Beta Blockers and Angiotensin Receptor Blockers in Bicuspid Aortic Valve Disease Aortopathy (BAV Study) (BAV)

Study Description

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Brief Summary:

The purpose of this study is to determine whether long-term treatment with a beta-blocker (BB) such as atenolol and/or an angiotensin receptor blocker (ARB) such as telmisartan, given to adult patients with bicuspid aortic valve (BAV) disease (aortopathy) reduces the widening (dilatation) of the aorta from its baseline size.

Condition or disease	Intervention/treatment	Phase
Cardiac Disease	Drug: Atenolol; Drug: Telmisartan	Phase 3

Detailed Description:

Bicuspid aortic valve (BAV) is the most common congenital heart disease lesion with an estimated 280 000 to 560 000 people affected in the Canada. Dilatation of the ascending aorta is a common feature in patients with BAV and is a result of inherent vascular abnormalities with superimposed effects of age and acquired cardiovascular risk factors. Severe aortic dilatation (> 50mm) leads to aortic dissection and premature death.

Histopathological studies of the aortas in patients with BAVs report similar findings to that of patients with Marfan syndrome. Beta Blocker (BB) therapy and more recently, Angiotensin Receptor Blocker (ARB) therapy, have been shown to decrease to rate of aortic dilatation and be of benefit to patients with Marfan syndrome. There is no such data however in patients with BAV and aortopathy.

Within the context of a randomized clinical trial, the investigators proposed to test the hypothesis that BB or ARB will reduce the rate of progressive aortic dilatation in adults with BAVs and ascending aortopathy as compared to placebo.

Design: Multicentre, randomized, double-blind, placebo-controlled, trial of adult patients with bicuspid aortic valve aortopathy. Patients who are eligible to take either study medication will be randomly allocated to participate in either the BB (atenolol) vs. placebo arm, or the ARB (telmisartan) vs. placebo arm. Patients who are ineligible for the BB arm will be assigned to the ARB vs. placebo arm and patients who are ineligible for the ARB arm will be assigned to the BB vs. placebo arm. Within each arm, all participants will be randomized to take either placebo or active medication. The atenolol arm will be up-titrated to100mg/day and the telmisartan arm will be up-titrated to 80 mg/day, or to the maximum tolerated dose.

Study Design

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Study Type :	Interventional (Clinical Trial)
Actual Enrollment :	85 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:	Prevention
Official Title:	Beta Blockers and Angiotensin Receptor Blockers in Bicuspid Aortic Valve Disease Aortopathy (BAV Study)
Study Start Date :	June 2011
Actual Primary Completion Date :	April 2016
Actual Study Completion Date :	November 2016

Arms and Interventions

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Arm	Intervention/treatment
Experimental: Atenolol; Atenolol or matching placebo 25 mg up-titrated to 100 mg.	Drug: Atenolol; Atenolol or matching placebo 25 mg up-titrated to 100 mg; Other Names: Atenolol 25/50/100 mg; or matched placebo
Experimental: Telmisartan; Telmisartan or matching placebo 40 mg up-titrated to 80mg	Drug: Telmisartan; Telmisartan or matching placebo 40 mg up-titrated to 80mg.; Other Names: Micardis 40/80 mg; or matched placebo

Outcome Measures

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Primary Outcome Measures :

1. Change from baseline in ascending aorta size, as evaluated by MRI [ Time Frame: Baseline, Year 3, Year 5 ]
   The primary analyses include the evaluation of the effects of monotherapy (atenolol vs. placebo, telmisartan vs. placebo) on the change in aortic root size measured at baseline, 3 years and 5 years.

Secondary Outcome Measures :

1. Rate of change in ascending aorta size evaluated by transthoracic echocardiography (TEE). [ Time Frame: Baseline, Year 1, year 2, Year 3, Year 4 and Final ]

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

• Age => 18 years
• Men and women with BAV and ascending aorta measuring > 37mm.
• Written informed consent

