BLAST: Effect of Bisoprolol on Progression of Aortic Stenosis

Sponsor

Asan Medical Center (Other)

Overall Status

Terminated

CT.gov ID

NCT01579058

Collaborator

Merck Sharp & Dohme LLC (Industry)

Enrollment

Locations

Arms

Duration (Months)

6.7

Patients Per Site

0.3

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Aortic stenosis has been thought to be a degenerative process basically induced by long-lasting mechanical stress, and hemodynamic factors such as shear forces, acceleration of blood flow, hypertension and rapid heart rate might contribute to progression of aortic stenosis. Peak aortic jet velocity is known to be associated with clinical outcomes in mild and moderate AS, and our previous study showed that rate of progression was significantly associated with baseline aortic jet velocity in mild aortic stenosis. Because beta-blocker therapy would decrease aortic jet velocity and heart rate, it might decrease hemodynamic stress and eventually slow down the degenerative process in patients whose disease is not too advanced for therapy to be effective. The investigators hypothesized that a beta-blocker therapy would decrease the rate of progression of aortic stenosis by modifying hemodynamic factors favorably in patients with mild to moderate aortic stenosis.

Condition or Disease	Intervention/Treatment	Phase
Aortic Stenosis	Drug: bisoprolol Drug: placebo	Phase 4

Detailed Description

Aortic stenosis (AS) is a gradually progressive disease, characterized by an increase in calcium deposition leading to progressive narrowing of the aortic valve (AV). There are currently no effective medical treatment to halt the disease process and surgical valve replacement remains the only proven therapy when the valve becomes severely stenotic. AS is mediated by a chronic inflammatory disease process, very similar to that seen in atherosclerosis, but lipid-lowering therapy did not slow the progression of AS in the SALTIRE, SEAS, or ASTRONOMER trials. It is possible that these trials may have targeted patients in whom disease was too advanced for lipid-lowering therapy to be effective, or in whom atherosclerotic mechanism was not the central pathogenic process in AS. Because identifying and treating patients in earlier stages of AS would not be cost-effective, it seems more logical to explore alternative pharmacological approaches.

AS has been thought to be a degenerative process basically induced by long-lasting mechanical stress, and hemodynamic factors such as shear forces, acceleration of blood flow, hypertension and rapid heart rate might contribute to progression of AS. Peak aortic jet velocity is known to be associated with clinical outcomes in mild and moderate AS, and our previous study showed that rate of progression was significantly associated with baseline aortic jet velocity in mild AS. Because beta-blocker therapy would decrease aortic jet velocity and heart rate, it might decrease hemodynamic stress and eventually slow down the degenerative process in patients whose disease is not too advanced for therapy to be effective. In a retrospective, observational study, beta-blocker therapy was associated with a favorable clinical outcome in AS.

The investigators hypothesized that bisoprolol, a new generation beta-blocker, would decrease the rate of progression of AS by modifying hemodynamic factors favorably in patients with mild to moderate AS.

Study Design

Study Type:

Interventional

Actual Enrollment :

20 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

A Randomized Trial of Beta-blocker Therapy in Aortic Stenosis

Study Start Date :

Jul 1, 2012

Actual Primary Completion Date :

May 1, 2014

Actual Study Completion Date :

May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: bisoprolol bisoprolol 5mg qd	Drug: bisoprolol bisoprolol 5mg qd for 4 years Other Names: Concor
Placebo Comparator: placebo placebo	Drug: placebo placebo for 4 years

Arm

Intervention/Treatment

Active Comparator: bisoprolol

bisoprolol 5mg qd

Drug: bisoprolol

bisoprolol 5mg qd for 4 years

Other Names:

Concor

Placebo Comparator: placebo

placebo

Drug: placebo

placebo for 4 years

Outcome Measures

Primary Outcome Measures

Change in peak aortic jet velocity from baseline to 4 years follow-up [4 years]
Change in peak aortic jet velocity from baseline to 4 years follow-up. For each patient, the change in peak aortic jet velocity is calculated as (peak aortic jet velocity at 4 year follow-up) - (peak aortic jet velocity at baseline) on Doppler echocardiography.

Secondary Outcome Measures

Change in mean pressure gradient across aortic valve [4 years]
Change in mean pressure gradient across aortic valve from baseline to 4 years follow-up
Change in aortic valve area [4 years]
Change in aortic valve area from baseline to 4 years follow-up
Change in BNP levels [4 years]
Change in BNP levels from baseline to 4 years follow-up
Change in E/E' ratio [4 years]
Change in the ratio of E velocity (early mitral inflow velocity) to E' velocity (early mitral annular velocity) from baseline to 4 years follow-up

Eligibility Criteria

Criteria

Ages Eligible for Study:

20 Years to 70 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Mild to moderate aortic stenosis defined by peak velocity of aortic jet between 2.0 and 3.5 m/sec
Untreated hypertension: systolic BP ≥ 140 or diastolic BP ≥ 90 mmHg Treated hypertension using dihydropiridine calcium channel blockers, ACE inhibitors, ARB or diuretics
Patients received no beta-blocker therapy for more than 12 months

Exclusion Criteria:

Symtomatic aortic stenosis: presence of exertional dyspnea, angina or syncope
Planned cardiac surgery (e.g., CABG, valve repair or replacement, or aneurysmectomy) or planned major non-cardiac surgery within the study period
Stroke or resuscitated sudden death in the past 6 months
Evidence of congestive heart failure, or left ventricular ejection fraction < 50%
Significant renal disease manifested by serum creatinine > 2.0mg/dL
History of intolerance to beta-blocker
History of adult asthma manifested by bronchospasm in the past 6 months, or currently taking regular anti-asthmatic medication(s)
Moderate or severe aortic regurgitation
Atrial fibrillation
Female of child-bearing potential who do not use adequate contraception and women who are pregnant or breast-feeding
A diagnosis of cancer (other than superficial squamous or basal cell skin cancer) in the past 3 years or current treatment for the active cancer
Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgment of the Investigator, would preclude safe completion of the study
Unwillingness or inability to comply with the procedures described in this protocol

Contacts and Locations

Locations

	Site	City	Country	Postal Code
1	Samsung Medical Center	Seoul	Korea, Republic of	135-710
2	Asan Medical Center	Seoul	Korea, Republic of	138-736
3	Seoul National University Hospital	Seoul	Korea, Republic of