Cardiac Disease
Conditions
Keywords
Congenital, Aortic Valve, Bicuspid, Aortopathy, bicuspid aortic valve aortopathy
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.
Interventions
DRUGAtenolol
Atenolol or matching placebo 25 mg up-titrated to 100 mg
DRUGTelmisartan
Telmisartan or matching placebo 40 mg up-titrated to 80mg.
Sponsors
Population Health Research Institute
Hamilton Health Sciences Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
Canada
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Atenolol Atenolol 25 mg up-titrated to 100 mg. | 18 |
| Telmisartan Telmisartan 40 mg up-titrated to 80mg | 26 |
| Atenolol Placebo Participants randomized to receive Atenolol placebo | 14 |
| Telmisartan Placebo Participants randomized to receive Telmisartan placebo | 27 |
| Total | 85 |
Baseline characteristics
| Characteristic | Atenolol | Telmisartan | Atenolol Placebo | Telmisartan Placebo | Total |
|---|---|---|---|---|---|
| Age, Continuous | 43.4 years STANDARD_DEVIATION 12.8 | 47 years STANDARD_DEVIATION 12.2 | 49.1 years STANDARD_DEVIATION 13.6 | 49.1 years STANDARD_DEVIATION 11.2 | 47.3 years STANDARD_DEVIATION 12.3 |
| Race/Ethnicity, Customized Asian | 2 Participants | 1 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized Black African | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized European | 15 Participants | 23 Participants | 12 Participants | 26 Participants | 76 Participants |
| Race/Ethnicity, Customized Native North American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race/Ethnicity, Customized South Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Female | 5 Participants | 7 Participants | 8 Participants | 7 Participants | 27 Participants |
| Sex: Female, Male Male | 13 Participants | 19 Participants | 6 Participants | 20 Participants | 58 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 18 | 0 / 26 | 0 / 14 | 0 / 27 |
| other Total, other adverse events | 10 / 18 | 13 / 26 | 10 / 14 | 18 / 27 |
| serious Total, serious adverse events | 0 / 18 | 2 / 26 | 1 / 14 | 2 / 27 |
Outcome results
Primary
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.
Time frame: The difference between baseline measures (2012-2013) and Year 3 measure (2015-2016)
Population: Intention to treat analysis method followed: patients completed final visit over the phone where aortic root size cannot be measured; patients refused a final visit, or patient's information was received through a third party. Patients missing primary outcome measures still followed for other analyses.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atenolol | Change From Baseline in Ascending Aorta Size, as Evaluated by MRI | .6 centimeters squared | Standard Deviation 1.4 |
| Telmisartan | Change From Baseline in Ascending Aorta Size, as Evaluated by MRI | .4 centimeters squared | Standard Deviation 1.3 |
| Atenolol Placebo | Change From Baseline in Ascending Aorta Size, as Evaluated by MRI | .7 centimeters squared | Standard Deviation 0.8 |
| Telmisartan Placebo | Change From Baseline in Ascending Aorta Size, as Evaluated by MRI | 1 centimeters squared | Standard Deviation 1.6 |
Secondary
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.
Time frame: The difference between baseline measures (2012-2013) and Year 3 measure (2015-2016)
Population: Discrepancy exists between participant flow numbers and patients analyzed for the following reasons: patients completed final visit over the phone where aortic root size cannot be measured; patients refused a final visit, patient's information was received through a third party. Pt's not removed as they are still included in other analyses
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Atenolol | Rate of Change in Ascending Aorta Size Evaluated by Transthoracic Echocardiography (TEE) | -.9 centimetres squared | Standard Deviation 3.2 |
| Telmisartan | Rate of Change in Ascending Aorta Size Evaluated by Transthoracic Echocardiography (TEE) | -.2 centimetres squared | Standard Deviation 4.5 |
| Atenolol Placebo | Rate of Change in Ascending Aorta Size Evaluated by Transthoracic Echocardiography (TEE) | -1.6 centimetres squared | Standard Deviation 4.3 |
| Telmisartan Placebo | Rate of Change in Ascending Aorta Size Evaluated by Transthoracic Echocardiography (TEE) | .3 centimetres squared | Standard Deviation 2.8 |