phosphodiesterase type 5 inhibition with tadalafil changes outcomes in heart failure

Conditions: Heart Failure; Pulmonary Hypertension

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

Keywords: heart failure pulmonary hypertension tadalafil phosphodiesterase type 5 inhibition