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Pulmonary vascular disease
Original article
Haemodynamic effects of riociguat in inoperable/recurrent chronic thromboembolic pulmonary hypertension
  1. Nick H Kim1,
  2. Andrea M D'Armini2,
  3. Friedrich Grimminger3,4,
  4. Ekkehard Grünig5,
  5. Marius M Hoeper4,6,
  6. Pavel Jansa7,
  7. Eckhard Mayer8,
  8. Claus Neurohr9,
  9. Gérald Simonneau10,
  10. Adam Torbicki11,
  11. Chen Wang12,
  12. Arno Fritsch13,
  13. Neil Davie13,
  14. Hossein-Ardeschir Ghofrani3,4,14
    1. 1Division of Pulmonary and Critical Care Medicine, University of California, San Diego, La Jolla, California, USA
    2. 2Division of Cardiothoracic Surgery, Foundation “I.R.C.C.S. Policlinico San Matteo”, University of Pavia School of Medicine, Pavia, Italy
    3. 3University of Giessen and Marburg Lung Center (UGMLC), Giessen, Germany
    4. 4German Center of Lung Research (DZL), Giessen, Germany
    5. 5Center for Pulmonary Hypertension, Thoraxclinic, University Hospital Heidelberg, Heidelberg, Germany
    6. 6Clinic for Respiratory Medicine, Hannover Medical School, Hannover, Germany
    7. 7Clinical Department of Cardiology and Angiology, First Faculty of Medicine and General Teaching Hospital, Prague, Czech Republic
    8. 8Kerckhoff Heart and Lung Center, Bad Nauheim, Germany
    9. 9Division of Pulmonary Diseases, Ludwig Maximilians University, Munich, Germany
    10. 10Assistance 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
    11. 11Department of Pulmonary Circulation and Thromboembolic Diseases, Medical Center of Postgraduate Education, Europejskie Centrum Zdrowia Otwock, Otwock, Poland
    12. 12Department of Respiratory Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao Yang Hospital, Capital Medical University, Beijing Key Laboratory of Respiratory and Pulmonary Circulation Disorders, Beijing, China
    13. 13Global Clinical Development, Bayer Pharma AG, Wuppertal, Germany
    14. 14Department of Medicine, Imperial College London, London, UK
    1. Correspondence to Dr Nick H Kim, Division of Pulmonary and Critical Care Medicine, University of California, San Diego, 9300 Campus Point Drive, MC 7381, La Jolla, CA 92037, USA; h33kim{at}ucsd.edu

    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/cm5 (95% CI −357 to −213); p<0.0001) and persistent/recurrent (n=72; −131 dyn s/cm5 (95% CI −214 to −48); p=0.0025) patients. Cardiac index improved in inoperable patients by a least-squares mean difference of +0.6 L/min/m2 (95% CI 0.4 to 0.7; p<0.0001), while in persistent/recurrent patients the change was +0.2 L/min/m2 (95% CI −0.1 to 0.5; p=0.17). Mean pulmonary artery pressure decreased in inoperable and persistent/recurrent patients(−4.7 mm Hg (95% CI −6.9 to −2.6; p<0.0001 and −4.8 mm Hg (–8.2 to −1.5; p=0.0055), respectively). For all patients, changes in 6 min walk distance correlated with changes in PVR (r=−0.29 (95% CI −0.41 to −0.17); p<0.0001) and cardiac index (r=0.23 (95% CI 0.10 to 0.35); p=0.0004).

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

    Trial registration number NCT00855465.

    This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

    https://doi.org/10.1136/heartjnl-2016-309621

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      Footnotes

      • Contributors NHK takes overall responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. NHK, FG, MMH, EM, GS and H-AG were members of the CHEST-1 steering committee and as such contributed to the conception and design of the CHEST-1 study. NHK, AMD'A, FG, EG, MMH, PJ, EM, CN, GS, AT, CW and H-AG recruited and treated patients in the CHEST-1 study. AF performed the statistical analysis. NHK, AMD'A, FG, EG, MMH, PJ, EM, CN, GS,AT,CW, AF, ND and H-AG contributed to the conception and design of this paper, the analysis and interpretation of the data and the drafting, critical review and approval of the final manuscript.

