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

ABSTRACT: We 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 Cyclase-Stimulator Trial 1 study.Patients with inoperable or persistent/recurrent CTEPH (n=261; mean± SD age 59±14?years; 66% women) were randomised to riociguat (up to 2.5?mg three times daily) or placebo. Haemodynamic parameters were assessed at baseline and week 16.Riociguat decreased pulmonary vascular resistance (PVR) in inoperable (n=189; least-squares mean difference: -285?dyn?s/cm5 (95% CI -357 to -213); p<0.0001) and persistent/recurrent (n=72; -131 dyn?s/cm5 (95% CI -214 to -48); p=0.0025) patients. Cardiac index improved in inoperable patients by a least-squares mean difference of +0.6?L/min/m2 (95% CI 0.4 to 0.7; p<0.0001), while in persistent/recurrent patients the change was +0.2?L/min/m2 (95% CI -0.1 to 0.5; p=0.17). Mean pulmonary artery pressure decreased in inoperable and persistent/recurrent patients(-4.7?mm?Hg (95% CI -6.9 to -2.6; p<0.0001 and -4.8?mm?Hg (-8.2 to -1.5; p=0.0055), respectively). For all patients, changes in 6?min walk distance correlated with changes in PVR (r=-0.29 (95% CI -0.41 to -0.17); p<0.0001) and cardiac index (r=0.23 (95% CI 0.10 to 0.35); p=0.0004).Riociguat improved haemodynamics in patients with inoperable CTEPH or persistent/recurrent CTEPH.NCT00855465.

SUBMITTER: Kim NH

PROVIDER: S-EPMC5529957 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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

Kim Nick H NH D'Armini Andrea M AM Grimminger Friedrich F Grünig Ekkehard E Hoeper Marius M MM Jansa Pavel P Mayer Eckhard E Neurohr Claus C Simonneau Gérald G Torbicki Adam A Wang Chen C Fritsch Arno A Davie Neil N Ghofrani Hossein-Ardeschir HA

Heart (British Cardiac Society) 20161223 8

<h4>Objective</h4>We 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 Cyclase-Stimulator Trial 1 study.<h4>Methods</h4>Patients with inoperable or persistent/recurrent CTEPH (n=261; mean± SD age 59±14 years; 66% women) were randomised to riociguat (up to 2.5 mg three times daily) or plac ...[more]

PMID: 28011757

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Project description:Objective:Inoperable chronic thromboembolic pulmonary hypertension (CTEPH) managed medically has a poor prognosis. Balloon pulmonary angioplasty (BPA) offers a new treatment for inoperable patients. The national BPA service for the UK opened in October 2015 and we now describe the treatment of our initial patient cohort. Methods:Thirty consecutive, inoperable, anatomically suitable, symptomatic patients on stable medical therapy for CTEPH were identified and offered BPA. They initially underwent baseline investigations including Cambridge Pulmonary Hypertension Outcome Review (CAMPHOR) quality of life (QoL) questionnaire, cardiopulmonary exercise test, 6 min walk distance (6MWD), transthoracic echocardiography, N-terminal probrain natriuretic peptide (NT pro-BNP) and right heart catheterisation. Serial BPA sessions were then performed and after completion, the treatment effect was gauged by comparing the same investigations at 3 months follow-up. Results:A median of 3 (IQR 1-6) BPA sessions per patient resulted in a significant improvement in functional status (WHO functional class ≥3: 24 vs 4, p<0.0001) and QoL (CAMPHOR symptom score: 8.7±5.4 vs 5.6±6.1, p=0.0005) with reductions in pulmonary pressures (mean pulmonary artery pressure: 44.7±11.0 vs 34.4±8.3 mm Hg, p<0.0001) and resistance (pulmonary vascular resistance: 663±281 vs 436±196 dyn.s.cm-5, p<0.0001). Exercise capacity improved (minute ventilation/carbon dioxide production: 55.3±12.2 vs 45.0±7.8, p=0.03 and 6MWD: 366±107 vs 440±94 m, p<0.0001) and there was reduction in right ventricular (RV) stretch (NT pro-BNP: 442 (IQR 168-1607) vs 202 (IQR 105-447) pg/mL, p<0.0001) and dimensions (mid RV diameter: 4.4±1.0 vs 3.8±0.7 cm, p=0.002). There were no deaths or life-threatening complications and the mild-moderate per-procedure complication rate was 10.5%. Conclusions:BPA is safe and improves the functional status, QoL, pulmonary haemodynamics and RV dimensions of patients with inoperable CTEPH.

Project description:BACKGROUND: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. METHODS: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. RESULTS: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. CONCLUSIONS: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. TRIAL REGISTRATION:ClinicalTrials.org NCT01784562 . Registered February 4, 2013.

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.).

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.

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

Publications

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

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