Heart Failure, Diastolic, Pulmonary Hypertension
Conditions
Keywords
HFpEF, PH
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)
Interventions
DRUGSildenafil
Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks
DRUGPlacebo
Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks
Sponsors
Pfizer
University Medical Center Groningen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| VO2max | baseline and 12 weeks | difference in change of VO2 max between baseline and 12 weeks between Sildenafil 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 |
| 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 |
Other
| Measure | Time frame |
|---|---|
| Echocardiographic Parameters of Diastolic LV Dysfunction | 12 weeks |
Countries
Netherlands
Participant flow
Recruitment details
Stabile outpatients with heart failure with preserved ejection fraction (HFpEF) and signs of pulmonary hypertension (PH) on echocardiogram were referred for right heart cath as part of clinical care. After heart catheter measurements , eligible patients were asked for participation. Recruitment from october 2011 until september 2014
Participants by arm
| Arm | Count |
|---|---|
| Sildenafil Sildenafil: Sildenafil administered orally 3 times per day 20 mg for the first 2 weeks, followed by 3 times 60 mg for 10 weeks | 26 |
| Placebo Placebo: Placebo tablets 3 times per day 20 mg foor de first 2 weeks, followed by 3 times 60 mg for 10 weeks | 26 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 4 | 1 |
| Overall Study | Death | 1 | 1 |
| Overall Study | refused second HC | 0 | 2 |
Baseline characteristics
| Characteristic | Sildenafil | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 72 years STANDARD_DEVIATION 12 | 76 years STANDARD_DEVIATION 7 | 74 years STANDARD_DEVIATION 10 |
| Region of Enrollment Netherlands | 26 participants | 26 participants | 52 participants |
| Sex: Female, Male Female | 20 Participants | 17 Participants | 37 Participants |
| Sex: Female, Male Male | 6 Participants | 9 Participants | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 22 / 26 | 21 / 26 |
| serious Total, serious adverse events | 4 / 26 | 3 / 26 |
Outcome results
Primary
Mean Pulmonary Artery Pressure Measured by Right Heart Catheterization
change of mean pulmonary artery pressure between baseline and 12 weeks measured by heart catheterisation
Time frame: baseline and 12 weeks
Population: 52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in mean pulmonary artery pressure could be evaluated in the intention to treat (ITT) analyses in 21 and 22 subjects of the Sildenafil and placebo treatment group
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sildenafil | Mean Pulmonary Artery Pressure Measured by Right Heart Catheterization | -2.4 mmHG |
| Placebo | Mean Pulmonary Artery Pressure Measured by Right Heart Catheterization | -4.7 mmHG |
95% CI: [-4.5, -0.3]
95% CI: [-7.1, -2.3]
Secondary
Cardiac Output Measured Invasively by Right Heart Catheterization
difference in change of cardiac output between baseline and 12 weeks between Sildenafil and Placebo group
Time frame: baseline and 12 weeks
Population: 52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in cardiac output could be evaluated in the ITT analyses in 20 and 22 subjects of the Sildenafil and placebo treatment group
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sildenafil | Cardiac Output Measured Invasively by Right Heart Catheterization | -0.4 mililiter/min |
| Placebo | Cardiac Output Measured Invasively by Right Heart Catheterization | -0.2 mililiter/min |
95% CI: [-0.9, 0.1]
95% CI: [-0.5, 0.1]
Secondary
VO2max
difference in change of VO2 max between baseline and 12 weeks between Sildenafil and placebo group
Time frame: baseline and 12 weeks
Population: 52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in VO2max could be evaluated in the ITT analyses in 18 and 22 subjects of the Sildenafil and placebo treatment group
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sildenafil | VO2max | 0.2 ml/kg/min |
| Placebo | VO2max | 0.7 ml/kg/min |
95% CI: [-0.9, 1.4]
95% CI: [-0.3, 1.6]
Secondary
Wedge Pressure Measured Invasively by Right Heart Catheterization
Difference in change of wedge pressure between baseline and 12 weeks between Sildenafil group and Placebo group
Time frame: baseline and 12 weeks
Population: 52 patients randomized. 26 Sildenafil arm: 26 placebo arm: change in wedge pressure could be evaluated in the ITT analyses in 21 and 22 subjects of the Sildenafil and placebo treatment group
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Sildenafil | Wedge Pressure Measured Invasively by Right Heart Catheterization | -0.5 mmHg |
| Placebo | Wedge Pressure Measured Invasively by Right Heart Catheterization | -3.5 mmHg |
95% CI: [-1.9, 1]
95% CI: [-5.2, -1.8]
Other Pre-specified
Echocardiographic Parameters of Diastolic LV Dysfunction
Time frame: 12 weeks