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Riociguat and the right ventricle in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension

Raymond L. Benza, David Langleben, Anna R. Hemnes, Anton Vonk Noordegraaf, Stephan Rosenkranz, Thenappan Thenappan, Paul M. Hassoun, Ioana R. Preston, Stefano Ghio, Roberto Badagliacca, Carmine D. Vizza, Irene M. Lang, Christian Meier, Ekkehard Grünig
European Respiratory Review 2022 31: 220061; DOI: 10.1183/16000617.0061-2022
Raymond L. Benza
1Dept of Medicine, Ohio State University Wexner Medical Center, Columbus, OH, USA
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  • For correspondence: Raymond.Benza@osumc.edu
David Langleben
2Center for Pulmonary Vascular Disease, Division of Cardiology, Jewish General Hospital, McGill University, Montreal, Canada
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Anna R. Hemnes
3Division of Allergy, Pulmonary and Critical Care Medicine, Dept of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
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Anton Vonk Noordegraaf
4VU University Medical Center, Pulmonary Diseases, Amsterdam, The Netherlands
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Stephan Rosenkranz
5Dept of Cardiology and Cologne Cardiovascular Research Center, Cologne University Heart Center, Cologne, Germany
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Thenappan Thenappan
6Cardiovascular Division, Dept of Medicine, University of Minnesota, Minneapolis, MN, USA
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Paul M. Hassoun
7Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, MD, USA
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Ioana R. Preston
8Pulmonary, Critical Care and Sleep Medicine Division, Tufts Medical Center, Boston, MA, USA
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Stefano Ghio
9Division of Cardiology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy
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Roberto Badagliacca
10Dept of Cardiology, La Sapienza University, Rome, Italy
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Carmine D. Vizza
10Dept of Cardiology, La Sapienza University, Rome, Italy
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Irene M. Lang
11Division of Cardiology, Dept of Internal Medicine II, Medical University of Vienna, Allgemeines Krankenhaus, Vienna, Austria
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Christian Meier
12Global Medical Affairs, Bayer AG, Berlin, Germany
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Ekkehard Grünig
13Centre for Pulmonary Hypertension, Thoraxklinik-Heidelberg gGmbH, Heidelberg University Hospital, Heidelberg, Germany
14Translational Lung Research Center Heidelberg (TLRC), Member of the German Center for Lung Research (DZL), Heidelberg, Germany
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  • FIGURE 1
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    FIGURE 1

    Effects of riociguat on the right ventricle in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. White dotted line indicates the position of the right ventricular (RV) wall in a healthy heart. RA: right atrium; PA: pulmonary artery; PVR: pulmonary vascular resistance; mPAP: mean pulmonary arterial pressure; CI: cardiac index; SVI: stroke volume index.

  • FIGURE 2
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    FIGURE 2

    Patients with pulmonary hypertension receiving riociguat show a significant reduction in right atrial (RA) and right ventricular (RV) areas compared with baseline at all time points. Figure modified from Marra et al. [36] and redistributed under the Creative Commons Attribution 4.0 International license: https://creativecommons.org/licenses/by/4.0/legalcode. #: compared to baseline.

Tables

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  • TABLE 1

    Overview of the effects of riociguat on the right ventricle in clinical studies

    Study designRiociguat treatmentChanges to the right ventricle following riociguat treatment compared with baseline#Reference
    Retrospective single-centre study of 39 patients with PH (21 PAH, 18 CTEPH) in PATENT-1, PATENT-2, PATENT PLUS, CHEST-1, CHEST-2 or CTEPH Early Access Study (EAS)1.0–2.5 mg three times daily for 3–12 monthsFunction
    • Increased TAPSE at 6 months (p=0.025) and 12 months (p=0.002)

    • Increased tricuspid annular velocity at 12 months (p=0.006)

    • Decreased systolic PA pressure and mPAP at 3 months (both p=0.03)

    • Increased CO and CI at 3 months (both p<0.001)

    • Decreased PVR at 3 months (p<0.001)

    Size
    • Decreased RV area at 3 months (p=0.002), 6 months and 12 months (both p<0.001)

    • Decreased RA area at 6 months (p=0.06) and 12 months (p<0.001)

