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Comparison of Transcatheter Versus Surgical Aortic Valve Replacement in Younger Low Surgical Risk Patients With Severe Aortic Stenosis (NOTION-2)

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ClinicalTrials.gov Identifier: NCT02825134
Recruitment Status : Recruiting
First Posted : July 7, 2016
Last Update Posted : October 18, 2018
Sponsor:
Collaborators:
Symetis SA
Boston Scientific Corporation
Abbott
Information provided by (Responsible Party):
Lars Soendergaard, Rigshospitalet, Denmark

Tracking Information
First Submitted Date  ICMJE June 29, 2016
First Posted Date  ICMJE July 7, 2016
Last Update Posted Date October 18, 2018
Study Start Date  ICMJE June 2016
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2016)
Composite rate of all-cause mortality, myocardial infarction and stroke [ Time Frame: at one year post-procedural. ]
VARC-2 definitions
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 16, 2018)
  • Device success (Absence of procedural mortality, correct positioning of a single valve into the proper anatomical location AND intended performanace of the prosthetic heart valve) [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions
  • Procedure time [ Time Frame: Intraoperative ]
  • Duration of index hospitalization [ Time Frame: Number of days from admission to discharge (expected an averge of 7 days) ]
  • Composite rate of all-cause mortality, myocardial infarction and stroke [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions
  • Cardiovascular mortality [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions
  • Stroke or TIA [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions
  • Bleeding (life-threatening, major or minor) [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions
  • Vascular complication (major or minor) [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 defintions
  • Acute kidney injury (stage 1, 2 or 3) [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 defintions
  • Echocardiographic aortic bioprosthesis performance (degree of paravalvular leakage, valve area, mean gradient) [ Time Frame: Before discharge from index hospitalization (expected an average of 7 days), at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions
  • NYHA functional class [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
  • Need for permanent pacemaker [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions
  • New onset atrial fibrillation captured on ECG [ Time Frame: Within discharge from index hospitalization (expected an average of 7 days), at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions
  • Time-related valve safety (echocardiographic structural valve deterioration, prosthetic valve endocarditis, prosthetic valve thrombosis, thrombo-embolic events OR VARC bleeding) [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions
  • Left ventricle remodeling as assesed by echocardiography [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
  • 1-year overall costs in both treatment arms. [ Time Frame: 1 year ]
  • Duration of stay on ICU after index procedure. [ Time Frame: Number of days from procedure to discharge from ICU ]
  • Incidence of early safety (all-cause mortality, all-stroke, life-threatening bleeding, acute kidney injury, coronary artery obstruction requiring intervention, Major vascular complication OR valve-related dysfunction requiring repeat procedure) [ Time Frame: at 30 days from index procedure ]
    VARC-II definitions
  • Clinical efficacy (all-cause mortality, all stroke, requiring hospitalization for valve-related symptoms or worsening congestive heart failure, NYHA class III or IV OR echocardiographic valve-related dysfunction) [ Time Frame: After 30 days of index procedure ]
    VARC-II definitions
  • Quality of life change from baseline [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    assesed by SF-36v2, EQ-5d and KCCQ
Original Secondary Outcome Measures  ICMJE
 (submitted: July 3, 2016)
  • Device success (Absence of procedural mortality, correct positioning of a single valve into the proper anatomical location AND intended performanace of the prosthetic heart valve) [ Time Frame: at 30 days, 1, 2, 3, 4 and 5 years post-procedural. ]
    VARC-2 definitions
  • Procedure time [ Time Frame: Intraoperative ]
  • Duration of index hospitalization [ Time Frame: Number of days from admission to discharge (expected an averge of 7 days) ]
  • Composite rate of all-cause mortality, myocardial infarction and stroke [ Time Frame: at 30 days, 2, 3, 4 and 5 years post-procedural. ]
    VARC-2 definitions
  • Cardiovascular mortality [ Time Frame: at 30 days, 1, 2, 3, 4 and 5 years post-procedural. ]
    VARC-2 definitions
  • Stroke or TIA [ Time Frame: at 30 days, 1, 2, 3, 4 and 5 years post-procedural. ]
    VARC-2 definitions
  • Bleeding (life-threatening, major or minor) [ Time Frame: at 30 days, 1, 2, 3, 4 and 5 years post-procedural. ]
    VARC-2 definitions
  • Vascular complication (major or minor) [ Time Frame: at 30 days, 1, 2, 3, 4 and 5 years post-procedural. ]
    VARC-2 defintions
  • Acute kidney injury (stage 1, 2 or 3) [ Time Frame: at 30 days, 1, 2, 3, 4 and 5 years post-procedural. ]
    VARC-2 defintions
  • Echocardiographic aortic bioprosthesis performance (degree of paravalvular leakage, valve area, mean gradient) [ Time Frame: Before discharge from index hospitalization (expected an average of 7 days), 3 months, 1, 2, 3, 4 and 5 years post-procedural. ]
    VARC-2 definitions
  • NYHA functional class [ Time Frame: at 30 days, 1, 2, 3, 4 and 5 years post-procedural. ]
  • Need for permanent pacemaker [ Time Frame: at 30 days, 1, 2, 3, 4 and 5 years post-procedural. ]
    VARC-2 definitions
  • New onset atrial fibrillation captured on ECG [ Time Frame: Within discharge from index hospitalization (expected an average of 7 days), 30 days, 1, 2, 3, 4 and 5 years post-procedural. ]
    VARC-2 definitions
  • Time-related valve safety (echocardiographic structural valve deterioration, prosthetic valve endocarditis, prosthetic valve thrombosis, thrombo-embolic events OR VARC bleeding) [ Time Frame: at 30 days, 1, 2, 3, 4 and 5 years post-procedural ]
    VARC-2 definitions
  • Left ventricle remodeling as assesed by echocardiography [ Time Frame: at 30 days, 1, 2, 3, 4 and years post-procedural. ]
  • 1-year overall costs in both treatment arms. [ Time Frame: 1 year ]
  • Duration of stay on ICU after index procedure. [ Time Frame: Number of days from procedure to discharge from ICU ]
  • Incidence of early safety (all-cause mortality, all-stroke, life-threatening bleeding, acute kidney injury, coronary artery obstruction requiring intervention, Major vascular complication OR valve-related dysfunction requiring repeat procedure) [ Time Frame: at 30 days from index procedure ]
    VARC-II definitions
  • Clinical efficacy (all-cause mortality, all stroke, requiring hospitalization for valve-related symptoms or worsening congestive heart failure, NYHA class III or IV OR echocardiographic valve-related dysfunction) [ Time Frame: After 30 days of index procedure ]
    VARC-II definitions
  • Quality of life change from baseline [ Time Frame: at 30 days, 1, 2, 3, 4 and years post-procedural. ]
    assesed by SF-36v2, EQ-5d and KCCQ
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Comparison of Transcatheter Versus Surgical Aortic Valve Replacement in Younger Low Surgical Risk Patients With Severe Aortic Stenosis
Official Title  ICMJE Nordic Aortic Valve Intervention Trial 2 - A Randomized Multicenter Comparison of Transcatheter Versus Surgical Aortic Valve Replacement in Younger Low Surgical Risk Patients With Severe Aortic Stenosis
Brief Summary

