Clinical Trial Details
— Status: Completed
Administrative data
| NCT number |
NCT01046838 |
| Other study ID # |
2009-011006-42 |
| Secondary ID |
|
| Status |
Completed |
| Phase |
Phase 4
|
| First received |
January 11, 2010 |
| Last updated |
May 23, 2012 |
| Start date |
December 2009 |
| Est. completion date |
May 2012 |
Study information
| Verified date |
May 2012 |
| Source |
Rigshospitalet, Denmark |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
Denmark: The Danish Medicines Agency |
| Study type |
Interventional
|
Clinical Trial Summary
In patients with Doppler echocardiographic signs of elevated LV filling pressures despite
preserved LV systolic function after AMI treatment with the phosphodiesterase inhibitor
sildenafil 40 mg three times daily for 9 weeks will compared with placebo
1. Improve resting LV filling and cardiac hemodynamics.
2. Improve exercise capacity.
3. Improve filling pattern and cardiac hemodynamics during exercise.
Description:
Background:
Acute myocardial infarction (AMI) is characterized by regional myocardial damage which may
lead to systolic and diastolic dysfunction with a subsequent risk of left ventricular (LV)
remodeling, local and systemic neurohormonal activation, vascular dysfunction and
development of heart failure. The pathophysiology and prognosis of LV systolic dysfunction
after AMI has been the focus of research for several decades. Insights from these studies
have led to several therapeutic interventions that improve outcome. In addition to depressed
systolic function, clinical or radiographic evidence of heart failure is a consistent and
powerful predictor of outcome in patients following AMI. Pulmonary congestion after AMI
reflects raised LV filling pressures but is frequently seen after what appears to be only
minor myocardial damage. The pathophysiological mechanism for this is incompletely
understood but may involve impaired active relaxation of the myocardium and increased LV
chamber stiffness, hence, abnormalities in diastolic function. Abnormal LV diastolic
function especially when chamber stiffness is increased is characterized by a
disproportionate increase in filling pressure during exercise and an inadequate increase of
cardiac output. During ventricular diastole the left atrium acts as a conduit between the
left ventricle and the pulmonary veins. Thus in case of increased filling pressures left
atrial pressure is elevated exposing the pulmonary vascular bed to increased pressures. In
accordance pulmonary artery pressure is frequently increased after AMI, even when systolic
function is preserved.
Several recent studies have demonstrated that Doppler echocardiographic indices suggestive
of increased filling pressure and increased pulmonary arterial pressure are associated with
excess mortality and morbidity after AMI . The optimal management of this large group of
patients is unknown, but in theory lowered preload improved cardiac output especially during
exercise and lowering of pulmonary arterial pressure could relive symptoms and improve
exercise capacity.
Sildenafil is a potent selective phosphodiesterase inhibitor that suppresses degradation of
cyclic GMP. In the pulmonary bed this leads to pulmonary vasodilation, in addition
sildenafil has been shown to improve endothelium dependent vasodilation thus augmenting
abnormal vascular tone . In patients with systolic heart failure sildenafil has been
demonstrated to lower pulmonary wedge pressure, improve cardiac index and lower pulmonary
arterial pressure without causing systemic hypotension . Thus in theory sildenafil may have
beneficial effects in patients at high risk of heart failure.
Hypothesis:
In patients with Doppler echocardiographic signs of elevated LV filling pressures despite
preserved LV systolic function after AMI treatment with the phosphodiesterase inhibitor
sildenafil 40 mg three times daily for 9 weeks will compared with placebo
1. Improve resting LV filling and cardiac hemodynamics.
2. Improve exercise capacity.
3. Improve filling pattern and cardiac hemodynamics during exercise.
Specific aims
Primary aims:
Among 70 patients with a recent AMI randomized to treatment with sildenafil 40 mg three
times daily compared with placebo for 9 weeks to compare
1. mitral filling pattern, diastolic E/e´ ratio and left atrial volume,
2. pulmonary wedge pressure, cardiac index and pulmonary artery pressure, at rest and
during submaximal exercise.
Secondary Aims Among 70 patients with a recent AMI randomized to sildenafil 40 mg three
times daily compared with placebo to compared exercise capacity judged by bicycle
ergometer testing.
Among 70 patients with a recent AMI randomized to sildenafil 40 mg three times daily
compared with placebo to compared changes in NT-pro BNP.
Among 70 patients with a recent AMI randomized to sildenafil 40 mg three times daily
compared with placebo to compared changes in diastolic E/e´ ratio during submaximal
exercise.
Among 70 patients with a recent AMI randomized to sildenafil 40 mg three times daily
compared with placebo to compare regional systolic function assessed with tissue
tracking.
Tertiary aims
To assess the correlation between diastolic E/e' and Doppler assessed cardiac index
during rest and exercise with pulmonary wedge pressure and cardiac index respectively.
To assess the association between exercise capacity and diastolic E/e', LA volume, and
nt-proBNP.
Among 70 patients with a recent AMI randomized to sildenafil 40 mg three times daily
compared with placebo to compare the prevalence of atrial arrhythmias after 9 weeks
treatment.
Methods
Design The study is a prospective single center randomized double blind study. Eligible
patients will be randomized to either conventional management and sildenafil for 4
months; or conventional management and placebo treatment.
Inclusion criteria
- Age >50 years
- Recent AMI (within 21 days) defined according to ESC/ACC guidelines
- Doppler echocardiographic signs of elevated filling pressures defined as
- diastolic E/e' ratio >15, or
- diastolic E/e' ratio 8-15 and left atrial volume index>32 ml/m2
- Preserved LV systolic function (EF>45%)
- Written informed consent
Exclusion criteria
- Ongoing myocardial ischemia
- Ongoing treatment with nitrates.
- Poor echocardiographic window
- Inability to exercise
- Permanent atrial fibrillation or paced rhythm
- Planned coronary artery bypass grafting
- Other noncardiac condition with expected survival less than 6 months
- Unwilling to participate
- Known intolerance to sildenafil
Study procedures
In possibly eligible patients a screening echocardiography is performed during
hospitalization at the coronary care unit 2144 or 3141 HS Rigshospitalet, Denmark. If
eligible and consent is obtained during hospitalisation an ambulatory exercise Doppler
echocardiography with simultaneous invasive recording of pulmonary wedge pressure,
pulmonary artery pressure and cardiac index and a 6 min walk test and maximal exercise
test is performed 1 week after revascularization. Patients are then randomized in a 1
to 1 fashion to placebo or sildenafil 20 mg three times daily. If tolerated dosage is
titrated every 2'nd week in the outpatient clinic to a target dose of 40 mg three times
daily. After 9 weeks of treatment exercise echocardiography and 6 min walk test are
repeated, in addition conventional maximal ergometer testing is performed.
Screening echocardiography 2 dimensional echocardiographic will be obtained from the
parasternal and apical windows. Pulsed Doppler measurements of mitral inflow will be
obtained with the transducer in the apical four-chamber view, with a 1-2 mm Doppler
sample volume placed between the tips of mitral leaflets during diastole. Tissue
Doppler imagining of the mitral annulus will be obtained from the apical 4-chamber view
with a 1.5-mm sample volume placed at the medial mitral annulus. All Doppler
echocardiographic examinations are done with horizontal sweep set to 100 mm/s. At least
3-5 cardiac cycles will be measured. LA volume will be obtained from the apical 4 and 2
chamber views with a zoomed image of the left atrium. Clinically indicted
echocardiograms performed in the echolab may be used as screening echocardiograms.
- Wall motion index will semiquantitatively using a descending scoring as previously
validated.
- Maximal left atrial volume will be measured at end-systole with the use of two
orthogonal apical views.
- From the pulsed wave mitral inflow signal, peak E wave velocity will be measured.
