Initial Dual Oral Combination Therapy Versus Standard-of-care Initial Oral Monotherapy Prior to Balloon Pulmonary Angioplasty in Patients With Inoperable Chronic Thromboembolic Pulmonary Hypertension

Inclusion Criteria: 1. Signed informed consent. 2. Male or female ≥18 and ≤ 80 years of age at inclusion. 3. Newly diagnosed and treatment-naïve subjects with CTEPH judged as inoperable due to surgically inaccessible lesions but eligible for balloon pulmonary angioplasty, riociguat and macitentan by multidisciplinary team assessment and fulfilling the following criteria: 1. Symptomatic pulmonary hypertension (PH) in WHO FC ≥ II. 2. Confirmation of diagnosis based on 2 of the 3 following methods: i. Ventilation-perfusion lung scan ii. Digital subtraction pulmonary angiography (DSA) iii. CT pulmonary angiography (CTPA). 4. Confirmation of inoperability based on CTPA scan and/or DSA. 5. Right-heart catheterization (RHC) in the 12-week period prior to screening visit or during screening period showing the following: 1. Mean pulmonary artery pressure (mPAP) ≥ 25 mmHg 2. Pulmonary artery wedge pressure (PAWP) ≤ 15 mmHg or left ventricular end diastolic pressure ≤ 15 mmHg 3. PVR at rest ≥ 400 dyn.sec.cm-5. 6. Subject anticoagulated (with either vitamin K antagonists or direct oral anticoagulants \[e.g., factor IIa inhibitors, factor Xa inhibitors\]), or treated with unfractionated heparin or low molecular weight heparin for at least 3 months prior to baseline RHC. 7. 6MWD ≥ 50m 8. Women of childbearing potential must: 1. Have a negative pre-treatment serum pregnancy test 2. Agree to use reliable contraception from screening up to 1 month following discontinuation of the last study treatment. Exclusion Criteria: 1. Previous pulmonary endarterectomy. 2. Previous balloon pulmonary angioplasty. 3. Any PAH-targeted therapy (e.g., any endothelin receptor antagonist (ERA), phosphodiesterase-5 inhibitor (PDE-5i), soluble guanylate cyclase stimulator, prostacyclin, prostacyclin analog, or prostacyclin receptor agonist) at any time prior to inclusion. 4. Ongoing or planned treatment with organic nitrates. 5. Known moderate-to-severe restrictive lung disease (i.e., total lung capacity \< 60% of predicted value) or obstructive lung disease (i.e., forced expiratory volume in one second \[FEV1\] \< 60% of predicted, with FEV1 / forced vital capacity \< 65%) or known significant chronic lung disease diagnosed by chest imaging (e.g., interstitial lung disease, emphysema). 6. Symptomatic coronary artery disease requiring nitrate use or intervention (e.g., Percutaneous Coronary Intervention, Coronary Artery Bypass Graft) anticipated in the 6-month period after inclusion. 7. Acute myocardial infarction ≤ 12 weeks prior to inclusion. 8. Left heart failure with an ejection fraction less than 40%. 9. Cerebrovascular events (e.g., transient ischemic attack, stroke) ≤ 12 weeks prior to inclusion. 10. History of life-threatening hemoptysis (\>100 mL in 24 h) or subjects who have previously undergone bronchial arterial embolization for hemoptysis. 11. Hemoglobin \< 100 g/L. 12. Serum aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 3 × upper limit of the normal range. 13. Documented severe hepatic impairment (with or without cirrhosis) according to National Cancer Institute organ dysfunction working group criteria, defined as total bilirubin \> 3 × upper limit of the normal range (ULN) accompanied by aspartate aminotransferase (AST) \> ULN; and/or Child-Pugh Class C. 14. Severe renal impairment (estimated creatinine clearance ≤ 30 mL/min/1.73 m²). 15. Systolic blood pressure \<95mmHg. 16. Treatment with strong cytochrome P450 3A4 (CYP3A4) inducers (e.g., rifabutin, rifampicin, carbamazepine, phenobarbital, phenytoin, St. John's wort) ≤ 28 days prior to inclusion. 17. Treatment with strong multi pathway P-glycoprotein (P-gp)/ breast cancer resistance protein (BCRP) inhibitors (e.g., lopinavir/ritonavir) ≤ 28 days prior to inclusion. 18. 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 ≤ 28 days prior to inclusion. 19. Known hypersensitivity to riociguat or macitentan or to any excipient of their formulation. 20. History of severe allergic-like reaction to intravascular administration of iodinated contrast media (including diffuse edema or facial edema with dyspnea, diffuse erythema with hypotension, laryngeal edema with stridor and/or hypoxia, bronchospasm, anaphylactic shock with hypotension and tachycardia). 21. Subject who cannot remain in a supine position for at least 120 min for any reason. 22. Pregnancy, breastfeeding, or intention to become pregnant during the study. 23. Subjects with underlying medical disorders and anticipated life expectancy \< 12 months (eg active cancer disease with localized and/or metastasized tumor mass). 24. Alcohol abuse (at investigator discretion) 25. Subject not covered by social security service. 26. Any factor or condition likely to affect protocol compliance of the subject, as judged by the investigator.