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PAH: treatment

placebo group; p<0.001). In CHEST-1, consistent with the effects observed for the 6MWD, riociguat had superior effects over placebo on the predefined secondary efficacy variables PVR (decrease by 226 in the riociguat group, and increase by 23

in the placebo group;

p<0.001), NT-proBNP (p<0.001) and WHO functional class (p=0.003). Both CTEPH groups showed a similar response to riociguat treatment. The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group).

Of 243 patients completing CHEST-1, 237 entered CHEST-2. At the cut-off (March 2014), 172 patients were ongoing, 171 had received ≥2 years of treatment and 18 switched to the commercial drug. The two year-survival of CTEPH for patients receiving riociguat was 93% and 10% were receiving additional PAH therapy. Riociguat is the first therapy to show sustained clinical effect in patients with CTEPH.21,22

During the CHEST-2 study24 (long-

term extension of CHEST-1), the clinical benefit and safety profile observed in CHEST-1 were maintained and patients previously treated with placebo during CHEST-1 improved to a similar extent as subjects on riociguat during the pivotal study. Serious cases of haemoptysis and pulmonary haemorrhage occurred during both studies. Haemoptysis occurred in riociguat group 10/490 (2.0%) versus 2/214 (0.9%) in placebo group, with one patient in riociguat group having a fatal outcome. In addition, pulmonary haemorrhage (3/642, 0.5%) occurred during the long-term extension period and all of them had a fatal outcome. During the study, the dose of the study drug was decreased in 18 patients (10%) in the riociguat group.

PH due to left ventricular or lung disease In the LEPHT study,25

administration of 26

riociguat at doses of 0.5–2.0mg for 16 weeks did not result in statistically significant improvements in mPAP compared with placebo in patients with symptomatic PH associated with left ventricular systolic dysfunction. However, treatment in the 2.0mg target dose arm (in comparison with placebo) resulted in consistent improvements in other haemodynamic parameters measured invasively and by echocardiography (left ventricular ejection fraction).

In an open-label, uncontrolled pilot

trial 22 patients with pulmonary hypertension associated with interstitial lung diseases (PH-ILD) received oral riociguat (1.0-2.5mg three-times daily) for 12 weeks. Primary end-points were safety and tolerability. After 12 weeks of therapy, mean cardiac output increased, pulmonary vascular resistance decreased and mean pulmonary arterial pressure remained unchanged. The 6MWD increased from 325±96m at baseline to 351±111 after 12 weeks. The authors concluded that further studies are necessary to evaluate the safety and efficacy in patients with PH-ILD.26 Riociguat is being currently studied also in patients with PH due to IIP and patients with SSc.27,28

Conclusions Riociguat is an efficacious treatment for PAH and CTEPH. On 8 October 2013, the US Food and Drug Administration approved riociguat (Adempas®

12. Bayer HealthCare AG. Investigator’s Brochure BAY 63-2521/Riociguat. Version 14.0 Date 22 Apr 2013.

13. Schermuly RT et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J 2008;32:881–91.

14. Lang M et al. The soluble guanylate cyclise stimulator riociguat ameliorates pulmonary hypertension induced by hypoxia and SU5416 in rats. PloS One 2012;7:e43433.

15. White RJ et al. Oral treprostinil diethanolamine provides sustained therapeutic plasma concentrations over a wide range of doses in patients with pulmonary arterial hypertension. Am J Respir Crit Care Med 2008;177:A261. Poster presented at: American Thoracic Society International Conference 2008.

16. Frey R et al. Single-dose pharmacokinetics, pharmacodynamics, tolerability, and safety of the soluble guanylate cyclase stimulator BAY 63-2521: an ascending-dose study in healthy male volunteers. J Clin Pharmacol 2008;48:926–34.

, Bayer) for

the treatment of PAH and CTEPH. EMA approval was granted in March 2014. Until now, it is the only treatment approved in both indications: PAH and CTEPH. l

References 1. Humbert M et al. Treatment of pulmonary arterial hypertension. N Engl J Med 2004;351:1425–36.

2. Giaid A, Saleh D. Reduced expression of endothelial nitric oxide synthase in the lungs of patients with pulmonary hypertension. N Engl J Med 1995;333:214–21.

3. Tuder RM et al. Prostacyclin synthase expression is decreased in lungs from patients with severe pulmonary hypertension. Am J Respir Crit Care Med 1999;159:1925–32.

4. Giaid A et al. Expression of endothelin-1 in lungs of patients with cryptogenic fibrosing alveolitis. Lancet 1993;341:1550–4.

5. Lucas KA et al. Guanylyl cyclases and signaling by cyclic GMP. Pharmacol Rev 2000;52:375–414.

6. Stasch JP et al. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation 2011;123:2263–73.

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8. Murad F. Shattuck Lecture. Nitric oxide and cyclic GMP in cell signalling and drug development. N Engl J Med 2006;355:2003–11.

9. Lubos E et al. Role of oxidative stress and nitric oxide in atherothrombosis. Front Biosci 2008;13:5323–44.

10. Tsai EJ, Kass DA. Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther 2009;122:216–38.

11. Vachiery JL. Prostacyclins in pulmonary arterial hypertension: the need for earlier therapy. Adv Ther 2011;28:251–69.

17. Grimminger F et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J 2009;33:785–92.

18. Skoro-Sajer N et al. Surgical specimens, haemodynamics and long-term outcomes after pulmonary endarterectomy. Thorax 2014;69:116–22.

19. Ghofrani HA et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med 2013;369:330–40.

20. Rubin LJ et al. Riociguat for the treatment of pulmonary arterial hypertension (PAH): A phase III long-term extension study (PATENT-2). Am J Resp Crit Care Med 2013;187:A3531.

21. Simonneau G, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: 2- year results from the CHEST-2 long-term extension. European Respiratory Society International Congress; 6–10 September 2014; Munich, Germany [P1802].

22. Rubin LJ et al. Riociguat for the treatment of pulmonary arterial hypertension: 2-year results from the PATENT-2 long-term extension. European Respiratory Society International Congress; 6–10 September 2014; Munich, Germany [P1803].

23. Ghofrani HA et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369:319–29.

24. Simonneau G et al. An interim analysis of the Phase III riociguat long-term extension study in CTEPH (CHEST-2). European Respiratory Society Annual Congress, Barcelona, 5–7 September 2013.

25. Bonderman D et al. Riociguat for patients with pulmonary hypertension caused by systolic left ventricular dysfunction: a phase IIb double-blind, randomized, placebo-controlled, dose-ranging hemodynamic study. Circulation 2013;128:502–11.

26. Hoeper MM et al. Riociguat for interstitial lung disease and pulmonary hypertension: a pilot trial. Eur Respir J 2013;41(4):853–60.

27. Clinical NCT02138825. 28. Clinical NCT02283762.

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