Sildenafil After the Fontan Operation (SAFO)

The Sildenafil After Fontan Operation Study

In this study, the investigators will evaluate the effect of sildenafil on exercise tolerance in patients with a single cardiac ventricle who have undergone the Fontan operation. The investigators will also evaluate echocardiographic measures of ventricular function and measure quality of life changes using two validated quality of life measures. The hypothesis is that sildenafil will result in increased exercise tolerance in patients who have had the Fontan operation as compared to placebo.

Study Overview

• Status: Completed
• Conditions: Tricuspid Atresia; Hypoplastic Left Heart Syndrome
• Intervention / Treatment: Drug: Sildenafil; Drug: Placebo

Detailed Description

The Fontan physiology is the end result of staged reconstruction of the heart and the major blood vessels in patients who have a single ventricle. After completion of the reconstruction, the great veins which usually bring blood back to the heart are connected directly to the pulmonary arteries, allowing blood from the body to bypass the heart and flow directly into the lungs. In this system, blood flow through the lungs is passive (not pumped) and the efficiency of flow through the cardiovascular system is related to the resistance to blood flow in the vessels of the lungs.

There are two potential problems that arise in this scenario, as a result of the resistance to blood flow in the vessels of the lungs. First, the amount of blood flow returning to the heart from the lungs may not be sufficient to allow the heart to function at maximum efficiency, compromising the heart's ability to keep up with the demands of the body. Second, if the resistance to blood flow in the lungs is high, pressure may be transmitted back into the great veins themselves and secondarily into the organs of the body causing mild, or sometimes significant, organ dysfunction. Not all patients with the Fontan physiology develop these problems, but we know that even in patients without obvious problems, the ability to keep up with an increased metabolic demand, as during exercise, in compromised.

Improving the efficiency of blood flow through the lungs should improve the return of blood to the heart and thereby diminish the pressure transmitted back to the vessels which passively deliver blood to the lungs. We believe that this change may manifest as diminished symptoms in those patients with known difficulties, or may allow for an increased ability to walk, run, or participate in sports in those without any overt symptoms. Most importantly, we speculate that improved efficiency of flow through the lungs, and the resulting improved cardiac output (blood flow through the body) will make patients more energetic and will make them feel better.

Sildenafil is an oral medication that has been used to treat patients with pulmonary hypertension, a disease in which there is abnormally elevated pressure in the vessels of the lung. In this disease, the resistance in the lungs is abnormally high, severely limiting the ability of the heart to keep up with the demands of the body. Sildenafil lowers the resistance in the vessels of the lungs and has been shown to improve exercise performance in patients with this disease. We believe that Sildenafil may have a similar benefit for our patients after Fontan operation in whom cardiac output is also limited by resistance of the blood vessels in the lungs.

In our study, we will compare the exercise capacity, echocardiographic measures of cardiac function, and the overall quality of life in patients with the Fontan before and after a six-week period of sildenafil administration. As a control, the same group of patients will take a placebo for a six-week period, also with before and after testing. We hypothesize that oral sildenafil will result in significant improvements in exercise capacity, energy levels, and echocardiographic measures of cardiac function and output in our study participants. We are hopeful that the findings of this investigation will directly help children and young adults with Fontan physiology.

• Study Type: Interventional
• Enrollment (Actual): 28
• Phase: Phase 2

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 8 years to 40 years (Child, Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• 8 years of age or older
• All participants must have had Fontan completion

Exclusion Criteria:

• Height less than 132 cm
• Unable to participate in exercise testing due to medical restrictions or physical limitations
• Fontan baffle obstruction or single lung physiology
• Coarctation of the aorta or neo-aorta (BP gradient > 20 mmHg)
• Severe ventricular dysfunction assessed qualitatively by echocardiography
• Severe atrioventricular valvar regurgitation assessed qualitatively by echocardiography
• Presence of electronic pacemaker
• History of treatment with sildenafil in the six weeks prior to enrollment in study
• Patients with severe renal impairment
• Patients with severe hepatic impairment
• Patients taking medications that inhibit or induce Cytochrome P450 3A4 (CYP3A4) (including grapefruit juice and St. John's Wort)
• Patients taking alpha-blockers and nitrates
• Parents/guardians or subjects who, in the opinion of the investigator, may be non-compliant with study schedules or procedures

