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 anegative 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 tissuedisease 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 (Woodunits) 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 beincluded);

2. PAH associated with thyroid disorders, glycogen storage disease, Gaucher disease,hereditary hemorrhagic telangiectasia, hemoglobinopathies, myeloproliferativedisorders and splenectomy;

3. Valvular disease with valvular lesions to be excluded by echocardiogram within 2 yearsprior to randomization (i.e., patients with tricuspid or pulmonary insufficiencysecondary 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 theupper 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 acuteadministration during a catheterization procedure to test vascular reactivity) or withany other PH specific medication;

14. Treatment or planned treatment with calcineurin-inhibitors (i.e., cyclosporine A andtacrolimus), CYP2C9 and CYP3A4 inhibitors (i.e., ketoconazole, fluconazole) within 1week of study start;

15. Treatment or planned treatment with nitrate drugs, short acting nitrate-containingmedications, 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 risingnt-BNP levels in the judgment of the investigators

19. Any contraindications specified in the product monographs of either ambrisentan orriociguat, including:

20. Patients at increased risk of hypotension with concomitant or underlying conditions suchas coronary artery disease, hypovolemia, severe left ventricular outflow obstruction orautonomic dysfunction; patients with resting hypotension 2. Patients with history ofserious hemoptysis or patients who have previously undergone bronchial arterialembolization 20. Patients with pulmonary veno-occlusive disease 21. Ongoing participationin any interventional clinical studies.