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 12-week, double-blind, randomised, placebo-controlled study (PATENT-1) investigated the efficacy and safety of riociguat in patients with symptomatic pulmonary arterial hypertension (PAH), both those who were receiving no other treatment for the condition and those who were receiving treatment with endothelin-receptor antagonists or non-intravenous prostanoids. The study was conducted at 124 centres in 30 countries.
Overall, 443 patients meeting the eligibility criteria with symptomatic PAH were randomly allocated (in a 2:4:1 ratio) to receive either placebo (n=126) or oral riociguat individually adjusted doses of up to 2.5 mg three times daily (2.5 mg–maximum group; n=254), or oral riociguat individually adjusted doses of up to 1.5 mg three times daily (1.5 mg–maximum group; n=63). The 1.5 mg–maximum group was included for exploratory purposes, to provide information about lower riociguat doses, and data from this group were not included in the efficacy analyses. Patients were followed up at weeks 2, 4, 6, and 8 (during the dose-adjustment phase) and at week 12 (at the end of the maintenance phase). The primary endpoint measure considered in the study was the change from baseline to the end of week 12 in the distance walked in 6 minutes. Secondary end point measures included the change in pulmonary vascular resistance, quality-of-life variables and safety. The following findings are reported:
• By week 12, the 6-minute walk distance had increased by a mean of 30 m in the 2.5 mg–maximum group and had decreased by a mean of 6 m in the placebo group (mean difference, 36 m; 95% confidence interval, 20 to 52; P<0.001).
• Prespecified subgroup analyses showed that riociguat improved the 6-minute walk distance both in patients who were receiving no other treatment for the disease and in those who were receiving endothelin-receptor antagonists or prostanoids.
• There were significant improvements in pulmonary vascular resistance (P<0.001), N-terminal pro–brain natriuretic peptide levels (P<0.001), WHO functional class (P=0.003), time to clinical worsening (P=0.005), and Borg dyspnoea score (P=0.002).
• The most common serious adverse event in the placebo group and the 2.5 mg–maximum group was syncope (4% and 1%, respectively).
The authors discuss limitations to their research and note, “An obvious limitation of PATENT-1 was the lack of follow-up efficacy measurements in patients who withdrew from the study. However, sensitivity analyses that were performed with a variety of approaches to impute missing data suggest that the results are dependable despite these losses to follow-up.” They add that other limitations included:
- The exclusion of certain patient groups with PAH (e.g. associated with HIV) and
- The exclusion of patients who were receiving treatment with PDE5 inhibitors or intravenous prostanoids.
They conclude that riociguat significantly improved the 6-minute walk distance, as well as pulmonary vascular resistance and several other secondary efficacy end points, in patients with symptomatic PAH.
The author of a related editorial highlights that a major limitation in this study is the modest effect size achieved. He notes, “This is particularly important, since 50% of the patients were receiving no other treatment for PAH and the rate of response to treatment among such patients is usually higher than the rate among patients who are receiving concomitant treatment for PAH.” He also adds that the results observed are “less impressive” than those seen with a trial investigating the use of sildenafil in PAH (SUPER trial). The author also notes that:
• An opportunity to show the drug’s effect on the right ventricle was lost.
• 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.