Phosphodiesterase Type 5 Inhibition With Tadalafil Changes Outcomes in Heart Failure

Inclusion Criteria:

- Male or female age 21 years or older.

- NYHA Class II-IV HF with LVSD (most recent LVEF < 0.40).

- At high risk of future clinical instability, indicated by EITHER:

a hospitalization for the primary reason of decompensated HF within the 12 months prior to
screening; OR a plasma B-type Natriuretic Peptide (BNP) level ≥ 300 pg/ml or N-terminal
prohormone of brain natriuretic peptide (NT-proBNP) ≥1800pg/ml measured during a period of
clinical stability in the 3 months prior to screening.

- Documented secondary PH within the last 6 months

- Medication and device treatment according to current American Heart
Association/American College of Cardiology (AHA/ACC) guidelines.

- Stable medical therapy for 30 days prior to randomization

- African-American patients intolerant of or otherwise unable or unwilling to utilize
isosorbide dinitrate/hydralazine therapy will be included.

- Willingness to comply with protocol, attend follow-up appointments, complete all
study assessments and provide written informed consent.

Exclusion Criteria:

- Concurrent or anticipated nitrate use for any reason, or nitrate use within the 14
days prior to screening through the day of randomization.

- Known allergy, hypersensitivity (anaphylaxis), or adverse reaction to tadalafil or
other Phosphodiesterase Type 5 (PDE5) inhibitor

- Erectile dysfunction treated with a PDE5 inhibitor.

- Severe renal dysfunction defined as an estimated glomerular filtration rate (GFR) <
30 ml/min/1.73 m^2 or requiring chronic dialysis

- Current use of alpha antagonists (except carvedilol or tamsulosin) or use of
cytochrome P450 3A4 inhibitors (ketoconazole, itraconazole, erythromycin, or
cimetidine). Patients who have used a protease inhibitor that is a P450 3A4 inhibitor
for longer than one week can be enrolled.

- Pulmonary arterial hypertension (World Health Organization (WHO) Group I, III-V) for
which PDE5 inhibitor therapy may be indicated

- Severe pulmonary disease requiring home oxygen therapy

- Comorbidities including clinically significant valvular stenosis (aortic valve area <
0.8 cm^2 or a mitral valve area <1.0 cm^2), uncontrolled hypertension (systolic blood
pressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg) or hypotension (systolic
blood pressure <85 mmHg)

- Chronic intravenous inotrope therapy

- Non-arteritic anterior ischemic optic neuropathy (NAION)

- ST elevation MI (STEMI) within 90 days prior to screening

- Coronary Artery Bypass Grafting (CABG) or mitral valve surgery, initiation of cardiac
resynchronization (CRT) or initiation of β-blocker therapy within the 6 months prior
to screening

- Infiltrative or inflammatory myocardial disease (e.g. amyloid, sarcoid)

- Heart transplant recipient

- United Network Organ Sharing (UNOS) status 1A or 1B

- Mechanical circulatory support (MCS) use or planned MCS use at time of consent

- Active malignancy (except non-melanoma skin cancer) requiring therapy other than
observation.

- Severe non-cardiac illness resulting in life expectancy judged less than three years

- Known chronic hepatic disease defined as aspartate aminotransferase (AST) and alanine
transaminase (ALT) levels > 3.0 times the upper limit of normal

- Inability to walk even a few steps due to non-cardiac (e.g. orthopedic) reasons

- Participation in any clinical trial within the last 30 days (with exception of
observational study)

- Previous randomization in PITCH-HF