STOP-RIO study: protocol for a randomised, controlled, open-label non-inferiority trial to test the safety of discontinuation of riociguat after balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension

INTRODUCTION: Balloon pulmonary angioplasty (BPA) improves haemodynamics and outcomes in patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Riociguat is frequently initiated before BPA to reduce procedural risks. However, evidence supporting continuation after successful BPA is lacking and current guidelines provide no criteria for treatment discontinuation. Consequently, many patients remain on long-term riociguat despite uncertain benefit, potential adverse effects and high costs. METHODS AND ANALYSIS: STOP-RIO is a multicentre, open-label, randomised, non-inferiority (NI) trial conducted in the two Dutch CTEPH expert centres. Seventy-four adult CTEPH patients treated with riociguat monotherapy with a mean pulmonary artery pressure (mPAP) <30 mmHg post-BPA will be randomised (1:1) to stop or continue the medication. The primary endpoint is the between-group difference in baseline-adjusted mPAP at rest measured by right heart catheterisation at 16 weeks. NI will be tested for the primary endpoint and for the two secondary endpoints highest in hierarchy N-terminal pro-B-type natriuretic peptide and 6-min walk distance. Additional secondary endpoints include haemodynamic parameters, safety outcomes, patient-reported outcomes and healthcare use. The primary analysis will be performed in a per-protocol population with secondary intention-to-treat and exploratory analyses. A prospective health economic evaluation will be conducted from a societal perspective. ETHICS AND DISSEMINATION: The study is conducted in accordance with the Declaration of Helsinki and Good Clinical Practice and has received ethical approval. Written informed consent will be obtained from all participants. Results will be disseminated through peer-reviewed publication and shared with patient organisations and scientific congress. TRIAL REGISTRATION NUMBER: EU Clinical Trials Register: 2024-5 19 225-38-00.