Clinical trial NCT01202721: Beta Blockers and Angiotensin Receptor Blockers in Bicuspid Aortic Valve Disease Aortopathy (BAV Study)
Official title: Beta Blockers and Angiotensin Receptor Blockers in Bicuspid Aortic Valve Disease Aortopathy (BAV Study)
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE3
Conditions: Cardiac Disease
Keywords: Congenital
Aortic Valve
Bicuspid
Aortopathy
bicuspid aortic valve aortopathy
Lead sponsor: Hamilton Health Sciences Corporation
Sponsor class: OTHER
Collaborators: name: Population Health Research Institute
First posted: 2010-09-16
Enrollment: 85
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

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.

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.

Eligibility 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

Primary outcomes:
measure: Change From Baseline in Ascending Aorta Size, as Evaluated by MRI
timeFrame: The difference between baseline measures (2012-2013) and Year 3 measure (2015-2016)
Secondary outcomes:
measure: Rate of Change in Ascending Aorta Size Evaluated by Transthoracic Echocardiography (TEE)
timeFrame: The difference between baseline measures (2012-2013) and Year 3 measure (2015-2016)
Other outcomes:
Locations:
city: Edmonton
country: Canada
facility: Mazankowski Alberta Heart Institute
state: Alberta
city: Vancouver
country: Canada
facility: University of British Columbia
state: British Columbia
city: Winnipeg
country: Canada
facility: St. Boniface Hospital
state: Manitoba
city: Hamilton
country: Canada
facility: Hamilton Health Sciences-General
state: Ontario
city: Hamilton
country: Canada
facility: Population Health Research Institute - Coordinating Centre
state: Ontario
city: London
country: Canada
facility: London Health Sciences Centre
state: Ontario
city: Toronto
country: Canada
facility: St. Michael's Hospital
state: Ontario
city: Toronto
country: Canada
facility: Toronto General Hospital/University of Toronto
state: Ontario
city: Laval
country: Canada
facility: Cité de la Santé de Laval
state: Quebec
city: Montreal
country: Canada
facility: McGill University Health Centre
state: Quebec
city: Montreal
country: Canada
facility: Jewish General Hospital
state: Quebec
city: Sherbrooke
country: Canada
facility: Centre Hospitalier Universitaire de Sherbrooke
state: Quebec
city: Regina
country: Canada
facility: Regina General Hospital
state: Saskatchewan
Study officials:
affiliation: MdGill University
name: Judith Therrien, MD
role: PRINCIPAL_INVESTIGATOR
References: