Riociguat

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Hossein Ardeschir Ghofrani - One of the best experts on this subject based on the ideXlab platform.

  • Riociguat treatment in patients with chronic thromboembolic pulmonary hypertension final safety data from the expert registry
    Respiratory Medicine, 2021
    Co-Authors: Hossein Ardeschir Ghofrani, Marc Humbert, Ekkehard Grunig, Gerald Simonneau, Henning Gall, Hans Klose, Michael Halank, Miguel Angel Gomez Sanchez, David Pittrow, David Langleben
    Abstract:

    Abstract 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.

  • efficacy and safety of Riociguat in combination therapy for patients with pulmonary arterial hypertension patent studies
    Pulmonary circulation, 2020
    Co-Authors: Ekkehard Grunig, David Langleben, Pavel Jansa, Franck Rahaghi, Namita Sood, Hossein Ardeschir Ghofrani, Stephan Rosenkranz, Ioana R Preston, Dennis Busse
    Abstract:

    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 (N = 131 pretreated patients) and placebo (N = 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.

  • effect of Riociguat and sildenafil on right heart remodeling and function in pressure overload induced model of pulmonary arterial banding
    BioMed Research International, 2018
    Co-Authors: Nabham Rai, Johannespeter Stasch, Hossein Ardeschir Ghofrani, Baktybek Kojonazarov, Norbert Weissmann, Swathi Veeroju, Yves Schymura, Wiebke Janssen, Astrid Wietelmann, Werner Seeger
    Abstract:

    Pulmonary arterial hypertension (PAH) is a progressive disorder characterized by remodeling of the pulmonary vasculature and a rise in right ventricular (RV) afterload. The increased RV afterload leads to right ventricular failure (RVF) which is the reason for the high morbidity and mortality in PAH patients. The objective was to evaluate the therapeutic efficacy and antiremodeling potential of the phosphodiesterase type 5 (PDE5) inhibitor sildenafil and the soluble guanylate cyclase stimulator Riociguat in a model of pressure overload RV hypertrophy induced by pulmonary artery banding (PAB). Mice subjected to PAB, one week after surgery, were treated with either sildenafil (100 mg/kg/d, n = 5), Riociguat (30 mg/kg/d, n = 5), or vehicle (n = 5) for 14 days. RV function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI), and histomorphometry. Both sildenafil and Riociguat prevented the deterioration of RV function, as determined by a decrease in RV dilation and restoration of the RV ejection fraction (EF). Although both compounds did not decrease right heart mass and cellular hypertrophy, Riociguat prevented RV fibrosis induced by PAB. Both compounds diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Treatment with either Riociguat or sildenafil prevented the progression of pressure overload-induced RVF, representing a novel therapeutic approach.

  • safety of Riociguat for the treatment of pulmonary hypertension data from the expert registry
    European Respiratory Journal, 2017
    Co-Authors: Henning Gall, Marc Humbert, Ekkehard Grunig, David Langleben, Hossein Ardeschir Ghofrani, Gerald Simonneau, Hans Klose, Michael Halank, Lisa Mielniczuk, Jeanluc Vachiery
    Abstract:

    Background: Riociguat is approved for the treatment of patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Aims: The EXPosurE Registry Riociguat (EXPERT: NCT02092818) aims to obtain long-term safety data on the use of Riociguat in clinical practice. Methods: EXPERT is an international, multicenter, prospective, non-interventional study. The study is currently ongoing and the primary endpoints are adverse event (AE) and serious AE (SAE) incidence, and all-cause mortality. The secondary endpoints include clinical effects and resource utilization. Data from the July 2017 interim analysis will be presented. Results: Baseline data were available for 713 patients (79% of the planned cohort) at the time of the July 10, 2016 analysis. Of these patients, 169 had PAH, 511 had CTEPH, and 33 had other forms of PH. At study entry, 54% of patients with PAH and CTEPH were pretreated (receiving Riociguat for ≥3 months), while 46% were newly treated (receiving Riociguat for Conclusions: The AEs and SAEs reported in EXPERT are consistent with the known safety profile of Riociguat, with no new safety signals identified. Newly treated patients were more likely to experience an AE than pretreated patients.

  • individual dose adjustment of Riociguat in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension
    Respiratory Medicine, 2017
    Co-Authors: Nicholas S Hill, Reiner Frey, Franck Rahaghi, Namita Sood, Hossein Ardeschir Ghofrani
    Abstract:

    Riociguat is a soluble guanylate cyclase stimulator that has been approved for the treatment of pulmonary arterial hypertension and inoperable chronic thromboembolic pulmonary hypertension or persistent/recurrent pulmonary hypertension following pulmonary endarterectomy. Riociguat is administered using an 8-week individual dose-adjustment scheme whereby a patient initially receives Riociguat 1.0 mg three times daily (tid), and the dose is then increased every 2 weeks in the absence of hypotension, indicated by systolic blood pressure measurements and symptoms, up to a maximum dose of 2.5 mg tid. The established Riociguat dose-adjustment scheme allows the dose of Riociguat to be individually optimized in terms of tolerability and efficacy. The majority of patients in the phase III clinical trials and their long-term extension phases achieved the maximum Riociguat dose, whereas some patients remained on lower doses. There is evidence that these patients may experience benefits at Riociguat doses lower than 2.5 mg tid, with improvement in exercise capacity being observed after only 2-4 weeks of treatment in the phase III studies and in the exploratory 1.5 mg-maximum patient group of PATENT-1. This review aims to provide an overview of the rationale behind the Riociguat dose-adjustment scheme and examine its application to both clinical trials and real-life clinical practice.

Dinesh Khanna - One of the best experts on this subject based on the ideXlab platform.

