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Effect of Bisoprolol on Progression of Aortic Stenosis (BLAST)

This study has been terminated.
(The sponsor discontinued to support the study.)
Sponsor:
Collaborator:
Merck Sharp & Dohme Corp.
Information provided by (Responsible Party):
Duk-Hyun Kang, Asan Medical Center
ClinicalTrials.gov Identifier:
NCT01579058
First received: April 14, 2012
Last updated: May 8, 2014
Last verified: May 2014
  Purpose

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 Intervention Phase
Aortic Stenosis
Drug: bisoprolol
Drug: placebo
Phase 4

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized Trial of Beta-blocker Therapy in Aortic Stenosis

Resource links provided by NLM:


Further study details as provided by Asan Medical Center:

Primary Outcome Measures:
  • Change in peak aortic jet velocity from baseline to 4 years follow-up [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    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 [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Change in mean pressure gradient across aortic valve from baseline to 4 years follow-up

  • Change in aortic valve area [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Change in aortic valve area from baseline to 4 years follow-up

  • Change in BNP levels [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    Change in BNP levels from baseline to 4 years follow-up

  • Change in E/E' ratio [ Time Frame: 4 years ] [ Designated as safety issue: No ]
    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


Estimated Enrollment: 150
Study Start Date: July 2012
Estimated Study Completion Date: July 2018
Estimated Primary Completion Date: July 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: bisoprolol
bisoprolol 5mg qd
Drug: bisoprolol
bisoprolol 5mg qd for 4 years
Other Name: Concor
Placebo Comparator: placebo
placebo
Drug: placebo
placebo for 4 years

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.

  Eligibility

Ages Eligible for Study:   20 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01579058

Locations
Korea, Republic of
Asan Medical Center
Seoul, Korea, Republic of, 138-736
Samsung Medical Center
Seoul, Korea, Republic of, 135-710
Seoul National University Hospital
Seoul, Korea, Republic of
Sponsors and Collaborators
Asan Medical Center
Merck Sharp & Dohme Corp.
Investigators
Principal Investigator: Duk-Hyun Kang, M.D. Asan Medical Center
  More Information

No publications provided

Responsible Party: Duk-Hyun Kang, Professor, Asan Medical Center
ClinicalTrials.gov Identifier: NCT01579058     History of Changes
Other Study ID Numbers: 2011-0884
Study First Received: April 14, 2012
Last Updated: May 8, 2014
Health Authority: South Korea: Korea Food and Drug Administration (KFDA)

Keywords provided by Asan Medical Center:
aortic stenosis
beta-blocker

Additional relevant MeSH terms:
Aortic Valve Stenosis
Constriction, Pathologic
Cardiovascular Diseases
Heart Diseases
Heart Valve Diseases
Pathological Conditions, Anatomical
Ventricular Outflow Obstruction
Bisoprolol
Adrenergic Agents
Adrenergic Antagonists
Adrenergic beta-1 Receptor Antagonists
Adrenergic beta-Antagonists
Antihypertensive Agents
Autonomic Agents
Cardiovascular Agents
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Peripheral Nervous System Agents
Pharmacologic Actions
Physiological Effects of Drugs
Sympatholytics
Therapeutic Uses

ClinicalTrials.gov processed this record on November 20, 2014