Abstract
Background
The ALLEGRA (Biosensors International) transcatheter heart valve is a self-expanding supra-annular bovine pericardial aortic valve. A new delivery system (IMPERIA™, Biosensors International) has been designed which allows the valve to be fully resheathed and repositioned in situ. The aim of this premarket study was to assess the safety and efficacy of transcatheter aortic valve implantation using the combination of the CE (Conformite Europeenne) marked ALLEGRA valve and the new IMPERIA delivery system.
Methods
One hundred thirty-seven patients were enrolled in 11 centers from January to November 2023. There were 30 roll-in patients, 91 in the intention-to-treat (ITT) population and 16 with degenerated surgical aortic bioprostheses. The primary outcome was device success according to the Valve Academic Research Consortium-2 from discharge up to 7 days in the ITT cohort.
Results
Implantation of the ALLEGRA valve was successful in 136 patients (99.3%). There were no device embolizations and no patient required a second valve. Device success was achieved in 91.9% of the ITT cohort. At 30 days, all-cause mortality was 2.2% in the native aortic stenosis (AS) cohort and 0% in the valve-in-valve cohort. New pacemaker implantation was required in 12.4% (17/137). There was no patient prosthesis mismatch (PPM) in the 121 patients with native AS and moderate PPM in 2/16 valve-in-valve patients.
Conclusions
This study confirms the safety and efficacy of transcatheter aortic valve implantation using the IMPERIA delivery system to implant the CE marked ALLEGRA transcatheter heart valve in patients with severe calcific native AS or a degenerated surgical aortic bioprostheses.
Highlights
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The EMPIRE 1 study confirms the safety and efficacy of the new IMPERIA delivery system when used to implant the ALLEGRA transcatheter aortic valve.
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There were no valve embolization and no patient required a second valve.
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There was no prosthesis patient mismatch in any of the patients with native aortic stenosis and only moderate mismatch in 2/16 valve-in-valve patients.
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At 30 days, all-cause mortality was 1.7% in patients with native aortic stenosis and 0% in the valve-in-valve cohort.
Introduction
Transcatheter aortic valve implantation (TAVI) has become the standard of care for patients suffering from severe symptomatic aortic valve stenosis (AS) with a high or prohibitive risk for surgical aortic valve replacement and is now a routine treatment alternative at heart centers globally. In parallel with increasing operator experience, preoperative computed tomography (CT) imaging and design improvements of existing TAVI systems have contributed to better clinical outcomes, but complications including paravalvular leakage (PVL), conduction system abnormalities, stroke, vascular injury, and residual high gradients after implantation resulting from patient prosthesis mismatch (PPM) still occur frequently.
The ALLEGRA TAVI System (NVT GmbH, Hechingen, Germany) was approved in Europe in 2017 for the treatment of patients with severe native aortic stenosis (AS) and in 2020 for the treatment of patients with degenerated surgical aortic bioprostheses (valve-in-valve [ViV]). The ALLEGRA transcatheter valve is a self-expanding supra-annular bovine pericardial aortic bioprosthesis with several unique features designed to provide patients with excellent hemodynamic performance and durability, including a short barrel shaped stent frame and a flexible outflow resulting in effective orifice areas (EOAs) which exceed the geometric orifice area. It also has a unique transfemoral delivery system which provides stable hemodynamics during implantation without an occlusive phase (“Permaflow”). Excellent short to medium term outcomes have been reported in patients treated for native AS and in the ViV setting. The current delivery system permits retrieval of the valve after the inflow has been opened and prior to final release but does not allow repositioning in situ. To provide operators with the ability to optimize implant depth and position, a new delivery system has been designed (IMPERIA) which allows the valve to be fully resheathed and repositioned in the aortic root. The invEstigation of the safety and perforMance of the NVT ALLEGRA THV System with a new delivery system in Patients with severe calcified aortIc stenosis or failed suRgical aortic bioprosthEsis (EMPIRE) I trial was designed to assess the safety and efficacy of TAVI performed using the combination of the current CE marked ALLEGRA valve and the new delivery system.
Methods
Study Design
EMPIRE I is a premarket, prospective, multicenter, single-arm study performed to obtain regulatory approval for the IMPERIA delivery system under the new European Union Medical Device Regulations.