  • response to Riociguat in systemic sclerosis a potential for disease modification by jain and dhir
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Dinesh Khanna, Oliver Distler
    Abstract:

    We thank Drs Jain and Dhir for their comments1 regarding our recent article in Annals of the Rheumatic Diseases entitled ‘Riociguat in patients with early diffuse cutaneous systemic sclerosis (RISE-SSc): randomised, double-blind, placebo-controlled multicentre trial’.2 We agree that forced vital capacity (FVC) in millilitres, as in the Safety and Efficacy of Nintedanib in Systemic Sclerosis (SENSCIS) trial,3 may be informative, and that the effects of Riociguat on swollen and tender joints are also of interest. We present below (table 1) the results from Riociguat Safety and Efficacy in patients with diffuse cutaneous Systemic Sclerosis …

  • op0249 long term extension results of rise ssc a randomized trial of Riociguat in patients with early diffuse cutaneous systemic sclerosis dcssc
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Dinesh Khanna, Cp Denton, Yannick Allanore, Masataka Kuwana, Marco Matuccicerinic, Janet E Pope, Melanie Wosnitza, Marieelise Truchetet, Gabriella Szucs, Wendy Stevens
    Abstract:

    Background: RISE-SSc (NCT02283762) was a multicenter Phase IIb trial of Riociguat in pts with early (duration ≤18 months) dcSSc and modified Rodnan skin score (mRSS) 10−22 units. Pts were randomized double-blind to placebo or Riociguat 0.5–2.5 mg t.i.d. for 52 weeks. The primary endpoint, mRSS change from baseline to Week (Wk) 52, did not reach statistical significance (p=0.08, Riociguat vs placebo), but there were favorable trends in some other outcomes. Objectives: To present open-label long-term extension (LTE) results of RISE-SSc. Methods: Pts who completed Wk 52 of double-blind therapy could enter LTE on Riociguat. Endpoints included mRSS, adverse events (AEs), and serious AEs (SAEs). Results: Of 60 pts randomized to Riociguat and 61 to placebo, 42 (Riociguat−Riociguat group) and 45 (former placebo group), respectively, entered LTE. At LTE start, mean±SD mRSS was 16.4±3.2 and 16.3±4.2 units, and mean disease duration was 8.9±7.8 and 8.9±5.8 months, in the Riociguat−Riociguat and former placebo groups, respectively. Other demographics/disease characteristics were also comparable. Median duration of Riociguat treatment was 1092 d in Riociguat−Riociguat pts and 649 d in former placebo pts. Throughout the study, mRSS decreased in both groups (Figure 1). From Wk 52 to last visit, mRSS fell by −3.02±5.51 in Riociguat−Riociguat patients and −3.96±5.43 in former placebo pts. Rates of mRSS regression (decrease by >5 units and ≥25% from Wk 52 to last visit) and of % declines in mRSS were similar in the two groups (Figure 2). mRSS progression (increase by >5 units and ≥25% from Wk 52 to last visit) occurred in 1 pt (2%) in each group. During the entire study, rescue therapy agents were used in 15 (36%) Riociguat−Riociguat pts and 17 (38%) former placebo pts. AEs were reported from Wk 52 to last visit in 82 pts (94%): 40 (95%) Riociguat−Riociguat and 42 (93%) former placebo. Most common AEs overall: nasopharyngitis (24%), gastroesophageal reflux disease (17%), diarrhea (15%), and hypotension (14%). AEs of special interest (dizziness, postural dizziness, or hypotension) occurred in 5 Riociguat−Riociguat pts (12%) and 4 former placebo pts (9%). SAEs were reported in 21 (24%) pts: 10 (24%) Riociguat−Riociguat pts and 11 (24%) former placebo pts, with no SAE reported in >1 patient, no SAEs of special interest, and no deaths. Conclusion: During LTE Riociguat treatment, mRSS decreased in both groups from Wk 52 onwards and mRSS progression was uncommon. Riociguat had acceptable safety, similar to the main study, with no new safety signal. Acknowledgments: RISE-SSc was jointly funded by Bayer AG and Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure of Interests: Dinesh Khanna Shareholder of: Eicos, Grant/research support from: NIH NIAID, NIH NIAMS, Consultant of: Acceleron, Actelion, Bayer, BMS, Boehringer-Ingelheim, Corbus, Galapagos, Genentech/Roche, GSK, Mitsubishi Tanabi, Sanofi-Aventis/Genzyme, UCB Pharma, Janet Pope Grant/research support from: AbbVie, Bristol-Myers Squibb, Eli Lilly & Company, Merck, Roche, Seattle Genetics, UCB, Consultant of: AbbVie, Actelion, Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Eicos Sciences, Eli Lilly & Company, Emerald, Gilead Sciences, Inc., Janssen, Merck, Novartis, Pfizer, Roche, Sandoz, Sanofi, UCB, Speakers bureau: UCB, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Bristol-Myers Squibb, Speakers bureau: Acetelion, Lilly, Boehringer Ingelheim, Masataka Kuwana Grant/research support from: Acetelion, Consultant of: Acetelion, Bayer, Chugai, Corbus Pharmaceuticals, CSL Behring and Reata Pharmaceuticals. He was a member of the SENSCIS trial Steering Committee (Boehringer Ingelheim), Christopher Denton Grant/research support from: GlaxoSmithKline, CSL Behring, and Inventiva, Consultant of: Medscape, Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Corbus Pharmaceuticals, Acceleron, Curzion and Bayer, Yannick Allanore Grant/research support from: BMS, Inventiva, Roche, Sanofi, Consultant of: Actelion, Bayer AG, BMS, BI, Melanie Wosnitza Employee of: Bayer AG, Marie-Elise Truchetet: None declared, Gabriella Szucs: None declared, Wendy Stevens: None declared, Viginia Steen Grant/research support from: The associated affiliation has received grants/research from Boehringer Ingelheim, Corbus Pharmaceuticals, CSL Behring, Eicos, Galapagos, Immune Tolerance Network, Reata, Consultant of: Virginia Steen has acted as a consultant for Boehringer Ingelheim, Corbus, CSL Behring, Eicos, Forbius, Chiara Stagnaro: None declared, Vanessa Smith Grant/research support from: The affiliated company received grants from Research Foundation - Flanders (FWO), Belgian Fund for Scientific Research in Rheumatic diseases (FWRO), Boehringer Ingelheim Pharma GmbH & Co and Janssen-Cilag NV, Consultant of: Boehringer-Ingelheim Pharma GmbH & Co, Speakers bureau: Actelion Pharmaceuticals Ltd, Boehringer-Ingelheim Pharma GmbH & Co and UCB Biopharma Sprl, Richard Silver: None declared, Elena Schiopu: None declared, Valeria Riccieri: None declared, Frank Kramer Employee of: Bayer AG, Sindhu Johnson Grant/research support from: Boehringer Ingelheim, Corbus Pharmaceuticals, GlaxoSmithKline, Roche, Merck, Bayer, Consultant of: Boehringer Ingelheim, Ikaria, Osamu Ishikawa: None declared, Tomonori Ishii: None declared, Eric Hachlla: None declared, Ellen De Langhe Consultant of: member of advisory board for Boehringer, Laszlo Czirjak Consultant of: Actelion, BI, Roche-Genentech, Lilly, Medac, Novartis, Pfizer, Bayer AG, Radim Becvař Consultant of: Actelion, Roche, Tatsuya Atsumi Grant/research support from: Eli Lily Japan K.K., Alexion Pharmaceuticals, Inc., Bristol-Myers Squibb Co., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Astellas Pharma Inc., Consultant of: Gilead Sciences, Inc., Eli Lilly Japan K.K., UCB Japan Co. Ltd., AbbVie Inc., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Speakers bureau: Eli Lilly Japan K.K., UCB Japan Co. Ltd., Bristol-Myers Squibb Co., AbbVie Inc., Eisai Co. Ltd., Otsuka Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Pfizer Inc., Chugai Pharmaceutical Co., Ltd., Mitsubishi Tanabe Pharma Co., Takeda Pharmaceutical Co., Ltd., Astellas Pharma Inc., Oliver Distler Grant/research support from: Grants/Research support from Actelion, Bayer, Boehringer Ingelheim, Competitive Drug Development International Ltd. and Mitsubishi Tanabe; he also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143)., Consultant of: Consultancy fees from Actelion, Acceleron Pharma, AnaMar, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer, CSL Behring, Catenion, ChemomAb, Curzion Pharmaceuticals, Ergonex, Galapagos NV, GSK, Glenmark Pharmaceuticals, Inventiva, Italfarmaco, iQvia, medac, Medscape, Mitsubishi Tanabe Pharma, MSD, Roche, Sanofi and UCB, Speakers bureau: Speaker fees from Actelion, Bayer, Boehringer Ingelheim, Medscape, Pfizer and Roche

