Publications by authors named "Pavel Jansa"

54 Publications

Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial.

Lancet Respir Med 2021 Mar 24. Epub 2021 Mar 24.

Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Saclay, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, and Inserm U999, Le Kremlin-Bicêtre, France.

Background: 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.

Methods: 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.

Findings: 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.

Interpretation: 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.

Funding: Bayer AG, Merck Sharp & Dohme.
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http://dx.doi.org/10.1016/S2213-2600(20)30532-4DOI Listing
March 2021

Computed tomography angiographic parameters of pulmonary artery as prognostic factors of residual pulmonary hypertension after pulmonary endarterectomy.

J Int Med Res 2021 Mar;49(3):3000605211002024

Department of Cardiovascular Surgery, General University Hospital in Prague and First Faculty of Medicine, Charles University in Prague, Czech Republic.

Objectives: This study aimed to retrospectively assess using computed tomography pulmonary angiography (CTPA) for predicting residual pulmonary hypertension (RPH) in patients with chronic thromboembolic pulmonary hypertension (CTEPH) after pulmonary endarterectomy (PEA).

Methods: We retrospectively analyzed data of 131 patients with CTEPH who underwent PEA in our center (2008-2015). We measured several diameters of the pulmonary artery and thoracic aorta preoperatively. We evaluated the relationship between these measurements (and their indices) and signs of RPH represented by pulmonary artery systolic pressure (PASP) estimated by echocardiography.

Results: Significant correlations were observed between the aortopulmonary index and prediction of any residual hypertension and moderate/severe hypertension 1 year after PEA, and any residual hypertension and severe hypertension 2 years after PEA. The aortopulmonary index was significantly related to a reduction in PASP 1 year after the operation. A lower aortopulmonary index (≤0.88 for the ascending aorta and ≤0.64 for the descending aorta) predicted lower RPH.

Conclusions: Preoperative CTPA parameters can be used to assess the risk of RPH after PEA. The aortopulmonary index has significant predictive value for RPH and a reduction in PASP after PEA. Lower values of the aortopulmonary index suggest a better outcome after PEA.
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http://dx.doi.org/10.1177/03000605211002024DOI Listing
March 2021

Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension: Final safety data from the EXPERT registry.

Respir Med 2021 Mar 12;178:106220. Epub 2020 Nov 12.

Department of Respiratory Medicine and the German Center for Lung Research, Hannover Medical School, Hannover, Germany.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH) following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.

Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits and collated via case report forms.

Results: In total, 956 patients with CTEPH were included in the analysis. The most common AEs in these patients were peripheral edema/edema (11.7%), dizziness (7.5%), right ventricular (RV)/cardiac failure (7.7%), and pneumonia (5.0%). The most common SAEs were RV/cardiac failure (7.4%), pneumonia (4.1%), dyspnea (3.6%), and syncope (2.5%). Exposure-adjusted rates of hemoptysis/pulmonary hemorrhage and hypotension were low and comparable to those in the long-term extension study of riociguat (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial [CHEST-2]).

Conclusion: Data from EXPERT show that in patients with CTEPH, the safety of riociguat in routine practice was consistent with the known safety profile of the drug, and no new safety concerns were identified.
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http://dx.doi.org/10.1016/j.rmed.2020.106220DOI Listing
March 2021

The prevalence and clinical outcome of supraventricular tachycardia in different etiologies of pulmonary hypertension.

PLoS One 2021 20;16(1):e0245752. Epub 2021 Jan 20.

1stFaculty of Medicine, 2nd Department of Medicine-Department of Cardiovascular Medicine, General University Hospital, Charles University, Prague, Czech Republic.

Purpose: Patients with pulmonary hypertension (PH) frequently suffer from supraventricular tachycardias (SVT). The main purpose of our study was to identify the cumulative incidence of SVT in patients with different etiologies of PH. The secondary objective was to analyse the clinical impact of SVT.

Methods: We retrospectively studied the prevalence of SVT and the clinical outcome in 755 patients (41% males; 60 ± 15 years; mean follow-up 3.8 ± 2.8 years) with PH of different etiologies. The prevalence of SVT was analysed separately in isolated pre-capillary PH (Ipc-PH) and in patients with combined post- and pre-capillary PH (Cpc-PH).

Results: The prevalence of SVT in the Ipc-PH group (n = 641) was 25% (n = 162). The most prevalent arrhythmias were atrial fibrillation followed by a typical atrial flutter (17% and 4.4% of all Icp-PH patients). An excessive prevalence of SVT was found in patients with pulmonary arterial hypertension associated with congenital heart disease (35%, p = 0.01). Out of the overall study population, Cpc-PH was present in 114 (15%) patients. Patients with Cpc-PH manifested a higher prevalence of SVT than subjects with Ipc-PH (58; 51% vs. 162; 25%; p <0.0001) and were more likely to have persistent or permanent atrial fibrillation (38; 29% vs. 61; 10%; p <0.0001). Parameters significantly associated with mortality in a multivariate analysis included age, male gender, functional exercise capacity and right atrial diameter (p < 0.05). Neither diagnosis of SVT nor type of arrhythmia predicted mortality.

Conclusions: The study detected a significant prevalence of SVT in the population of PH of different origins. Different spectrum and prevalence of arrhythmia might be expected in different etiologies of PH. Patients with an elevated post-capillary pressure showed a higher arrhythmia prevalence, predominantly due to an excessive number of atrial fibrillations. The diagnosis of SVT was not associated with mortality.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0245752PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817034PMC
January 2021

Riociguat treatment in patients with pulmonary arterial hypertension: Final safety data from the EXPERT registry.

Respir Med 2020 Dec 3;177:106241. Epub 2020 Dec 3.

University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany; Member of the German Center for Lung Research (DZL), Germany.

Objective: The soluble guanylate cyclase stimulator riociguat is approved for the treatment of adult patients with pulmonary arterial hypertension (PAH) and inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension following Phase 3 randomized trials. The EXPosurE Registry RiociguaT in patients with pulmonary hypertension (EXPERT) study was designed to monitor the long-term safety of riociguat in clinical practice.

Methods: EXPERT was an international, multicenter, prospective, uncontrolled, non-interventional cohort study of patients treated with riociguat. Patients were followed for at least 1 year and up to 4 years from enrollment or until 30 days after stopping riociguat treatment. Primary safety outcomes were adverse events (AEs) and serious adverse events (SAEs) coded using Medical Dictionary for Regulatory Activities preferred terms and System Organ Classes version 21.0, collected during routine clinic visits (usually every 3-6 months) and collated via case report forms.

