Project: Research project

Project Details


DESCRIPTION (the applicant's description verbatim): Background: Mitral
regurgitation (MR) is frequent and its prevalence is increasing with aging of
the population. Organic MR, due to primary valvular lesions has severe
consequences determined by its degree, with left ventricular (LV) remodeling
and dysfunction, left atrial (LA) enlargement, leading to poor clinical
outcome. Surgery can eliminate MR, but carries notable risks and is not
applicable to all patients. Therefore, chronically decreasing MR, protecting LV
and LA with vasoactive treatment are major goals of medical therapy. However,
effects of chronic oral vasoactive treatment of MR are controversial and
uncertain and recent practice guidelines underscored these gaps in knowledge
and did not recommend vasoactive treatment of MR. Hence, a trial of treatment
of organic MR is needed. A large trial with mortality-morbidity end-points is
desirable but premature without knowledge of magnitude of mechanistic effects
of vasoactive treatment. Our pilot studies suggest that sustained improvement
of degree of' MR, LV remodeling and LA enlargement can be achieved with tissue
angiotensin blockade. The improvement of these intermediate endpoints,
mechanistically linked to outcome, is measurable with non-invasive quantitative
techniques and forms the basis of the present clinical trial proposal.
Hypothesis: Chronic tissue angiotensin blockade therapy using either
angiotensin-II receptor blocker (Candesartan Cilexetil) or tissue
angiotensin-converting enzyme inhibition (Ramipril) in two arms, weighed
against placebo produces a sustained reduction of the consequences of organic
MR. Specific aims are that treatment improves a) degree of MR (decreases
regurgitant volume, primary end-point), b) LV remodeling (decreases LV
end-diastolic volume index, second end-point), and c) LA enlargement (decreases
LA volume, third end-point) as compared to placebo. Population: Patients with
MR organic (intrinsic valve disease), isolated (no other valve disease), equal
to or greater than moderate (regurgitant volume equal to or greater than 30
mL/beat). Methods: A randomized clinical trial, placebo controlled,
double-blind, without crossover, of 1 year oral treatment with potent tissue
angiotensin blockade (with one arm using Candesartan and one arm using
Ramipril) titrated to the maximally tolerated dose. The trial is preceded by an
acute study to determine tolerance. End-points are measured by
Doppler-Echocardiography for quantitation of MR (regurgitant volume) using
combination of 3 simultaneous methods (quantitative Doppler, two-dimensional
echocardiography, proximal flow convergence) and combination of
echocardiography and electron beam computed tomography for LV and LA volume
measurement. This single center study seeks to enroll a total of 135 patients.
The analysis will be based on intention to treat and compare changes in
regurgitant volume, LV end-diastolic volume index and LA volume measured after
one year of treatment with active drugs or placebo. The results of this
clinical trial should provide strong evidence regarding medical treatment of
patients with organic MR and define future strategies to minimize mortality and
morbidity of organic MR.
StatusNot started