A randomized clinical trial investigating transcatheter (TAVR) versus surgical (SAVR) aortic valve replacement in patients 75 years of age or younger suffering from severe aortic valve stenosis.

Study hypothesis: The clinical outcome (composite endpoint of all-cause mortality, MI and stroke) obtained within 1 year after TAVR is non-inferior to SAVR.

Detailed Description

BACKGROUND: Acquired aortic valve stenosis (AS) is the most common heart valve disease in the Western World with a prevalence of 2-7% at the age of >65 years. If untreated, it may lead to heart failure and death. Surgical aortic valve replacement (SAVR) until recent years has been the definitive treatment for patients with severe symptomatic AS. A less invasive transcatheter aortic valve replacement (TAVR) has been developed and has been a treatment of choice mostly for elderly high risk or inoperable patients. As TAVR technology is continuously evolving and improving, it may be anticipated that it will become a valuable alternative - and even the preferred choice of treatment - for younger, low-risk patients with severe aortic valve stenosis in the near future. However, to date, there is no clinical evidence that supports this hypothesis.

AIM: The purpose of the study is to compare TAVR and SAVR with regard to the intra- and post-procedural morbidity and mortality rate, hospitalization length, functional capacity, quality of life, and valvular prosthesis function in younger, low risk patients with severe AS, scheduled for aortic valve replacement.

POPULATION: Younger low risk patients with severe aortic valve stenosis, which are scheduled for aortic valve replacement using a bioprosthesis. Subjects fulfilling the inclusion criteria, not having any exclusion criteria, and consenting to the trial will be randomized 1:1 to TAVR or SAVR with 496 patients in each group.

DESIGN: The study is a randomized clinical multicenter trial. Central randomization with variable block size and stratification by gender and coronary comorbidity will be used. An independent event committee blinded to treatment allocation will adjudicate safety endpoints. Interim analysis is planned after the first 20 events included in the primary end-point (all-cause mortality, stroke or myocardial infarction).

INTERVENTIONS:

TAVR: Any CE-Mark approved transcatheter aortic bioprosthesis may be used in the study, and the choice is at the discretion of the local TAVR team. The transfemoral TAVR procedure may be performed under general anaesthesia, local anaesthesia/conscious sedation, or local anesthesia. Percutaneous coronary intervention (PCI) can be performed up to 30 days prior to TAVR or as a hybrid procedure.

