Evaluation of Sildenafil for the Treatment of Moderate Congestive Heart Failure
Evaluation of Sildenafil for the Treatment of Moderate Congestive Heart Failure
The purpose of the study is to evaluate whether sildenafil helps treat heart failure. Some
 patients with heart failure have high blood pressure in the lungs (referred to as "pulmonary
 hypertension"). Sildenafil is a medication that is used to treat high blood pressure in the
 lungs and may reduce symptoms of heart failure. Studies have looked at the short-term benefit
 of sildenafil in patients with congestive heart failure, but this study will look at the
 longer-term benefits of 12 weeks of therapy with sildenafil.
Objective: To determine the effect of acute and long-term treatment with sildenafil on the
 clinical status of patients with moderate HF. Secondary Objectives: To determine the effect
 of acute and long-term treatment with sildenafil on cardiopulmonary exercise performance, the
 effect of acute and long-term treatment with sildenafil on neurohormonal activation, the
 effect of acute and long-term treatment with sildenafil on hemodynamics, and the effect of
 long-term treatment with sildenafil on quality of life. Background: Secondary pulmonary
 hypertension (PH) is a frequent manifestation of heart failure resulting in impaired vascular
 reactivity and permeability which contributes to the symptoms of HF. Levels of endothelin-1
 (ET-1), a potent vasoconstrictor, are increased in patients with HF. At the same time,
 pulmonary artery nitric oxide (NO) production is decreased. NO increases concentrations of
 the second messenger cyclic-GMP, ultimately leading to vasodilation. This imbalance between
 NO-dependent vasodilation and ET-1 induced vasoconstriction likely contributes to the
 development of secondary pulmonary hypertension. cGMP is metabolized by the type 5 isoform of
 phosphodiesterase (PDE5) an enzyme that is highly expressed in the lung. Sildenafil, a
 selective PDE5 inhibitor, has been used extensively for the treatment of erectile dysfunction
 and has recently been approved for use in the treatment of PH. Recent studies of short-term
 administration of sildenafil in HF patients with secondary PH have demonstrated reductions in
 pulmonary arterial pressure, pulmonary vascular resistance, pulmonary capillary wedge
 pressure, and systemic vascular resistance while increasing cardiac index and exercise
 performance. However, it remains to be seen if sildenafil is safe and effective in the
 long-term treatment of heart failure. Methods: This will be an open-label, pilot study
 designed to evaluate the safety and efficacy of sildenafil for the treatment of moderate
 heart failure. The primary endpoint will be change in 6-minute walk test distance. Secondary
 endpoints will be changes in peak oxygen consumption (measured by cardiopulmonary exercise
 testing), neurohormones (b-type natriuretic peptide, catecholamines, ET-1), quality of life
 scores. Additionally, we will attempt to analyze responsiveness to sildenafil on the basis of
 PDE5 polymorphisms. Study procedures will be performed at the UNM General Clinical Research
 Center and the UNM Congestive Heart Failure Clinic. Patients will be hospitalized for 3 days
 to analyze safety and efficacy of sildenafil administered three times daily. Patients will
 complete exercise testing, neurohormone, and hemodynamic assessments at baseline (day 1) and
 following 24 hours of sildenafil treatment. The patients will then be discharged to complete
 a 12-week maintenance phase of treatment. At the conclusion of the maintenance phase the
 patients will be readmitted for 2 day to have repeat measurements performed. The main
 analysis will be done using paired t-tests. All statistical analysis will be performed using
 SAS v6.12.
Inclusion Criteria:

 -  Age greater than 18 years

 -  Diagnosis of chronic heart failure with an ejection fraction less than or equal to 45%
 per either an echocardiogram, nuclear cardiolyte stress test, or cardiac
 catheterization performed within the past 6 months.

 -  New York Heart Association Functional Class III

 -  Must be on optimal heart failure therapy according to AHA/ACC heart failure
 guidelines, including treatment with ACEI and beta-blocker therapy, or have documented
 rationale for variation, including intolerance, contraindication, patient preference,
 or personal physician's judgment

 Exclusion Criteria:

 -  Comorbid disease or behavioral or other limitations that: 1) interfere with performing
 exercise test, or 2) prevent completion of 12 week study

 -  Currently pregnant or intent to become pregnant in the next 12 weeks or currently
 breastfeeding.

 -  Major cardiovascular event or cardiovascular procedure within the prior 6 weeks

 -  History of Chronic Obstructive Pulmonary Disease or Reactive Airway Disease

 -  Known hypersensitivity to sildenafil

 -  Current use of medications known to be a potent inhibitor of CYP3A4 (e.g., ritonavir,
 ketoconazole, itraconazole)

 -  Current or recent (within 6 months) use of organic nitrate medications (e.g.
 isosorbide dinitrate, sublingual nitroglycerin)

 -  Known diagnosis of pulmonary veno-occlusive disease or non-arteritic anterior ischemic
 optic neuropathy