Results: In total, 326 patients with PAH were included in the analysis. The most common AEs in these patients were dizziness (11.7%), right ventricular (RV)/cardiac failure (10.7%), edema/peripheral edema (10.7%), diarrhea (8.6%), dyspnea (8.0%), and cough (7.7%). The most common SAEs were RV/cardiac failure (10.1%), pneumonia (6.1%), dyspnea (4.0%), and syncope (3.4%). The exposure-adjusted rate of hemoptysis/pulmonary hemorrhage was 2.5 events per 100 patient-years.

Conclusion: Final data from EXPERT show that in patients with PAH, the safety of riociguat in clinical practice was consistent with clinical trials, with no new safety concerns identified and a lower exposure-adjusted rate of hemoptysis/pulmonary hemorrhage than in the long-term extension of the Phase 3 trial in PAH.
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http://dx.doi.org/10.1016/j.rmed.2020.106241DOI Listing
December 2020

Incidence of symptomatic venous thromboembolism following hospitalization for coronavirus disease 2019: Prospective results from a multi-center study.

Thromb Res 2021 02 11;198:135-138. Epub 2020 Dec 11.

Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.

Background: Thrombosis and pulmonary embolism appear to be major causes of mortality in hospitalized coronavirus disease 2019 (COVID-19) patients. However, few studies have focused on the incidence of venous thromboembolism (VTE) after hospitalization for COVID-19.

Methods: In this multi-center study, we followed 1529 COVID-19 patients for at least 45 days after hospital discharge, who underwent routine telephone follow-up. In case of signs or symptoms of pulmonary embolism (PE) or deep vein thrombosis (DVT), they were invited for an in-hospital visit with a pulmonologist. The primary outcome was symptomatic VTE within 45 days of hospital discharge.

Results: Of 1529 COVID-19 patients discharged from hospital, a total of 228 (14.9%) reported potential signs or symptoms of PE or DVT and were seen for an in-hospital visit. Of these, 13 and 12 received Doppler ultrasounds or pulmonary CT angiography, respectively, of whom only one patient was diagnosed with symptomatic PE. Of 51 (3.3%) patients who died after discharge, two deaths were attributed to VTE corresponding to a 45-day cumulative rate of symptomatic VTE of 0.2% (95%CI 0.1%-0.6%; n = 3). There was no evidence of acute respiratory distress syndrome (ARDS) in these patients. Other deaths after hospital discharge included myocardial infarction (n = 13), heart failure (n = 9), and stroke (n = 9).

Conclusions: We did not observe a high rate of symptomatic VTE in COVID-19 patients after hospital discharge. Routine extended thromboprophylaxis after hospitalization for COVID-19 may not have a net clinical benefit. Randomized trials may be warranted.
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http://dx.doi.org/10.1016/j.thromres.2020.12.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7836837PMC
February 2021

ERS Statement on Chronic Thromboembolic Pulmonary Hypertension.

Eur Respir J 2020 Dec 17. Epub 2020 Dec 17.

Université Paris-Saclay; Inserm UMR_S 999, Service de Pneumologie, Hôpital Bicêtre (AP-HP), Le Kremlin-Bicêtre, France.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare complication of acute pulmonary embolism, either symptomatic or not. The occlusion of proximal pulmonary arteries by fibrotic intravascular material, in combination with a secondary microvasculopathy of vessels less than 500 µm, leads to increased pulmonary vascular resistance and progressive right heart failure. The mechanism responsible for the transformation of red clots into fibrotic material remnants has not yet been elucidated. In patients with pulmonary hypertension, the diagnosis is suspected when a ventilation/perfusion lung scan shows mismatched perfusion defects and confirmed by right heart catheterisation and vascular imaging. Today, in addition to lifelong anticoagulation, treatment modalities include surgery, angioplasty and medical treatment according to the localisation and characteristics of the lesions.This Statement outlines a review of the literature and current practice concerning diagnosis and management of CTEPH. It covers the definitions, diagnosis, epidemiology, follow up after acute pulmonary embolism, pathophysiology, treatment by pulmonary endarterectomy, balloon pulmonary angioplasty, drugs and their combination, rehabilitation and new lines of research in CTEPH.It represents the first collaboration of the European Respiratory Society (ERS), the International CTEPH Association (ICA) and the European Reference Network (ERN)-Lung in the pulmonary hypertension domain. The Statement summarises current knowledge but does not make formal recommendations for clinical practice.
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http://dx.doi.org/10.1183/13993003.02828-2020DOI Listing
December 2020

Balloon Pulmonary Angioplasty in Patients with Chronic Thromboembolic Pulmonary Hypertension: Impact on Clinical and Hemodynamic Parameters, Quality of Life and Risk Profile.

J Clin Med 2020 Nov 9;9(11). Epub 2020 Nov 9.

2nd Department of Medicine-Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital, 128 08 Prague, Czech Republic.

Balloon pulmonary angioplasty (BPA) is a novel treatment option for patients with chronic thromboembolic pulmonary hypertension (CTEPH) who are not eligible for pulmonary endarterectomy (PEA) or suffer from persistent pulmonary hypertension after PEA. The aim of this study was to evaluate the real-life efficacy and safety of BPA in a consecutive group of patients who were diagnosed and treated in the national referral center for CTEPH in the Czech Republic. Here we report data from 160 BPA procedures performed in 64 patients. Efficacy analysis was performed in the subgroup of 25 patients who completed BPA series. Significant improvements were observed in New York Heart Association functional class (4% to 79% in I/II, < 0.001), 6 min walking test distance (+54.3 m, < 0.001), risk profile (15.8% to 68.5% with presence of 2/3 low risk criteria, < 0.001), pulmonary artery mean pressure (-18%, < 0.001), pulmonary vascular resistance (-32%, < 0.001), stroke volume (+17%, = 0.011) and quality of life (+37% in assessment of overall health status by a patient, < 0.001). We observed 1 fatal periprocedural complication (1.6% of all 64 patients) and 19 BPA-related non-fatal complications (11.9% of all 160 interventions) that predominantly included hemoptysis (10.0% of all sessions). Overall survival at 12 months was 94.6%.
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http://dx.doi.org/10.3390/jcm9113608DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697583PMC
November 2020

Efficacy and safety of riociguat in combination therapy for patients with pulmonary arterial hypertension (PATENT studies).

Pulm Circ 2020 Jul-Sep;10(3):2045894020942121. Epub 2020 Jul 16.

Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, and Institut National de la Santé et de la Recherche Médicale Unité 999, Le Kremlin-Bicêtre, France.