  • Riociguat in patients with early diffuse cutaneous systemic sclerosis rise ssc randomised double blind placebo controlled multicentre trial
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Dinesh Khanna, Yannick Allanore, Christopher P Denton, Masataka Kuwana, Marco Matuccicerinic, Janet E Pope, Tatsuya Atsumi, R Becvař, Laszlo Czirjak, Eric Hachulla
    Abstract:

    Objectives Riociguat is approved for pulmonary arterial hypertension and has antiproliferative, anti-inflammatory and antifibrotic effects in animal models of tissue fibrosis. We evaluated the efficacy and safety of Riociguat in patients with early diffuse cutaneous systemic sclerosis (dcSSc) at high risk of skin fibrosis progression. Methods In this randomised, double-blind, placebo-controlled, phase IIb trial, adults with dcSSc of Results At week 52, change from baseline in mRSS units was –2.09±5.66 (n=57) with Riociguat and –0.77±8.24 (n=52) with placebo (difference of least squares means –2.34 (95% CI –4.99 to 0.30; p=0.08)). In patients with interstitial lung disease, forced vital capacity declined by 2.7% with Riociguat and 7.6% with placebo. At week 14, average Raynaud’s condition score had improved ≥50% in 19 (41.3%)/46 patients with Riociguat and 13 (26.0%)/50 patients with placebo. Safety assessments showed no new signals with Riociguat and no treatment-related deaths. Conclusions Riociguat did not significantly benefit mRSS versus placebo at the predefined p

  • a multicenter randomized double blind placebo controlled pilot study to assess the efficacy and safety of Riociguat in systemic sclerosis associated digital ulcers
    Arthritis Research & Therapy, 2019
    Co-Authors: Vivek Nagaraja, Cathie Spino, Erica Bush, Peisuen Tsou, Robyn T Domsic, Robert Lafyatis, Tracy M Frech, Jessica K Gordon, Virginia D Steen, Dinesh Khanna
    Abstract:

    To determine the effect of Riociguat, an oral, selective soluble guanylate cyclase stimulator, on the net digital ulcer (DU) burden in systemic sclerosis (SSc). Participants with SSc-related active or painful indeterminate DUs were recruited in a multicenter, double-blind, randomized, placebo-controlled, proof-of-concept trial. Eligible participants were required to have at least one visible, active ischemic DU or painful indeterminate DU at screening, located at or distal to the proximal interphalangeal joint and that developed or worsened within 8 weeks prior to screening. Participants were randomized 1:1 to placebo or Riociguat in individualized doses (maximum of 2.5 mg three times daily) during an 8-week titration period, followed by an 8-week stable dosing period. This was followed by an optional 16-week open-label extension phase for participants with active DU/reoccurrence of DUs within 1 month of the end of the main treatment phase. The primary endpoint was the change from baseline to week 16 in net ulcer burden (NUB), analyzed using ANCOVA. Other endpoints included plasma biomarkers and proportion of participants with treatment-emergent adverse events (AEs). Seventeen participants (eight placebo, nine Riociguat) were randomized at five centers. Six participants in each group transitioned to the open-label extension. Baseline characteristics were comparable between the treatment groups, except participants randomized to placebo were older and had longer disease duration (p < 0.05). At baseline, the mean (SD) NUB was 2.5 (2.0) in the placebo and 2.4 (1.4) in the Riociguat. No significant treatment difference was observed in the change from baseline to 16 weeks in NUB (adjusted mean treatment difference − 0.24, 95% CI (− 1.46, 0.99), p = 0.70). Four participants experienced five serious AE (four in Riociguat and one in placebo); none was considered related to study medication. Statistically significant elevation of cGMP was observed at 16 weeks in the Riociguat group (p = 0.05); no other biomarkers showed significant changes. In the open-label extension, participants in the Riociguat-Riociguat arm had complete healing of their DUs. In participants with SSc-DU, treatment with Riociguat did not reduce the number of DU net burden compared with placebo at 16 weeks. Open-label extension suggests that longer duration is needed to promote DU healing, which needs to be confirmed in a new trial. ClinicalTrials.gov, NCT02915835 . Registered on September 27, 2016.

