Sildenafil in HFpEF (Heart Failure With Preserved Ejection Fraction) and PH

Phase 3

Completed

Conditions: Heart Failure, Diastolic
Pulmonary Hypertension

Interventions: Drug: Sildenafil
Drug: Placebo

Registration Number: NCT01726049

Lead Sponsor: University Medical Center Groningen

Brief Summary: Aim of the study is to investigate whether Sildenafil treatment results in a reduction of pulmonary artery pressure without decrease of cardiac output (CO) and in improvement of exercise capacity in patients with heart failure with preserved ejection fraction (HFpEF) with pulmonary hypertension ( PH).

Detailed Description: Rationale: Treatment of diastolic left heart failure is a challenging task. Compared to systolic left heart failure the level of evidence for known medical treatment regiments is low. Sildenafil, a phosphodiesterase 5 (PDE 5) inhibitor and effective therapy for pulmonary arterial hypertension acts as a selective pulmonary vasodilator by inhibiting the impaired nitric oxide (NO) pathway. Reducing the pulmonary vascular resistance would be the primary target by treatment of diastolic left heart failure with PH. But clinical and hemodynamical studies to evaluate the role of Sildenafil in diastolic heart failure, also called heart failure with preserved ejection fraction (HFpEF) with secondary pulmonary hypertension are lacking. Our hypothesis is that Sildenafil decreases pulmonary artery pressure in patients with HFpEF and pulmonary hypertension.

Objective: To investigate whether Sildenafil treatment results in a hemodynamic improvement and in an improvement of exercise capacity in these patients.

Study design: single-center, prospective, randomized, placebo controlled study. Study population: 52 patients with HFpEF and PH Intervention : One group receives three times daily 20 mg Sildenafil for 2 weeks followed by three times daily 60 mg Sildenafil for 10 weeks. The other group receives three times daily 20 mg of Placebo, followed by 3 times daily 60 mg placebo.

Main study parameters/endpoints:

Primary objectives

1. To investigate whether Sildenafil treatment results in a reduction of pulmonary artery pressure (PAP) in HFpEF patients with PH (investigated invasively by right heart catheterization) .

Secondary objectives

1. To investigate whether Sildenafil treatment results in an reduction of wedge pressure in HFpEF patients.

2. To investigate whether Sildenafil treatment results in an improvenemt of cardiac output (CO) in HFpEF patients.

3. To investigate whether Sildenafil treatment results in improvement of exercise capacity in these patients ( defined as change in VO2max)

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 52

Inclusion Criteria

>18 years
Written inform consent
PH secondary to diastolic left heart failure defined as
PAP mean >25 mmHg
Wedge mean >15 mmHg
Normal systolic left ventricular (LV) function on echo/nuclear imaging (left ventricular ejection fraction (LVEF) > or =45%)
New York Heart Association class (NYHA) II-IV despite heart failure therapy

Exclusion Criteria

Severe noncardiac limitation to exercise (as severe chronic obstructive pulmonary disease)
Other cause of PH besides diastolic heart failure
Coronary ischemia or recent myocardial infarction (<6 months)
Hypotension ( <90/50 mmHg)
Ongoing nitrate therapy
Ongoing therapy with citochrome P450 3A4 ( CYP3A4) inhibitors (ketoconazole, erythromycin, cimetidine, clarithromycin, itraconazole, voriconazole and protease inhibitors) or CYP3A4 inductors(carbamacepine, phenytoin, phenobarbital, rifampicin, Sint Janskruid ). Furthermore patients will be informed not to drink grapefruit juice while on study medication because of the known impact of grape fruit on pharmacokinetics of Sildenafil.
Ongoing therapy with alpha -inhibitors
Significant mitral or aortic valve dysfunction
Severe liver dysfunction
Pregnancy
Unable to read and comprehend Dutch language

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Sildenafil	Sildenafil	Sildenafil orally 3 times 20mg for 2 weeks , followed by 3 times 60 mg for 10 weeks
Placebo	Placebo	placebo orally 3 times 20mg tablets, followed by 3 times 60 mg for 10 weeks

Primary Outcome Measures

Name	Time	Method
Mean Pulmonary Artery Pressure Measured by Right Heart Catheterization	baseline and 12 weeks	change of mean pulmonary artery pressure between baseline and 12 weeks measured by heart catheterisation

Secondary Outcome Measures

Name	Time	Method
VO2max	baseline and 12 weeks	difference in change of VO2 max between baseline and 12 weeks between Sildenafil and placebo group
Wedge Pressure Measured Invasively by Right Heart Catheterization	baseline and 12 weeks	Difference in change of wedge pressure between baseline and 12 weeks between Sildenafil group and Placebo group
Cardiac Output Measured Invasively by Right Heart Catheterization	baseline and 12 weeks	difference in change of cardiac output between baseline and 12 weeks between Sildenafil and Placebo group