Dataset Information

Effect of riociguat on pulmonary arterial compliance in the PATENT and CHEST studies.

ABSTRACT: Pulmonary arterial compliance is a measure of the pulsatile afterload of the right ventricle. Lower pulmonary arterial compliance is associated with reduced right ventricular function and worse prognosis in pulmonary hypertension. The effect of pulmonary vasodilators on pulmonary arterial compliance has not been evaluated in detail in pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. In this post hoc analysis of patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension in the PATENT and CHEST studies, we evaluated the change in pulmonary arterial compliance with riociguat versus placebo. Association of pulmonary arterial compliance with clinical outcomes was assessed using Kaplan-Meier and Cox proportional hazards analyses. Compared with placebo, riociguat significantly improved pulmonary arterial compliance in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulmonary arterial compliance at baseline was associated with survival and clinical worsening-free survival in pulmonary arterial hypertension but only with clinical worsening-free survival in chronic thromboembolic pulmonary hypertension. In patients with pulmonary arterial hypertension, pulmonary arterial compliance at follow-up ≥1.6 mL/mmHg was associated with better outcomes than pulmonary arterial compliance <1.6 mL/mmHg. In patients with chronic thromboembolic pulmonary hypertension, pulmonary arterial compliance at follow-up did not predict outcomes. Cox proportional hazards analyses showed no association between change in pulmonary arterial compliance and outcomes in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. In conclusion, riociguat improved pulmonary arterial compliance in patients with pulmonary arterial hypertension or chronic thromboembolic pulmonary hypertension. Pulmonary arterial compliance at baseline or follow-up, rather than change in pulmonary arterial compliance, is of prognostic importance for outcomes.

SUBMITTER: Thenappan T

PROVIDER: S-EPMC7686638 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:BackgroundThe evidence regarding triple oral combination therapy for patients with pulmonary arterial hypertension (PAH) is scarce. This study was performed to investigate the effectiveness and safety of triple oral combination therapy with macitentan, riociguat, and selexipag.MethodsAmong consecutive patients with PAH who were referred to our hospital from 2009 to 2020, those who underwent triple oral combination therapy using macitentan, riociguat, and selexipag were retrospectively analyzed. Hemodynamic and echocardiographic assessments and Kaplan-Meier analyses of all-cause death and initiation of prostacyclin infusion were conducted.ResultsTwenty-six patients underwent this combination therapy. These patients were predominantly female (73.1%) with a median age of 38 years at baseline and nine patients were taking some PAH medications at baseline. The median time from initiation of the first PAH drug to the third PAH drug in treatment naïve patients was 24 days (interquartile range, 12-47 days). Four patients (15.0%) discontinued taking any of the three vasodilators because of adverse events, and 17 patients (65.4%) reached the maximum dose of all three drugs. The mean pulmonary arterial pressure, pulmonary vascular resistance, and cardiac output improved by 29%, 65%, and 82%, respectively (median observation period: 441 days) and similar improvements were observed in treatment-naïve patients at baseline. The survival rate and prostacyclin infusion-free rate since administration of all three vasodilators was 93.3% and 74.6% at 3 years, respectively. When patients were divided by risk stratification, the prostacyclin-free rate at 3 years was 92.9% in low-/intermediate-risk patients and 55.0% in high-risk patients.ConclusionTriple oral combination therapy with macitentan, riociguat, and selexipag sufficiently improved clinical parameters and was well tolerated in patients with PAH. This combination could be a particularly promising strategy in patients with low/intermediate risk and possibly even in half of patients with high risk. Further studies are needed to validate these findings.The reviews of this paper are available via the supplemental material section.

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

Effect of riociguat on pulmonary arterial compliance in the PATENT and CHEST studies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets