Riociguat for the Treatment of Pulmonary Arterial Hypertension

Study Questions:

Is riociguat, a soluble guanylate cyclase stimulator, beneficial in the treatment of pulmonary arterial hypertension (PAH)?


PATENT-1 was a double-blind, placebo-controlled study, in which 443 patients with symptomatic PAH were randomized to receive placebo (126 patients), riociguat in individually adjusted doses of up to 2.5 mg three times daily (254 patients), or riociguat in individually adjusted doses that were capped at 1.5 mg three times daily (63 patients). The 1.5 mg–maximum group was included for exploratory purposes. Patients who were receiving no other treatment for PAH and patients who were receiving endothelin-receptor antagonists or (nonintravenous) prostanoids were eligible. The primary endpoint was the change from baseline to the end of week 12 in the distance walked in 6 minutes (6MWD). Among the secondary endpoints included the change in pulmonary vascular resistance (PVR), N-terminal pro–brain natriuretic peptide (NT-proBNP), World Health Organization (WHO) functional class (FC), time to clinical worsening, and safety.


There was no difference between groups for the following: female 79%, age 51 years, idiopathic PAH 61%, connective tissue disease 25%, WHO FC II-III 95%, and 6MWD 363 m. By week 12, the 6MWD 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 (least-squares mean difference, 36 m; p < 0.001). Prespecified subgroup analyses showed that riociguat improved the 6-MWD both in patients who were receiving no other treatment for the disease (50%) and in those receiving PAH-specific therapy. There were significant improvements in PVR (p < 0.001), NT-proBNP levels (p < 0.001), WHO functional class (p = 0.003), and time to clinical worsening (p = 0.005). 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 concluded that riociguat significantly improved exercise capacity and secondary efficacy endpoints in patients with PAH.


The magnitude of improvement (36 m 6MWD) is comparable to that observed in studies of other PH-specific treatments. The improvement with riociguat was negated in part by the 45% who were WHO FC I-II. Pharmaceutical industry designed trials in PAH have generally included patients with both idiopathic PAH and associated with connective tissue disease, a practice that results in lack of power to assess the benefit in other group 1 PAH-associated diseases such as scleroderma, portal PH, and congenital heart disease.

Clinical Topics: Heart Failure and Cardiomyopathies, Pulmonary Hypertension and Venous Thromboembolism, Pulmonary Hypertension

Keywords: Hypertension, Pulmonary, Pyrazoles

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