Upfront Combination Pulmonary Arterial Hypertension Therapy

You may be eligible if

• 1. Signed informed consent prior to initiation of any study mandated procedure;
• 2. Males or females ≥ 18 years of age i. Women of childbearing potential must have a negative pre-treatment pregnancy test and must use reliable methods of contraception.
• ii. Women not of childbearing potential are defined as postmenopausal (i.e., amenorrhea for at least 1 year), or documented surgically or naturally sterile.
• 3. Patients with symptomatic Functional Class III PAH in the following categories:
• i. Idiopathic (IPAH) ii. Familial (FPAH) iii. Associated with connective tissue disease iv. Associated with drugs or toxins;
• 4. PAH diagnosed by right heart catheterization, defined as:
• i. Mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg ii. PVR \> 3 mmHg/l/min (Wood units) or \> 240 dyn sec cm-5 iii. Pulmonary capillary wedge pressure (PCWP) ≤ 15 mmHg;
• 5. 150 m ≤ 6 Minute Walk Test (6MWT) distance ≤ 480 m
• 2. PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease, hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferative disorders and splenectomy;
• 3. Valvular disease with valvular lesions to be excluded by echocardiogram within 2 years prior to randomization (i.e., patients with tricuspid or pulmonary insufficiency secondary to PAH can be included);
• 4. Restrictive lung disease: total lung capacity (TLC) \< 60% of normal predicted value;
• 5. Obstructive lung disease: forced expiratory volume/forced vital capacity (FEV1/FVC) \< 0.5;
• 6. Moderate to severe hepatic impairment, i.e., Child-Pugh Class B or C;
• 7. Pregnancy or breast-feeding;
• 8. Systolic blood pressure \< 95 mmHg;
• 9. Body weight \< 40 kg;
• 10. Hemoglobin \> 25% below the lower limit of the normal range;
• 11. Aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) \> 1.5 times the upper limit of normal ranges;
• 12. Renal insufficiency as defined by creatinine clearance \< 30 mL/min or on dialysis
• 13. Treatment with phosphodiesterase type 5 inhibitors, any prostanoid (excluding acute administration during a catheterization procedure to test vascular reactivity) or with any other PH specific medication;
• 14. Treatment or planned treatment with calcineurin-inhibitors (i.e., cyclosporine A and tacrolimus), CYP2C9 and CYP3A4 inhibitors (i.e., ketoconazole, fluconazole) within 1 week of study start;
• 15. Treatment or planned treatment with nitrate drugs, short acting nitrate-containing medications, alpha blockers or protease inhibitors (i.e., ritonavir);
• 16. Known hypersensitivity to ambrisentan, riociguat or any of their excipients;
• 17. Patients with any contraindication to riociguat treatment or ERA treatment
• 18. Patients with syncope, a rapid rate of symptom progression or with high or rising nt-BNP levels in the judgment of the investigators
• 19. Any contraindications specified in the product monographs of either ambrisentan or riociguat, including:
• 1\. Patients at increased risk of hypotension with concomitant or underlying conditions such as coronary artery disease, hypovolemia, severe left ventricular outflow obstruction or autonomic dysfunction; patients with resting hypotension 2. Patients with history of serious hemoptysis or patients who have previously undergone bronchial arterial embolization 20. Patients with pulmonary veno-occlusive disease 21. Ongoing participation in any interventional clinical studies.