Discontinuation Versus Continuation of Riociguat Monotherapy in Chronic Thromboembolic Pulmonary Hypertension Successfully Treated With Balloon Pulmonary Angioplasty

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:

• WHO FC I or II
• Pulmonary vascular resistance (PVR) < 3 Wood units
• 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