ACURATE IDE: Safety and Effectiveness Study of ACURATE Valve for Transcatheter Aortic Valve Replacement

To evaluate safety and effectiveness of the ACURATE Transfemoral Aortic Valve System for transcatheter aortic valve replacement (TAVR) in subjects with severe native aortic stenosis who are indicated for TAVR.

Subjects will be enrolled at up to 85 centers in the United States, Canada, Europe, and Australia. There will be up to 2,820 subjects in ACURATE IDE.

The ACURATE IDE study cohorts include the following.

* Main Randomized Cohort: A prospective, multicenter, 1:1 randomized controlled trial (RCT; ACURATE versus a commercially available balloon-expandable SAPIEN 3™ Transcatheter Heart Valve or future iteration \[SAPIEN 3; Edwards Lifesciences LLC, Irvine, CA, USA\] or a commercially available self-expanding CoreValve® Transcatheter Aortic Valve Replacement System, CoreValve® Evolut™ R Recapturable TAVR System, EVOLUT™ PRO System, or future iteration \[CoreValve; Medtronic, Inc., Dublin, Ireland\]). There will be up to 1,500 subjects in the RCT.
* Roll-In Cohort: A non-randomized roll-in phase with the test device. Centers that do not have implantation experience with the ACURATE neo™ Aortic Bioprosthesis (transfemoral delivery; Boston Scientific Corporation, Marlborough, MA, USA) will perform at least 2 roll-in cases before commencing treatment in the randomized cohort. Centers with prior experience with ACURATE are not required to do roll-in cases. Data from roll-in subjects will be summarized separately from the randomized cohort and will not be included in the primary endpoint analysis.
* 4D CT Imaging Substudy: Selected centers with the ability to perform high quality 4D computer tomography (CT) scans will include subjects in a 4D CT Imaging Substudy to assess the prevalence of reduced leaflet mobility and hypoattenuated leaflet thickening (HALT) and the relationship, if any, to clinical events. Subjects will be randomized to test (ACURATE) and control device.
* ACURATE Prime™ XL Nested Registry: A non-randomized, nested registry cohort of subjects who will receive the ACURATE Prime™ Transfemoral Aortic Valve System XL (ACURATE Prime XL Nested Registry). Participating centers will be a subset of United States centers that have enrolled subjects in ACURATE IDE. Data from subjects in this nested registry will be summarized separately from the randomized and roll-in cohorts.
* ACURATE Extended Durability Study: An additional 1:1 randomized study (ACURATE versus a commercially available balloon-expandable SAPIEN 3™ Transcatheter Heart Valve or future iteration \[SAPIEN 3; Edwards Lifesciences LLC, Irvine, CA, USA\] or a commercially available self-expanding CoreValve® Transcatheter Aortic Valve Replacement System, CoreValve® Evolut™ R Recapturable TAVR System, EVOLUT™ PRO System, or future iteration \[CoreValve; Medtronic, Inc., Dublin, Ireland\]) including only subjects considered to be at low surgical risk. Subjects will receive ACURATE neo2 (S, M, or L valve sizes) or ACURATE Prime XL. Data from subjects in the Extended Durability Study will be summarized separately from other cohorts.
* ACURATE Continued Access Study (CAS): An additional cohort of subjects receiving ACURATE neo2 (S, M, and L valve sizes) or ACURATE Prime XL. Data from subjects in the ACURATE CAS will be summarized separately from other cohorts and will be used to further assess performance and safety.

All subjects implanted will be followed at baseline, peri- and post-procedure, at discharge or 7 days post-procedure (whichever comes first), 30 days, 6 months, and then annually for up to 10 years post-procedure. Enrolled subjects who do not have a study device implanted will be assessed through 1-year post-procedure for safety/adverse events.

Eligibility Criteria:
Inclusion Criteria:

* IC1. Subject has documented severe symptomatic native aortic stenosis defined as follows: aortic valve area (AVA) ≤1.0 cm2 (or AVA index ≤0.6 cm2/m2) AND a mean pressure gradient ≥40 mmHg, OR maximal aortic valve velocity ≥4.0 m/s, OR Doppler velocity index ≤0.25 as measured by echocardiography and/or invasive hemodynamics.

Note: In cases of low flow, low gradient aortic stenosis with left ventricular dysfunction (ejection fraction \<50%), dobutamine can be used to assess the grade of aortic stenosis (maximum dobutamine dose of 20 mcg/kg/min recommended); the subject may be enrolled if echocardiographic criteria are met with this augmentation.