      • Collaborators Full list of CHEST-1 investigators: Argentina: E Perna, Australia: T Williams, Austria: I Lang and C Kaehler, Belgium: M Delcroix and J-L Vachiery, Brazil: J Arakaki, D Waetge and G Meyer, Canada: J Granton, A Hirsch, D Helmersen, S Mehta and L Mielniczuk, China: Z Liu, C Wang, Z Cheng, Z Jing and L Pan, Czech Republic: P Jansa, Denmark: J-E Nielsen-Kudsk, France: G Simonneau, I Franchon, A Chaouat, P De Groote, E Bergot, F Bauer, C Dromer and C-H Marquette, Germany: H-A Ghofrani, M Hoeper, C Neurohr, H Wilkens, G Hoffken, S Rosenkranz, H Wirtz, R Ewert, E Grünig, H Klose, A Filusch and M Held, Italy: AM D'Armini and M Morsolini, Japan: Y Fukumoto, N Tanabe, M Sano, M Hatano, Y Takeda, M Sakuma, T Higo, T Satoh, M Ohe, M Owa, O Okazaki, M Ajioka, M Iwabuchi, M Takata and Y Akashi, Netherlands: A Boonstra, Mexico: C Sanchez Diaz, U Martinez, M Gamba and T Pulido Zamudio, Poland: A Torbicki and P Podolec, Portugal: G Castro, Republic of Korea: S Lee and H Kim, Russia: O Moiseeva and A Chernyavsky, Slovakia: I Simkova, Spain: MA Gomez Sanchez and JA Barbera, Switzerland: R Speich, Taiwan: Y-H Lin, Turkey: G Karabiyikoglu, N Mogulkoc and G Okumus, UK: J Pepke-Zaba, A Peacock and L Howard, USA: R Allen, N Sood, S Chaparro, F Torres, G Heresi, A Zaiman, K Kerr, H Farber and S Hansdottir.

      • Funding This study was funded by Bayer Pharma AG (Berlin, Germany). Editorial assistance was provided by Adelphi Communications (Bollington, UK), sponsored by Bayer Pharma AG.

      • Competing interests NHK reports personal fees and non-financial support from Bayer HealthCare Pharmaceuticals; grants and personal fees from Actelion; grants from Gilead, Lung LLC and United Therapeutics. AMD'A reports personal fees from Bayer HealthCare Pharmaceuticals and personal fees from Actelion. FG reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and personal fees from Actelion, Lilly, Novartis and Pfizer. EG reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals, grants and personal fees from Actelion, GSK, Lilly and Pfizer, non-financial support from Alexion and personal fees from Miltenyi, Novartis and United Therapeutics. MMH reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and personal fees from Actelion, GSK, Lilly, Novartis and Pfizer. PJ, an investigator for Actelion, reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and personal fees from AOP. EM reports personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and personal fees from Actelion, GSK and Pfizer. CN reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and personal fees from Actelion, GSK, Novartis and Pfizer. GS reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals, Actelion, GSK, Lilly and Pfizer and personal fees and non-financial support from Novartis. AT reports grants, personal fees and non-financial support from Bayer HealthCare Pharmaceuticals and grants and personal fees from Actelion, GSK and AOP. CW has nothing to report. AF is an employee of Bayer Pharma AG. ND is an employee of Bayer Pharma AG. H-AG reports grants from Actelion, Bayer HealthCare Pharmaceuticals, Ergonex and Pfizer and personal fees from Actelion, Bayer HealthCare Pharmaceuticals, Ergonex, Gilead, GSK, Merck, Novartis and Pfizer.

      • Provenance and peer review Not commissioned; externally peer reviewed.