Upfront Combination Pulmonary Arterial Hypertension Therapy

Inclusion Criteria:

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

Exclusion Criteria:

1. PAH associated with any other condition than those described in the inclusion criteria (patients with PAH associated with portal hypertension, HIV and CHD should not be included);
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.