  • fri0303 the effects of Riociguat on raynaud s phenomenon and digital ulcers in patients with diffuse systemic sclerosis results from the phase iib rise ssc study
    Annals of the Rheumatic Diseases, 2019
    Co-Authors: Dinesh Khanna, Yannick Allanore, Christopher P Denton, Masataka Kuwana, Marco Matuccicerinic, Janet E Pope, J Pena, Kaisa Laapas, Zhen Yao, Melanie Hemmrich
    Abstract:

    Background Riociguat is a soluble guanylate cyclase stimulator approved for treatment of pulmonary arterial hypertension associated with connective tissue disease. Through its vasodilatory and anti-remodeling properties, it was predicted that Riociguat might relieve Raynaud’s phenomenon (RP) attacks and reduce net digital ulcer (DU) burden in patients with diffuse cutaneous systemic sclerosis (dcSSc). Objectives We present exploratory endpoints from the RISE-SSc study (NCT02283762) on the effects of Riociguat on RP and DUs in early dcSSc patients. Methods RISE-SSc was a Phase IIb, multicenter, randomized, double-blind, placebo-controlled study. Inclusion criteria were: SSc fulfilling ACR/EULAR criteria, diffuse cutaneous involvement, disease duration ≤18 months, and modified Rodnan skin score 10−22 units. Patients were assigned to placebo or Riociguat individually adjusted from 0.5 mg up to 2.5 mg, 3 times daily. Exploratory efficacy endpoints included 1) change in Raynaud’s attacks from baseline to Week 14, assessed by: Raynaud’s condition score; patient/physician assessment of RP; attack symptoms, attack duration, and average number of attacks per day; and 2) change in net DU burden from baseline to Week 52, assessed by ulcer count, ulcer burden, and visual analog score for patient-reported severity. Blood samples for exploratory evaluation of biomarkers were taken on Day 0, Week 14 and for discontinuation before Week 14. Results 60 patients were treated with Riociguat and 61 with placebo. None of the effects of Riociguat on RP or DUs were statistically significant vs placebo. However, there was a greater relative reduction in attack duration, attack frequency, pain, numbness, tingling, and patient/physician global assessment in the Riociguat group vs placebo, from baseline to Week 14. Reductions in net DU burden were –0.09±0.50 for Riociguat and –0.08±1.47 for placebo (estimated treatment difference: –0.11 [95% CI: –0.38, 0.17; p=0.44]) at Week 52. At Week 14, 2 patients in the Riociguat group and 6 in the placebo group had developed new DUs. At Week 52, 5 and 12 patients, respectively, had developed new DUs. The total numbers of new DUs were 4 and 6 with Riociguat and placebo, respectively, at Week 14, and 12 and 65, respectively, at Week 52 (Figure). Riociguat was associated with reductions vs placebo in serum sPECAM-1 (p=0.004) and CXCL-4 (p=0.008), potentially indicating anti-vasculopathy properties of Riociguat. Conclusion Riociguat did not produce statistically significant changes in DUs. Riociguat may reduce the development of new DUs in patients with early dcSSc and may favourably improve cytokine vasculopathy. Left: Number of patients with new digital ulcers Right: Total number of new digital ulcers New digital ulcers are defined as ulcers not existing at baseline. Acknowledgement Adelphi Communications Ltd, Bollington, UK provided medical writing support. Disclosure of Interests Dinesh Khanna Shareholder of: Eicos Sciences, Inc, Grant/research support from: Bayer, BMS, Pfizer, Horizon, Consultant for: Actelion Acceleron, Arena, Bayer, BI, BMS, CSL Behring, Corbus, Cytori, GSK, Genentech/Roche, Galapagos, Employee of: Elcos Sciences, Inc, Yannick Allanore Grant/research support from: Inventiva, F Hoffman La-Roche, Sanofi, BMS, Pfizer, Consultant for: Actelion, Bayer, BMS, Boehringer, Roche, Sanofi, Christopher Denton Grant/research support from: GlaxoSmithKline, Inventiva, CSF Behring, Consultant for: Roche-Genentech, Actelion, GlaxoSmithKline, Sanofi Aventis, Inventiva, CSL Behring, Boehringer Ingelheim, Bayer, Masataka Kuwana Grant/research support from: Actelion, Consultant for: Chugai, Reata, GlaxoSmithKline, Bayer, Boehringer-Ingelheim, Corpus, CSL-Berling, Mochida, Speakers bureau: Actelion, Pfizer, Bayer, Nippon Shinyaku, Chugai, Marco Matucci-Cerinic Grant/research support from: Actelion, MSD, Pfizer, BMS, Chemomab, Sanipedia, Speakers bureau: Actelion, BMS; MSD, Janssen, Janet Pope Consultant for: Eli Lilly and Company, Janethe de Oliveria Pena Employee of: Bayer, Kaisa Laapas Employee of: StatFinn Oy, partly insourced to Bayer, Zhen Yao Employee of: Bayer, Melanie Hemmrich Employee of: Bayer AG, Oliver Distler Grant/research support from: Prof. Distler received research funding from Actelion, Bayer, Boehringer Ingelheim and Mitsubishi Tanabe to investigate potential treatments of scleroderma and its complications, Consultant for: Prof. Distler has/had consultancy relationship within the last 3 years with Actelion, AnaMar, Bayer, Boehringer Ingelheim, ChemomAb, espeRare foundation, Genentech/Roche, GSK, Inventiva, Italfarmaco, iQvia, Lilly, medac, MedImmune, Mitsubishi Tanabe Pharma, Pharmacyclics, Novartis, Pfizer, Sanofi, Serodapharm and UCB in the area of potential treatments of scleroderma and its complications. In addition, he had/has consultancy relationship within the last 3 years with A. Menarini, Amgen, Abbvie, GSK, Mepha, MSD, Pfizer and UCB in the field of arthritides and related disorders