Patient Screening and Selection
Patients with either symptomatic severe calcific AS defined according to Valve Academic Research Consortium-2 (VARC-2) or a degenerated surgical bioprosthesis were screened in 11 sites in Spain, Germany, and the Netherlands and, if eligible, were invited to participate. After providing written informed consent, the clinical and imaging data were presented to a Central Screening Committee (CSC) who had to confirm suitability. Clinical specialists analyzed all CT scans and provided at least 2 independent reports to the CSC. An independent Clinical Events Committee, Data Safety Monitoring Board, and Echocardiographic Core Laboratory (Cardialysis, Rotterdam, The Netherlands) assessed adverse events, patient safety, and echocardiograms, respectively. The primary endpoint was the rate of device success as defined by VARC-2 at discharge from index procedure or 7 days post implant, whichever came first. We used VARC-2 as this was also employed in the study from which the performance goal was derived. The study is registered at ClinicalTrials.gov ( NCT05478161 ), complies with the Declaration of Helsinki, and was approved by the relevant national and local ethics committees and competent authorities. Patients were informed about the study details and provided written informed consent prior to participation. The study was executed with the assistance of a contract research organization (Cardialysis, Rotterdam, The Netherlands).
As this was a first-in-human study, each site was required to treat 3 roll-in patients prior to entering subjects into the intention-to-treat (ITT) cohort. Roll-in patients underwent the same procedures as those in the ITT cohort ( Figure 1 ). In parallel, sites could also enroll patients with degenerated surgical bioprostheses into a ViV substudy. Patients were considered enrolled after the informed consent was signed, all eligibility criteria were met and confirmed by the local heart team, participation has been approved by the CSC, and vascular access had been obtained.
Study Device and Valve Implantation
The intention in all patients was to implant the current commercially available ALLEGRA valve using the new IMPERIA delivery system ( Figure 2 ). The valve has 3 pairs of radiopaque markers on the stent frame positioned at the level of the new valve plane on either side of the commissural fixation points and the delivery system also has a marker band. These markers can be used to guide and optimize valve implantation. It is available in 3 sizes (23, 27, and 31 mm) covering an annulus perimeter size range of 16.5 mm to 27.0 mm. The new IMPERIA delivery system has an integrated wire reinforced sheath with a hydrophilic coating and a winding mechanism to progressively open the valve from inflow to outflow and then close it if repositioning is required. The shaft of the delivery catheter is 15 Fr with an 18 Fr cartridge for all 3 valve sizes. Accordingly, the iliofemoral vascular anatomy had to allow the safe placement of an 18 Fr internal diameter sheath. There is an automatic safety lock mechanism to prevent accidental release. At the safety lock position, the valve is sufficiently functioning to provide approximately 80% of maximal flow and can be fully resheathed and repositioned up to 3 times if necessary. The instructions for use recommend predilatation in all native cases with optional postdilatation.
Study Endpoints and Assessments
Patients were assessed at baseline, during the procedure, discharge, 30 days, 6 and 12 months. The primary endpoint was device success rate as defined in VARC-2 at 7 days (discharge from index procedure or 7 days postimplant, whichever comes first) in the native ITT cohort. Secondary endpoints include procedural success, assessment of the functional status and the need for new permanent pacemaker implantations. Additional endpoints including cardiovascular death, early safety and hemodynamic parameters were adjudicated according to the VARC-2.
Statistical Analysis
The performance goal was derived from the CoreValve EvolutR CE Mark Clinical Study which used the same primary endpoint. In that study, 22% of patients failed to meet the criteria for device success. We chose an upper boundary for device failure of 33% representing a relative increase of 1.5. This is in line with previous trials of cardiovascular devices including new TAVI systems. Based on this, a sample size of 88 evaluable patients was needed to provide 80% power with a one-sided type I error of 5%. Allowing for a drop-out rate of 5%, 92 patients with native AS needed to be enrolled. The main analysis group for this report are the patients with native AS who were enrolled into the ITT population. Study success will be declared if the null hypothesis of no difference between the performance goal and the observed device failure rate can be rejected. In addition, we separately report results for the 30 roll-in patients and the 16 ViV patients.
Baseline categorical variables are presented as percentages and continuous variables as mean ± SD or median and interquartile range. Event rates are reported as Kaplan-Meier estimates. An interim analysis was performed after all patients had completed 30 days follow-up. Since this interim analysis was to assess safety and did not influence the conduct of the study, no adjustment of p values is necessary. The analysis was prespecified in the clinical investigation plan and the statistical analysis plan. All statistical analyses were performed using Statistical Analysis Systems software version 9.4 (SAS Institute, Cary, North Carolina).
