Study rationale and design

Study rationale

Clinical data indicate that 20–60% of patients with PAH receiving PDE5i do not reach or maintain treatment goals.1, 2, 3 Escalation of therapy, including combination therapy, is an option in these patients4, 5; however, combination therapy may have additional side effects,6 and important financial considerations.7, 8

The riociguat mode of action
A prospective randomized, international, multicenter, double-arm, controlled, 24-week open-label Phase IV study assessing the effect of switching to riociguat compared with maintenance of stable PDE5i in patients with PAH at intermediate risk.

Patient population

Patients treated with a stable dose of PDE5i±ERA for 5 weeks, at intermediate risk

Intermediate risk, as indicated by:

  • 6MWD 165-440 m

Primary endpoint (centrally adjudicated)

  • Clinical improvement at Week 24, defined as 2 out of 3:
    • 6MWD improvements by ≥ 10% or ≥ 30 m
    • WHO FC I/II
    • NT-proBNP decrease by ≥ 30%
  • Absence of clinical worsening

Study sites

The REPLACE study was conducted in 81 centers in 22 countries


Study overview

Play Video

Professor Marius Hoeper introduces the study design and its rationale

Study results

See the video presentation of the study results and supporting data


Find resources associated with the study, including other riociguat publications

  1. Chockalingam A et al. Int J Cardiol 2005;99:91–95.
  2. Leuchte HH et al. Chest 2004;125:580–586.
  3. Galiè N et al. N Engl J Med 2015;373:834–844.
  4. Galiè N et al. Eur Respir J 2015;46:903–975.
  5. Lajoie AC et al. Lancet Respir Med 2016;4:291–305.
  6. Liu HL et al. Chest 2016;150:353–366.
  7. Hill NS et al. J Manag Care Spec Pharm 2016;22:S3–S21.
  8. Wilkens H et al. Respir Med 2010;104:902–910.
  9. Ghofrani HA et al. Nat Rev Drug Discov 2006;5:689–702.
  10. Archer SL et al. Am J Respir Crit Care Med 1998;158:1061–1067.
  11. Giaid A and Saleh S. N Engl J Med 1995;333:214–221.
  12. Kielsten JT et al. Arterioscler Thromb Vasc Biol 2005;25:1414–1418.
  13. Migneault A et al. Am J Respir Crit Care Med 2005;171:506–513.
  14. Tsai EJ and Kass DA. Pharmcol Ther 2009;122:216–238.
  15. Stasch JP et al. Nature 2001;410:212–215.
  16. Stasch JP et al. Circulation 2011;123:2263–2273.
  17. Hoeper MM et al. Eur Respir J 2017;50:1602425.
  18. Hoeper, M. M et al. Am J Respir Crit Care Med 195: A2296.
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