Safety and Efficacy of the Symetis ACURATE Neo/TF Compared to the Edwards SAPIEN 3 Bioprosthesis.

Aortic Valve Stenosis Clinical Trial

— SCOPE I  

Official title:

Safety and Efficacy of the Symetis ACURATE Neo/TF Compared to the Edwards SAPIEN 3 Bioprosthesis for Transcatheter Aortic Valve Implantation by Transfemoral Approach.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03011346
• Other study ID #: V 4.0, 13.08.2018
• Status: Completed
• Phase: N/A
• Start date: February 8, 2017
• Est. completion date: February 16, 2022

Study information

• Verified date: March 2022
• Source: University Hospital Inselspital, Berne
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Transcatheter aortic valve implantation (TAVI) is an established treatment option for patients with severe symptomatic aortic stenosis and at increased risk for surgical aortic valve replacement (SAVR). Many novel devices are currently being developed and established transcatheter heart valves undergo design reiterations to address limitations and reduce complication rates associated with the device and implantation procedure. However, device comparisons by use of randomized trials are scarce in particular for newer generation transcatheter valves. The aim of this study is to assess non-inferiority of the self-expandable Symetis ACURATE neo/TF in comparison to the balloon-expandable Edwards SAPIEN 3 transcatheter aortic valve bioprosthesis with regard to early safety and clinical efficacy at 30 days.

Description:

Background:

Transcatheter aortic valve implantation (TAVI) is an established and valuable treatment option for patients with severe symptomatic aortic stenosis and at increased risk for surgical aortic valve replacement (SAVR). The use of TAVI is rapidly expanding worldwide and the indications for TAVI are widening into lower risk populations in view of favorable outcomes among high and intermediate risk patients. Many novel devices are currently developed or established devices undergo design reiterations to address limitations, such as vascular access complications, paravalvular regurgitation, and atrio-ventricular conductance disturbances. However, device comparisons by use of randomized trials are scarce in particular for newer generation transcatheter valves.

The Symetis ACURATE neo/TF, a self-expandable transcatheter valve delivered via transfemoral access, gained Conformité Européenne (CE) marking in September 2014 after showing favorable procedural and short term results. The SCOPE I trial will compare its performance to the balloon-expandable Edwards SAPIEN 3, a widely used and well-established transcatheter heart valve of the second generation, in a randomized fashion.

Objectives:

The primary objective is the comparison of the Symetis ACURATE neo/TF to the Edwards SAPIEN 3 transcatheter aortic bioprosthesis with regard to early safety and clinical efficacy at 30 days. Secondary objectives involve the comparison between the two devices with regard to secondary clinical and echocardiographic endpoints at 30 days, 1 year and 3 years.

Methods:

Sample Size: Based on an anticipated incidence proportion of 22% for the primary non-hierarchical composite endpoint at 30 days in both treatment arms, a non-inferiority margin of 7.7%, a power of 80%, a one-tailed significance level of α = 0.05, and a low attrition rate, the total required sample size amounts to 730 patients.

Design: Patients will be allocated to the Symetis ACURATE neo/TF or the Edwards SAPIEN 3 bioprosthesis at a 1:1 ratio by means of a randomly permuted block randomisation stratified on study center and Society of Thoracic Surgeons' predicted risk of mortality score (STS-PROM) strata (< 3%, ≥ 3 to < 8%, ≥ 8%).

Analysis: Estimates of the risk-differences between the two treatment arms with regard to the primary endpoint will be pooled over the predefined STS-PROM strata by means of the Cochran-Mantel-Haenszel method and Wald-type confidence limits will be calculated using the Sato variance estimator. The non-inferiority assumption will be tested at a one-sided significance level with a type I error rate (α) = 0.05. The analysis of the primary composite endpoint will be conducted according to the intention-to-treat (ITT) and the per protocol (PP) principle and non-inferiority should be claimed only if met by both.

