Effect of riociguat on exercise following balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension in Japan (THERAPY-HYBRID-BPA): a multicentre, double-blind, randomised, controlled, phase 4 trial.

Background: Balloon pulmonary angioplasty (BPA) and medical therapy are the most common treatment options for inoperable chronic thromboembolic pulmonary hypertension (CTEPH), but their combined use has not been sufficiently studied. This study aimed to evaluate the efficacy during an exercise test and the safety of the continuation of riociguat post-BPA in patients with inoperable CTEPH and normalised haemodynamic variables.

Methods: This multicentre, double-blind, randomised, controlled, phase 4 trial was conducted at four high-volume CTEPH centres in Japan. Patients aged 18-85 years with a confirmed diagnosis of inoperable, WHO functional class II-IV CTEPH, and a resting mean pulmonary arterial pressure (mPAP) of 25 mm Hg or higher and pulmonary vascular resistance of 3·0 Wood units or higher on right-heart catheterisation, received riociguat and BPA at screening. Screened patients with a resting cardiac index of less than 5·0 L/min per m and mPAP of less than 25 mm Hg 3 months after the final BPA procedure were randomly assigned (1:1) either to receive placebo three times daily for 16 weeks or to continue taking riociguat three times daily for 16 weeks at a dose established during the screening period, which varied per patient from 1·0 mg to 2·5 mg. Randomisation was done via an online system with a block size of 8 based on the allocation factors of medical institution and riociguat dose at allocation; patients and investigators were masked to treatment assignment. The primary endpoint was the change in peak cardiac index calculated using the direct Fick method during a cardiopulmonary exercise test (CPET) from baseline to week 16, and was measured in the full analysis set (ie, all randomly assigned patients apart from those who had withdrawn consent, had severe protocol violations, or had never taken the active drug or placebo) in all patients with available data. The safety analysis included all patients who had taken at least one dose of the active drug or placebo. The trial was registered with the Japan Registry of Clinical Trials (jRCTs041200052) and ClinicalTrials.gov (NCT04600492) and is now closed.

Findings: Between Nov 25, 2020, and May 16, 2023, 74 patients (including 58 female patients and 16 male patients) were enrolled and randomly assigned, 36 to the riociguat-discontinuing group and 38 to the riociguat-continuing group. 32 patients in the riociguat-discontinuing group and 34 in the riociguat-continuing group were included in the primary analysis after exclusion of patients with missing data. The adjusted mean of peak cardiac index during CPET changed from baseline to week 16 by -1·11 L/min per m (95% CI -2·14 to -0·09) in the riociguat-discontinuing group and by -0·03 L/min per m (-1·04 to 0·99) in the riociguat-continuing group (intergroup difference 1·09 L/min per m [95% CI 0·20-1·97]; p=0·017). Non-serious adverse events occurred in ten (28%) patients in the riociguat-discontinuing group and 14 (38%) patients in the riociguat-continuing group (p=0·36). No deaths were observed.

Interpretation: Our findings suggested that the continuation of riociguat post-BPA might attenuate the worsening of exercise intolerance without increasing the risk of adverse events; discontinuation might require more careful consideration. These results should be explored in long-term studies.

Funding: Bayer Yakuhin, Bayer, and Merck Sharp & Dohme.