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 toscreening; OR a plasma B-type Natriuretic Peptide (BNP) level ≥ 300 pg/ml or N-terminalprohormone of brain natriuretic peptide (NT-proBNP) ≥1800pg/ml measured during a period ofclinical stability in the 3 months prior to screening.

• Documented secondary PH within the last 6 months

• Medication and device treatment according to current American HeartAssociation/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 utilizeisosorbide dinitrate/hydralazine therapy will be included.

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

Exclusion Criteria:

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

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

• Erectile dysfunction treated with a PDE5 inhibitor.

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

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

• Pulmonary arterial hypertension (World Health Organization (WHO) Group I, III-V) forwhich 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 bloodpressure ≥180 mmHg or diastolic blood pressure ≥100 mmHg) or hypotension (systolicblood 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 cardiacresynchronization (CRT) or initiation of β-blocker therapy within the 6 months priorto 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 thanobservation.

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

• Known chronic hepatic disease defined as aspartate aminotransferase (AST) and alaninetransaminase (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 ofobservational study)

• Previous randomization in PITCH-HF