    • Decreased RV free wall thickness at 3 months (p<0.05), 6 months and 12 months (both p<0.01)

    Other remodelling
    • Improved RV remodelling at 6 months (p=0.003) and 12 months (p=0.03)

    [35]
    Retrospective multicentre study of 71 patients with PH (32 PAH, 39 CTEPH) in phase II, PATENT-1, PATENT-2, PATENT PLUS, CHEST-1, CHEST-2 or CTEPH EAS (RIVER study)1.0–2.5 mg three times daily for 3–12 monthsFunction
    • Improved RV systolic function at 12 months (p=0.016)

    • Increased TAPSE at 12 months (p<0.001)

    • Decreased tricuspid regurgitation velocity at 12 months (p=0.005)

    • RV fractional area change at 12 months (p<0.001)

    Size
    • Decreased RV area at 3 months, 6 months and 12 months (all p<0.001)

    • Decreased RA area at 6 months and 12 months (both p<0.001)

    • Decreased RV thickness at 12 months (p=0.023)

    Other remodelling
    • Decreased PA diameter at 12 months (p=0.014)

    [36]
    Retrospective study of 27 patients with PH (7 PAH, 20 CTEPH)Mean dose of 7.3±0.7 mg administered for a mean 220 daysFunction
    • Increased RV fractional area change (p=0.005)

    • Decreased RV global longitudinal strain (p=0.0006)

    Size
    • Decreased basal, mid and longitudinal RV diameters (all p=0.001)

    • Decreased RV end-diastolic area index (p=0.0005)

    [37]
    Retrospective analysis of 45 patients with PH (14 PAH, 31 CTEPH)Mean final daily dose of 7.2±0.9 mg administered for a mean 234 daysFunction
    • Decreased mPAP (p=0.008)

    • Increased CI (p=0.04)

    • Decreased PVR (p=0.016)

    • Increased RV systolic excursion velocity (p=0.001)

    • Decreased RV global longitudinal strain (p<0.001)

    • Increased fractional area change (p<0.001)

    • Decreased RV dyssynchrony index (p=0.012)

    • Decreased estimated PA systolic pressure (p<0.001)

    • Decreased tricuspid regurgitation pressure gradient (p<0.001)

    Size
    • Decreased RV basal (p<0.001), mid (p<0.001) and longitudinal (p=0.002) diameters

    • Decreased RV end-diastolic and end-systolic area indices (p<0.001)

    • Decreased RA area index (p=0.0014)

    [38]
    Post hoc analysis of 341 patients with PAH in PATENT-1 and 238 patients with CTEPH in CHEST-1Up to 2.5 mg three times daily for 12 weeks for PATENT-1 and 16 weeks for CHEST-1Function compared with placebo treated
    • Increased stroke volume, SVI and cardiac efficiency in PATENT-1 and CHEST-1 (all p<0.0001)

    • Increased RV work in PATENT-1 (p=0.0002) and CHEST-1 (p=0.0317)

    • Increased RV work index in PATENT-1 (p<0.0001) and CHEST-1 (p=0.0338)

    • Increased RV power in PATENT-1 (p=0.0002) and CHEST-1 (p=0.0317)

    • Decreased PA elastance in PATENT-1 and CHEST-1 (both p<0.0001)

    [39]
    Single-centre prospective randomised open-label trial of 21 patients with CTEPH who had mPAP <30 mmHg after undergoing BPAUp to 2.5 mg three times daily for 6 months (8 of the 10 patients in the riociguat arm received less than the maximum dose)Function at peak workload compared with standard of care treated
    • Increased CO and decreased PVR at 6 months (both p<0.01)

    • Trend of improved mPAP–CO slope at 6 months (p=0.09)

    [40]
    Post hoc analysis of the RESPITE study in 61 patients with PAH1.0–2.5 mg three times daily for 24 weeks following a 1–3-day PDE5i treatment-free periodFunction following switch
    • Increased cardiac efficiency (p=0.0004)

    • Increased stroke volume (p=0.0044)

    • Increased SVI (p=0.0052)

    • Maintained RV work (p=0.1770)

    • Maintained RV work index (p=0.0793)

    • Maintained RV power (p=0.1770)

    • Maintained PA elastance (p=0.0888)