Many patients with pulmonary arterial hypertension do not achieve treatment goals with monotherapy, and therefore combination therapy is becoming the standard of care. The soluble guanylate cyclase stimulator riociguat is licensed for the treatment of pulmonary arterial hypertension; here we present findings from patients who were receiving combined riociguat plus endothelin receptor antagonists or non-intravenous prostanoids in the randomized, placebo-controlled PATENT-1 study and its open-label extension (PATENT-2). Moreover, we include new data from patients receiving early sequential combination therapy (three to six months of endothelin receptor antagonist treatment) or long-term background endothelin receptor antagonist therapy (>6 months). Patients were randomized to riociguat 2.5 mg-maximum ( = 131 pretreated patients) and placebo ( = 60 pretreated patients). Riociguat improved 6-min walking distance (PATENT-1 primary endpoint), functional capacity, and hemodynamics after 12 weeks in pretreated patients. The placebo-corrected changes in 6-min walking distance were +24 m in endothelin receptor antagonist-pretreated patients and +106 m in the small group of prostanoid-pretreated patients. In the early sequential combination and long-term background endothelin receptor antagonist groups, the placebo-corrected changes in 6-min walking distance were +65 m (95% CI: 17 to 113 m) and +13 m (95% CI: -8 to 33 m), respectively. In conclusion, these data suggest that early sequential combination of an endothelin receptor antagonist plus riociguat is a feasible treatment option. Both early sequential therapy and long-term background endothelin receptor antagonist plus riociguat were well tolerated in the PATENT studies.
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http://dx.doi.org/10.1177/2045894020942121DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7366414PMC
July 2020

Atrial fibrillation and atrial tachycardia in patients with chronic thromboembolic pulmonary hypertension treated with pulmonary endarterectomy.

Eur Heart J Suppl 2020 Jul 15;22(Suppl F):F30-F37. Epub 2020 Jul 15.

2nd Department of Medicine - Department of Cardiovascular Medicine, General University Hospital in Prague, 1st Faculty of Medicine, Charles University, U Nemocnice 2, Prague 128 08, Czech Republic.

Atrial fibrillation (AF) and atrial tachycardia (AT) are frequently observed in patients with chronic thromboembolic pulmonary hypertension (CTEPH) who were treated with pulmonary endarterectomy (PEA). Their prevalence and impact on prognosis of patients are not known. We analysed the prevalence of AF/AT and the clinical outcome in 197 patients with CTEPH treated with PEA (median age 62; interquartile range 53-68 years; 62% males). The prevalence of AF/AT was 29% (57 patients). Compared to patients without arrhythmia, the subjects with AF/AT were older [60 (50-67) vs. 62 (57-70) years], manifested an increased size of the left atrium [39 (35-44) vs. 45 (40-50) mm], had a reduced 6-min walking distance [411 (321-506) vs. 340 (254-460) m], and higher pulmonary artery systolic pressure after PEA [38 (30-47) vs. 45 (38-71) mmHg], all results with -value <0.05. During the follow-up with a median 4.2 (1.6-6.3) years, 45 (23%) patients died. In a multivariate Cox regression model only the male gender [hazard ratio (HR) 2.27, 95% confidence interval (CI) 1.15-4.50], a reduced 6-min walking distance (HR 3.67, 95% CI 1.74-7.73), and an increased New York Heart Association class (HR 8.56, 95% CI 4.17-17.60) were associated with mortality ( < 0.05). The prevalence of AF/AT in patients with CTEPH treated with PEA is high. Arrhythmias are associated with reduced functional capacity but not with mortality.
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http://dx.doi.org/10.1093/eurheartj/suaa096DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7361671PMC
July 2020

Identifying potential parameters associated with response to switching from a PDE5i to riociguat in RESPITE.

Int J Cardiol 2020 Oct 24;317:188-192. Epub 2020 May 24.

Clinic for Respiratory Medicine, Hannover Medical School, member of the German Center for Lung Research (DZL), Hannover, Germany.

Background: RESPITE evaluated patients with pulmonary arterial hypertension and an inadequate response to phosphodiesterase type 5 inhibitors (PDE5i) who switched to riociguat. This post hoc analysis assessed response to this switch in parameters associated with clinical improvement.

Methods: RESPITE was a 24-week, uncontrolled pilot study (n = 61). Differences in functional, hemodynamic, and cardiac function parameters, REVEAL risk score (RRS), and biomarkers were compared between responders (free from clinical worsening, World Health Organization functional class I/II, and ≥30 m improvement in 6-min walking distance at Week 24) and non-responders.

Results: Of 51 patients (84%) completing RESPITE, 16 (31%) met the responder endpoint. At baseline, there were significant differences between responders and non-responders in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth/differentiation factor 15 (GDF-15), and RRS, whereas there were no differences in hemodynamics or cardiac function. At Week 24, responders had significant improvements in pulmonary arterial compliance, pulmonary vascular resistance, and mean pulmonary arterial pressure, while non-responders showed no significant change. Cardiac efficiency and stroke volume index significantly improved irrespective of responder status.

Conclusions: NT-proBNP, GDF-15, and RRS were identified as potential predictors of response in patients switching from PDE5i to riociguat. Further prospective controlled studies are needed to confirm the association of these parameters with response.
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http://dx.doi.org/10.1016/j.ijcard.2020.05.044DOI Listing
October 2020

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

Pulm Circ 2020 Jan-Mar;10(1):2045894019898031. Epub 2020 Feb 10.

Division of Systems Biomedicine and Pharmacology, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands.

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 (CL/F) and for apparent riociguat clearance through remaining pathways (CL/F), respectively. CL/F, CL/F, Vd/F of riociguat and M1, and clearance of M1 (CL/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.
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http://dx.doi.org/10.1177/2045894019898031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7011339PMC
February 2020

The impact of riociguat on clinical parameters and quality of life in patients with chronic thromboembolic pulmonary hypertension - results of a retrospective clinical registry.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2020 Jan 20. Epub 2020 Jan 20.

2 nd Department of Medicine - Department of Cardiovascular Medicine, First Faculty of Medicine, Charles University and General University Hospital in Prague, Czech Republic.

Aims: The primary objective of the registry was to assess the impact of riociguat on clinical parameters and quality of life in patients with chronic thromboembolic pulmonary hypertension (CTEPH) that was inoperable or persistent/recurrent after pulmonary endarterectomy (PEA). In contrast to randomized pivotal trials, this non-interventional registry evaluated the effectiveness and safety of riociguat in a real-world setting.

Methods: Retrospective data were collected from patients' charts as recorded in routine clinical practice from the initiation of riociguat therapy up to approximately 5 months and 1 year after this initiation.

