Riociguat belongs to a new class of treatments for pulmonary hypertension (PH) called soluble guanylate cyclase stimulators. The drug works on the nitric oxide pathway involved in the pathogenesis of PH and is administered orally.
This phase 3, 16-week, double-blind, randomised, placebo-controlled study (CHEST-1) investigated the efficacy and safety of riociguat in patients with chronic thromboembolic PH who were considered to be ineligible for surgery or who had persistent or recurrent pulmonary hypertension after pulmonary endarterectomy. The study was conducted at 89 centres in 26 countries and included patients aged 18 – 80 years old.
A total of 261 patients meeting the eligibility criteria were randomly allocated (in a 1:2 ratio) to receive placebo (n=88) or riociguat (n=173). Riociguat was adjusted from a starting dose of 1 mg three times daily according to systolic systemic arterial pressure and signs or symptoms of hypotension (final range, 0.5 mg to 2.5 mg three times daily). The primary end point measure considered in the study was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary outcome measures included assessment of pulmonary vascular resistance and safety. The results found:
• By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001).
• Pulmonary vascular resistance decreased by 226 dyn•sec•cm–5 in the riociguat group and increased by 23 dyn•sec•cm–5 in the placebo group (mean difference, –246 dyn•sec•cm–5; 95% CI, –303 to –190; P<0.001).
• Riociguat was also associated with significant improvements in the N-terminal pro–brain natriuretic peptide level (P<0.001) and WHO functional class (P=0.003).
• 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).
The authors note, “An obvious limitation of CHEST-1 was the lack of follow-up efficacy measurements in patients who withdrew from the study. However, sensitivity analyses that used a variety of approaches to impute missing data suggest that the results are reliable, despite these losses to follow-up.” They conclude that riociguat significantly improved the 6-minute walk distance, pulmonary vascular resistance, and other clinical outcomes in patients with inoperable chronic thromboembolic PH.
The author of a related editorial highlights the following:
• A major limitation in this study was the failure to assess the effects of riociguat on the right ventricle. He notes, “The 6-minute walk distance is as reflective of right ventricular or skeletal-muscle function as it is of reduction in pulmonary vascular resistance, the authors' presumed mechanism of benefit.”
• The benefits with pulmonary endarterectomy (a 100-m increase in 6-minute walk distance) exceed the benefits with riociguat (an increase of 46 m as compared with placebo). He writes, “Patients who are suitable candidates for surgery should continue to undergo surgery and not be relegated to an inferior treatment.”
• The relationship to the sponsoring company (Bayer HealthCare), including the fact that the statistician was employed by Bayer HealthCare
Riociguat has been filed for approval in Europe and the United States. The U.S FDA granted it a priority review in April 2013.