This confirms the findings of the previous population pharmacokinetic studies based on data from randomized clinical trials.

Riociguat for idiopathic interstitial pneumonia-associated pulmonary hypertension (RISE-IIP): a randomised, placebo-controlled phase 2b study

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

RIOCIGUAT IN PATIENTS WITH CHRONIC THROMBOEMBOLIC PULMONARY HYPERTENSION AND SEVERE RENAL IMPAIRMENT

Objective: To demonstrate the efficiency and safety of using riociguat in patients with chronic thromboembolic pulmonary hypertension (CTEPH) and severe renal impairment with creatinine clearance (CrCL) <15 ml/min. Design and method: A 51-year old female was admitted to pulmonary hypertension department with shortness of breath during minimal exertion and cough. At the age of 37 she underwent allogeneic kidney transplantation due to terminal renal impairment, which developed as a result of chronic glomerulonephritis. Nephropathy of transplanted kidney progressed within following 3 years to creatinine level 350–400 μmol/l. At the age of 49 the patient had pulmonary embolism. After 1 year of anticoagulation therapy there was diagnosed CTEPH, WHO-FC III. Due to severity of renal impairment thrombendarterectomy and balloon pulmonary angioplasty weren’t performed. In department echocardiography showed increased systolic pulmonary artery pressure (PAP) (80 mmHg), mean PAP (44 mmHg). 6-minute walking distance (6MWD) was 360 m. Right heart catheterization and angiopulmonography were not performed due to the high risk of worsening of renal function. The patient was administered riociguat 0.5 mg with gradual increase to 1 mg 3 times a day. Because the product label states, that patients with renal impairment have increased riociguat exposure, daily dose wasn’t enlarged more. Results: After 2 weeks with riociguat we revealed disappearance of cough, increased physical activity (6MWD 416 m), decreased systolic and mean PAP (72 and 41 mmHg). In control blood tests there were no signs of renal function worsening: creatinine before treatment 356 vs after 387 μmol/l, CrCL by Cockroft-Golt – 14 vs 13 ml/min, urea – 18.4 vs 20.3 mmol/l. At 6 months follow-up we observed further reduction of systolic and mean PAP (67 and 39 mmHg), increase of 6MWD (430 m). The sings of renal impairment were at the same level: creatinine 385 μmol/l, CrCL 13 ml/min, urea 21.9 mmol/l. Conclusions: The administration of riociguat for patients with CTEPH and severe renal impairment with CrCL <15 ml/min can be effective and safe, if provided strict control of renal function and carefully adjusted dose.

Pulmonary hypertension due to interstitial lung disease.

Pulmonary hypertension has been reported to complicate the course of a number of fibrotic lung diseases, including idiopathic pulmonary fibrosis, chronic hypersensitivity pneumonitis and nonspecific interstitial pneumonitis. Most commonly, mild elevations in the mean pulmonary artery pressure are seen in patients with advanced pulmonary fibrosis. However, some patients may develop severe pulmonary hypertension, which appears out of proportion to the degree of their restrictive lung disease. The benefits of pulmonary vasodilator therapy have yet to be established in pulmonary hypertension complicating fibrotic lung disease. In fact, one recent clinical trial examining riociguat in patients with pulmonary hypertension complicating idiopathic interstitial pneumonias was terminated early for an increased risk of death or hospitalization. Multiple clinical trials on this topic are currently ongoing, including studies examining inhaled pulmonary vasodilator therapies. The development of pulmonary hypertension is associated with increased exertional oxygen requirements, worsened functional capacity and attenuated life expectancy. It is hoped that continued research will find an effective therapy for this condition, which will improve quality of life and extend life expectancy in patients with this condition.

Balloon pulmonary angioplasty vs riociguat in patients with inoperable chronic thromboembolic pulmonary hypertension: A systematic review and meta‐analysis

