Dataset Information

Riociguat for the treatment of pulmonary hypertension: Chinese subgroup analyses and comparison.

ABSTRACT:

Objective

PATENT-1 and CHEST-1 were pivotal, international phase III trials assessing riociguat for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Here we compare Chinese patients from these studies with the overall populations, and report the clinical effect and safety of riociguat in Chinese patients with PAH and CTEPH.

Methods

PATENT-1 was a 12-week, randomised, double-blind, placebo-controlled trial of riociguat (maximum 2.5 mg three times daily or 1.5 mg three times daily (exploratory) in patients with PAH. CHEST-1 was a 16-week, randomised, double-blind, placebo-controlled trial of riociguat (maximum 2.5 mg three times daily) in patients with inoperable CTEPH or persistent/recurrent pulmonary hypertension after pulmonary endarterectomy. The primary endpoint in each study was change from baseline to study end in 6 min walking distance (6MWD). Secondary endpoints included pulmonary vascular resistance (PVR), N-terminal prohormone of brain natriuretic peptide, WHO functional class (FC), and time to clinical worsening.

Results

Chinese patients in PATENT-1 (n=77) and CHEST-1 (n=32) were younger and had better baseline 6MWD and WHO FC versus the overall population. Riociguat increased 6MWD versus placebo in Chinese patients in PATENT-1 and CHEST-1, with a greater increase observed in CHEST-1 (least-squares mean differences +46 m and +102 m in PATENT-1 and CHEST-1, respectively). Riociguat also improved several secondary endpoints in both studies, and was well tolerated.

Conclusions

Chinese patients displayed differences in baseline characteristics versus the overall populations in PATENT-1 and CHEST-1. Riociguat improved 6MWD, PVR, WHO FC, and other clinical outcomes in Chinese patients with PAH or CTEPH.

Trial registration number

PATENT-1: NCT00810693, Results; CHEST-1 NCT00855465, Results.

SUBMITTER: Wang C

PROVIDER: S-EPMC4898635 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Riociguat for the treatment of pulmonary hypertension: Chinese subgroup analyses and comparison.

Wang Chen C Jing Zhi-Cheng ZC Huang Yi-Gao YG Zhou Da-Xin DX Liu Zhi-Hong ZH Meier Christian C Nikkho Sylvia S Curram John J Zhang Peng P He Jian-Guo JG

Heart Asia 20160517 1

<h4>Objective</h4>PATENT-1 and CHEST-1 were pivotal, international phase III trials assessing riociguat for pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Here we compare Chinese patients from these studies with the overall populations, and report the clinical effect and safety of riociguat in Chinese patients with PAH and CTEPH.<h4>Methods</h4>PATENT-1 was a 12-week, randomised, double-blind, placebo-controlled trial of riociguat (maximum 2.5 mg ...[more]

PMID: 27326239

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Project description:IntroductionPulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are rare, life-threatening diseases in which chronically elevated pressure in the pulmonary arteries results in vascular remodeling and right heart failure. Treatment goals are to improve patient functioning, exercise capacity, and symptoms; delay disease progression; normalize the right ventricular function; and, ultimately, improve survival. Therapeutic management centers on the affected physiologic pathways and includes endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclins. Recently, riociguat, a novel therapeutic agent that stimulates soluble guanylate cyclase via the nitric oxide pathway, was approved for the treatment of both PAH and CTEPH. Clinical trial data show that riociguat significantly improves exercise capacity as well as hemodynamic parameters in PAH/CTEPH.MethodsWe report on the early use of riociguat at our center-a large, metropolitan pulmonary hypertension treatment facility that cares for >250 patients with PAH/CTEPH. Through our initial clinical experience, we offer evidence on the benefits of riociguat in three patients with PAH associated with different etiologies, symptoms, and treatment goals.ResultsOverall, patients at our center who have received riociguat have experienced clinical benefits, including improvement in symptomatic and hemodynamic parameters, increase in 6-min walk distance, and improvement or stabilization of World Health Organization functional class. In several cases, initial response to riociguat has been encouraging and has helped patients reach their treatment goals. Riociguat appears to be well tolerated, with only one patient experiencing mild, self-limiting side effects.ConclusionNovel agents are continuously being introduced into the PAH/CTEPH armamentarium, and clinicians must decide how best to integrate them into their existing treatment algorithms. This case series offers initial evidence from our practice on the benefits of riociguat in optimizing hemodynamic and functional parameters. These benefits have been observed in PAH associated with different etiologies and functional status, and in both first-line and combination use.FundingBayer HealthCare Pharmaceuticals.

Project description:BackgroundRiociguat 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.MethodsRandomized 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.ResultsFour 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.ConclusionsWe 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.

Project description:This analysis aimed to characterize the pharmacokinetics (PK) and PK/pharmacodynamic (PK/PD) relationship of riociguat and its metabolite M1 in patients with chronic thromboembolic pulmonary hypertension (CTEPH) or pulmonary arterial hypertension (PAH). Blood samples were collected in two phase 3 studies-PATENT-1 (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 12 weeks; PAH) and CHEST-1 (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1; 16 weeks; CTEPH)-and long-term extensions. Patients were initially randomized to receive placebo or riociguat, and they received riociguat in the extensions. Nonlinear mixed-effects modeling was used to develop a population PK model describing riociguat PK. PK/PD relationships were investigated by comparing derived PK parameters with changes in PD parameters. Covariate analyses included smoking status, bosentan comedication, bilirubin levels, and baseline creatinine clearance. The PK of riociguat/M1 was described by a one-compartment model. Mean population estimates for riociguat absorption rate constant, clearance, and volume of distribution were 2.17/h, 1.81 L/h, and 32.3 L, respectively; for M1 they were 0.258/h, 3.16 L/h, and 124 L. Interindividual variability was moderate for riociguat and moderate to high for M1. There was no evidence of time- or dose-dependent changes in riociguat/M1 PK. Riociguat clearance was higher in smokers (120% increase) and bosentan-treated patients (36% increase) than in nonsmokers and those not receiving bosentan. There was an inverse correlation between bilirubin and riociguat clearance. In PK/PD analyses, 6-minute walk distance was related to hemodynamic parameters, particularly pulmonary vascular resistance. Riociguat PK were described by a one-compartment model. Effects of covariates on riociguat and M1 PK were established, and a PK/PD relationship was demonstrated. (ClinicalTrials.gov identifiers: PATENT-1, NCT00810693; PATENT-2, NCT00863681; CHEST-1, NCT00855465; CHEST-2, NCT00910429.).

Dataset Information

Riociguat for the treatment of pulmonary hypertension: Chinese subgroup analyses and comparison.

Objective

Methods

Results

Conclusions

Trial registration number

Publications

Riociguat for the treatment of pulmonary hypertension: Chinese subgroup analyses and comparison.

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