Marius M Hoeper - One of the best experts on this subject based on the ideXlab platform.

  • Riociguat treatment in patients with pulmonary arterial hypertension final safety data from the expert registry
    Respiratory Medicine, 2021
    Co-Authors: Marius M Hoeper, Marc Humbert, Ekkehard Grunig, Gerald Simonneau, Henning Gall, Hans Klose, Michael Halank, Miguel Angel Gomez Sanchez, David Pittrow, David Langleben
    Abstract:

    Abstract 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.

  • Riociguat for idiopathic interstitial pneumonia associated pulmonary hypertension rise iip a randomised placebo controlled phase 2b study
    The Lancet Respiratory Medicine, 2019
    Co-Authors: Steven D Nathan, Harold R Collard, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, A Keogh, H Leuchte
    Abstract:

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

  • rise iip Riociguat for the treatment of pulmonary hypertension associated with idiopathic interstitial pneumonia
    European Respiratory Journal, 2017
    Co-Authors: Steven D Nathan, Harold R Collard, Tamera J Corte, Fernando J. Martinez, Jurgen Behr, Vincent Cottin, Marius M Hoeper, A Keogh, H Leuchte, Nesrin Mogulkoc
    Abstract:

    Pulmonary hypertension (PH) complicating idiopathic interstitial pneumonias (IIPs) is associated with impaired functional ability and poor outcomes. Whether treating PH in IIP is beneficial remains unknown. RISE-IIP (NCT02138825) was a randomised, placebo (PBO)-controlled study to evaluate the efficacy and safety of Riociguat in patients with IIP, FVC ≥45% predicted and mean pulmonary artery pressure ≥25 mmHg. Patients were randomised to Riociguat up to 2.5 mg tid or PBO for 26 weeks followed by an open-label extension where all patients received Riociguat. The primary endpoint was change from baseline to week 26 in 6-minute walk distance (6MWD). Secondary endpoints included clinical worsening (all-cause mortality, hospitalisation due to worsening cardiopulmonary status, 15% decrease in 6MWD or worsening of WHO FC). Of 147 randomised patients, 73 received Riociguat and 74 PBO. The study was stopped early (mean treatment duration 121±66 days) at the recommendation of the Data Monitoring Committee due to increased SAEs (37% Riociguat vs 23% PBO in the blinded phase) and increased mortality in Riociguat patients. There were 11 deaths in the blinded phase (8 Riociguat, 3 PBO), and 9 in the extension (1 former Riociguat, 8 former PBO). Riociguat did not improve 6MWD vs PBO at 26 week (least squares mean difference +21 m; 95% CI –9 to +52 m). There was no difference in proportion of subjects with clinical worsening: 47% Riociguat vs 49% PBO. In patients with PH-IIP, Riociguat was associated with increased SAEs and mortality, and an unfavourable risk:benefit ratio. The current study did not reveal a potential aetiology for the observed mortality effect.

  • comparison of hemodynamic parameters in treatment naive and pre treated patients with pulmonary arterial hypertension in the randomized phase iii patent 1 study
    Journal of Heart and Lung Transplantation, 2017
    Co-Authors: Nazzareno Galie, Marc Humbert, Marius M Hoeper, A Keogh, Friedrich Grimminger, Ekkehard Grunig, Zhicheng Jing, David Langleben, Lewis J Rubin, Arno Fritsch
    Abstract:

    Background Detailed hemodynamic data from the phase III PATENT-1 study of Riociguat in patients with pulmonary arterial hypertension (PAH) were investigated. Methods Patients with PAH who were treatment naive or pre-treated with endothelin receptor antagonists or non-intravenous prostanoids were randomly assigned to Riociguat up to 2.5 mg 3 times a day or placebo. Hemodynamic parameters were assessed at baseline and week 12. Results Riociguat significantly decreased pulmonary vascular resistance in treatment-naive ( n = 221; least squares [LS] mean difference −266 dyne∙sec∙cm −5 [95% confidence interval (CI) −357 to −175; p n = 222; LS mean difference −186 dyne∙sec ∙cm −5 [95% CI −252 to −120; p p p = 0.0056 and p = 0.0019 for treatment-naive and pre-treated patients, respectively), mean arterial pressure (both p p p p = 0.0004, respectively). Results were similar in patients pre-treated with endothelin receptor antagonists and patients pre-treated with non-intravenous prostanoids. Improvements in 6-minute walking distance correlated very weakly with improvements in pulmonary vascular resistance ( r = −0.21 [95% CI −0.30 to −0.11; p r = 0.16 [95% CI 0.06 to 0.25; p Conclusions Riociguat significantly improved hemodynamic parameters in pre-treated and treatment-naive patients with PAH.

  • haemodynamic effects of Riociguat in inoperable recurrent chronic thromboembolic pulmonary hypertension
    Heart, 2017
    Co-Authors: Nick H Kim, Marius M Hoeper, Friedrich Grimminger, Ekkehard Grunig, Pavel Jansa, Gerald Simonneau, Andrea Maria Darmini, Eckhard Mayer, Claus Neurohr, Adam Torbicki
    Abstract:

    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 5 (95% CI −357 to −213); p 5 (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 2 (95% CI 0.4 to 0.7; p 2 (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 Conclusions Riociguat improved haemodynamics in patients with inoperable CTEPH or persistent/recurrent CTEPH. Trial registration number NCT00855465.