BackgroundsNo previous meta‐analyses have compared the efficacy and safety of BPA with riociguat therapy in inoperable CTEPH patients.MethodsRelevant published studies were searched in the PubMed, Embase and ClinicalTrial.gov databases.ResultsTwenty‐three clinical trials including 1454 patients (631 underwent BPA; 823 underwent riociguat therapy) were analyzed. BPA was associated with a greater improvement in RAP (mean difference (MD) = −3.53 mmHg, 95% CI: [−4.85, −2.21] vs MD = −1.05 mmHg, 95% CI: [−1.82, −0.29]); mPAP (MD = −15.02 mmHg, 95% CI: [−17.32, −12.71] vs MD = −4.19 mmHg, 95% CI: [−5.58, −2.80]); PVR (standard MD = −1.32 woods, 95% CI: [−1.57, −1.08] vs standard MD = −0.65 woods, 95% CI: [−0.79, −0.50]); NYHA functional class (RR = 6.78, 95% CI: [3.14, 14.64] vs RR = 1.49, 95% CI: [1.07, 2.07]); and 6MWD (MD = 71.66 m, 95% CI: [58.34, 84.99] vs MD = 45.25 m, 95% CI: [36.51, 53.99]) than riociguat treatment. However, the increase in CO was greater with riociguat (MD = 0.78 L/min, 95% CI: [0.61, 0.96]) than with BPA (MD = 0.33 L/min, 95% CI: [0.06, 0.59]). No significant difference in cardiac index (CI) was found between BPA (MD = 0.40 L/min/m2, 95% CI: [0.21, 0.58]) and riociguat (MD = 0.40 L/min/m2, 95% CI: [0.26, 0.54]). The most common complications of BPA were pulmonary injury (0.3%‐5.6%) and pulmonary edema (0.8%‐28.6%). The most common adverse events of riociguat were headache, dizziness, hypotension and nasopharyngitis.ConclusionsOur meta‐analysis indicates that BPA might be associated with greater improvements in exercise tolerance and pulmonary hemodynamics except for cardiac output and cardiac index than riociguat therapy. However, both of them were well tolerated.

Practical management of riociguat in patients with pulmonary arterial hypertension.

Riociguat is one of several approved therapies available for patients with pulmonary arterial hypertension (PAH). Treatment should be initiated and monitored at an expert center by a physician experienced in treating PAH, and the dose adjusted in the absence of signs and symptoms of hypotension. In certain populations, including patients with hepatic or renal impairment, the elderly, and smokers, riociguat exposure may differ, and dose adjustments should therefore be made with caution according to the established scheme. Common adverse events are often easily managed, particularly if they are discussed before starting therapy. Combination therapy with riociguat and other PAH-targeted agents is feasible and generally well tolerated, although the coadministration of phosphodiesterase type 5 inhibitors (PDE5i) and riociguat is contraindicated. An open-label, randomized study is currently ongoing to assess whether patients who do not achieve treatment goals while receiving PDE5i may benefit from switching to riociguat. In this review, we provide a clinical view on the practical management of patients with PAH receiving riociguat, with a focus on the opinions and personal experience of the authors.The reviews of this paper are available via the supplemental material section.

Initial Riociguat Monotherapy and Transition from Sildenafil to Riociguat in Patients with Idiopathic Pulmonary Arterial Hypertension: Influence on Right Heart Remodeling and Right Ventricular\u2013Pulmonary Arterial Coupling

PurposeTo evaluate the influence of riociguat on World Health Organization functional class (WHO FC), 6-min walk distance (6MWD), right heart remodeling, and right ventricular–pulmonary arterial (RV–PA) coupling in patients with idiopathic pulmonary arterial hypertension (IPAH) who are treatment-naïve or who have failed to achieve treatment goals with sildenafil therapy.MethodsTwenty patients with IPAH were enrolled: 12 had not previously received PAH-targeted therapy (treatment-naïve subgroup) and 8 had been receiving sildenafil therapy but failed to achieve treatment goals; on entering this pilot study these 8 patients were switched from sildenafil to riociguat therapy (treatment-switch subgroup). Patients received riociguat individually dose-adjusted up to a maximum of 2.5 mg three times daily. After 12 weeks, patients were assessed for WHO FC, 6MWD, right heart remodeling, and RV–PA coupling.ResultsRiociguat significantly improved WHO FC in treatment-naïve patients (from 0/4/8/0 patients in WHO I/II/III/IV at baseline to 1/6/5/0 at week 12) and in treatment-switch patients (from 0/4/4/0 patients in WHO I/II/III/IV at baseline to 1/4/3/0 at week 12). Additionally, treatment-naïve and treatment-switch patients showed significant improvements at week 12 versus baseline in 6MWD (increases of + 76.8 m and + 71.6 m, respectively), RV systolic function, and RV–PA coupling.ConclusionThese results support the proven efficacy of riociguat in patients with IPAH, including treatment-naïve patients and those switching to riociguat following failure to achieve treatment goals with sildenafil, and suggest that it may be possible to delay disease progression in this patient group.

