Effect of Beta Blockade on Left Ventricular Remodeling and Function in Moderate to Severe Asymptomatic Aortic Regurgitation (BAR)

The primary objective of this study is to evaluate the effect of beta-blocker on left ventricular (LV) remodeling in asymptomatic patients with moderate to severe aortic regurgitation.

Study Overview

• Status: Completed
• Conditions: Aortic Valve Insufficiency
• Intervention / Treatment: Drug: Metoprolol; Drug: Placebo

Detailed Description

The left ventricle responds to the volume load of chronic aortic regurgitation (AR) with a series of compensatory mechanisms, including an increase in end-diastolic volume, an increase in chamber compliance that accommodates the increased volume without an increase in filling pressures, and a combination of eccentric and concentric hypertrophy. The greater diastolic volume permits the ventricle to eject a large total stroke volume to maintain forward stroke volume in the normal range. This is accomplished through rearrangement of myocardial fibers with the addition of new sarcomeres and development of eccentric LV hypertrophy. As a consequence left ventricular ejection fraction will remain in the normal range.

The clinical course of chronic aortic regurgitation is characterized by a prolonged phase of stability during which the left ventricle adapts to the volume overload. Eventually myocardial failure ensues through a series of complex events that include changes in myocyte phenotype due to re-expression of fetal genes, cellular apoptosis alteration in the expression and function of contractile proteins and changes in the extracellular matrix.

The role of long-term vasodilator therapy in the care of asymptomatic patients with severe aortic regurgitation is controversial. Vasodilator therapy has been used to reduce the regurgitant volume, afterload, left ventricular volumes, and wall stress in an effort to preserve left ventricular function and reduce left ventricular mass. Thus time to surgical intervention has been found to be delayed by calcium antagonists, ACE-inhibitors and hydralazine, while a more recent study did not find any effect of nifedipine or enalapril on time to surgery or left ventricular volume and function.

The decision to recommend operative intervention to the asymptomatic patient with chronic, severe aortic regurgitation (AR) is very difficult because aortic valve replacement (AVR) continues to entail immediate risk, and biologic and mechanical valves still have problems resulting in significant morbidity and mortality. On the other hand, the mortality rate in asymptomatic patients with AR is very low, and surgery does not improve the quality of life. Thus, the indication in asymptomatic patients must be delayed until changes occur that will predict an increased risk of operative or long-term death after AVR. At present indication for aortic valve replacement is development of symptoms, an increase in left ventricular volume or a decline in left ventricular function.

• Study Type: Interventional
• Enrollment (Actual): 75
• Phase: Phase 4

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 70 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Moderate to severe aortic valve insufficiency
• Asymptomatic

Exclusion Criteria:

• Arrhythmia
• Other severe valve disease

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: RANDOMIZED
• Interventional Model: PARALLEL
• Masking: DOUBLE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
PLACEBO_COMPARATOR: Placebo	Drug: Placebo; Patients with moderate to severe aortic valve insufficiency will be randomized to Placebo
ACTIVE_COMPARATOR: Metoprolol	Drug: Metoprolol; Patients with moderate to severe aortic valve insufficiency will be randomized to Metoprolol

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Left ventricular end-diastolic volume	6 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Left ventricular end-systolic volume	6 months

Collaborators and Investigators

• Sponsor: Oslo University Hospital
• Collaborators: Haukeland University Hospital; University Ghent; University Hospital, Akershus; University Hospital, Gentofte, Copenhagen

Publications and helpful links

General Publications

• Broch K, Urheim S, Lonnebakken MT, Stueflotten W, Massey R, Fossa K, Hopp E, Aakhus S, Gullestad L. Controlled release metoprolol for aortic regurgitation: a randomised clinical trial. Heart. 2016 Feb;102(3):191-7. doi: 10.1136/heartjnl-2015-308416. Epub 2015 Dec 9.

Study record dates

Study Major Dates

• Study Start: August 1, 2010
• Primary Completion (ACTUAL): August 1, 2014
• Study Completion (ACTUAL): September 1, 2014

Study Registration Dates

• First Submitted: July 5, 2010
• First Submitted That Met QC Criteria: July 6, 2010
• First Posted (ESTIMATE): July 7, 2010

Study Record Updates

• Last Update Posted (ESTIMATE): September 25, 2014
• Last Update Submitted That Met QC Criteria: September 24, 2014
• Last Verified: September 1, 2014

More Information

Terms related to this study

• Keywords: Beta-blocker; Aortic valve insufficiency
• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Pathological Conditions, Anatomical; Aortic Valve Disease; Heart Valve Diseases; Aortic Valve Insufficiency; Ventricular Remodeling; Physiological Effects of Drugs; Adrenergic beta-Antagonists; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Anti-Arrhythmia Agents; Antihypertensive Agents; Autonomic Agents; Peripheral Nervous System Agents; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Metoprolol
• Other Study ID Numbers: EUDRACTNR: 2007-000518-34