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

NCT ID: NCT01157572

Last Updated: 2014-09-25

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 75 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2010-08-31
• Study Completion Date: 2014-09-30

Brief Summary

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.

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.

Conditions

Aortic Valve Insufficiency

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

Metoprolol

Group Type: ACTIVE_COMPARATOR

Metoprolol

Intervention Type: DRUG

Patients with moderate to severe aortic valve insufficiency will be randomized to Metoprolol

Placebo

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Patients with moderate to severe aortic valve insufficiency will be randomized to Placebo

Interventions

Metoprolol

Patients with moderate to severe aortic valve insufficiency will be randomized to Metoprolol

Intervention Type: DRUG

Placebo

Patients with moderate to severe aortic valve insufficiency will be randomized to Placebo

Intervention Type: DRUG

Eligibility Criteria

Inclusion Criteria

• Moderate to severe aortic valve insufficiency
• Asymptomatic

Exclusion Criteria

• Arrhythmia
• Other severe valve disease

• Minimum Eligible Age: 18 Years
• Maximum Eligible Age: 70 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

University Ghent

OTHER

Sponsor Role: collaborator

University Hospital, Gentofte, Copenhagen

OTHER

Sponsor Role: collaborator

University Hospital, Akershus

OTHER

Sponsor Role: collaborator

Haukeland University Hospital

OTHER

Sponsor Role: collaborator

Oslo University Hospital

OTHER

Sponsor Role: lead

Responsible Party

Stig Urheim

MD, PhD

Responsibility Role: PRINCIPAL_INVESTIGATOR

References

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.

Reference Type: DERIVED

PMID: 26661319 (View on PubMed)

Other Identifiers

EUDRACTNR: 2007-000518-34

Identifier Type: -

Identifier Source: org_study_id