Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but severe complication of acute pulmonary embolism, characterized by persistent obstruction of the pulmonary arteries by organized thrombi and secondary microvasculopathy. International guidelines recommend a multimodal approach combining pulmonary endarterectomy (PEA), balloon pulmonary angioplasty (BPA), and medical treatment with riociguat, to address the full spectrum of CTEPH lesions. BPA and riociguat are recommended for symptomatic patients with inoperable CTEPH or persistent pulmonary hypertension after PEA. Riociguat is administered before BPA to reduce periprocedural complications by improving pulmonary hemodynamics. While this pre-BPA strategy is well established, post-BPA management is poorly studied, especially in patients achieving therapeutic goals, defined as WHO functional class I or II and near-normal resting pulmonary hemodynamics (70 to 80% of cases). In such cases, riociguat monotherapy is often continued long-term, despite its cost, burden, and potential side effects, which may negatively impact patients' quality of life. Retrospective single-center studies suggest that discontinuation of medical treatment does not lead to significant clinical deterioration. Therefore, we propose conducting a multicenter trial using a PROBE (prospective, randomized, open-label, blinded endpoint) design and a Bayesian approach to test if stopping riociguat monotherapy after successful BPA is associated with an acceptably low risk of clinical worsening over a follow-up period of at least one year compared to continuation. The trial will also assess the cost-effectiveness of riociguat discontinuation.

Inclusion Criteria:

• 1. Signed informed consent and willingness to accept either discontinuation or continuation of riociguat monotherapy

• 2. Age ≥18 years

• 3. Diagnosis of inoperable CTEPH or persistent PH after PEA, with achievement of therapeutic goals following BPA, defined as:

  1. WHO FC I or II
  2. Pulmonary vascular resistance (PVR) < 3 Wood units
  3. Mean pulmonary artery pressure (mPAP) < 30 mmHg

• 4. Treatment with riociguat monotherapy for ≥6 months, with stable dose for ≥3 months prior to enrollment

• 5. Last BPA session performed ≥6 months prior to enrollment

• 6. 6-minute walk distance (6MWD) ≥ 150 meters

• 7. For women of childbearing potential: highly effective contraception

Exclusion Criteria:

• 1. Background treatment with any PH-targeted therapy other than riociguat, (e.g., any endothelin receptor antagonist (ERA), phosphodiesterase-5 inhibitor (PDE-5i), parenteral prostanoids, prostacyclin receptor agonist)
• 2. Post-capillary pulmonary hypertension, defined as pulmonary artery wedge pressure (PAWP) > 15 mmHg
• 3. Significant obstructive or restrictive lung disease, defined as:
• FEV₁ < 60% predicted, with FEV₁/FVC < 65%
• and/or total lung capacity (TLC) < 60% predicted
• or known significant chronic lung disease on imaging (e.g., interstitial lung disease, emphysema)
• 4. Severe hepatic impairment, defined as:
• Child-Pugh class B or C
• and/or liver aminotransferase levels > 3× upper limit of normal (ULN)
• 5. Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m²).
• 6. Left heart failure with left ventricular ejection fraction (LVEF) < 40%
• 7. Ongoing or planned treatment with organic nitrates.
• 8. Concomitant treatment with strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., rifabutin, rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort)
• 9. Concomitant treatment with strong multi pathway P-glycoprotein (P-gp)/ breast cancer resistance protein (BCRP) inhibitors (e.g., lopinavir/ritonavir).
• 10. Treatment with a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir) or a moderate dual CYP3A4/CYP2C9 inhibitor (e.g., fluconazole, amiodarone) or co-administration of a combination of moderate CYP3A4 and moderate CYP2C9 inhibitors.
• 11. History of life-threatening hemoptysis (>100 mL within 24 hours) or prior bronchial artery embolization for hemoptysis
• 12. Pregnancy, breastfeeding, or intention to become pregnant during the study period
• 13. Severe comorbidities or underlying conditions with an anticipated life expectancy < 12 months, including active malignancy with localized or metastatic disease
• 14. Lack of coverage by national health or social security systems
• 15. Alcohol abuse, as determined by the investigator
• 16. Any condition or factor likely to interfere with protocol compliance, in the opinion of the investigator
• 17. Patient under guardianship or curatorship
• 18. Participation in another interventional trial or being in the exclusion period following a previous research involving the human person