* IC2. Subject has a documented aortic annulus size of ≥20.5 mm and ≤29 mm based on the center's assessment of pre-procedure diagnostic imaging (and confirmed by the Case Review Committee \[CRC\]) and, for the Main Randomized Cohort and the Extended Durability Study, is deemed treatable with an available size of both test and control device.
* IC3. For subjects with symptomatic aortic valve stenosis per IC1 definition above, functional status is NYHA Functional Class ≥ II.
* IC4. Heart team (which must include an experienced cardiac interventionalist and an experienced cardiac surgeon) agrees that the subject is indicated for TAVR, is likely to benefit from valve replacement, and TAVR is appropriate.
* IC5. Subject (or legal representative) understands the study requirements and the treatment procedures, and provides written informed consent.
* IC6. Subject, family member, and/or legal representative agree(s) and subject is capable of returning to the study hospital for all required scheduled follow up visits.
* IC7. Subject is expected to be able to take the protocol-required adjunctive pharmacologic therapy.

Exclusion Criteria:

* EC1. Subject has a unicuspid or bicuspid aortic valve.
* EC2. Subject has had an acute myocardial infarction within 30 days prior to the index procedure (defined as Q-wave MI or non-Q-wave MI with total CK elevation ≥ twice normal in the presence of CK-MB elevation and/or troponin elevation).
* EC3. Subject has had a cerebrovascular accident or transient ischemic attack clinically confirmed by a neurologist or neuroimaging within the past 6 months prior to study enrollment.
* EC4. Subject is on renal replacement therapy or has eGFR \<20.
* EC5. Subject has a pre-existing prosthetic aortic or mitral valve.
* EC6. Subject has severe (4+) aortic, tricuspid, or mitral regurgitation.
* EC7. Subject has moderate or severe mitral stenosis (mitral valve area ≤1.5 cm2 and diastolic pressure half-time ≥150 ms, Stage C or D76).
* EC8. Subject has a need for emergency surgery for any reason.
* EC9. Subject has a history of endocarditis within 6 months of index procedure or evidence of an active systemic infection or sepsis.
* EC10. Subject has echocardiographic evidence of new intra-cardiac vegetation or intraventricular or paravalvular thrombus requiring intervention.
* EC11. Subject has platelet count \<50,000 cells/mm3 or \>700,000 cells/mm3, or white blood cell count \<1,000 cells/mm3.
* EC12. Subject has had a gastrointestinal bleed requiring hospitalization or transfusion within the past 3 months, or has other clinically significant bleeding diathesis or coagulopathy that would preclude treatment with required antiplatelet regimen, or will refuse transfusions.
* EC13. Subject has known hypersensitivity to contrast agents that cannot be adequately pre-medicated, or has known hypersensitivity to the protocol required medications (aspirin, all P2Y12 inhibitors, heparin), or to the individual components of the test or control valve (nickel, titanium, stainless steel, platinum, iridium or polyethylene terephthalate \[PET\]).
* EC14. Subject has a life expectancy of less than 12 months due to non-cardiac, comorbid conditions based on the assessment of the investigator at the time of enrollment.
* EC15. Subject has hypertrophic cardiomyopathy.
* EC16. Subject has any therapeutic invasive cardiac or vascular procedure within 30 days prior to the index procedure (except for balloon aortic valvuloplasty, pacemaker implantation, or implantable cardioverter defibrillator implantation, which are allowed).
* EC17. Subject has untreated coronary artery disease, which in the opinion of the treating physician is clinically significant and requires revascularization.
* EC18. Subject has severe left ventricular dysfunction with ejection fraction \<20%.
* EC19. Subject is in cardiogenic shock or has hemodynamic instability requiring inotropic support or mechanical support devices.
* EC20. Subject has arterial access that is not acceptable for the study device (test or control) delivery systems as defined in the device (test or control) Directions For Use.
* EC21. Subject has either of the following:

  * Severe vascular disease that would preclude safe access (e.g., aneurysm with thrombus that cannot be crossed safely; marked tortuosity; significant narrowing of the abdominal aorta; severe unfolding of the thoracic aorta; or thick, protruding, ulcerated atheroma in the aortic arch), OR
  * Severe/eccentric calcification of the aortic annulus that would prevent safe implantation of the TAVR prosthesis.
* EC22. Subject has current problems with substance abuse (e.g., alcohol, etc.) that may interfere with the subject's participation in this study.
* EC23. Subject is participating in another investigational drug or device study that has not reached its primary endpoint or subject intends to participate in another investigational device clinical trial within 12 months after index procedure.
* EC24. Subject has untreated conduction system disorder (e.g., Type II second degree atrioventricular block) that in the opinion of the treating physician is clinically significant and requires a pacemaker implantation. Enrollment is permissible after permanent pacemaker implantation.
* EC25. Subject has severe incapacitating dementia.

Additional exclusion criteria apply to subjects considered for enrollment in the CT Imaging Substudy as listed below.

* AEC1. Subject has eGFR \<30 mL/min (chronic kidney disease stage IV or stage V)
* AEC2. Subject has atrial fibrillation that cannot be rate controlled to ventricular response rate \< 60 bpm.
* AEC3. Subject is expected to undergo chronic anticoagulation therapy after the index procedure.

Note: Subjects treated with short-term anticoagulation post procedure can be included in the CT Imaging Substudy; in these subjects the 30-day imaging will be performed 30 days after discontinuation of anticoagulation.