Phosphodiesterase Type 5 Inhibition With Tadalafil Changes Outcomes in Heart Failure
Condition: Heart Failure; Pulmonary Hypertension
MeSH terms: Hypertension, Pulmonary; Hypertension; Heart Failure
Intervention: Tadalafil; Placebo for tadalafil
Intervention MeSH terms: Tadalafil
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 23.0
Sex: All
Minimum age: 21 Years
Healthy volunteers: No
Keywords: Heart failure; Pulmonary hypertension; tadalafil; Phosphodiesterase Type 5 Inhibition

Summary:

      This study is a multi-center, prospective, randomized, double blind, placebo-controlled
      clinical trial. Subjects in the study will be adults with New York Heart Association (NYHA)
      Class II-IV heart failure (HF) due to left ventricular systolic dysfunction (LVSD), left
      ventricular ejection fraction (LVEF) <0.40, and secondary pulmonary hypertension (PH). The
      purpose of the study is to evaluate the safety, effectiveness, and effects of tadalafil
      compared to placebo on the subjects' functional capacity / quality of life.
    

Eligibility criteria:

        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