Results: In total, 51 patients from a single site were enrolled. After 5 months (mean duration) of riociguat treatment, the following improvements from baseline were observed: change of distance in the 6-minute walking distance (6MWD) (P=0.066); change of score from the quality of life questionnaire (EQ5D-5L) (P=0.020), and overall self-assessment of health status (P=0.001). New York Heart Association (NYHA) class improved in 24.3% of patients. After 11.2 months (mean duration) of riociguat treatment, the following improvements from baseline were observed: change of distance in the 6MWD test (P=0.006), and overall self-assessment of health status (P=0.009). NYHA class improved in 46.4% of patients. Riociguat was well tolerated. In total, 4 patients reported side effects, with hospitalization required in one case and 2 patients who had to discontinue the treatment. Annual survival rate was 89.1%.

Conclusion: Riociguat improves functional NYHA class, distance in the 6MWD test and quality of life in a real-world patient population.
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http://dx.doi.org/10.5507/bp.2019.061DOI Listing
January 2020

Prediction Score for persisting perfusion defects after pulmonary embolism.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2020 Dec 13;164(4):394-400. Epub 2019 Sep 13.

Clinical Department of Cardiology and Angiology, 1st Faculty of Medicine, 2nd Medical Department, Charles University, U Nemocnice 499/2, 128 08 Praha 2 - Nove Mesto, Czech Republic.

Aims: Long-term persistence of perfusion defect after pulmonaryembolism (PE) may lead to the development of chronic thromboembolic pulmonary hypertension. Identification of patients at risk of such a complication using a scoring system would be beneficial in clinical practice. Here, we aimed to derive a score for predicting persistence of perfusion defects after PE.

Methods: 83 patients after PE were re-examined 6, 12 and 24 months after the PE episode. Data collected at the time of PE and perfusion status during follow-ups were used for modelling perfusion defects persistence using the Cox proportional hazards model and validated using bootstrap method.

Results: A simple scoring system utilizing two variables (hemoglobin levels and age at the time of PE) was developed. Patients with hemoglobin levels over 140 g/L who were older than 65 years were at the highest risk of perfusion defects; in patients with the same hemoglobin levels and age <65 years, the risk was reduced by 79%, and by 89% in patients with hemoglobin <140 g/L.

Conclusion: The proposed scoring system may be useful in clinical practice for identifying patients with high risk of persisting perfusion defects, flagging them for closer follow up, thus improving the effectiveness of long-term treatment of patients after PE.
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http://dx.doi.org/10.5507/bp.2019.033DOI Listing
December 2020

The left atrial substrate plays a significant role in the development of complex atrial tachycardia in patients with precapillary pulmonary hypertension.

BMC Cardiovasc Disord 2019 06 28;19(1):157. Epub 2019 Jun 28.

2nd Department of Medicine - Department of Cardiovascular Medicine, General University Hospital in Prague, U Nemocnice 2, 12808, Prague, Czech Republic.

Background: Atrial fibrillation (AF) and related atrial tachyarrhythmias (AT), including type I atrial flutter (AFL) are frequently observed in patients with pulmonary hypertension (PH). Their relationship to hemodynamic changes, atrial size, and ventricular function are still not fully verified.

Methods: We retrospectively studied hemodynamic data, echocardiographic findings and arrhythmia incidence in 814 patients with invasively diagnosed precapillary PH (aged 59 ± 14 years; 46% males). Patients with combined or post-capillary PH were excluded.

Results: AF / AT were identified in 225 (28%) of all the study population. Compared to the subgroup without arrhythmia, patients with AF / AT had elevated right atrial pressure (11 ± 5 vs. 9 ± 5 mmHg), wedge pressure (11 ± 3 vs. 10 ± 3), a more enlarged right atrium (50 ± 12 vs. 47 ± 11 mm) and an increased left atrial diameter in the parasternal long axis projection, p <  0.05 for all comparisons. In the multivariate model, the left atrial size, patient age, arterial hypertension, diabetes and type of PH were associated with AF / AT occurrence, p <  0.05. Patients with type I AFL were more frequently male (39 (80%) vs. 62 (42%)), were younger (61 ± 11 vs. 67 ± 10 years), had increased pulmonary artery mean pressure (50 ± 12 vs. 45 ± 12 mmHg), less advanced left atrial dilatation (38 ± 10 vs. 42 ± 7 mm), and a more enlarged right atrium (56 ± 12 vs. 48 ± 11) as compared to subjects with AF or other AT, p <  0.05.

Conclusions: The evidence of elevated wedge pressure and the enlargement of the left atrium especially in patients with AF suggest a parallel involvement of the left atrial substrate in arrhythmia formation despite invasively confirmed evidence of purely isolated precapillary PH. Substantial differences were noticed between patients with type I AFL and the remaining patients with other arrhythmia types.
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http://dx.doi.org/10.1186/s12872-019-1142-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6599239PMC
June 2019

Surgical treatment of chronic thromboembolic pulmonary hypertension.

Vnitr Lek 2019 ;65(5):353-358

Chronic thromboembolic pulmonary hypertension (CTEPH) is a disease characterized by a mean pulmonary artery pressure that exceeds 25 mm Hg and is caused by intraluminal thrombi organisation, stenosis and occlusions of pulmonary artery and its branches and peripheral vascular remodelation. It is a chronic complication of acute pulmonary embolism. The obstruction of pulmonary artery branches increases pulmonary vascular resistance (PVR) and this leads to the right ventricular overload and right-sided heart failure. The treatment of choice is surgical pulmonary endarterectomy (PEA), a procedure that is performed in deep hypothermic cardiac arrest. The only center that specializes into the surgical treatment of patients with CTEPH in the Czech Republic is the Complex Cardiovascular Centre at the General Teaching Hospital in Prague. Between years 2004-2017 there were 314 patients opera-ted (including 50 patients from Slovakia, where this treatment is not available). Patients with peripheral type of CTEPH, who are not indicated for operation and also patients with residual pulmonary hypertension after PEA can be indicated for specific vasodilatation therapy. In indicated cases the treatment may involve the balloon angioplasty or lung transplantation.
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August 2019

Integrating Data From Randomized Controlled Trials and Observational Studies to Assess Survival in Rare Diseases.

Circ Cardiovasc Qual Outcomes 2019 05;12(5):e005095

Division of Cardiovascular Diseases, Allegheny General Hospital, Pittsburgh, PA (R.B.).

