Switching sildenafil to riociguat in chronic thromboembolic pulmonary hypertension after balloon pulmonary angioplasty - the S2R study

Background Riociguat has been approved for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH), while phosphodiesterase type 5 inhibitor (PDE5i) has been previously used as an off-label. In patients with pulmonary arterial hypertension (PAH), switching sildenafil to riociguat was associated with greater clinical improvement. Balloon pulmonary angioplasty (BPA) is one of the treatment options for inoperative CTEPH patients, and previous studies have shown that compared to riociguat, BPA was associated with a greater reduction in mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) in CTEPH patients. However, the potential benefits of switching PDE5i to riociguat after BPA in CTEPH patients are unknown. Purpose To assess the safety and efficacy of switching PDE5i to riociguat after BPA in CTEPH patients. Methods This was a prospective, open-labelled, single-centre study conducted in Hong Kong. CTEPH patients who had completed BPA procedures and remained in WHO functional class III were recruited. At baseline, their sildenafil was switched to riociguat after a 24-hour washout period. Then, riociguat was titrated up to 2.5mg t.i.d. over 8 weeks, followed by 16 weeks of the maintenance phase. The primary endpoints were the changes in mPAP and PVR at week 26. The secondary endpoints included changes in cardiac index, WHO functional class, NT-proBNP level and 6-minute walking distance test (6MWD), treatment-related adverse events and any clinical worsening. Results Between July 2024 and January 2025, 16 patients (age 62.3±14.6 years; 75% female) were recruited, and 14 (87.5%) completed the 26-week follow-up. At week 26, the mPAP reduced by 4.79mmHg [Confidence Interval (CI) -8.05 to -1.52; p=0.007] and the PVR reduced by 2.16 Wood units [CI -3.64 to -0.69; p=0.007;]. All of the secondary endpoints also showed significant improvement. The cardiac index increased by 0.37 L/min/m2 [CI 0.03 to 0.71; p=0.036], the WHO functional class improved by -0.79 [p=0.024], NT-proBNP decreased by 461 ng/L [CI -909.04 to -12.96; p=0.045) and the 6MWD improved by 25.02m [CI 4.32 to 45.72; p=0.02]. 11 patients (68.75%) reported at least one treatment-related adverse drug event. The most common adverse events were hypotension (25%) followed by nasopharyngitis (18.75%). Four of these adverse events (dyspepsia, headache, nasopharyngitis and vomiting) led to temporary interruption of riociguat. Four patients experienced clinical worsening, including two deaths due to pneumonia and subdural haematoma, which were not treatment-related. Another two patients experienced unplanned hospitalisations due to pulmonary hypertension. Conclusion In patients with CTEPH who have completed BPA treatment, switching PDE5i to riociguat improved pulmonary haemodynamics and functional outcomes despite significant treatment-related adverse events. These findings support the use of riociguat for CTEPH patients after BPA.