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出境医 / 临床实验 / Danish National Randomized Study on Early Aortic Valve Replacement in Patients With Asymptomatic Severe Aortic Stenosis (DANAVR)

Danish National Randomized Study on Early Aortic Valve Replacement in Patients With Asymptomatic Severe Aortic Stenosis (DANAVR)

Study Description
Brief Summary:
The purpose of this study is to examine the impact of early surgery in patients with asymptomatic severe aortic valve stenosis with signs of subclinical LV dysfunction despite preserved LVEF, with a watchfull waiting approach.

Condition or disease Intervention/treatment Phase
Aortic Valve Stenosis Diastolic Dysfunction Procedure: Aortic valve replacement Not Applicable

Detailed Description:

Since the seminal paper by Ross and Braunwald, the development of symptoms has been regarded as one of the most important precursors of a poor outcome in aortic stenosis (AS), and is today half a century later, still the leading reason for referral for aortic valve replacement (AVR). The development of symptoms is however often preceded by structural changes in the left ventricle (LV).These changes including concentric remodeling and LV hypertrophy have been regarded as compensative measures to adapt the LV to increased ventricular afterload. Although LV hypertrophy may preserve wall-stress in the normal range and increase contractility allowing the preservation of stroke volume, this occurs at the expense of increased filling pressures. Diastolic dysfunction with increased filling pressure lead to left atrial (LA) dilatation and significantly contributes to the development of symptoms.

Despite successful surgery, AS patients have increased long-term mortality and morbidity compared to the general population, and the outcome is largely determined by the degree of preoperative structural LV and LA alterations. This has led to the theory that AVR prior to the development of symptoms could improve outcome, a view supported by prospective and retrospective studies.These studies were however small, with some important limitations. In addition, there has been a concern that operative risk and prosthetic valve related long-term morbidity and mortality does not justify surgery on every asymptomatic patient with severe AS. Numerous studies have suggested that markers of LV structure and function, particularly LA volume index,E/e' and brain natriuretic peptides (BNP) all reflecting LV filling pressures may identify patients with benefit of early AVR. Accordingly, the most recent European guideline for management of valvular disease has implemented BNP as a class IIa recommendation for AVR in asymptomatic AS patients,although no randomized studies have demonstrated that early surgery based on these markers improve prognosis.

The purpose of this study is thus to evaluate if early AVR in patients with signs of elevated LV filling pressuresmay improve long-term outcome in patients with asymptomatic severe AS, compared to conventional symptom-guided surgery.

Study Design
Layout table for study information
Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 1700 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Danish National Randomized Study on Early Aortic Valve Replacement in Patients With Asymptomatic Severe Aortic Stenosis
Actual Study Start Date : January 1, 2020
Estimated Primary Completion Date : September 1, 2029
Estimated Study Completion Date : September 1, 2029
Arms and Interventions
Arm Intervention/treatment
Active Comparator: Early intervention
Patients will undergo aortic valve replacement immediately
 Procedure: Aortic valve replacement
Open heart surgery or transcatheter surgery
No Intervention: Watchfull waiting
Patients will be followed and treated as recommended by guidelines.
Outcome Measures
Primary Outcome Measures :
  1. all-cause mortality [ Time Frame: After 379 events (approx 5 years) ]
    All-cause mortality assessed by Danish patient records


Secondary Outcome Measures :
  1. Combined endpoint [ Time Frame: After 379 events (approx 5 years) ]
    All-cause mortality + hospitalization due to heart failure and stroke

  2. all-cause mortality in patients with low-gradient AS [ Time Frame: After 379 events (approx 5 years) ]
    All-cause mortality in patients with meangradient <40 mmHg

  3. Combined endpoint in low-gradient AS [ Time Frame: After 379 events (approx 5 years) ]
    All-cause mortality + hospitalization to heart failure and stroke when MG<40 mmHg


Other Outcome Measures:
  1. Pericardiocentesis [ Time Frame: 5 years ]
    Need of pericariocentesis

  2. sternal infection [ Time Frame: 5 years ]
    hospitalization due to sternal infection

  3. Persistent renal failure [ Time Frame: 5 years ]
    complete loss of renal function exceeding 4 weeks.

  4. endocarditis [ Time Frame: 5-years ]
    hospitalization due to endocarditis

  5. major bleeding [ Time Frame: 5 years ]
    intracerebral bleeding or bleeding resulting in substantial hemodynamic compromise requiring treatment instability


Eligibility Criteria
Layout table for eligibility information
Ages Eligible for Study:   18 Years to 85 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • 1. Severe AS defined as

    1. aortic valve area (AVA) ≤1 cm2, AND
    2. Transvalvular maximum velocity (Vmax) ≥3.5 m/s AND

    3. AS severity evaluated severe by a heart valve team conference. In cases where severity is not unambiguous an integrative approach will be utilized combining echocardiographic markers of valve severity and LV function, and if necessary aortic valve calcification estimated by non-contrast CT.

