A Randomized Clinical Trial of Metoprolol in Participants With Mitral Regurgitation.
A Randomized Clinical Trial of Metoprolol in Participants With Mitral Regurgitation.
Mitral valve regurgitation (leakage of the mitral valve of the heart) is frequent and
 currently there is no specific medical therapy. Mitral regurgitation is a slowly progressive
 disease that frequently requires surgical treatment. This randomized clinical trial will use
 Metoprolol, a common beta-blocker medication, to determine if medical treatment impacts
 mitral valve disease progression.
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. Recent animal data suggest that
 beta-blockade in organic MR has significant positive effect, particularly on LV remodeling.
 Therefore, chronically decreasing MR, protecting LV and LA with beta-blockade are major goals
 of medical therapy. However, effects of chronic oral beta-blockade of human MR are uncertain
 and recent practice guidelines underscored these gaps in knowledge and did not recommend
 beta-blockade 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 beta-blockade. The improvement of these intermediate end-points,
 mechanistically linked to outcome, is measurable with non-invasive quantitative techniques
 and forms the basis of the present clinical trial proposal. Hypothesis: Chronic beta-blockade
 therapy using Metoprolol 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) d moderate (regurgitant volume *30
 mL/beat). Methods: A randomized clinical trial, placebo controlled, double-blind, without
 crossover, of 12 months oral treatment with potent beta-blockade (Metoprolol XL 50 to 200mg
 QD) 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 echocardiography for LV and
 LA volume measurement. In addition cardiopulmonary exercise testing will measure peak O2
 consumption at baseline and follow-up. This study seeks to enroll a total of 60 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
 drug 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.
Inclusion criteria: Patients a) 21 years old or older, with b) MR observed with color flow
 imaging, c) due to organic mitral valve disease demonstrated by Echocardiography (not
 normal valve as in functional or ischemic MR), c) isolated (no valve disease other than
 functional tricuspid regurgitation by Doppler-Echocardiography), d) pure (no mitral
 stenosis by Doppler-Echocardiography), e) quantifiable by Doppler-Echocardiography, f) of
 degree * moderate, defined as RVol * 30 mL/beat, g) occurring on native valves, h) with
 echocardiographic imaging allowing assessment of LA and LV, and i) asymptomatic (or mildly
 symptomatic but not considered as candidates for immediate surgery by their attending
 physician).