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

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.

Study Overview

• Status: Terminated
• Conditions: Cardiac Disease
• Intervention / Treatment: Drug: Atenolol; Drug: Telmisartan

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 Type: Interventional
• Enrollment (Actual): 85
• Phase: Phase 3

Contacts and Locations

Study Locations

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

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / 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: or matched placebo; Micardis 40/80 mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Ascending Aorta Size, as Evaluated by MRI	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 3 years. Change is measured in centimeters squared (final measurement - baseline measurement). Original outcome measure time frame was scheduled for 5 years, however due to poor study participant and site recruitment study was closed early and final outcome measures taken at approximately 3 years.	The difference between baseline measures (2012-2013) and Year 3 measure (2015-2016)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Rate of Change in Ascending Aorta Size Evaluated by Transthoracic Echocardiography (TEE)	Rate of change in ascending aorta size evaluated by transthoracic echocardiography (ECHO) at 3 years. Change is measured in centimeters squared (final measurement - baseline measurement). Time frame was scheduled for 5 years, however due to poor study participant and site recruitment study was closed early and final outcome measures taken at approximately 3 years.	The difference between baseline measures (2012-2013) and Year 3 measure (2015-2016)

Collaborators and Investigators

• Sponsor: Hamilton Health Sciences Corporation
• Collaborators: Population Health Research Institute
• Investigators: Principal Investigator: Judith Therrien, MD, MdGill University

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2011
• Primary Completion (Actual): April 19, 2016
• Study Completion (Actual): November 1, 2016

Study Registration Dates

• First Submitted: September 14, 2010
• First Submitted That Met QC Criteria: September 15, 2010
• First Posted (Estimate): September 16, 2010

Study Record Updates

• Last Update Posted (Actual): September 18, 2019
• Last Update Submitted That Met QC Criteria: August 12, 2019
• Last Verified: August 1, 2019

More Information

Terms related to this study

• Keywords: Aortic Valve; Congenital; Bicuspid; Aortopathy; bicuspid aortic valve aortopathy
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Congenital Abnormalities; Heart Valve Diseases; Heart Defects, Congenital; Cardiovascular Abnormalities; Heart Diseases; Aortic Valve Disease; Bicuspid Aortic Valve Disease; 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; Angiotensin II Type 1 Receptor Blockers; Angiotensin Receptor Antagonists; Sympatholytics; Adrenergic beta-1 Receptor Antagonists; Telmisartan; Atenolol
• Other Study ID Numbers: BAV-15JUNE2010