Background Conducting randomized controlled trials to investigate survival in a rare disease like pulmonary arterial hypertension has considerable ethical and logistical constraints. In many studies, such as the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) randomized controlled trial, evaluating survival is further complicated by bias introduced by allowing active therapy among placebo-treated patients who clinically deteriorate. Methods and Results SERAPHIN enrolled and followed patients in the same time frame as the US Registry to Evaluate Early And Long-term PAH Disease Management, providing an opportunity to compare observed survival for SERAPHIN patients with predicted survival had they received real-world treatment as in the Registry to Evaluate Early And Long-term PAH Disease Management. From the Registry to Evaluate Early And Long-term PAH Disease Management (N=3515), 734 patients who met SERAPHIN eligibility criteria were selected and their data used to build a prediction model for time to death up to 3 years based on 10 baseline prognostic variables. The model was used to predict a survival curve for each of the 742 SERAPHIN patients via their baseline variables. The average of these predicted survival curves was compared with observed survival of the placebo (n=250) and macitentan 10 mg (n=242) groups using a log-rank test and Cox proportional hazard model. Observed mortality risk for patients randomized to placebo, 62% of whom were taking background pulmonary arterial hypertension therapy, tended to be lower than that predicted for all SERAPHIN patients (16% lower; P=0.259). The observed placebo survival curve closely approximated the predicted survival curve for the first 15 months. Beyond that time, observed risk of mortality decreased compared with predicted mortality, potentially reflecting the impact of crossover of patients in the placebo group to active therapy. Over 3 years, risk of mortality observed with macitentan 10 mg was 35% lower than predicted mortality ( P=0.010). Conclusions These analyses show that, in a rare disease, real-world observational data can complement randomized controlled trial data to overcome some challenges associated with assessing survival in the setting of a randomized controlled trial. Clinical Trial Registration https://www.clinicaltrials.gov . Unique identifiers: NCT00660179 and NCT00370214.
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http://dx.doi.org/10.1161/CIRCOUTCOMES.118.005095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665498PMC
May 2019

Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial.

Lancet Respir Med 2019 03 23;7(3):239-248. Epub 2018 Nov 23.

Department of Internal Medicine II, Division of Cardiology, Medical University of Vienna, Vienna, Austria. Electronic address:

Background: Treprostinil, a prostacyclin analogue, is effective for the treatment of pulmonary arterial hypertension. However, information is scarce regarding treprostinil for treatment of chronic thromboembolic pulmonary hypertension (CTEPH). The aim of this study was to examine the efficacy and safety of subcutaneous treprostinil in this setting.

Methods: In this 24-week, randomised, double-blind controlled trial, we enrolled patients with CTEPH, classified as non-operable, or with persistent or recurrent pulmonary hypertension after pulmonary endarterectomy, in six European expert centres in Austria, Czech Republic, Germany, and Poland. Patients in WHO functional class III or IV with a 6-min walk distance of 150-400 m were randomly assigned at a 1:1 allocation ratio to continuous high-dose subcutaneous treprostinil (target dose around 30 ng/kg per min at week 12) or low-dose subcutaneous treprostinil (target dose around 3 ng/kg per min at week 12). The primary endpoint was the change from baseline in 6-min walk distance at week 24. All patients who received at least one dose of the study drug were included in the intention-to-treat efficacy and safety analyses based on assessment of adverse events. The trial was registered at ClinicalTrialsRegister.eu EudraCT number 2008-006441-10 and ClinicalTrials.gov, number NCT01416636.

Findings: From March 9, 2009, to June 9, 2016, 105 patients were enrolled with 53 (50%) patients randomly assigned to high-dose and 52 (50%) patients to low-dose subcutaneous treprostinil. At week 24, marginal mean 6-min walk distance improved by 44·98 m (95% CI 27·52 to 62·45) in the high-dose group, and by 4·29 m (95% CI -13·34 to 21·92) in the low-dose group (treatment effect 40·69 m, 95% CI 15·86 to 65·53, p=0·0016). 12 serious adverse events were reported in ten (19%) of 52 patients from the low-dose group and 16 serious adverse events were reported in nine (17%) of 53 patients from the high-dose group. The most common treatment-related adverse events in both groups were infusion site pain and other infusion site reactions.

Interpretation: Treatment with subcutaneous treprostinil was safe, and improved exercise capacity in patients with severe CTEPH. Subcutaneous treprostinil provides a parenteral treatment option for patients of WHO functional class III or IV and those who do not tolerate other therapies or need combination treatment.

Funding: SciPharm Sàrl.
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http://dx.doi.org/10.1016/S2213-2600(18)30367-9DOI Listing
March 2019

Residual pulmonary hypertension after pulmonary endarterectomy: A meta-analysis.

J Thorac Cardiovasc Surg 2018 09 17;156(3):1275-1287. Epub 2018 May 17.

2nd Department of Cardiovascular Surgery, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic. Electronic address:

Objective: Chronic thromboembolic pulmonary hypertension is surgically treated through pulmonary endarterectomy. Although pulmonary endarterectomy is the treatment of choice for chronic thromboembolic pulmonary hypertension in terms of both functional outcomes and survival, many patients experience persistent pulmonary hypertension after pulmonary endarterectomy. The study objective was to calculate the pooled estimates of outcomes after pulmonary endarterectomy, including persistent pulmonary hypertension.

Methods: Meta-analyses were conducted on published studies reporting residual/persistent/recurrent pulmonary hypertension in 4868 patients with chronic thromboembolic pulmonary hypertension after pulmonary endarterectomy. The rate of persistent pulmonary hypertension and change in mean pulmonary artery pressure, pulmonary vascular resistance, and 6-minute walk distance after pulmonary endarterectomy were outcomes of interest.

Results: Twenty-five percent of patients with chronic thromboembolic pulmonary hypertension were diagnosed with persistent pulmonary hypertension after pulmonary endarterectomy. Pulmonary endarterectomy reduced mean pulmonary artery pressure and pulmonary vascular resistance by approximately 21 mm Hg (standardized mean difference, 1.75; 95% confidence interval, -1.62 to 1.88; P < .00001) and 561 dyn.s/cm (standardized mean difference, 1.64; 95% confidence interval, -1.58 to 1.70; P < .00001), respectively. Conversely, 6-minute walk distance increased by 96 m (standardized mean difference, -0.83; 95% confidence interval, -0.91 to -0.76; P < .00001) after pulmonary endarterectomy.

Conclusions: Pulmonary endarterectomy is the gold standard treatment for chronic thromboembolic pulmonary hypertension and provides immediate correction of hemodynamic parameters in most patients. However, in up to one quarter of operable cases, pulmonary hypertension persists after surgery. In those patients with persistent pulmonary hypertension, continued medical management with newer agents may be required to improve pulmonary hemodynamics and, therefore, patient outcomes.
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http://dx.doi.org/10.1016/j.jtcvs.2018.04.110DOI Listing
September 2018

Association between six-minute walk distance and long-term outcomes in patients with pulmonary arterial hypertension: Data from the randomized SERAPHIN trial.

PLoS One 2018 28;13(3):e0193226. Epub 2018 Mar 28.

Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France.

