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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

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.


Condition or disease Intervention/treatment Phase
Aortic Valve Stenosis Cardiovascular Diseases Heart Diseases Heart Valve Diseases Ventricular Outflow Obstruction Device: Transcatheter aortic valve replacement Device: Surgical aortic valve replacement Not Applicable

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 992 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Outcomes Assessor)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : June 2016
Estimated Primary Completion Date : June 2020
Estimated Study Completion Date : June 2029

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Transcatheter aortic valve replacement
Transcatheter aortic valve replacement
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

Active Comparator: Surgical aortic valve replacement
Surgical aortic valve replacement
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




Primary Outcome Measures :
  1. Composite rate of all-cause mortality, myocardial infarction and stroke [ Time Frame: at one year post-procedural. ]
    VARC-2 definitions


Secondary Outcome Measures :
  1. 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

  2. Procedure time [ Time Frame: Intraoperative ]
  3. Duration of index hospitalization [ Time Frame: Number of days from admission to discharge (expected an averge of 7 days) ]
  4. 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

  5. Cardiovascular mortality [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions

  6. Stroke or TIA [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions

  7. 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

  8. Vascular complication (major or minor) [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 defintions

  9. 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

  10. 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

  11. NYHA functional class [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
  12. Need for permanent pacemaker [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
    VARC-2 definitions

  13. 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

  14. 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

  15. Left ventricle remodeling as assesed by echocardiography [ Time Frame: at 30 days, 1 year and annually thereafter up to 10 years post-procedure ]
  16. 1-year overall costs in both treatment arms. [ Time Frame: 1 year ]
  17. Duration of stay on ICU after index procedure. [ Time Frame: Number of days from procedure to discharge from ICU ]
  18. 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

  19. 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

  20. 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



Information from the National Library of Medicine

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, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

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): NCT02825134


Contacts
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Contact: Lars Søndergaard, MD; DMSc Lars.Soendergaard.01@regionh.dk

