Pulmonary hypertension is associated with high morbidity and a poor prognosis.  Medical therapies including PDE-5 inhibitors and ET-1 antagonists have led to symptomatic gains in carefully selected groups of patients, but the need for further developments remains apparent. Riociguat, the first in class of a new group which act as stimulators of soluble guanylate cyclase, was trialled in two simultaneously released studies: PATENT-1 investigating patients with primary pulmonary arterial hypertension and CHEST-1 investigating patients with chronic thromboembolic pulmonary hypertension.

PATENT-1 randomised 443 patients with symptomatic pulmonary arterial hypertension, who were either receiving no treatment or were receiving ET-1 antagonists or (nonintravenous) prostanoids, to receive placebo or riociguat in individually adjusted doses of up to 2.5 mg three times daily.  The primary end point was change from baseline to week 12 in 6 minute walk distance.  CHEST-1 randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat.  The primary end point was the change from baseline to week 16 in 6 minute walk distance. Both studies also examined a number of secondary end points including the change in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, World Health Organization (WHO) functional class, time to clinical worsening, score on the Borg dyspnoea scale, quality-of-life variables, and safety.

Both studies produced highly statistically significant increases in their primary end-points (PATENT-1, a mean 30m increase (P<0.001) and CHEST-1, a mean 39m increase (P<0.001)) with achieved distance rising by 10-15% from baseline, a figure similar to the gains seen in the landmark PDE-5 and ET-1 trials. Similar highly significant changes were seen in secondary end-points in both studies with no common serious adverse events seen that were more common with the study drug than placebo.
Conclusions:

In these two large double-blind placebo controlled studies, riociguat significantly improved exercise capacity and secondary efficacy end points in patients with pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension, offering a valuable new option for treatment in these conditions.

• Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, Keogh AM, Langleben D, Kilama MO, Fritsch A, Neuser D and Rubin LJ. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013 Jul 25;369(4):330-40.
• Ghofrani HA, D’Armini AM, Grimminger F, Hoeper MM, Jansa P, Kim NH, Mayer E, Simonneau G, Wilkins MR, Fritsch A, Neuser D, Weimann G and Wang C. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med. 2013 Jul 25;369(4):319-29.