Background: Patients with pulmonary arterial hypertension who achieve a six-minute walk distance of 380-440 m may have improved prognosis. Using the randomized controlled trial of macitentan in pulmonary arterial hypertension (SERAPHIN), the association between six-minute walk distance and long-term outcomes was explored.

Methods: Patients with six-minute walk distance data at Month 6 were dichotomized as above or below the median six-minute walk distance (400 m) and assessed for future risk of pulmonary arterial hypertension-related death or hospitalization and all-cause death. Additionally, six-minute walk distance values at baseline, Month 6 and the change from baseline to Month 6 were categorized by quartiles. All associations were analyzed by the Kaplan-Meier method using a log-rank test and Cox regression models.

Results: Patients with a six-minute walk distance >400 m vs. ≤400 m at Month 6 have a reduced risk of pulmonary arterial hypertension-related death or hospitalization (hazard ratio 0.48; 95% confidence interval 0.33-0.69). The risk was also lower for patients with higher quartiles of six-minute walk distance at baseline or Month 6 (baseline: hazard ratio [Q4 (>430 m) vs. Q1 (≤300 m)] 0.23; 95% confidence interval 0.15-0.36; Month 6: hazard ratio [Q4 (>455 m) vs. Q1 (≤348 m)] 0.33; 95% confidence interval 0.19-0.55). In contrast, six-minute walk distance changes at Month 6 were not associated with the risk of pulmonary arterial hypertension-related death or hospitalization (p = 0.477). These findings were consistent when adjusted for known confounders. Similar results were observed for the risk of all-cause death up to end of study.

Conclusions: Patients with pulmonary arterial hypertension walking >400 m had better long-term prognosis. Although changes in six-minute walk distance were not associated with long-term outcomes, assessing absolute six-minute walk distance values remains important in the clinical management of patients with pulmonary arterial hypertension.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193226PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5873992PMC
June 2018

Pulmonary Arterial Hypertension-Related Morbidity Is Prognostic for Mortality.

J Am Coll Cardiol 2018 02;71(7):752-763

Istituto di Malattie dell'Apparato Cardiovascolare, Università di Bologna, Bologna, Italy.

Background: Registry data suggest that disease progression in pulmonary arterial hypertension (PAH) is indicative of poor prognosis. However, the prognostic relevance of PAH-related morbidity has not been formally evaluated in randomized controlled trials.

Objectives: The purpose of these analyses was to assess the impact of morbidity events on the risk of subsequent mortality using the landmark method and data from the SERAPHIN and GRIPHON studies.

Methods: For each study, the risk of all-cause death up to the end of the study was assessed from the landmark time point (months 3, 6, and 12) according to whether a patient had experienced a primary endpoint morbidity event before the landmark. Each analysis was conducted using data from all patients who were available for survival follow-up at the landmark.

Results: In the SERAPHIN study, on the basis of the 3-month landmark time point, patients who experienced a morbidity event before month 3 had an increased risk of death compared with patients who did not (hazard ratio [HR]: 3.39; 95% confidence interval [CI]: 1.94 to 5.92). In the GRIPHON study, on the basis of the 3-month landmark time point, there was also an increased risk with a HR of 4.48; (95% CI: 2.98 to 6.73). Analyses based on 6-month and 12-month landmarks also showed increased risk in patients who experienced morbidity events, albeit with a reduced HR.

Conclusions: These results demonstrate the prognostic relevance of PAH-related morbidity as defined in the SERAPHIN and GRIPHON studies, highlighting the importance of preventing disease progression in patients with PAH and supporting the clinical relevance of SERAPHIN and GRIPHON morbidity events. (Study of Macitentan [ACT-064992] on Morbidity and Mortality in Patients With Symptomatic Pulmonary Arterial Hypertension [SERAPHIN]; NCT00660179; Selexipag [ACT-293987] in Pulmonary Arterial Hypertension [GRIPHON]; NCT01106014).
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http://dx.doi.org/10.1016/j.jacc.2017.12.010DOI Listing
February 2018

Reperfusion after pulmonary embolism - long-term follow-up, risk factors, clinical impact.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018 Jun 24;162(2):121-126. Epub 2018 Jan 24.

Clinical Department of Cardiology and Angiology, 1 st Faculty of Medicine, 2.

Background And Aim: Thromboembolic disease is the third most common cardiovascular disorder and deep vein thrombosis carries the risk of pulmonary embolism (PE). Questions related to reperfusion after PE remain, especially risk factors. Incomplete reperfusion after PE is closely related to the development of chronic thromboembolic pulmonary hypertension. The aim of this study was to determine the relation between reperfusion after PE in the long term over a period of 24 months, laboratory results and clinical risk factors found during the initial PE event.

Patients And Methods: 85 consecutive patients with a first episode of acute PE, diagnosed at 4 cardiology clinics, were followed up using clinical evaluation, scintigraphy and echocardiography (6, 12 and 24 months after the PE. 35 patients were in the low risk category (41%), 42 (49%) in the intermediate risk group and 8 (9%) in the high risk category.

Results: Perfusion defects persisted in 20 patients (26%) after 6 months, in 19 patients (25%) after 12 months and in 14 patients (19%) after 24 months. The incidence was more frequent in older patients, with more serious (higher risk) PE, increased right ventricular internal diameter during the initial episode, and more significant tricuspid insufficiency in the initial echocardiography. Notably, higher hemoglobin levels were also shown as a significant risk factor. The presence of perfusion defects after 24 months correlated with a concurrent higher pulmonary pressure but not with either patient function or adverse events (recurrence of PE, re-hospitalization or bleeding). In 3 cases (4% of patients), long-term echocardiographic evidence of pulmonary hypertension was detected.

Conclusion: Even after 24 months from acute PE with adequate anticoagulation treatment, incomplete reperfusion was found in 19% of patients with a corresponding risk of chronic thromboembolic pulmonary disease and hypertension.
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http://dx.doi.org/10.5507/bp.2018.001DOI Listing
June 2018

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

BMC Pulm Med 2017 Dec 28;17(1):216. Epub 2017 Dec 28.

Division of Cardiothoracic Surgery, Foundation "IRCCS Policlinico San Matteo", University of Pavia School of Medicine, Pavia, Italy.

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.
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http://dx.doi.org/10.1186/s12890-017-0563-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745920PMC
December 2017

Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial.

Am J Cardiovasc Drugs 2018 Feb;18(1):1-11

Cardiopulmonary Department, Ignacio Chávez National Heart Institute, Mexico City, Mexico.