In case non-inferiority is established, a superiority analysis will be performed using a two-tailed significance level with a type I error rate of α = 0.05. Further secondary analyses will evaluate between group differences in relation to demographic, clinical, procedural, functional and imaging characteristics. Pre-specified subgroup analyses will be conducted by use of appropriate interaction tests contrasting categories of sex, STS-PROM score (< 3%, ≥ 3 to < 8%, ≥ 8%), left ventricular ejection fraction (< 50% vs. ≥ 50%), and native aortic valve eccentricity index (≤ 0.25 vs. > 0.25).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 739
• Est. completion date: February 16, 2022
• Est. primary completion date: May 2, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 75 Years and older

Eligibility

Inclusion Criteria:

• Patient with severe aortic stenosis defined by an aortic valve area (AVA) < 1cm2 or AVA indexed to body surface area (BSA) of < 0.6 cm2/m2, including low-flow severe aortic stenosis defined by stroke volume index (SVI) < 35ml/m2, as assessed by integration of echocardiographic and invasive measurements

• Subject is symptomatic (heart failure symptoms with New York Heart Association (NYHA) Functional Class > I, angina or syncope)

• Patient is considered at increased risk for mortality if undergoing conventional surgical aortic valve replacement or judged as not operable as determined either

• by a Logistic EuroSCORE > 20 % OR

• by a STS-PROM score > 10% OR

• by the heart team consisting of at least one cardiologist and cardiac surgeon based on the integration of individual clinical and anatomical factors not captured by risk-scores, the patient's age, frailty and life-expectancy

• The heart team agrees on eligibility of the patient for participation and that TAVI by transfemoral access constitutes the most appropriate treatment modality, from which the patient will likely benefit most

• Aortic annulus dimensions suitable for both valve types (area range: 338-573 mm2 AND perimeter range: 66-85 mm) based on ECG-gated multislice computed tomographic measurements. Findings of transesophageal echocardiography (TEE) and conventional aortography should be integrated in the anatomic assessment if available

• Arterial aorto-iliac-femoral axis suitable for transfemoral access with a minimum access vessel diameter = 6 mm as assessed by multislice computed tomographic angiography and/or conventional angiography

• Written informed consent of the patient or her/his legal representative

• Patient understands the purpose, the potential risks as well as benefits of the trial and is willing to participate in all parts of the follow-up

Exclusion Criteria:

• Non-valvular aortic stenosis

• Congenital aortic stenosis or unicuspid or bicuspid aortic valve

• Non-calcific acquired aortic stenosis

• Anatomy not appropriate for transfemoral transcatheter aortic valve implantation due to size of the aortic annulus or degree or eccentricity of calcification of the native aortic valve or tortuosity of the aorta or ilio-femoral arteries

• Emergency procedure including patients in cardiogenic shock (low cardiac output, vasopressor dependence, mechanical hemodynamic support)

• Severely reduced left ventricular (LV) function (ejection fraction < 20%)

• Pre-existing prosthetic heart valve in aortic position

• Presence of mitral valve prosthesis

• Concomitant planned procedure except for percutaneous coronary intervention (PCI)

• Planned non-cardiac surgery within 30 days

• Stroke within 30 days of the procedure.

• Myocardial infarction within 30 days of the procedure (except type 2)

• Evidence of intra-cardiac mass, thrombus or vegetation

• Severe coagulation conditions

• Inability to tolerate anticoagulation/anti-platelet therapy

• Active bacterial endocarditis or other active infections

• Hypertrophic cardiomyopathy with or without obstruction

• Contraindication to contrast media or allergy to nitinol

• Participation in another trial, which would lead to deviations in the preparation or performance of the intervention or the post-implantation management from this protocol

Related Conditions & MeSH terms

• Aortic Valve Stenosis

Intervention

Device:
• Symetis ACURATE neo/TF transfemoral TAVI system
Transcatheter aortic valve implantation of a Symetis ACURATE neo/TF bioprosthesis by transfemoral access, pre-dilatation mandatory.
• Edwards Sapien 3 Transcatheter Heart Valve
Transcatheter aortic valve implantation of an Edwards Sapien 3 bioprosthesis by transfemoral access.