      2. Considered to be asymptomatic (estimated by a consultant in cardiology) 3. Considered to be candidate for AVR (transcatheter AVR/surgical AVR) 4. Sign of increased LV filling pressures18 or reduced longitudinal LV systolic function

    1. Left atrial volume index (LAVi) > 34 ml/m2; OR
    2. ratio of early diastolic peak mitral inflow velocity (E) to early mitral annulus diastolic velocity (e') ratio E/e'avg>13; OR
    3. Threefold elevation in NT-proBNP compared to the upper expected age and gender value. OR
    4. GLS>-15 5. Age ≥18 years 6. Signed informed consent

Exclusion Criteria:

  1. LVEF<50%
  2. Very severe AS defined as Vmax>5 m/s.
  3. Concomitant severe valvular disease other than AS
  4. Previous valvular surgery
  5. Estimated glomerular filtration rate<30 ml/min/m2
  6. Dementia
  7. Women of childbearing potential
  8. Inability to provide informed consent
  9. Age>85 years.
  10. Supravalvular or subvalvular AS
Contacts and Locations

Contacts
Layout table for location contacts
Contact: Jordi S Dahl, MD, PhD +4523823016 jordi.dahl@rsyd.dk
Contact: Jacob E Møller, MD, PhD jem@dadlnet.dk

Locations
Layout table for location information
Denmark
Odense University Hospital Recruiting
Odense, Fyn, Denmark, 5000
Contact: Jordi S Dahl, MD, Ph.D    23823016    jordi.dahl@rsyd.dk   
Sponsors and Collaborators
Odense University Hospital
Rigshospitalet, Denmark
Aarhus University Hospital
Aalborg University Hospital
Zealand University Hospital
Tracking Information
First Submitted Date  ICMJE May 31, 2019
First Posted Date  ICMJE June 3, 2019
Last Update Posted Date September 14, 2020
Actual Study Start Date  ICMJE January 1, 2020
Estimated Primary Completion Date September 1, 2029   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 9, 2020) 		all-cause mortality [ Time Frame: After 379 events (approx 5 years) ]
All-cause mortality assessed by Danish patient records
Original Primary Outcome Measures  ICMJE
 (submitted: May 31, 2019) 		all-cause mortality [ Time Frame: 5 years ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 9, 2020)
  • Combined endpoint [ Time Frame: After 379 events (approx 5 years) ]
    All-cause mortality + hospitalization due to heart failure and stroke
  • all-cause mortality in patients with low-gradient AS [ Time Frame: After 379 events (approx 5 years) ]
    All-cause mortality in patients with meangradient <40 mmHg
  • Combined endpoint in low-gradient AS [ Time Frame: After 379 events (approx 5 years) ]
    All-cause mortality + hospitalization to heart failure and stroke when MG<40 mmHg
Original Secondary Outcome Measures  ICMJE
 (submitted: May 31, 2019) 		Combined endpoint [ Time Frame: 5 years ]
All-cause mortality + hospitalization due to heart failure and stroke
Current Other Pre-specified Outcome Measures
 (submitted: May 31, 2019)
  • Pericardiocentesis [ Time Frame: 5 years ]
    Need of pericariocentesis
  • sternal infection [ Time Frame: 5 years ]
    hospitalization due to sternal infection
  • Persistent renal failure [ Time Frame: 5 years ]
    complete loss of renal function exceeding 4 weeks.
  • endocarditis [ Time Frame: 5-years ]
    hospitalization due to endocarditis
  • major bleeding [ Time Frame: 5 years ]
    intracerebral bleeding or bleeding resulting in substantial hemodynamic compromise requiring treatment instability
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Danish National Randomized Study on Early Aortic Valve Replacement in Patients With Asymptomatic Severe Aortic Stenosis
Official Title  ICMJE Danish National Randomized Study on Early Aortic Valve Replacement in Patients With Asymptomatic Severe Aortic Stenosis
Brief Summary The purpose of this study is to examine the impact of early surgery in patients with asymptomatic severe aortic valve stenosis with signs of subclinical LV dysfunction despite preserved LVEF, with a watchfull waiting approach.
Detailed Description