SERAPHIN was a double-blind, placebo-controlled, event-driven phase III trial that evaluated the effects of long-term treatment with macitentan, an oral endothelin receptor antagonist, in patients with pulmonary arterial hypertension (PAH). The majority of patients were receiving PAH therapy at enrollment, providing the opportunity to evaluate the efficacy and safety of macitentan in combination with other PAH therapies (predominantly phosphodiesterase type 5 inhibitors [PDE-5i]). In patients receiving background therapy, macitentan reduced the risk of morbidity/mortality by 38% compared with placebo (hazard ratio [HR] 0.62; 95% confidence level [CL] 0.43-0.89; p = 0.009). Furthermore, patients receiving macitentan and background therapy had a 37% reduction in the risk of being hospitalized for PAH (HR 0.63; 95% CL 0.41-0.96) compared with patients receiving background therapy only (placebo arm). Macitentan treatment in combination with background therapy was also associated with improvements in exercise capacity, functional class, cardiopulmonary hemodynamics, and health-related quality of life compared with background therapy alone. The safety profile of macitentan as part of a combination therapy regimen was consistent with that of macitentan in the overall SERAPHIN population. The SERAPHIN study has provided evidence that combination therapy with macitentan and a PDE-5i is effective and well tolerated in the management of PAH. Based on these data, and those from subsequent long-term trials, combination therapy is increasingly recognized as an important treatment option for improving long-term outcomes in PAH.

Clinical Trial Registration Number: NCT00660179.
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http://dx.doi.org/10.1007/s40256-017-0260-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5772137PMC
February 2018

RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors.

Eur Respir J 2017 09 9;50(3). Epub 2017 Sep 9.

The Cardiovascular Institute, Allegheny General Hospital, Pittsburgh, PA, USA.

A proportion of pulmonary arterial hypertension (PAH) patients do not reach treatment goals with phosphodiesterase-5 inhibitors (PDE5i). RESPITE investigated the safety, feasibility and benefit of switching from PDE5i to riociguat in these patients.RESPITE was a 24-week, open-label, multicentre, uncontrolled study. Patients in World Health Organization (WHO) functional class (FC) III, with 6-min walking distance (6MWD) 165-440 m, cardiac index <3.0 L·min·m and pulmonary vascular resistance >400 dyn·s·cm underwent a 1-3 day PDE5i treatment-free period before receiving riociguat adjusted up to 2.5 mg maximum Exploratory end-points included change in 6MWD, WHO FC, -terminal prohormone of brain natriuretic peptide (NT-proBNP) and safety.Of 61 patients enrolled, 51 (84%) completed RESPITE. 50 (82%) were receiving concomitant endothelin receptor antagonists. At week 24, mean±sd 6MWD had increased by 31±63 m, NT-proBNP decreased by 347±1235 pg·mL and WHO FC improved in 28 patients (54%). 32 patients (52%) experienced study drug-related adverse events and 10 (16%) experienced serious adverse events (2 (3%) study drug-related, none during the PDE5i treatment-free period). Six patients (10%) experienced clinical worsening, including death in two (not study drug-related).In conclusion, selected patients with PAH may benefit from switching from PDE5i to riociguat, but this strategy needs to be further studied.
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http://dx.doi.org/10.1183/13993003.02425-2016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5898946PMC
September 2017

Sildenafil dosed concomitantly with bosentan for adult pulmonary arterial hypertension in a randomized controlled trial.

BMC Cardiovasc Disord 2017 09 6;17(1):239. Epub 2017 Sep 6.

Pfizer Inc, 4 E Carol Ave, Burlingame, New York, CA, 94010, USA.

Background: Few controlled clinical trials exist to support oral combination therapy in pulmonary arterial hypertension (PAH).

Methods: Patients with PAH (idiopathic [IPAH] or associated with connective tissue disease [APAH-CTD]) taking bosentan (62.5 or 125 mg twice daily at a stable dose for ≥3 months) were randomized (1:1) to sildenafil (20 mg, 3 times daily; n = 50) or placebo (n = 53). The primary endpoint was change from baseline in 6-min walk distance (6MWD) at week 12, assessed using analysis of covariance. Patients could continue in a 52-week extension study. An analysis of covariance main-effects model was used, which included categorical terms for treatment, baseline 6MWD (<325 m; ≥325 m), and baseline aetiology; sensitivity analyses were subsequently performed.

Results: In sildenafil versus placebo arms, week-12 6MWD increases were similar (least squares mean difference [sildenafil-placebo], -2.4 m [90% CI: -21.8 to 17.1 m]; P = 0.6); mean ± SD changes from baseline were 26.4 ± 45.7 versus 11.8 ± 57.4 m, respectively, in IPAH (65% of population) and -18.3 ± 82.0 versus 17.5 ± 59.1 m in APAH-CTD (35% of population). One-year survival was 96%; patients maintained modest 6MWD improvements. Changes in WHO functional class and Borg dyspnoea score and incidence of clinical worsening did not differ. Headache, diarrhoea, and flushing were more common with sildenafil.

Conclusions: Sildenafil, in addition to stable (≥3 months) bosentan therapy, had no benefit over placebo for 12-week change from baseline in 6MWD. The influence of PAH aetiology warrants future study.

Trial Registration: ClinicalTrials.gov NCT00323297 (registration date: May 5, 2006).
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http://dx.doi.org/10.1186/s12872-017-0674-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5586020PMC
September 2017

SERAPHIN haemodynamic substudy: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension.

Eur Heart J 2017 04;38(15):1147-1155

Department of Pulmonary Circulation and Thromboembolic Diseases, Medical Center for Postgraduate Education, ECZ-Otwock, Poland.

Aims: The effect of macitentan on haemodynamic parameters and NT-proBNP levels was evaluated in pulmonary arterial hypertension (PAH) patients in the SERAPHIN study. Association between these parameters and disease progression, assessed by the primary endpoint (time to first morbidity/mortality event), was explored.

Methods And Results: Of the 742 randomized patients, 187 with right heart catheterization at baseline and month 6 participated in a haemodynamic sub-study. Prespecified endpoints included change from baseline to month 6 in cardiac index (CI), right atrial pressure (RAP), mean pulmonary arterial pressure (mPAP), pulmonary vascular resistance (PVR), mixed-venous oxygen saturation, and NT-proBNP. Exploratory analyses examined associations between CI, RAP, and NT-proBNP and disease progression using the Kaplan-Meier method and Cox regression models. Macitentan improved CI, RAP, mPAP, PVR and NT-proBNP vs. placebo at month 6. Absolute levels of CI, RAP and NT-proBNP at baseline and month 6, but not their changes, were associated with morbidity/mortality events. Patients with CI > 2.5 L/min/m2, RAP < 8 mmHg, or NT-proBNP < 750 fmol/ml at month 6 had a lower risk of morbidity/mortality than those not meeting these thresholds (HR 0.49, 95% CL 0.28-0.86; HR 0.72, 95% CL 0.42-1.22; and HR 0.22, 95% CL 0.15-0.33, respectively).