SAVR: The surgical SAVR technique follows standard protocol of the local department of cardio-thoracic surgery. The operation is performed under general anesthesia, which follows standard protocol of the department of anesthesiology. A commercial available surgical aortic bioprosthesis at the surgeons discretion will be implanted. Concomitant coronary artery bypass graft (CABG) surgery may be performed.

END POINTS: The primary endpoint is the composite rate of all-cause mortality death, myocardial infarction and stroke within one year after the procedure (VARC-2 defintions). Secondary endpoints are listed below. Follow-up will be performed after 30 days, 3 months, 1 year and yearly thereafter for a minimum of 5 years.

Study Type  ICMJE Interventional
Study Phase  ICMJE Not Applicable
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE
  • Aortic Valve Stenosis
  • Cardiovascular Diseases
  • Heart Diseases
  • Heart Valve Diseases
  • Ventricular Outflow Obstruction
Intervention  ICMJE
  • Device: Transcatheter aortic valve replacement
    Retrograde transfemoral transcatheter aortic valve replacement with any CE mark approved aortic bioprosthesis with or without concomitant percutaneous coronary intervention.
    Other Names:
    • Transcatheter aortic valve implantation
    • TAVR
    • TAVI
  • Device: Surgical aortic valve replacement
    Conventional surgical aortic valve replacement with a bioprosthesis using normothermic cardiopulmonary bypass and cold blood cardioplegia cardiac arrest with or without concomitant coronary artery bypass graft surgery.
    Other Name: SAVR
Study Arms  ICMJE
  • Experimental: Transcatheter aortic valve replacement
    Transcatheter aortic valve replacement
    Intervention: Device: Transcatheter aortic valve replacement
  • Active Comparator: Surgical aortic valve replacement
    Surgical aortic valve replacement
    Intervention: Device: Surgical aortic valve replacement
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: July 3, 2016)
992
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE June 2029
Estimated Primary Completion Date June 2020   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Age 75 years or younger.
  • Severe calcific AS (Valve area <1cm2 (or <0.6 cm2/m2) AND one of the two following criteria: mean gradient >40mmHg or peak jet velocity >4.0m/s, OR in presence of low flow, low gradient with reduced or normal LVEF<50%, a dobutamine stress echo should verify true severe AS rather than pseudo-AS
  • Symptomatic with angina pectoris, dyspnea or exercise-induced syncope or near syncope OR asymptomatic with abnormal exercise test showing symptoms on exercise clearly related to AS or systolic LV dysfunction (LVEF <50%) not due to another cause.
  • Anticipated usage of biological aortic valve prosthesis.
  • Low risk for conventional surgery (STS Score <4%).
  • Suitable for both SAVR and transfemoral TAVR.
  • Life expectancy >1 year after the intervention.
  • Informed consent to participate in the study after adequate information about the study before randomization and intervention.

Exclusion Criteria:

  • Coronary artery disease, not suitable for both percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG).
  • Coronary angiogram with a SYNTAX-score >22.
  • LVEF <25% without contractile reserve during dobutamine stress echocardiography.
  • Porcelain aorta, which prevents open-heart surgery.
  • Bicuspid valve with aorta ascendens diameter ≥45mm
  • Severe femoral, iliac or aortic atherosclerosis, calcification, coarctation, aneurysm or tortuosity, which prevents transfemoral TAVR.
  • Need for open heart surgery other than SAVR with or without CABG.
  • Myocardial infarction within last 30 days
  • Stroke or TIA within the last 30 days. NOTION-2, 01. February 2017, version 5 9
  • Current endocarditis, intracardiac tumor, thrombus or vegetation.
  • Ongoing severe infection requiring intravenous antibiotics.
  • Unstable pre-procedural condition requiring intravenous inotropes or mechanical assist device (IABP, Impella) on the day of intervention.
  • Kidney disease requiring dialysis or severely impaired lung function (FEV1 and/or diffusion capacity <40% of predicted).
  • Allergy to heparin, iodid contrast agent, warfarin, aspirin or clopidogrel.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 75 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Lars Søndergaard, MD; DMSc Lars.Soendergaard.01@regionh.dk
Listed Location Countries  ICMJE Denmark,   Finland,   Iceland,   Norway,   Sweden
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02825134
Other Study ID Numbers  ICMJE H-15019580
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Lars Soendergaard, Rigshospitalet, Denmark
Study Sponsor  ICMJE Rigshospitalet, Denmark
Collaborators  ICMJE
  • Symetis SA
  • Boston Scientific Corporation
  • Abbott
Investigators  ICMJE
Principal Investigator: Lars Søndergaard, MD; DMSc Rigshospitalet, Denmark
Principal Investigator: Peter S Olsen Rigshospitalet, Denmark
PRS Account Rigshospitalet, Denmark
Verification Date October 2018

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