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

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ClinicalTrials.gov Identifier: NCT03972644
Recruitment Status : Recruiting
First Posted : June 3, 2019
Last Update Posted : September 14, 2020
Sponsor:
Collaborators:
Rigshospitalet, Denmark
Aarhus University Hospital
Aalborg University Hospital
Zealand University Hospital
Information provided by (Responsible Party):
Jordi Dahl, Odense University Hospital

Study Description
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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
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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

Resource links provided by the National Library of Medicine


Arms and Interventions
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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
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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
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Information from the National Library of Medicine

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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
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03972644


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

Locations
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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
More Information
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Responsible Party: Jordi Dahl, Associate Professor, MD, Ph.D., Odense University Hospital
ClinicalTrials.gov Identifier: NCT03972644    
Other Study ID Numbers: S-20190006
First Posted: June 3, 2019    Key Record Dates
Last Update Posted: September 14, 2020
Last Verified: September 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Aortic Valve Stenosis
Constriction, Pathologic
Pathological Conditions, Anatomical
Aortic Valve Disease
 Heart Valve Diseases
Heart Diseases
Cardiovascular Diseases
Ventricular Outflow Obstruction