Evaluation of Sildenafil for the Treatment of Moderate Congestive Heart Failure

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