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

Phase 3

Terminated

Conditions: Cardiac Disease

Interventions: Drug: Telmisartan
Drug: Atenolol

Registration Number: NCT01202721

Lead Sponsor: Hamilton Health Sciences Corporation

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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 85

Inclusion Criteria

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

General Study Exclusion Criteria

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
Systolic blood pressure < 100 mmHg
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.
Ascending aorta measuring ≥ 50mm, requiring prophylactic ascending aorta surgery
Unable to provide informed consent
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.
Prior surgery on ascending aorta or aortic root (balloon valvuloplasty, aortic valvotomy or post coarctation surgery are acceptable)
Women who are pregnant at screening visit
Contraindication to MRI (claustrophobia, pacemaker, metallic clip in eye or brain)
History of any illness which limits the participants' ability to complete the study

Additional Exclusion Criteria for BB arm only

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

Additional Exclusion Criteria for ARB arm only

Women who are pregnant, lactating or who intend to become pregnant during the course of the study
Women who are of childbearing age and are not on reliable, accepted form of birth control
Hyperkalemia [serum potassium > 5.5 mmol/L] or renal dysfunction [GFR<45% measured by MDRD)
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.)
History of bilateral renal artery stenosis or unilateral renal artery stenosis to a solitary kidney
History of hepatic insufficiency and hepato-biliary obstruction
History of fructose intolerance

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Telmisartan	Telmisartan	Telmisartan or matching placebo 40 mg up-titrated to 80mg
Atenolol	Atenolol	Atenolol or matching placebo 25 mg up-titrated to 100 mg.

Primary Outcome Measures

Name	Time	Method
Change From Baseline in Ascending Aorta Size, as Evaluated by MRI	The difference between baseline measures (2012-2013) and Year 3 measure (2015-2016)	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.

Secondary Outcome Measures

Name	Time	Method
Rate of Change in Ascending Aorta Size Evaluated by Transthoracic Echocardiography (TEE)	The difference between baseline measures (2012-2013) and Year 3 measure (2015-2016)	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.

Trial Locations

Locations (13): Hamilton Health Sciences-General
🇨🇦
Hamilton, Ontario, Canada
St. Michael's Hospital
🇨🇦
Toronto, Ontario, Canada
Cité de la Santé de Laval
🇨🇦
Laval, Quebec, Canada
McGill University Health Centre
🇨🇦
Montreal, Quebec, Canada
Centre Hospitalier Universitaire de Sherbrooke
🇨🇦
Sherbrooke, Quebec, Canada
St. Boniface Hospital
🇨🇦
Winnipeg, Manitoba, Canada
University of British Columbia
🇨🇦
Vancouver, British Columbia, Canada
Toronto General Hospital/University of Toronto
🇨🇦
Toronto, Ontario, Canada
Jewish General Hospital
🇨🇦
Montreal, Quebec, Canada
Population Health Research Institute - Coordinating Centre
🇨🇦
Hamilton, Ontario, Canada
Mazankowski Alberta Heart Institute
🇨🇦
Edmonton, Alberta, Canada
London Health Sciences Centre
🇨🇦
London, Ontario, Canada
Regina General Hospital
🇨🇦
Regina, Saskatchewan, Canada