- From the tissue Doppler assessment of the medial mitral annulus early (E')
diastolic velocity will be recorded. Diastolic E/e' ratio will be calculated.
Resting echocardiography Doppler echocardiography will be performed on a GE medical
Vivid 7 ultrasound machine by a single investigator. Images will be obtained from the
parasternal and apical windows. M-mode recordings will be done in the parasternal
long-axis view. Pulsed Doppler measurements of mitral inflow will be obtained with the
transducer in the apical four-chamber view, with a 1-2 mm Doppler sample volume placed
between the tips of mitral leaflets during diastole. Tissue Doppler imagining of the
mitral annulus will be obtained from the apical 4-chamber view with a 1.5-mm sample
volume placed at the medial and lateral mitral annulus. All Doppler echocardiographic
examinations are done with horizontal sweep set to 100 mm/s. At least 3-5 cardiac
cycles will be measured. Finally color coded real time tissue Doppler images will be
acquired in the apical windows, with the lowest possible depth and smallest angle.
- End-systolic, end-diastolic volume and ejection fraction will be calculated
according to the Simpson modified biplane method.
- Wall motion index will semiquantitatively be assessed according to the
recommendations of the American Society of Echocardiography.
- Maximal left atrial volume will be measured at end-systole with the use of two
orthogonal apical views with zoom of the left atrium.
- From the pulsed wave mitral inflow signal, peak E wave velocity, peak A wave
velocity, and mitral E-wave deceleration time will be measured.
- From peak tricuspid regurgitant velocity and size of inferior v. cava pulmonary
arterial systolic pressure will be estimated.
- From the tissue Doppler assessment of the medial mitral annulus early (E')
diastolic velocity will be recorded. Diastolic E/e' ratio will be calculated.
- From color coded tissue Doppler images systolic longitudinal fibre shortening will
be assessed using tissue tracking.
- From 2dimensional images speckle tracing will be performed to assess radial and
longitudinal LV function.
Exercise echocardiography Exercise echocardiography is performed at cardiac intensive
care unit 2143. Before exercise a Swan Ganz catheter is introduced with a seldinger
technique through the right jugular vein. Simultaneous with resting echocardiography
pulmonary artery pressure, left atrial pressure, cardiac index and pulmonary wedge
pressure is recorded. Patients are then exercised on a supine bicycle with increasing
workload to 100W with increments of 25W every 2'nd min. At 100W echocardiography is
repeated with simultaneous assessment of pulmonary artery pressure, left atrial
pressure, pulmonary wedge pressure and cardiac index.
Neurohormonal analyses Prior to surgery and at each follow-up visit venous blood
samples will be drawn for analysis of plasma N-terminal proBNP, and of plasma
N-terminal ANP concentrations. In addition plasma will be frozen at each visit for
possible later analysis.
Six minutes walk test A 6 min. walk test will be performed at baseline 9 weeks.
Exercise test A conventional bicycle ergometer test is performed at hospital discharge
and after 4 months. Maximal exercise is achieved by increments on 25W every 2'nd min.
with continuous ECG recording and assessment of blood pressure every 2'nd min.
Feasibility and sample size estimation From a recent study at a tertiary invasive
centre including 380 patients with AMI, (Aberdeen AMI study, Hillis et al ESC 2006), it
was found that among 219 patients EF was >45%. Among those patients E/e' >15 was found
in 41 patients, and in further 48 E/e' 8-15 and left atrial volume index >32 ml/m2 was
found. Thus 40% of patients with LVEF>45% would be potentially eligible. Annually 2500
patients are admitted or transferred to RH with AMI.
Based on a standard deviation of E/e' of 5 (estimated from potentially eligible
patients from the Aberdeen AMI study), an alpha of 0.05 and beta of 0.80 a sample of 70
patients will allow detection of a difference in E/e' of 3.6. Sample size estimation is
performed according to Altmann using nomogram.