    [41]
    Retrospective analysis of 28 patients with CTEPH who were switched from sildenafil to riociguatUp to 2.5 mg three times daily for a median follow-up time of 5.8 (3.6–7.9) months following switchingFunction following switch
    • Decreased PVR (p=0.005)

    • Decreased systemic vascular resistance (p=0.001)

    • Decreased mPAP (p=0.03)

    • Increased CO (p=0.002)

    [42]
    Single-centre retrospective analysis of 26 patients with PAH receiving triple therapy with riociguat, macitentan and selexipagOf 26 patients, 24 received riociguat up-titrated to maximum tolerated dose for a median observation period of 441 daysFunction
    • Decreased mean RA pressure (p=0.005)

    • Decreased mPAP (p<0.001)

    • Increased CO (p<0.001)

    • Increased CI (p<0.001)

    • Decreased PVR (p<0.001)

    • Increased TAPSE (p=0.001)

    • Increased RV systolic excursion velocity (p=0.001)

    • Increased fractional area change (p<0.001)

    Size
    • Decreased RV end-systolic area (p=0.006)

    [43]
    Prospective study of 6 patients with CTEPH0.5–2.5 mg three times daily for 6 monthsFunction
    • Increased RV SVI (p=0.03)

    • Trend of increased RV ejection fraction (p=0.09)

    Other remodelling
    • Trend of decreased myocardial fibrosis volume and mass (both p=0.09)

    [44]
    Single-site pilot study of 20 patients with PAH (12 treatment-naïve patients and 8 who were switched from sildenafil to riociguat)1.0–2.5 mg three times daily for 12 weeksFunction
    • Decreased systolic PA pressure (p=0.003)

    • Decreased mPAP (p=0.007)

    • Increased RV fractional area change (p=0.04)

    • Decreased RV end-diastolic volume (p=0.003)

    • Decreased RV end-systolic volume (p=0.002)

    Size
    • Decreased RV basal diameter in treatment-naïve patients only (p=0.03); not significant in switched patients

    Other remodelling
    • Decreased RV–PA coupling (p=0.02)

    [45]

    RV: right ventricular; PH: pulmonary hypertension; PAH: pulmonary arterial hypertension; CTEPH: chronic thromboembolic pulmonary hypertension; TAPSE: tricuspid annular plane systolic excursion; PA: pulmonary artery; mPAP: mean pulmonary arterial pressure; CO: cardiac output; CI: cardiac index; PVR: pulmonary vascular resistance; RA: right atrial; BPA: balloon pulmonary angioplasty; PDE5i: phosphodiesterase-5 inhibitors; SVI: stroke volume index. #: outcomes compared with baseline unless otherwise stated.

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    Riociguat and the right ventricle in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension
    Raymond L. Benza, David Langleben, Anna R. Hemnes, Anton Vonk Noordegraaf, Stephan Rosenkranz, Thenappan Thenappan, Paul M. Hassoun, Ioana R. Preston, Stefano Ghio, Roberto Badagliacca, Carmine D. Vizza, Irene M. Lang, Christian Meier, Ekkehard Grünig
    European Respiratory Review Dec 2022, 31 (166) 220061; DOI: 10.1183/16000617.0061-2022

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    Riociguat and the right ventricle in pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension
    Raymond L. Benza, David Langleben, Anna R. Hemnes, Anton Vonk Noordegraaf, Stephan Rosenkranz, Thenappan Thenappan, Paul M. Hassoun, Ioana R. Preston, Stefano Ghio, Roberto Badagliacca, Carmine D. Vizza, Irene M. Lang, Christian Meier, Ekkehard Grünig
    European Respiratory Review Dec 2022, 31 (166) 220061; DOI: 10.1183/16000617.0061-2022
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    • Article
      • Abstract
      • Abstract
      • Introduction
      • Effect of riociguat on the right ventricle in preclinical models
      • Effect of riociguat on RV function in clinical studies
      • Effect of riociguat on RV hypertrophy in clinical studies
      • Effect of riociguat on other aspects of RV remodelling in clinical studies
      • Conclusions
      • Supplementary material
      • Acknowledgements
      • Footnotes
      • References
    • Figures & Data
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    • PDF

    Subjects

    • Pulmonary vascular disease
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