A novel oral agent, riociguat, a soluble guanylate cyclase stimulator, significantly improves exercise capacity and pulmonary vascular resistance in patients with pulmonary hypertension, according to results of two separate trials published July 24 in the New England Journal of Medicine.

In the phase 3 PATENT-1  (Pulmonary Arterial Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1) trial, investigators randomly assigned 443 symptomatic patients with pulmonary arterial hypertension to receive adjusted doses of riociguat up to 2.5 mg three times a day, doses capped at 1.5 mg three times daily or placebo for 12 weeks.

Results showed that by week 12, the 2.5 mg group of patients had significant improvement in six-minute walk distance by a mean of 30 m compared with patients in the placebo group who had a decrease of 6 m (p < 0.001). The 2.5 mg group also had a significant decrease in pulmonary vascular resistance of 223 dyn · sec · cm-5 versus 9 dyn · sec · cm-5 in the placebo group (p < 0.001). Further, the 2.5 mg group saw significant improvements in NT-proBNP levels, World Health Organization functional class, time to clinical worsening and Borg dyspnea score.

Meanwhile, the phase 3 CHEST-1  (Chronic Thromboembolic Pulmonary Hypertension Soluble Guanylate Cyclase-Stimulator Trial 1) trial randomized 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive up to 2.5 mg of riociguat three times a day or placebo for 16 weeks.

By week 16, the treated group had significantly increased its six-minute walk distance by a mean of 39 m compared with a decrease of 6 m in the placebo group (p < 0.001). In addition, pulmonary vascular resistance significantly decreased by 226 dyn • sec • cm-5 with riociguat treatment compared with an increase of 23 dyn • sec • cm-5 in the placebo group (p < 0.001). As in the PATENT-1 trial, there were also significant improvements in NT-proBNP levels and World Health Organization functional class in the riociguat-treated patients.

In an accompanying editorial, Stephen L. Archer, MD, FACC, notes that although there was a modest improvement in the six-minute walk distance with riociguat, it appears to be safe and is a promising drug therapy for pulmonary arterial hypertension as well as a potentially effective oral therapy for inoperable thromboembolic pulmonary hypertension.

Patients in each trial have been enrolled in PATENT-2 and CHEST-2, respectively.

Keywords: Endarterectomy, Guanylate Cyclase, Guanosine Monophosphate, Hypertension, Pulmonary, Pyrimidines, Vascular Resistance, Pyrazoles, Dyspnea, Nitric Oxide, Natriuretic Peptide, Brain