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  • comparison of hemodynamic parameters in treatment naive and pre treated patients with pulmonary arterial hypertension in the randomized phase iii patent 1 study
    Journal of Heart and Lung Transplantation, 2017
    Co-Authors: Nazzareno Galie, Marc Humbert, Marius M Hoeper, A Keogh, Friedrich Grimminger, Ekkehard Grunig, Zhicheng Jing, David Langleben, Lewis J Rubin, Arno Fritsch
    Abstract:

    Background Detailed hemodynamic data from the phase III PATENT-1 study of Riociguat in patients with pulmonary arterial hypertension (PAH) were investigated. Methods Patients with PAH who were treatment naive or pre-treated with endothelin receptor antagonists or non-intravenous prostanoids were randomly assigned to Riociguat up to 2.5 mg 3 times a day or placebo. Hemodynamic parameters were assessed at baseline and week 12. Results Riociguat significantly decreased pulmonary vascular resistance in treatment-naive ( n = 221; least squares [LS] mean difference −266 dyne∙sec∙cm −5 [95% confidence interval (CI) −357 to −175; p n = 222; LS mean difference −186 dyne∙sec ∙cm −5 [95% CI −252 to −120; p p p = 0.0056 and p = 0.0019 for treatment-naive and pre-treated patients, respectively), mean arterial pressure (both p p p p = 0.0004, respectively). Results were similar in patients pre-treated with endothelin receptor antagonists and patients pre-treated with non-intravenous prostanoids. Improvements in 6-minute walking distance correlated very weakly with improvements in pulmonary vascular resistance ( r = −0.21 [95% CI −0.30 to −0.11; p r = 0.16 [95% CI 0.06 to 0.25; p Conclusions Riociguat significantly improved hemodynamic parameters in pre-treated and treatment-naive patients with PAH.

  • haemodynamic effects of Riociguat in inoperable recurrent chronic thromboembolic pulmonary hypertension
    Heart, 2017
    Co-Authors: Nick H Kim, Marius M Hoeper, Friedrich Grimminger, Ekkehard Grunig, Pavel Jansa, Gerald Simonneau, Andrea Maria Darmini, Eckhard Mayer, Claus Neurohr, Adam Torbicki
    Abstract:

    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 5 (95% CI −357 to −213); p 5 (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 2 (95% CI 0.4 to 0.7; p 2 (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 Conclusions Riociguat improved haemodynamics in patients with inoperable CTEPH or persistent/recurrent CTEPH. Trial registration number NCT00855465.

  • Riociguat for the treatment of pulmonary arterial hypertension associated with connective tissue disease results from patent 1 and patent 2
    Annals of the Rheumatic Diseases, 2017
    Co-Authors: Marc Humbert, Friedrich Grimminger, Hossein Ardeschir Ghofrani, Gerry J Coghlan, Jianguo He, Gabriela Riemekasten, Carmine Dario Vizza, Annette Boeckenhoff
    Abstract:

    Background The 12-week, phase III Pulmonary Arterial hyperTENsion sGC-stimulator Trial (PATENT)-1 study investigated Riociguat in patients with pulmonary arterial hypertension (PAH). Here, we present a prospectively planned analysis of the safety and efficacy of Riociguat in the subgroup of patients with PAH associated with connective tissue disease (PAH-CTD). Methods Patients with PAH-CTD were further classified post hoc as having PAH associated with systemic sclerosis or PAH-other defined CTD. In PATENT-1, patients received Riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo. Efficacy endpoints included change from baseline in 6-minute walking distance (6MWD; primary endpoint), haemodynamics and WHO functional class (WHO FC). In the long-term extension PATENT-2, patients received Riociguat (maximum 2.5 mg three times daily); the primary endpoint was safety and tolerability. Results In patients with PAH-CTD, Riociguat increased mean 6MWD, WHO FC, pulmonary vascular resistance and cardiac index. Improvements in 6MWD and WHO FC persisted at 2 years. Two-year survival of patients with PAH-CTD was the same as for idiopathic PAH (93%). Riociguat had a similar safety profile in patients with PAH-CTD to that of the overall population. Conclusions Riociguat was well tolerated and associated with positive trends in 6MWD and other endpoints that were sustained at 2 years in patients with PAH-CTD. Trial registration numbers PATENT-1 (NCT00810693), PATENT-2 (NCT00863681).

  • soluble guanylate cyclase stimulator Riociguat and phosphodiesterase 5 inhibitor sildenafil ameliorate pulmonary hypertension due to left heart disease in mice
    International Journal of Cardiology, 2016
    Co-Authors: Kabita Pradhan, Xia Tian, Norbert Weissmann, Werner Seeger, Akylbek Sydykov, Argen Mamazhakypov, Balram Neupane, Himal Luitel, Friedrich Grimminger
    Abstract:

    Abstract Background Presence of pulmonary hypertension (PH) and right ventricular dysfunction worsens prognosis in patients with chronic heart failure (CHF). Preclinical and clinical studies suggest a role for the impaired nitric oxide (NO)-soluble guanylate cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signaling pathway in both PH and CHF. Hence, we examined the effects of the NO–sGC–cGMP pathway modulation by the PDE5 inhibitor sildenafil or sGC stimulator Riociguat on pulmonary hemodynamics and heart function in a murine model of secondary PH induced by transverse aortic constriction. Methods C57Bl/6N mice were subjected to transverse aortic constriction (TAC) for 6weeks to induce left heart failure and secondary PH and were subsequently treated with either sildenafil (100mg/kg/day) or Riociguat (10mg/kg/day) or placebo for 2weeks. Results Six weeks after surgery, TAC induced significant left ventricular hypertrophy and dysfunction associated with development of PH. Treatment with Riociguat and sildenafil neither reduced left ventricular hypertrophy nor improved its function. However, both sildenafil and Riociguat ameliorated PH, reduced pulmonary vascular remodeling and improved right ventricular function. Conclusions Thus, modulation of the NO–sGC–cGMP pathway by the PDE5 inhibitor sildenafil or sGC stimulator Riociguat exerts direct beneficial effects on pulmonary hemodynamics and right ventricular function in the experimental model of secondary PH due to left heart disease and these drugs may offer a new therapeutic option for therapy of this condition.