Locations

Country	Name	City	State
Germany	Klinkum Augsburg	Augsburg
Germany	Zentralklinik Bad Berka	Bad Berka
Germany	Herz- und Gefässzentrum Bad Beversen	Bad Bevensen
Germany	Kerckhoff-Klinik	Bad Nauheim
Germany	Herz- und Gefäss-Klinik GmbH Bad Neustadt	Bad Neustadt An Der Saale	Bad Neustadt
Germany	St.-Johannes-Hospital	Dortmund
Germany	Herzzentrum Dresden	Dresden
Germany	Universitäres Herzzentrum Hamburg GmbH	Hamburg
Germany	Klinik für Herzchirurgie Karlsruhe	Karlsruhe
Germany	Städtisches Klinikum Karlsruhe	Karlsruhe
Germany	ViDia Kliniken	Karlsruhe
Germany	Herzzentrum Uniklinik Köln	Köln
Germany	Herzzentrum Leipzig	Leipzig
Germany	Deutsches Herzzentrum München	München
Germany	Klinik und Poliklinik für Herz-, Thorax- und herznahe Gefäßchirurgie	Regensburg
Netherlands	University Medical Center Utrecht	Utrecht
Switzerland	Bern University Hospital	Bern
Switzerland	Luzerner Kantonsspital	Luzern
Switzerland	Universitätsspital Zürich	Zürich
United Kingdom	St Thomas' Hospital	London

Sponsors (1)

Lead Sponsor	Collaborator
University Hospital Inselspital, Berne

Countries where clinical trial is conducted

Germany,  Netherlands,  Switzerland,  United Kingdom, 

References & Publications (1)