Conclusions: For all treatment groups, baseline and month 6 values of CI, RAP, and NT-proBNP, but not their changes, were associated with morbidity/mortality events, confirming their relevance in predicting disease progression in patients with PAH. By improving those parameters, macitentan increased the likelihood of reaching threshold values associated with lower risk of morbidity/mortality.
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http://dx.doi.org/10.1093/eurheartj/ehx025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5400052PMC
April 2017

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

Heart 2017 04 23;103(8):599-606. Epub 2016 Dec 23.

University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany.

Objective: 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.

Methods: 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.

Results: Riociguat decreased pulmonary vascular resistance (PVR) in inoperable (n=189; least-squares mean difference: -285 dyn s/cm (95% CI -357 to -213); p<0.0001) and persistent/recurrent (n=72; -131 dyn s/cm (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/m (95% CI 0.4 to 0.7; p<0.0001), while in persistent/recurrent patients the change was +0.2 L/min/m (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).

Conclusions: Riociguat improved haemodynamics in patients with inoperable CTEPH or persistent/recurrent CTEPH.

Trial Registration Number: NCT00855465.
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http://dx.doi.org/10.1136/heartjnl-2016-309621DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5529957PMC
April 2017

Macitentan Improves Health-Related Quality of Life for Patients With Pulmonary Arterial Hypertension: Results From the Randomized Controlled SERAPHIN Trial.

Chest 2017 Jan 23;151(1):106-118. Epub 2016 Sep 23.

Assistance Publique-Hôpitaux de Paris, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin-Bicêtre, France; Université Paris-Sud, Laboratoire d'Excellence en Recherche sur le Médicament et Innovation Thérapeutique, Le Kremlin-Bicêtre, France, and INSERM U-999, Centre chirurgical Marie Lannelongue, Le Plessis Robinson, France.

Background: Pulmonary arterial hypertension (PAH) leads to reduced health-related quality of life (HRQoL). The objectives of this analysis were to evaluate the effect of macitentan on HRQoL in patients with PAH in the Study with an Endothelin Receptor Antagonist in Pulmonary Arterial Hypertension to Improve Clinical Outcome (SERAPHIN) study. The association between baseline HRQoL and long-term outcomes was also investigated.

Methods: Patients were randomized to placebo, macitentan 3 mg, or macitentan 10 mg once daily. Patients aged 14 years or older completed the 36-Item Short Form Survey (SF-36) at baseline, at month 6 and month 12, and at the end of treatment (EOT). The absolute change from baseline to month 6 in SF-36 scores was calculated. The time to a clinically meaningful deterioration in the SF-36 physical component summary and mental component summary (PCS and MCS) scores and associations between baseline PCS/MCS scores and time to morbidity/mortality events were also assessed.

Results: At month 6, macitentan 10 mg significantly improved seven of eight SF-36 domains and the PCS and MCS scores vs placebo. Macitentan 10 mg significantly reduced the risk of a three-point or greater deterioration in PCS (hazard ratio [HR], 0.60; 95% CI, 0.47-0.76; P < .0001) and MCS scores (HR, 0.76; 95% CI, 0.61-0.95; P = .0173) until EOT vs placebo. Patients with a baseline PCS score greater than the median baseline value had a significantly reduced risk of morbidity/mortality compared with patients with a PCS score less than the median; a similar result was observed for the MCS score.

Conclusions: Macitentan significantly improved HRQoL in patients with PAH compared with placebo and significantly reduced the risk of a clinically meaningful HRQoL deterioration. An association between better baseline HRQoL and improved long-term outcomes was shown.

Trial Registry: ClinicalTrials.gov; No.: NCT00660179; URL: clinicaltrials.gov.
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http://dx.doi.org/10.1016/j.chest.2016.08.1473DOI Listing
January 2017

Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial.

Lancet Respir Med 2016 05 8;4(5):361-71. Epub 2016 Apr 8.

Université Paris-Sud, Université Paris-Saclay, Le Kremlin Bicêtre, France; AP-HP, Service de Pneumologie, Hôpital Bicêtre, Le Kremlin Bicêtre, France; Inserm UMR_S 999, Hôpital Marie Lannelongue, Le Plessis Robinson, France.

Background: Pulmonary arterial hypertension is a chronic disease associated with poor long-term outcomes. Identifying predictors of long-term outcome in pulmonary arterial hypertension is important to assess disease severity and guide treatment. We investigate associations between efficacy parameters and long-term outcomes in patients with pulmonary arterial hypertension receiving riociguat in the PATENT-2 study. We also present safety and efficacy data from the final data cutoff of PATENT-2, where most patients had received at least 2 years of riociguat treatment.

Methods: Eligible patients from the PATENT-1 study entered the PATENT-2 open-label extension, which will continue until all patients transition to the commercial drug. All patients received riociguat individually adjusted to a maximum dose of 2·5 mg three times a day. The primary endpoint was safety and tolerability, assessed with recording adverse events, serious adverse events, discontinuations, and deaths; exploratory assessments included 6-min walking distance (6MWD), WHO functional class, N-terminal prohormone of brain natriuretic peptide (NT-proBNP)concentrations, Borg dyspnoea score, health-related quality of life (EQ-5D score), survival, and clinical worsening-free survival. Association between efficacy parameters and long-term outcomes was assessed using Kaplan-Meier analyses and a Cox proportional-hazards regression model. PATENT-2 is registered at ClinicalTrials.gov, number NCT00863681.

Findings: 396 patients entered PATENT-2, of whom 197 patients were receiving riociguat monotherapy and 199 were receiving riociguat in combination with endothelin receptor antagonists or prostanoids, or both. A significant association was noted between 6MWD, NT-proBNP concentration, and WHO functional class and overall survival at baseline (p=0·0006, 0·0225, and 0·0191, respectively), and at follow-up (p=0·021, 0·0056, and 0·0048, respectively). Riociguat was well tolerated in PATENT-2. Serious adverse events were recorded in 238 (60%) of the total population, and 45 (11%) patients discontinued treatment because of an adverse event. Improvements in 6MWD, WHO functional class, and NT-proBNP concentrations were maintained after 2 years of treatment.

Interpretation: These results support the long-term use of riociguat in patients with pulmonary arterial hypertension, and emphasise the prognostic value of 6MWD, WHO functional class, and NT-proBNP concentrations.

Funding: Bayer Pharma AG.
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http://dx.doi.org/10.1016/S2213-2600(16)30019-4DOI Listing
May 2016