Results
Study Population
One hundred seventy-six patients were screened between January and November 2023. Subsequently 30 patients with native AS underwent roll-in procedures and 91 patients with native AS were recruited into the ITT cohort. An additional 16 patients underwent ViV procedures. Patient demographics and baseline data are shown in Table 1 . The average age of the roll-in and ITT cohorts was 82.7 ± 5.9 and 82.1 ± 4.7 years, 66.7 and 68.1% were female and 46.7 and 57.1% were in New York Heart Association (NYHA) class III or IV. In the roll-in and ITT populations, Society of Thoracic Surgeons risk scores were 4.0% ± 2.9% and 4.2% ± 2.8% and European System for Cardiac Operative Risk Evaluation II risk scores were 3.5% ± 2.1% and 3.8% ± 2.6% respectively. The ViV patients were aged 80.0 ± 5.3 years, 31.2% were female and 75% were in NYHA class III or IV. The Society of Thoracic Surgeons and European System for Cardiac Operative Risk Evaluation II risk scores in the ViV cohort were 11.1% ± 15.1% and 16.6% ± 19.7% respectively.
| Roll-in (native) (N = 30) | ITT (native) (N = 91) | Total native (N = 121) | ViV (N = 16) | Total (N = 137) | |
|---|---|---|---|---|---|
| Age (y) | 82.7 ± 5.9 | 82.1 ± 4.7 | 82.2 ± 5.0 | 80.0 ± 5.3 | 81.9 ± 5.1 |
| Gender (male) | 33.3% (10) | 31.9% (29) | 32.2% (39) | 68.8% (11) | 36.5% (50) |
| STS score (%) | 4.0 ± 2.9 | 4.2 ± 2.8 | 4.1 ± 2.8 | 11.1 ± 15.1 | 4.9 ± 6.1 |
| EuroSCORE (%) | 3.5 ± 2.1 | 3.8 ± 2.6 | 3.7 ± 2.5 | 16.6 ± 19.7 | 5.2 ± 81 |
| NYHA class III/IV | 46.7% (14) | 57.1% (52) | 54.5% (66) | 75.0% (12) | 56.9% (78) |
| Coronary artery stenosis >50% | 33.3% (10) | 23.1% (10) | 25.6% (31) | 56.3% (9) | 29.2% (40) |
| Angina (stable) | 10% (3) | 7.7% (7) | 8.3% (10) | 6.3% (1) | 8.0% (11) |
| Previous myocardial infarction | 13.3% (4) | 12.1% (11) | 12.4% (15) | 18.8% (3) | 13.1% (18) |
| Previous cardiac decompensation | 6.7% (2) | 11.0% (10) | 9.9% (12) | 37.5% (6) | 13.1% (18) |
| Pulmonary hypertension | 13.3% (4) | 13.2% (12) | 13.2% (16) | 31.3% (5) | 15.3% (21) |
| Previous endocarditis | 0.0% (0) | 0.0% (0) | 0.0% (0) | 6.3% (1) | 0.7% (1) |
| Atrial fibrillation or flutter | 20.0% (6) | 30.8% (28) | 28.1% (34) | 25.0% (4) | 27.7% (38) |
| LBBB/RBBB | 3.3% (1) | 8.8% (8) | 7.4% (9) | 37.5% (6) | 10.9% (15) |
| Previous stroke | 6.7% (2) | 5.5% (5) | 5.8% (7) | 6.3% (1) | 5.8% (8) |
| COPD | 3.3% (1) | 5.5% (5) | 5.0% (6) | 18.8% (3) | 6.6% (9) |
| Chronic renal insufficiency | 36.7% (11) | 22.0% (20) | 25.6% (31) | 31.3% (5) | 26.3% (36) |
| Diabetes type II | 33.3% (10) | 24.2% (22) | 28.1% (34) | 37.5% (6) | 29.2% (40) |
| Permanent pacemaker | 3.3% (1) | 8.8% (8) | 7.4% (9) | 18.8% (3) | 8.8% (12) |
| Cancer | 10% (3) | 9.9% (9) | 9.9% (12) | 0.0% (0) | 8.8% (12) |
Baseline CT Parameters
In the patients with native AS, the perimeter derived diameter ranged from 19.1 mm to 26.8 mm in keeping with the recommended sizing of the ALLEGRA valve ( Table 2 ). Volumetric calcification measurements suggested that on average the patients with native AS had severe calcification. A list of the type and size of the treated surgical valves is included in Supplementary Table 1 .
