Trial Outcomes & Findings for Safety and Efficacy Study of Lotus Valve for Transcatheter Aortic Valve Replacement (NCT NCT02202434)

912 subjects randomized from 22Sep2014 to 24Dec2015. 102 subjects enrolled in the Roll-in cohort. 295 subjects enrolled in the US CAS from 25Feb2016 to 23Feb2017. Enrollment in the LOTUS Edge Valve System - Single-arm Edge Nested Reg is ongoing. Enrollment in the LOTUS Edge Valve System - Single-arm 29mm Reg and Roll-in Cohorts has not begun.

The non-randomized Roll-In phase with only the test device was for centers with no previous experience implanting the Lotus Valve System. Each performed at least two Roll-In cases before starting RCT. Only cohorts that have completed enrollment, reached primary endpoint and were submitted for regulatory approval are included in the Results Section

Safety and Efficacy Study of Lotus Valve for Transcatheter Aortic Valve Replacement

Composite of all-cause mortality, stroke, life-threatening and major bleeding events, stage 2 or 3 acute kidney injury, or major vascular complications

Composite of all-cause mortality, disabling stroke, or moderate or greater paravalvular aortic regurgitation (based on core lab assessment).

Moderate or greater paravalvular aortic regurgitation based on Independent echocardiographic core lab assessment performed using the Unifying 5-Class Grading Scheme for Aortic Regurgitation by Pibarot et al (J Am Coll Cardiol Img 2015: 8: 340-60). The grading scheme ranges from Trace (the least clinically significant) to severe (the most clinically significant).

Successful deployment of the study valve

Successful retrieval of the study valve if retrieval is attempted

Successful repositioning of the study valve if repositioning is attempted

Grade of aortic valve regurgitation: paravalvular, central, and combined. An Independent echocardiographic core lab assessment was performed using the Unifying 5-Class Grading Scheme for Aortic Regurgitation for the locations paravalvular, central and combined. The grading scheme has a range from Trace to Severe. A grade of Trace is the least clinically significant (better outcome) and a grade of Severe is the most clinically significant (worse outcome).

Defined as implantation of the study device in the absence of death, disabling stroke, major vascular complications, and life-threatening or major bleeding

Defined as absence of procedural mortality, correct positioning of a single transcatheter valve into the proper anatomical location , intended performance of the study device (effective orifice area \[EOA\] \>0.9 cm2 for body surface area (BSA) \<1.6 m2 and EOA \>1.1 cm2 for BSA ≥1.6 m2 plus either a mean aortic valve gradient \<20 mm Hg or a peak velocity \<3m/sec, and no moderate or severe prosthetic valve aortic regurgitation) plus no serious adverse events

Assessed by an independent core laboratory, including effective orifice area, mean and peak aortic gradients, and peak aortic velocity

Assessed by an independent core laboratory - mean and peak aortic gradients

Assessed by an independent core laboratory - peak aortic velocity

Grade of aortic valve regurgitation: paravalvular, central, and combined. An Independent echocardiographic core lab assessment was performed using the Unifying 5-Class Grading Scheme for Aortic Regurgitation for the locations paravalvular, central and combined. The grading scheme has a range from Trace to Severe. A grade of Trace is the least clinically significant (better outcome) and a grade of Severe is the most clinically significant (worse outcome).

SF-12 and Kansas City Cardiomyopathy - Baseline scores and changes from Baseline at 30 days, 6 months and 1 year * SF-12 Item Short Form Health Survey (SF-12): Measures functional health and well-being. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. * Kansas City Cardiomyopathy Questionnaire (KCCQ): Quantifies physical function, symptoms, social function, self-efficacy and knowledge, and quality of life. Scores are transformed to a range of 0-100, in which higher scores reflect better health status.

All-cause, Cardiovascular, and Non-cardiovascular

Disabling Stroke and Non-disabling Stroke

Periprocedural (≤72 hours post index procedure) and spontaneous (\>72 hours post index procedure)

Life-threatening (or disabling) and major (defined below) Life-threatening or Disabling Bleeding * Fatal bleeding (Bleeding Academic Research Consortium \[BARC\] type 5124,125) * Bleeding in a critical organ, such as intracranial, intraspinal, intraocular, or pericardial necessitating pericardiocentesis, or intramuscular with compartment syndrome (BARC type 3b and 3c) * Bleeding causing hypovolemic shock or severe hypotension requiring vasopressors or surgery (BARC type 3b) * Overt source of bleeding with drop in hemoglobin of ≥5 g/dL or whole blood or packed red blood cells (RBC) transfusion ≥4 units (BARC type 3b) Major Bleeding (BARC type 3a) * Overt bleeding either associated with a drop in the hemoglobin level of at least 3.0g/dL or requiring transfusion of 2 or 3 units of whole blood/RBC, or causing hospitalization or permanent injury, or requiring surgery AND does not meet criteria of life-threatening or disabling bleeding

Acute kidney injury based on the AKIN System Stage 3 (including renal replacement therapy) or Stage 2 Change in serum creatinine (up to 7 days) compared to baseline: * Stage 1: Increase in serum creatinine to 150-199% (1.5-1.99 × increase compared with baseline) OR increase of ≥0.3 mg/dl (≥26.4 mmol/L) * Stage 2: Increase in serum creatinine to 200-299% (2.0-2.99 × increase compared with baseline) * 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- Based on urine output (up to 7 days): * Stage 1: \<0.5 ml/kg per hour for \>6 but \<12 hours * Stage 2: \<0.5 ml/kg per hour for \>12 but \<24 hours * Stage 3: \<0.3 ml/kg per hour for ≥24 hours or anuria for ≥12 hours Note 1: Subjects receiving renal replacement therapy are considered to meet Stage 3 criteria irrespective of other criteria.

Major vascular complication - including access site related and non access site related

Repeat procedure for valve-related dysfunction (surgical or interventional therapy)

Hospitalization for valve-related symptoms or worsening congestive heart failure (New York Hear Association \[NYHA\] class III or IV)

New permanent pacemaker implantation resulting from new or worsened conduction disturbances

New onset of atrial fibrillation or atrial flutter

Coronary obstruction

Ventricular septal perforation

Mitral apparatus damage

Cardiac tamponade

Prosthetic aortic valve malpositioning, including valve migration, valve embolization, or ectopic valve deployment

Prosthetic aortic valve thrombosis

Prosthetic aortic valve endocarditis