Lanz J, Kim WK, Walther T, Burgdorf C, Möllmann H, Linke A, Redwood S, Thilo C, Hilker M, Joner M, Thiele H, Conzelmann L, Conradi L, Kerber S, Schymik G, Prendergast B, Husser O, Stortecky S, Heg D, Jüni P, Windecker S, Pilgrim T; SCOPE I investigators. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Modified* combined early safety and clinical efficacy as defined by the Valve Academic Research Consortium-2 (VARC-2)	(* "NYHA class III or IV" is omitted due to lack of objectiveness in its ascertainment); All-cause mortality; All stroke (disabling and non-disabling); Life-threatening or disabling bleeding; Acute kidney injury (stage 2 or 3, including renal replacement therapy); Coronary artery obstruction requiring intervention; Major vascular complication; Valve related dysfunction requiring repeat procedure (balloon aortic valvuloplasty, TAVI or SAVR in a separate intervention); Rehospitalization for valve-related symptoms or worsening congestive heart failure; Valve-related dysfunction: prosthetic aortic valve stenosis (mean gradient = 20 mmHg, effective orifice area = 0.9-1.1cm2 and/or Doppler velocity index < 0.35) AND/OR = moderate prosthetic valve regurgitation)	30 days
Secondary	Device success	Combined endpoint composed of: Absence of procedural mortality AND; Correct positioning of a single prosthetic heart valve into the proper anatomical location AND; Intended performance of the prosthetic heart valve (no prosthesis-patient mismatch and mean aortic valve gradient < 20 mmHg or peak velocity < 3 m/s, AND no moderate or severe prosthetic valve regurgitation)	30 days
Secondary	Early safety	Combined endpoint composed of: All-cause mortality; All stroke (disabling and non-disabling); Life-threatening or disabling bleeding; Acute kidney injury - stage 2 or 3 (including renal replacement therapy); Coronary artery obstruction requiring intervention; Major vascular complication; Valve-related dysfunction requiring repeat procedure (balloon aortic valvuloplasty, TAVI, or SAVR)	30 days
Secondary	Clinical efficacy	Combined endpoint composed of: All-cause mortality; All stroke (disabling and non-disabling); Requiring hospitalizations for valve-related symptoms or worsening congestive heart failure; NYHA class III or IV; Valve-related dysfunction (mean aortic valve gradient = 20 mmHg, effective orifice area (EOA) = 0.9-1.1 cm2 and/or Doppler velocity index (DVI) < 0. 35 m/s, AND/OR moderate or severe prosthetic valve regurgitation)	30 days
Secondary	Time-related valve safety	Combined endpoint composed of: Structural valve deterioration (Valve-related dysfunction (mean aortic valve gradient = 20 mmHg, EOA = 0.9-1.1 cm2 (depending on body surface area (BSA)) and/or DVI < 0.35 m/s AND/OR moderate or severe prosthetic valve regurgitation)) OR Requiring repeat procedure (TAVI or SAVR); Prosthetic valve endocarditis; Prosthetic valve thrombosis; Thrombo-embolic events (e.g. stroke); VARC bleeding, unless clearly unrelated to valve therapy (e.g. trauma)	30 days, 1 year
Secondary	All-cause mortality		30 days, 1 year, 3 years
Secondary	All stroke (disabling and non-disabling)		30 days, 1 year, 3 years
Secondary	Life-threatening or disabling bleeding	Fatal bleeding (Bleeding Academic Research Consortium (BARC) type 5)OR; Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome (BARC type 3b and 3c) OR; Bleeding causing hypovolaemic shock or severe hypotension requiring vasopressors or surgery (BARC type 3b) OR; Overt source of bleeding with drop in haemoglobin =5 g/dL or whole blood or packed red blood cells (RBCs) transfusion =4 units (BARC type 3b)	30 days, 1 year, 3 years
Secondary	Acute kidney injury (stage 2 or 3, including renal replacement therapy)	Stage 2: Increase in serum creatinine to 200-299% (2.0-2.99 × increase compared with baseline) OR Urine output <0.5 mL/kg/h for >12 but <24 h; Stage 3: Increase in serum creatinine to =300% (>3 × increase compared with baseline) OR serum creatinine of =4.0 mg/dL (=354 mmol/L) with an acute increase of at least 0.5 mg/dL (44 mmol/L) OR Urine output <0.3 ml/kg/h for =24 h OR Anuria for =12 h Notes: The increase in creatinine must occur within 48 h. Patients receiving renal replacement therapy are considered to meet Stage 3 criteria irrespective of other criteria.	30 days, 1 year, 3 years
Secondary	Coronary artery obstruction requiring intervention		30 days, 1 year, 3 years
Secondary	Major vascular complication	Aortic dissection, aortic rupture, annulus rupture, left ventricle perforation, or new apical aneurysm/pseudo-aneurysm OR; Access-related vascular injury (dissection, stenosis, perforation, rupture, arterio-venous fistula, pseudoaneurysm, haematoma, irreversible nerve injury, compartment syndrome, percutaneous closure device failure) leading to death, life-threatening or major bleeding, visceral ischaemia, or neurological impairment OR; Distal embolization (non-cerebral) from a vascular source requiring surgery or resulting in amputation or irreversible end-organ damage OR; Use of unplanned endovascular or surgical intervention associated with death, major bleeding, visceral ischaemia or neurological impairment OR; Any new ipsilateral lower extremity ischaemia documented by patient symptoms, physical exam, and/or decreased or absent blood flow on lower extremity angiogram OR; Surgery for access site-related nerve injury OR; Permanent access site-related nerve injury	30 days, 1 year, 3 years
Secondary	Valve related dysfunction requiring repeat procedure (balloon aortic valvuloplasty, TAVI or SAVR in a separate intervention)		30 days, 1 year, 3 years
Secondary	Rehospitalization for valve-related symptoms or worsening congestive heart failure		30 days, 1 year, 3 years
Secondary	Valve-related dysfunction: prosthetic aortic valve stenosis AND/OR = moderate prosthetic valve regurgitation	Prosthetic aortic valve stenosis: mean gradient = 20 mmHg, EOA = 0.9-1.1cm2 and/or DVI < 0.35)	30 days, 1 year, 3 years
Secondary	Conversion to open heart surgery		procedural
Secondary	Annular rupture		procedural
Secondary	New pacemaker implantation		30 days, 1 year, 3 years
Secondary	Valve thrombosis	Any thrombus attached to or near an implanted valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently large to warrant treatment. Note that valve-associated thrombus identified at autopsy in a patient whose cause of death was not valve-related should not be reported as valve thrombosis.	30 days, 1 year, 3 years
Secondary	Mean trans-prosthetic aortic gradient		30 days, 1 year, 3 years
Secondary	Aortic regurgitation		30 days, 1 year, 3 years
Secondary	Kansas City Cardiomyopathy Questionnaire (KCCQ)-12 score		30 days, 1 year, 3 years