  • predictors of long term outcomes in patients treated with Riociguat for chronic thromboembolic pulmonary hypertension data from the chest 2 open label randomised long term extension trial
    The Lancet Respiratory Medicine, 2016
    Co-Authors: Friedrich Grimminger, Pavel Jansa, Hossein Ardeschir Ghofrani, Gerald Simonneau, Andrea Maria Darmini, Nick H Kim, Eckhard Mayer, Tomas Pulido
    Abstract:

    Summary Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare, debilitating, and life-threatening disease. We investigated associations between markers of disease severity and long-term outcomes in patients with inoperable CTEPH or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy (PEA) who were receiving the soluble guanylate cyclase stimulator Riociguat. We also present safety and efficacy from the final data cutoff of CHEST-2, where most patients had received Riociguat for at least 2 years. Methods Eligible patients from the CHEST-1 study entered the CHEST-2 open-label extension study, in which all patients received Riociguat individually adjusted to a maximum dose of 2·5 mg three times per day. The primary endpoint was safety and tolerability. We did exploratory assessments of associations between markers of disease severity (6-min walking distance [6MWD], N-terminal prohormone of brain natriuretic peptide [NT-proBNP] concentration, and WHO functional class) at baseline and follow-up with overall survival and clinical worsening-free survival. We used Kaplan-Meier and Cox proportional hazards analyses. CHEST-2 is registered at ClinicalTrials.gov, number NCT00910429. Findings 237 patients entered CHEST-2. At 2 years, overall survival was 93% (95% CI 89–96) and clinical worsening-free survival was 82% (77–87). A significant association with overall survival was seen for 6MWD and NT-proBNP concentration at baseline (p=0·0199 and p=0·0183, respectively) and at follow-up (p=0·0385 and p=0·0068, respectively). Change from baseline in 6MWD was also significantly associated with survival (p=0·0047). WHO functional class at baseline and follow-up showed no significant association with overall survival but was associated with clinical worsening-free survival. Riociguat was well tolerated by most patients and no new safety signals were identified. Serious adverse events were seen in 129 (54%) of 237 patients, and 14 (6%) discontinued Riociguat therapy because of adverse events. Interpretation Riociguat may be used long term in patients with CTEPH. 6MWD and NT-proBNP concentration are good prognostic markers. Funding Bayer Pharma AG.

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  • comparison of hemodynamic parameters in treatment naive and pre treated patients with pulmonary arterial hypertension in the randomized phase iii patent 1 study
    Journal of Heart and Lung Transplantation, 2017
    Co-Authors: Nazzareno Galie, Marc Humbert, Marius M Hoeper, A Keogh, Friedrich Grimminger, Ekkehard Grunig, Zhicheng Jing, David Langleben, Lewis J Rubin, Arno Fritsch
    Abstract:

    Background Detailed hemodynamic data from the phase III PATENT-1 study of Riociguat in patients with pulmonary arterial hypertension (PAH) were investigated. Methods Patients with PAH who were treatment naive or pre-treated with endothelin receptor antagonists or non-intravenous prostanoids were randomly assigned to Riociguat up to 2.5 mg 3 times a day or placebo. Hemodynamic parameters were assessed at baseline and week 12. Results Riociguat significantly decreased pulmonary vascular resistance in treatment-naive ( n = 221; least squares [LS] mean difference −266 dyne∙sec∙cm −5 [95% confidence interval (CI) −357 to −175; p n = 222; LS mean difference −186 dyne∙sec ∙cm −5 [95% CI −252 to −120; p p p = 0.0056 and p = 0.0019 for treatment-naive and pre-treated patients, respectively), mean arterial pressure (both p p p p = 0.0004, respectively). Results were similar in patients pre-treated with endothelin receptor antagonists and patients pre-treated with non-intravenous prostanoids. Improvements in 6-minute walking distance correlated very weakly with improvements in pulmonary vascular resistance ( r = −0.21 [95% CI −0.30 to −0.11; p r = 0.16 [95% CI 0.06 to 0.25; p Conclusions Riociguat significantly improved hemodynamic parameters in pre-treated and treatment-naive patients with PAH.

  • Riociguat for pulmonary arterial hypertension associated with congenital heart disease
    Heart, 2015
    Co-Authors: Stephan Rosenkranz, Arno Fritsch, Reiner Frey, Gerrit Weimann, Hossein Ardeschir Ghofrani, Maurice Beghetti, Dunbar D Ivy, Soundos Saleh
    Abstract:

