SIDAMI - Sildenafil and Diastolic Dysfunction After Acute Myocardial Infarction (AMI)
SIDAMI - Sildenafil and Diastolic Dysfunction After Acute Myocardial Infarction (AMI)
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.
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.
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

 -  Non-arteritic anterior ischaemic optic neuropathy