Sequential treatment with sildenafil and riociguat in patients with persistent or inoperable chronic thromboembolic pulmonary hypertension improves functional class and pulmonary hemodynamics

BackgroundThis 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. MethodsThe 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. ResultsCompared 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. ConclusionsReplacing sildenafil with riociguat in patients with inoperable or persistent CTEPH may improve pulmonary hemodynamics and FC.

Soluble guanylate cyclase stimulators and phosphodiesterase-5 inhibitors in therapy of some groups of pulmonary hypertension

Pulmonary hypertension (PH) is a large group of diseases characterized by pulmonary artery pressure (PAP) > 25 mm Hg. Currently, specific medications are available for several groups of PH only. These are prostacyclin analogues, soluble guanylate cyclase (sGC) stimulators (sGCS), phosphodiesterase-5 inhibitors (iPDE-5), and endothelin receptor antagonists. Modern evidence-based pharmacological treatment of PH and therapeutic algorithm have been described in this review. Particular attention was paid to mechanisms of dysregulation of vascular tone including nitric oxide (NO-sGC-cGMP) pathway that is a target for sGCS and iPDE-5. A new class of sGCS principally differs from iPDE-5 and is very important for clinical practice. Safety, availability and benefit of switching from iPDE-5 to riociguat was investigated in the RESPITE trial. Results of main clinical trials of efficacy and safety of riociguat in patients with pulmonary arterial hypertension and thromboembolic PH were also discussed in this review.

Modern view on the place of riociguat in the treatment of pulmonary hypertension.

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

Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study

BackgroundFollowing 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.MethodsWe 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.ResultsIn 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.ConclusionsRiociguat 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.Trial registrationClinicalTrials.org NCT01784562. Registered February 4, 2013.

Riociguat for patients with chronic thromboembolic pulmonary hypertension: Usefulness of transitioning from phosphodiesterase type 5 inhibitor.

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.

Riociguat: a soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension.

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

Comparison of hemodynamic parameters in treatment-naïve and pre-treated patients with pulmonary arterial hypertension in the randomized phase III PATENT-1 study

Detailed hemodynamic data from the phase III PATENT-1 study of riociguat in patients with pulmonary arterial hypertension (PAH) were investigated. Patients with PAH who were treatment naïve or pre-treated with endothelin receptor antagonists or non-intravenous prostanoids were randomly assigned to riociguat up to 2.5 mg 3 times a day or placebo. Hemodynamic parameters were assessed at baseline and week 12. Riociguat significantly decreased pulmonary vascular resistance in treatment-naïve (n = 221; least squares [LS] mean difference -266 dyne∙sec∙cm-5 [95% confidence interval (CI) -357 to -175; p < 0.0001]) and pre-treated (n = 222; LS mean difference -186 dyne∙sec ∙cm-5 [95% CI -252 to -120; p < 0.0001]) patients and significantly increased cardiac index (LS mean difference +0.7 [95% CI 0.5 to 0.8] and +0.5 [95% CI 0.3 to 0.7], respectively [both p < 0.0001]). Mean pulmonary artery pressure (p = 0.0056 and p = 0.0019 for treatment-naïve and pre-treated patients, respectively), mean arterial pressure (both p < 0.0001), and systemic vascular resistance (both p < 0.0001) were significantly reduced, and there was an increase in mixed venous oxygen saturation (p < 0.0001 and p = 0.0004, respectively). Results were similar in patients pre-treated with endothelin receptor antagonists and patients pre-treated with non-intravenous prostanoids. Improvements in 6-minute walking distance correlated very weakly with improvements in pulmonary vascular resistance (r = -0.21 [95% CI -0.30 to -0.11; p < 0.0001]) and cardiac index (r = 0.16 [95% CI 0.06 to 0.25; p < 0.0016]). Riociguat significantly improved hemodynamic parameters in pre-treated and treatment-naïve patients with PAH.

Haemodynamic effects of riociguat in inoperable/recurrent chronic thromboembolic pulmonary hypertension

ObjectiveWe compared the haemodynamic effects of riociguat in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) or persistent/recurrent CTEPH after pulmonary endarterectomy in the Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate...

Riociguat for the treatment of pulmonary hypertension: a safety evaluation

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