Atrial Fibrillation Clinical Trial
Official title:
Left Ventricular Reverse Remodelling After Aortic Valve Replacement in Severe Valvular Aortic Stenosis - Effect of Blockade of the Angiotensin-II Receptor
The consequence of aortic valve stenosis (AVS) is increased pressure load on the left
ventricle which causes left ventricular (LV) hypertrophy, and myocardial stretch will cause
activation of cardiac peptides and activation of the renin angiotensin aldosterone system
(RAAS). The consequence of LV hypertrophy is increased chamber-stiffness and delayed active
LV relaxation which initially will cause diastolic and later systolic dysfunction. In heart
failure (HF) and ischemic heart disease the degree of diastolic dysfunction has been
demonstrated to correlate with functional class, neurohormonal activation and prognosis
which also recently have been suggested for AVS.
With longstanding elevated filling pressures the left atrium (LA) will dilate. Only limited
data are available on the degree and importance of LA dilatation in AVS.
When apparent, symptoms of HF in AVS are associated with high mortality rates. If LV
systolic dysfunction also is present prognosis will deteriorate further. In these cases
aorta valve replacement (AVR) is recommended. AVR will normalize pressure overload and
thereby decreases LV hypertrophy. Previously it was believed that in time LV hypertrophy
regressed towards normal and even normalized. Recent studies however have demonstrated that
LV hypertrophy regression mainly happens during the first year after AVR, and little
subsequent changes are seen during the remaining 10 years. Furthermore, patients that
experience most regression of hypertrophy have more favourable outcome and better functional
class than patients with less regression of hypertrophy. Thus absence of reverse remodelling
is associated with poor outcome after AVR. Importantly the regression of LV hypertrophy is
closely paralleled by decreasing RAAS hyperactivity.
RAAS hyperactivity may be attenuated pharmacologically with angiotensin II receptor blockers
(ARB) which in systemic hypertension with LV hypertrophy has been associated with reverse
remodelling.
The hypothesis is that in patients undergoing AVR for symptomatic AVS, 12 months post
operative blockade of the angiotensin II receptor will accelerate LV and LA reverse
remodelling, reduce filling pressures and suppress neurohormonal activation compared with
conventional therapy. This will lead to improved exercise tolerance and due to improved left
atrial function reducing the risk of atrial arrythmias.
1. Background:
Aortic valve stenosis (AVS) is the most common valvular disease in the western world.
The prevalence increases with age where "degenerative" changes of the aortic valve with
thickening, accumulation of calcium and progressive dysfunction of the valve usually
becomes apparent in patients older than 60 years. Although the development of AVS
generally is believed to be a degenerative process more recent studies have
demonstrated AVS is caused by a complex process of increased cellularity, lipid
accumulation, extracellular matrix deposition, and with disease progression
calcification of lesions. Although mild and moderate AVS generally is well tolerated
severe AVS is associated with considerable morbidity and mortality, and valve
replacement is generally required.
The consequence of AVS is increased pressure load on the left ventricle which causes
changes in the ventricular structure. Pressure overload causes replication of the
sarcomeres leading to left ventricular (LV) hypertrophy, and myocardial stretch will
cause activation of cardiac peptides and activation of the renin angiotensin
aldosterone system (RAAS). With progression of disease, RAAS activation will, through
stimulation of the angiotensin-II receptor mediate fibroblast proliferation, promote
fibrosis and directly affect the extracellular matrix. The consequence of LV
hypertrophy and interstitial fibrosis is increased chamber-stiffness and delayed active
LV relaxation which initially will cause diastolic (increased LV end-diastolic
pressure) and later in the disease progression also systolic dysfunction. In congestive
heart failure and ischemic heart disease the degree of diastolic dysfunction has been
demonstrated to correlate with functional class, neurohormonal activation and prognosis
which also recently has been suggested for AVS. Thus, although not fully elucidated the
transition from well compensated hypertrophy caused by pressure overload to symptomatic
heart failure may be related to evolving diastolic dysfunction. With longstanding
elevated filling pressures the left atrium will dilate due to chronically increased
atrial afterload. Only limited data are available on the degree and importance of LA
dilatation in AVS.
When apparent, symptoms of heart failure in AVS is associated with high mortality
rates. If LV systolic dysfunction also is present prognosis will deteriorate further.
In these cases aorta valve replacement (AVR) is recommended. AVR will normalize
pressure overload and thereby decreases LV hypertrophy. Previously it was believed that
in time LV hypertrophy regressed towards normal and even normalized. More recent
studies however have demonstrated that LV hypertrophy regression mainly happens during
the first 12-18 months after AVR, and little subsequent changes are seen during the
remaining 10 years. Furthermore, patients that experience most regression of
hypertrophy has more favourable outcome and better functional class than patients with
less regression of hypertrophy. Thus absence of reverse remodelling is associated with
poor outcome after AVR. Importantly the regression of LV hypertrophy is closely
paralleled by decreasing RAAS hyperactivity.