General Study Exclusion Criteria

1. History of cardiac diseases, such as

   • Symptomatic aortic stenosis or aortic regurgitation referred for surgical intervention or asymptomatic severe aortic stenosis or regurgitation based on current guidelines
   • Uncontrolled heart failure, right ventricular failure due to pulmonary hypertension
   • Cardiogenic shock
2. Systolic blood pressure < 100 mmHg
3. History of drug sensitivity, contraindication or adverse reaction to both BB and ARB. Participants who are able to tolerate only a BB will be allocated to the BB vs. placebo arm, and participants who are able to tolerate only an ARB will be allocated to the ARB vs. placebo arm, assuming no other exclusion criteria are met.
4. Ascending aorta measuring ≥ 50mm, requiring prophylactic ascending aorta surgery
5. Unable to provide informed consent
6. Need for both BB and ARB for treatment of concomitant medical conditions for which there are no other alternatives. Participants who are taking an ARB which cannot be discontinued will be allocated to the BB arm, and participants who are taking a BB which cannot be discontinued will be allocated to the ARB arm, if no other exclusion criteria are met.
7. Prior surgery on ascending aorta or aortic root (balloon valvuloplasty, aortic valvotomy or post coarctation surgery are acceptable)
8. Women who are pregnant at screening visit
9. Contraindication to MRI (claustrophobia, pacemaker, metallic clip in eye or brain)
10. History of any illness which limits the participants' ability to complete the study

Additional Exclusion Criteria for BB arm only

1. Heart rate <60 bpm
2. Heart block (1st, 2nd and 3rd degree AV block on ECG), or sick sinus syndrome
3. Asthma of sufficient severity to represent a contraindication to BB use in the judgment of the patient's physician
4. History of severe peripheral artery disorders
5. History of pheochromocytoma without the use of alpha-adrenergic blockers
6. History of metabolic acidosis

Additional Exclusion Criteria for ARB arm only

1. Women who are pregnant, lactating or who intend to become pregnant during the course of the study
2. Women who are of childbearing age and are not on reliable, accepted form of birth control
3. Hyperkalemia [serum potassium > 5.5 mmol/L] or renal dysfunction [GFR<45% measured by MDRD)
4. Patients being treated with an ACE Inhibitor that cannot be discontinued. (These patients may be randomized in the BB arm if no exclusion criteria are met.)
5. History of bilateral renal artery stenosis or unilateral renal artery stenosis to a solitary kidney
6. History of hepatic insufficiency and hepato-biliary obstruction
7. History of fructose intolerance

Contacts and Locations

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Locations

Canada, Alberta
Mazankowski Alberta Heart Institute
Edmonton, Alberta, Canada, T6G 2B7
Canada, British Columbia
University of British Columbia
Vancouver, British Columbia, Canada, V6Z 1Y6
Canada, Manitoba
St. Boniface Hospital
Winnipeg, Manitoba, Canada
Canada, Ontario
Hamilton Health Sciences-General
Hamilton, Ontario, Canada, L8L 2X2
Population Health Research Institute - Coordinating Centre
Hamilton, Ontario, Canada, L8L2X2
London Health Sciences Centre
London, Ontario, Canada, N6A 5A5
St. Michael's Hospital
Toronto, Ontario, Canada, M5B 1W8
Toronto General Hospital/University of Toronto
Toronto, Ontario, Canada
Canada, Quebec
Cité de la Santé de Laval
Laval, Quebec, Canada, H7M 3L9
McGill University Health Centre
Montreal, Quebec, Canada, H3A 1A1
Jewish General Hospital
Montreal, Quebec, Canada, H3T 1E2
Centre Hospitalier Universitaire de Sherbrooke
Sherbrooke, Quebec, Canada, J1H 5N4
Canada, Saskatchewan
Regina General Hospital
Regina, Saskatchewan, Canada, S4P 0W5

Sponsors and Collaborators

Hamilton Health Sciences Corporation

Population Health Research Institute

Investigators

Principal Investigator:	Judith Therrien, MD	MdGill University

More Information

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Responsible Party:	Hamilton Health Sciences Corporation
ClinicalTrials.gov Identifier:	NCT01202721 History of Changes
Other Study ID Numbers:	BAV-15JUNE2010
First Posted:	September 16, 2010
Last Update Posted:	December 12, 2016
Last Verified:	December 2016

Keywords provided by Hamilton Health Sciences Corporation:

Congenital; Aortic Valve; Bicuspid; Aortopathy; bicuspid aortic valve aortopathy

Additional relevant MeSH terms:

Heart Diseases; Heart Valve Diseases; Aortic Valve Stenosis; Cardiovascular Diseases; Ventricular Outflow Obstruction; Telmisartan; Atenolol; Angiotensin Receptor Antagonists; Adrenergic beta-Antagonists; Antihypertensive Agents; Angiotensin II Type 1 Receptor Blockers	Molecular Mechanisms of Pharmacological Action; Adrenergic Antagonists; Adrenergic Agents; Neurotransmitter Agents; Physiological Effects of Drugs; Anti-Arrhythmia Agents; Sympatholytics; Autonomic Agents; Peripheral Nervous System Agents; Adrenergic beta-1 Receptor Antagonists