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Sildenafil, then Placebo; Sildenafil will be given at a dose of 20 mg three times-a-day for six weeks followed by a six week washout period followed by placebo for an additional six weeks.	Drug: Sildenafil; One 20 mg capsule of sildenafil will be taken by mouth three times-a-day.; Other Names: Viagra; Revatio; Drug: Placebo; One placebo capsule will be taken by mouth three times-a-day.
Active Comparator: Placebo, then Sildenafil; Placebo will be given for six weeks followed by a six week washout period followed by Sildenafil which will be given at a dose of 20 mg three times-a-day for six weeks	Drug: Sildenafil; One 20 mg capsule of sildenafil will be taken by mouth three times-a-day.; Other Names: Viagra; Revatio; Drug: Placebo; One placebo capsule will be taken by mouth three times-a-day.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Oxygen Consumption (mL/kg/Min) at 6 Weeks	Oxygen consumption measurements were taken at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.	Baseline and 6 Weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Mean Heart Rate (Bpm) at 6 Weeks	Heart rate was measured at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.	Baseline and 6 Weeks
Change From Baseline in Mean Respiratory Rate (Breaths/Min) at 6 Weeks	Respiratory rate was measured at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.	Baseline and 6 Weeks
Change From Baseline in Mean Minute Ventilation (L/Min) at 6 Weeks	Minute ventilation measurements were taken at peak exercise. Subjects were exercised to maximal volition with an electronically braked cycle ergometer. The protocol consisted of 3 minutes of pedaling in an unloaded state followed by a ramp increase in work rate (watts) to maximal exercise. Metabolic and ventilatory data were obtained throughout the exercise study and for the first 2 minutes of recovery on a breath-by-breath basis with a metabolic cart.	Baseline and 6 Weeks

Collaborators and Investigators

• Sponsor: Children's Hospital of Philadelphia
• Collaborators: The Mark H. and Blanche M. Harrington Foundation
• Investigators: Principal Investigator: Jack Rychik, MD, Children's Hospital of Philadelphia

Publications and helpful links

General Publications

• Goldberg DJ, French B, McBride MG, Marino BS, Mirarchi N, Hanna BD, Wernovsky G, Paridon SM, Rychik J. Impact of oral sildenafil on exercise performance in children and young adults after the fontan operation: a randomized, double-blind, placebo-controlled, crossover trial. Circulation. 2011 Mar 22;123(11):1185-93. doi: 10.1161/CIRCULATIONAHA.110.981746. Epub 2011 Mar 7.

Study record dates

Study Major Dates

• Study Start: December 1, 2007
• Primary Completion (Actual): April 1, 2009
• Study Completion (Actual): July 1, 2009

Study Registration Dates

• First Submitted: July 25, 2007
• First Submitted That Met QC Criteria: July 25, 2007
• First Posted (Estimate): July 27, 2007

Study Record Updates

• Last Update Posted (Estimate): May 5, 2015
• Last Update Submitted That Met QC Criteria: May 4, 2015
• Last Verified: May 1, 2015

More Information

Terms related to this study

• Keywords: Hypoplastic Left Heart Syndrome; Other Single Ventricle Anatomy; Tricuspid Atresia
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Congenital Abnormalities; Heart Valve Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Hypoplastic Left Heart Syndrome; Tricuspid Atresia; Molecular Mechanisms of Pharmacological Action; Vasodilator Agents; Urological Agents; Enzyme Inhibitors; Phosphodiesterase Inhibitors; Phosphodiesterase 5 Inhibitors; Sildenafil Citrate
• Other Study ID Numbers: IRB 2007-4-5034