RAAS hyperactivity may be attenuated pharmacologically using angiotensin converting
enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB) which in systemic
hypertension with LV hypertrophy has been associated with reverse remodelling. This may
at least partly be associated with increased collagenase activity and depressed
collagen synthesis. Thus attenuation of RAAS hyperactivity may in theory lead to
decreased myocardial fibrosis and improving the diastolic function of the LV. The
effect of ARB treatment in patients with AVS that have undergone AVR is not known.
2. Hypothesis:
In patients undergoing AVR for symptomatic valvular aortic stenosis, 12 months post
operative blockade of the angiotensin II receptor will accelerate LV and LA reverse
remodelling, reduce filling pressures and suppress neurohormonal activation compared
with conventional therapy. This will lead to improved exercise tolerance and due to
improved left atrial function reducing the risk of atrial arrythmias.
3. Specific Objectives:
3.1 Primary Objectives
- In a consecutive population undergoing AVR for symptomatic AVS to compare
1. LV mass index
2. LA volume index
3. Plasma nt-pro BNP concentration after 12 months treatment with candesartan
compared with conventional treatment
3.2 Secondary Objectives
- In a consecutive population undergoing AVR for symptomatic AVS to compare
1. Diastolic E/e' ratio
2. Overall LV function assessed by the Doppler echocardiographic Tei Index
3. Regional LV function assessed with tissue Doppler imaging
4. LV end systolic and end diastolic volume index after 12 months treatment with
candesartan compared with conventional treatment.
3.3 Tertiary Objectives
- In a consecutive population undergoing AVR for symptomatic AVS to compare the
occurrence and atrial arrhythmias assessed with 48h Holter after 12 months
treatment with candesartan compared with conventional management.
- In a consecutive population undergoing AVR for symptomatic AVS to compare exercise
capacity after 12 months treatment with candesartan compared with conventional
management.
- In a consecutive population undergoing AVR for symptomatic AVS to assess serial
changes in LV diastolic, overall LV function and regional LV systolic function 12
months after valve replacement
- In a consecutive population undergoing AVR for symptomatic AVS to assess serial
changes in plasma nt-pro BNP, ANP, and renin 12 months after valve replacement.
4. Methods:
4.1 Design
The study is a prospective single center randomized study (PROBE design). Eligible patients
will be randomized to either conventional management or conventional management and 12
months treatment with candesartan. Treatment with candesartan will be unblinded but all
neurohormonal analyses and analyses of LV and LA size and function will be performed blinded
for treatment allocation and clinical data.
4.4 Study Procedures
Patients scheduled for elective aortic valve replacement for severe AVS at Odense University
Hospital will consecutively be offered participation in the study at hospital admission (2
days prior to surgery). If patient consent is obtained patients will undergo the study
program. Baseline echocardiography, neurohormonal analyses, and 6 min walk test will be
performed the day before surgery. After surgery and when the patient is transferred from
cardiac intensive care unit to step down unit treatment with candesartan (Atacand®) 8 mg
daily is initiated, and during hospitalization patients are titrated to 32 mg. After
hospital discharge patients will be followed in the heart failure clinic at Odense
University Hospital. Study medication will be handed to the patient at each visit.
Enrollment is planned to start February 2006 and continue for 18 months or until 140
patients have been enrolled.
4.4.1 Echocardiography
Doppler echocardiography will be performed prior to valve replacement, and repeated 3, 6,
and 12 months after surgery. Examinations will be performed on a GE medical Vivid 5
ultrasound machine. 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 imaging 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. Finally color coded real time tissue Doppler images will be
acquired in the apical windows.
- End-systolic, end-diastolic volume and ejection fraction will be calculated according
to the Simpson modified biplane method.
- LV mass will be estimated using 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.
- 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 pulsed wave Doppler
recording of LV outflow ejection time will be recorded. From these recordings Tei index
will be assessed.
- 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 function will be graded in grades 0-3 and
diastolic E/e' ratio calculated.
- From color coded tissue Doppler images systolic longitudinal fibre shortening will be
assessed using tissue tracking, and systolic strain will be assessed on a regional
basis.
4.4.2 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 prior
to surgery and after 6 and 12 months treatment with candesartan RAAS activity will be
assessed using plasma-renin activity, plasma-aldosterone, and plasma-noradrenalin. In
addition plasma will be frozen at each visit for possible later analysis.
4.4.3 Six Minutes Walk Test
A 6 min. walk test will be performed at baseline and at each outpatient visit (3, 6, 9 and
12 month).
4.4.3 Holter Monitoring
At the 12 months visit a 2-channel 48 hours Holter monitoring will be performed and analyzed
for occurrence of atrial arrhythmias.
4.4.4 Blood Pressure
Measurement of blood pressure will be done standardized after 30 min of rest at each visit.
Target blood pressure will be 140/80 mmHg or less and treatment instituted when appropriate.
4.4.5 Study Events
During the study period hospitalizations for worsening of heart failure, fatal / nonfatal
stroke, fatal/nonfatal acute coronary syndrome, hospitalization for atrial arrhythmias, and
death from all causes will be recorded.
;
Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment
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