Locations
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Denmark
Rigshospitalet, Copenhagen University Hospital Recruiting
Copenhagen, Denmark, 2100
Contact: Lars Søndergaard       Lars.Soendergaard.01@regionh.dk   
Contact: Peter S Olsen       Peter.Skov.Olsen@regionh.dk   
Odense University Hospital Not yet recruiting
Odense, Denmark, 5000
Contact: Henrik Nissen       henrik.nissen@rsyd.dk   
Contact: Bo Kjeldsen       bo.kjeldsen@rsyd.dk   
Aalborg University Hospital Not yet recruiting
Ålborg, Denmark, 9100
Contact: Jan Ravnkilde       jan.ravkilde@rn.dk   
Contact: Jørn Sollid       joas@rn.dk   
Aarhus University hospital Recruiting
Århus, Denmark, 8000
Contact: Evald H Christiansen       evalchri@rm.dk   
Contact: Kaj Erik Klaaborg       kajklaab@rm.dk   
Finland
Helsinki University Central Hospital Recruiting
Helsinki, Finland, FI00029
Contact: Mika Laine       mika.laine@hus.fi   
Kuopio University Hospital Not yet recruiting
Kuopio, Finland, 70210
Contact: Heikki Miettinen       heikki.miettinen@kuh.fi   
Contact: Martin Maaroos       martin.maaroos@kuh.fi   
Oulu University Hospital Recruiting
Oulu, Finland, 90220
Contact: Timo Mäkikallio       timo.makikallio@ppshp.fi   
Contact: Vesa Anttila       vesa.anttila@ppshp.fi   
Tampere University Hospital Not yet recruiting
Tampere, Finland, 33521
Contact: Markku Eskola       markku.eskola@sydansairaala.fi   
Contact: Pasi Maaranen       pasi.maaranen@sydanairaala.fi   
Turku University Hospital Recruiting
Turku, Finland, 20520
Contact: Mikko Savotaus       mikko.savontaus@tyks.fi   
Contact: Markus Malmberg       markus.malmberg@tyks.fi   
Iceland
Landspital Recruiting
Reykjavík, Iceland, 101
Contact: Ingibjörg J Gudmundsdóttir       ig@landspitali.is   
Norway
Haukeland University Hospital Recruiting
Bergen, Norway, 5021
Contact: Öjvind Bleie       oyvind.bleie@helse-bergen.no   
Contact: Rune Haaverstad       rune.haaverstad@helse-bergen.no   
Feiring Klinikkene Not yet recruiting
Feiring, Norway, 2093
Contact: Yngvar Myreng       yngvar.myreng@feiringklinikken.no   
Contact: Stein-Erik Rynning       stein.rynning@feiringklinikken.no   
Oslo University Hospital Recruiting
Oslo, Norway, 2009
Contact: Lars Aaberge       laraabe@ous-hf.no   
Contact: Kjell-Arne Rein       kjrein@ous-hf.no   
University Hospital of North Norway Not yet recruiting
Tromsø, Norway, 9019
Contact: Terje Steigen       terje.steigen@unn.no   
Contact: Rolf Busund       rolf.busund@unn.no   
St. Olav's University Hospital Not yet recruiting
Trondheim, Norway, 7030
Contact: Knut Hegbom       knut.hegbom@stolav.no   
Contact: Peder Kvitting       peder.kvitting@helse-bergen.no   
Sweden
Sahlgrenska University Hospital Not yet recruiting
Göteborg, Sweden, 413 45
Contact: Truls Råmunddal       Truls.Ramunddal@wlab.gu.se   
Linköping University Hospital Not yet recruiting
Linköping, Sweden, 581 85
Contact: Niels Erik Nielsen       niels-erik.nielsen@regionostergotland.se   
Contact: Henrik Ahn       henrik.ahn@regionostergotland.se   
Skåne University Hospital Not yet recruiting
Lund, Sweden, 222 41
Contact: Matthias Götberg       matthias.gotberg@skane.se   
Contact: Henrik Bjursten       henrik.bjursten@skane.se   
Karolinska University Hospital Recruiting
Stockholm, Sweden, 171 76
Contact: Andreas Rück       andreas.ruck@karolinska.se   
Contact: Göran Källner       goran.kallner@karolinska.se   
University hospital of Umeå Not yet recruiting
Umeå, Sweden, 901 85
Contact: Johan Nilsson       johan.nilsson@vll.se   
Contact: Anne-Marie N Grenholm       annemarie.grenholm@vll.se   
Uppsala University Hospital Not yet recruiting
Uppsala, Sweden, 751 85
Contact: Stefan James       stefan.james@ucr.uu.se   
Contact: Anders Jönsson       anders.jonsson@ucr.uu.se   
Örebro University Hospital Not yet recruiting
Örebro, Sweden, 701 85
Contact: Thomas Kellerth       thomas.kellerth@orebroll.se   
Contact: Örjan Friberg       orjan.friberg@orebroll.se   
Sponsors and Collaborators
Rigshospitalet, Denmark
Symetis SA
Boston Scientific Corporation
Abbott
Investigators
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Principal Investigator: Lars Søndergaard, MD; DMSc Rigshospitalet, Denmark
Principal Investigator: Peter S Olsen Rigshospitalet, Denmark

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Responsible Party: Lars Soendergaard, Professor of cardiology Lars Søndergaard; MD, DMSc, Rigshospitalet, Denmark
ClinicalTrials.gov Identifier: NCT02825134     History of Changes
Other Study ID Numbers: H-15019580
First Posted: July 7, 2016    Key Record Dates
Last Update Posted: October 18, 2018
Last Verified: October 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Lars Soendergaard, Rigshospitalet, Denmark:
heart valve disease
valvular bioprosthesis
aortic valve replacement
Randomized clinical trial
Additional relevant MeSH terms:
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Heart Diseases
Aortic Valve Stenosis
Heart Valve Diseases
Ventricular Outflow Obstruction
Constriction, Pathologic
Cardiovascular Diseases
Pathological Conditions, Anatomical