CHEST-1 (2013)

Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe and progressive disease where surgical pulmonary endarterectomy (PEA) is the curative treatment. However, a significant proportion of patients are not surgical candidates or have persistent PH after PEA, for whom no approved medical therapies existed. This study aimed to evaluate the efficacy and safety of riociguat, a soluble guanylate cyclase stimulator, in this challenging patient population.

CHEST-1 was a phase 3, randomized, double-blind, placebo-controlled trial. It enrolled patients with inoperable CTEPH or persistent/recurrent PH after PEA. Patients were randomized to receive riociguat (individually titrated up to 2.5 mg three times daily) or placebo, with the primary endpoint being the change from baseline in 6-minute walk distance (6MWD) at 16 weeks.

Riociguat significantly improved 6MWD compared to placebo, with a mean difference of 46 m (95% CI 25 to 67; p < 0.001). Secondary endpoints also showed significant improvements with riociguat, including pulmonary vascular resistance (PVR) (-246 dyn.s.cm-5 vs -24 dyn.s.cm-5, p < 0.001) and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels. Clinical worsening events were also significantly reduced in the riociguat group. The most common adverse events were headache, dyspepsia, dizziness, and nausea.

Riociguat is an effective and generally well-tolerated medical therapy for patients with inoperable CTEPH or persistent/recurrent PH after PEA, improving exercise capacity and pulmonary hemodynamics.

The study duration was relatively short (16 weeks), limiting conclusions about long-term efficacy and safety. The study population was also highly selected, potentially limiting generalizability to all CTEPH patients.