    Objective The Pulmonary Arterial hyperTENsion sGC-stimulator Trial-1 (PATENT-1) was a randomised, double-blind, placebo-controlled phase III trial evaluating Riociguat in patients with pulmonary arterial hypertension (PAH). PATENT-2 was an open-label long-term extension to PATENT-1. Here, we explore the efficacy and safety of Riociguat in the subgroup of patients with persistent/recurrent PAH after correction of congenital heart disease (PAH-CHD) from the PATENT studies. Methods In PATENT-1, patients received Riociguat (maximum 2.5 or 1.5 mg three times daily) or placebo for 12 weeks; efficacy assessments included change from baseline to study end in 6-min walking distance (6MWD; primary), pulmonary vascular resistance (PVR), N-terminal of the prohormone of brain natriuretic peptide (NT-proBNP), WHO functional class (WHO FC) and time to clinical worsening. In PATENT-2, eligible patients from PATENT-1 received long-term Riociguat (maximum 2.5 mg three times daily); the primary assessment was safety and tolerability. All PAH-CHD patients had a corrected cardiac defect. Results In PATENT-1, Riociguat increased mean±SD 6MWD from baseline to week 12 by 39±60 m in patients with PAH-CHD versus 0±42 m for placebo. Riociguat also improved several secondary variables versus placebo, including PVR (−250±410 vs −66±632 dyn·s/cm 5 ), NT-proBNP (−164±317 vs −46±697 pg/mL) and WHO FC (21%/79%/0% vs 8%/83%/8% improved/stabilised/worsened). One patient experienced clinical worsening (Riociguat 1.5 mg group). Riociguat was well tolerated. In PATENT-2, Riociguat showed sustained efficacy and tolerability in patients with PAH-CHD at 2 years. Conclusions Riociguat was well tolerated in patients with PAH-CHD and improved clinical outcomes including 6MWD, PVR, WHO FC and NT-proBNP. Trial registration number The clinical trials numbers are NCT00810693 for PATENT-1 and NCT00863681 for PATENT-2.

  • effect of Riociguat on pulmonary arterial compliance pac in patients with pah in patent 1
    European Respiratory Journal, 2015
    Co-Authors: Ioana R Preston, Arno Fritsch, Hossein Ardeschir Ghofrani, Sylvia Nikkho, Paul M Hassoun, Nadine Alnaamani, Stefano Ghio, Adam Torbicki
    Abstract:

    Background: PAC is determined by pulmonary artery stiffness and is a physiologic descriptor of right ventricular afterload. PAC was shown to predict survival in a small study of PAH pts, but changes in PAC in response to therapy have never been reported in PAH. Aims: This post-hoc analysis assessed the effect of the sGC stimulator Riociguat on PAC in PAH pts in PATENT-1. Methods: Pts (n=443) received Riociguat up to 2.5 mg tid (2.5 mg–max), Riociguat up to 1.5 mg tid (exploratory arm), or placebo for 12 wks. PAC and systemic arterial compliance (SAC) were defined as stroke volume/(systolic blood pressure–diastolic blood pressure) in the pulmonary and systemic circulation, respectively. Results: PAC values were abnormally low at baseline (Table 1) and correlated significantly with NT-proBNP (r=–0.30; p Conclusions: In PATENT-1, Riociguat significantly improved pulmonary artery stiffness in pts with PAH. Improvements in PAC correlated with improvements in pulmonary hemodynamics.

  • effect of Riociguat on pulmonary arterial compliance pac in patients with cteph in the chest 1 study
    European Respiratory Journal, 2015
    Co-Authors: Ioana R Preston, Arno Fritsch, Hossein Ardeschir Ghofrani, Adam Torbicki, Sylvia Nikkho, Paul M Hassoun, Nadine Alnaamani, Stefano Ghio
    Abstract:

    Background: PAC is determined by pulmonary artery stiffness and is a physiologic descriptor of right ventricular afterload. In CTEPH pts, PAC after PEA predicts functional capacity and is an important marker of outcome, but changes in PAC in response to therapy have never been reported. Aims: This post-hoc analysis assessed the effect of the sGC stimulator Riociguat on PAC in pts with inoperable CTEPH or persistent/recurrent PH following PEA enrolled in CHEST-1. Methods: Pts (n=261) received Riociguat up to 2.5 mg tid or placebo for 16 wks. PAC and systemic arterial compliance (SAC) were defined as stroke volume/(systolic blood pressure–diastolic blood pressure) in the pulmonary and systemic circulation, respectively. Results: PAC values were abnormally low at baseline (Table 1) and correlated significantly with NT-proBNP (r=–0.24; p=0.0005), PVR (r=–0.49; p Conclusions: In CHEST-1, Riociguat significantly improved pulmonary artery stiffness in pts with inoperable CTEPH or persistent/recurrent PH following PEA. Improvement in PAC was associated with improvement in cardiac index.

  • Riociguat for the treatment of chronic thromboembolic pulmonary hypertension a long term extension study chest 2
    European Respiratory Journal, 2015
    Co-Authors: Gerald Simonneau, Marius M Hoeper, Friedrich Grimminger, Pavel Jansa, Hossein Ardeschir Ghofrani, Andrea Maria Darmini, Nick H Kim, Chen Wang, Martin R Wilkins, Arno Fritsch
    Abstract:

    Riociguat is a soluble guanylate cyclase stimulator approved for the treatment of inoperable and persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH). In the 16-week CHEST-1 study, Riociguat showed a favourable benefit–risk profile and improved several clinically relevant end-points in patients with CTEPH. The CHEST-2 open-label extension evaluated the long-term safety and efficacy of Riociguat. Eligible patients from CHEST-1 received Riociguat individually adjusted up to a maximum dose of 2.5 mg three times daily. The primary objective was the safety and tolerability of Riociguat; exploratory efficacy end-points included 6-min walking distance (6MWD) and World Health Organization (WHO) functional class (FC). Overall, 237 patients entered CHEST-2 and 211 (89%) were ongoing at this interim analysis (March 2013). The safety profile of Riociguat in CHEST-2 was similar to CHEST-1, with no new safety signals. Improvements in 6MWD and WHO FC observed in CHEST-1 persisted for up to 1 year in CHEST-2. In the observed population at 1 year, mean±sd 6MWD had changed by +51±62 m (n=172) versus CHEST-1 baseline (n=237), and WHO FC had improved/stabilised/worsened in 47/50/3% of patients (n=176) versus CHEST-1 baseline (n=236). Long-term Riociguat had a favourable benefit–risk profile and apparently showed sustained benefits in exercise and functional capacity for up to 1 year. Riociguat shows favourable benefit–risk profile in CTEPH patients, with benefits in 6MWD and WHO FC for up to 1 year

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