A Long Term Study to Find Out if Macitentan is an Effective and Safe Treatment for Patients With Heart Failure With Preserved Ejection Fraction and Pulmonary Vascular Disease

Inclusion Criteria:

1. Signed and dated ICF.

2. Subject remained in the main study (SERENADE/AC-055G202, NCT03153111) for 52 weeks
after randomization.

3. A woman of childbearing potential is eligible only if the following applies:

- Negative pre-treatment serum pregnancy test.

- Agreement to undertake monthly pregnancy tests from the enrollment visit up to at
least 30 days after study treatment discontinuation.

- Agreement to use reliable contraception from at least 30 days prior to the
enrollment visit up to at least 30 days after study treatment discontinuation.

Exclusion Criteria:

1. Premature discontinuation of study treatment in the main study (SERENADE/AC-055G202,
NCT03153111) due to an adverse event related to:

1. Edema or fluid retention

2. Worsening of heart failure

3. Liver aminotransferase elevation

2. Liver aminotransferase elevations, at the enrollment visit, fulfilling the following
criteria:

1. Alanine amino transferase (ALT) / aspartate aminotransferase (AST) ≥ 8 × the
upper limit of normal (ULN)

2. ALT/AST ≥ 3 × ULN and associated clinical symptoms of liver injury, e.g., nausea,
vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu-like
syndrome (arthralgia, myalgia, fever)

3. ALT/AST ≥ 3 × ULN and associated increase in total bilirubin to ≥ 2 × ULN

3. Treatment with the following forbidden medications within 1 month prior to the
enrollment visit:

1. Treatments that may interfere with the assessment of efficacy (i.e., endothelin
receptor antagonists, prostanoids, phosphodiesterase-5 inhibitors, guanylate
cyclase stimulators)

2. Strong cytochrome P-450 3A4 (CYP3A4) inducers such as rifabutin, rifampin,
rifampicin, rifapentin, carbamazepine, phenobarbital, phenytoin, or St. John's
wort

3. Strong CYP3A4 inhibitors such as ketoconazole, itraconazole, voriconazole,
clarithromycin, telithromycin, nefazodone, ritonavir, and saquinavir.

4. any other investigational treatment

4. Pregnant, planning to be become pregnant or lactating.

5. Any known factor or disease that might interfere with treatment compliance, study
conduct, or interpretation of the results, such as drug or alcohol dependence or
psychiatric disease.