Since the seminal paper by Ross and Braunwald, the development of symptoms has been regarded as one of the most important precursors of a poor outcome in aortic stenosis (AS), and is today half a century later, still the leading reason for referral for aortic valve replacement (AVR). The development of symptoms is however often preceded by structural changes in the left ventricle (LV).These changes including concentric remodeling and LV hypertrophy have been regarded as compensative measures to adapt the LV to increased ventricular afterload. Although LV hypertrophy may preserve wall-stress in the normal range and increase contractility allowing the preservation of stroke volume, this occurs at the expense of increased filling pressures. Diastolic dysfunction with increased filling pressure lead to left atrial (LA) dilatation and significantly contributes to the development of symptoms.

Despite successful surgery, AS patients have increased long-term mortality and morbidity compared to the general population, and the outcome is largely determined by the degree of preoperative structural LV and LA alterations. This has led to the theory that AVR prior to the development of symptoms could improve outcome, a view supported by prospective and retrospective studies.These studies were however small, with some important limitations. In addition, there has been a concern that operative risk and prosthetic valve related long-term morbidity and mortality does not justify surgery on every asymptomatic patient with severe AS. Numerous studies have suggested that markers of LV structure and function, particularly LA volume index,E/e' and brain natriuretic peptides (BNP) all reflecting LV filling pressures may identify patients with benefit of early AVR. Accordingly, the most recent European guideline for management of valvular disease has implemented BNP as a class IIa recommendation for AVR in asymptomatic AS patients,although no randomized studies have demonstrated that early surgery based on these markers improve prognosis.

The purpose of this study is thus to evaluate if early AVR in patients with signs of elevated LV filling pressuresmay improve long-term outcome in patients with asymptomatic severe AS, compared to conventional symptom-guided surgery.
Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Aortic Valve Stenosis
  • Diastolic Dysfunction
Intervention  ICMJE Procedure: Aortic valve replacement
Open heart surgery or transcatheter surgery
Study Arms  ICMJE
  • Active Comparator: Early intervention
    Patients will undergo aortic valve replacement immediately
    Intervention: Procedure: Aortic valve replacement
  • No Intervention: Watchfull waiting
    Patients will be followed and treated as recommended by guidelines.
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: May 31, 2019) 		1700
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 1, 2029
Estimated Primary Completion Date September 1, 2029   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • 1. Severe AS defined as

    1. aortic valve area (AVA) ≤1 cm2, AND
    2. Transvalvular maximum velocity (Vmax) ≥3.5 m/s AND

    3. AS severity evaluated severe by a heart valve team conference. In cases where severity is not unambiguous an integrative approach will be utilized combining echocardiographic markers of valve severity and LV function, and if necessary aortic valve calcification estimated by non-contrast CT.

      2. Considered to be asymptomatic (estimated by a consultant in cardiology) 3. Considered to be candidate for AVR (transcatheter AVR/surgical AVR) 4. Sign of increased LV filling pressures18 or reduced longitudinal LV systolic function

    1. Left atrial volume index (LAVi) > 34 ml/m2; OR
    2. ratio of early diastolic peak mitral inflow velocity (E) to early mitral annulus diastolic velocity (e') ratio E/e'avg>13; OR
    3. Threefold elevation in NT-proBNP compared to the upper expected age and gender value. OR
    4. GLS>-15 5. Age ≥18 years 6. Signed informed consent

Exclusion Criteria:

  1. LVEF<50%
  2. Very severe AS defined as Vmax>5 m/s.
  3. Concomitant severe valvular disease other than AS
  4. Previous valvular surgery
  5. Estimated glomerular filtration rate<30 ml/min/m2
  6. Dementia
  7. Women of childbearing potential
  8. Inability to provide informed consent
  9. Age>85 years.
  10. Supravalvular or subvalvular AS
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 85 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Jordi S Dahl, MD, PhD +4523823016 jordi.dahl@rsyd.dk
Contact: Jacob E Møller, MD, PhD jem@dadlnet.dk
Listed Location Countries  ICMJE Denmark
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03972644
Other Study ID Numbers  ICMJE S-20190006
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Jordi Dahl, Odense University Hospital
Study Sponsor  ICMJE Odense University Hospital
Collaborators  ICMJE
  • Rigshospitalet, Denmark
  • Aarhus University Hospital
  • Aalborg University Hospital
  • Zealand University Hospital
Investigators  ICMJE Not Provided
PRS Account Odense University Hospital
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP

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