| Roll-in (native) (N = 30) | ITT (native) (N = 91) | Total native (N = 121) | ViV (N = 16) | Total (N = 137) | |
|---|---|---|---|---|---|
| Aortic annulus | |||||
| Perimeter derived diameter (mm) | 23.7 ± 1.7 | 23.6 ± 1.7 | 23.6 ± 1.7 | 20.9 ± 2.0 | 23.3 ± 1.9 |
| Perimeter (mm) | 74.1 ± 5.4 | 73.9 ± 5.4 | 74.0 ± 5.4 | 65.8 ± 6.4 | 73.0 ± 6.1 |
| Area (mm 2 ) | 425.7 ± 65.4 | 424.6 ± 61.4 | 424.9 ± 62.1 | 343.1 ± 67.5 | 415.6 ± 67.7 |
| Left ventricular outflow tract | |||||
| Perimeter derived diameter (mm) | 23.4 ± 2.2 | 23.2 ± 1.7 | 23.3 ± 2.0 | 25.6 ± 3.7 | 23.6 ± 2.4 |
| Perimeter (mm) | 72.9 ± 5.3 | 73.4 ± 6.8 | 73.3 ± 6.4 | 80.3 ± 11.6 | 74.1 ± 7.5 |
| Area (mm 2 ) | 397. 3 ± 65.7 | 405.5 ± 78.7 | 403.5 ± 75.5 | 501.4 ± 154.4 | 415.0 ± 93.2 |
| Sinus of Valsalva width | |||||
| Left coronary (mm) | 30.5 ± 2.6 | 30.7 ± 2.6 | 30.6 ± 2.6 | 30.5 ± 2.7 | 30.6 ± 2.6 |
| Right coronary (mm) | 28.9 ± 2.5 | 29.3 ± 2.5 | 29.2 ± 2.5 | 29.5 ± 3.3 | 29.2 ± 2.6 |
| Noncoronary (mm) | 30.2 ± 3.0 | 30.7 ± 2.8 | 30.5 ± 2.8 | 31.9 ± 4.7 | 30.7 ± 3.0 |
| Sino-tubular junction diameter (mm) | 27.5 ± 2.7 | 28.1 ± 2.6 | 26.8 ± 2.5 | 29.1 ± 3.6 | 26.9 ± 2.7 |
| Membranous septum length (mm) | 4.8 ± 2.3 | 5.1 ± 2.2 | 5.0 ± 2.2 | 5.6 ± 2.8 | 5.1 ± 2.3 |
| Aorta to annulus angle (°) | 47.4 ± 9.7 | 47.7 ± 10.2 | 47.6 ± 10.1 | 43.3 ± 9.8 | 47.1 ± 10.1 |
| Calcification | |||||
| Total (mm 3 ) | 803.4 ± 373.9 | 856.0 ± 505.1 | 842.9 ± 474.8 | 317.2 ± 226.7 | 795.1 ± 317.2 |
| Noncoronary cusp (mm 3 ) | 343.1 ± 160.2 | 365.3 ± 208.2 | 359.9 ± 197.1 | 138.8 ± 130.8 | 339.6 ± 202.1 |
| Right coronary cusp (mm 3 ) | 231.8 ± 121.9 | 260.0 ± 205.9 | 253.1 ± 188.8 | 91.0 ± 97.3 | 238.3 ± 188.0 |
| Left coronary cusp (mm 3 ) | 232.3 ± 170.0 | 232.0 ± 169.5 | 232.1 ± 168.9 | 108.8 ± 109.3 | 220.8 ± 167.9 |
| Femoral access | |||||
| Common iliac mean diameter (mm) | 9.4 ± 1.4 | 9.3 ± 1.5 | 9.3 ± 1.5 | 9.7 ± 1.7 | 9.3 ± 1.5 |
| External iliac mean diameter (mm) | 7.8 ± 1.3 | 7.5 ± 1.3 | 7.6 ± 1.3 | 8.2 ± 2.0 | 7.6 ± 1.4 |
| Common femoral mean diameter (mm) | 7.8 ± 1.2 | 7.6 ± 1.2 | 7.7 ± 1.2 | 7.8 ± 1.5 | 7.7 ± 1.2 |
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