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Transcatheter Aortic Valve Implantation with ACURATE neo: Results from the PROGRESS PVL Registry

Transcatheter Aortic Valve Implantation with ACURATE neo: Results from the PROGRESS PVL Registry Hindawi Journal of Interventional Cardiology Volume 2022, Article ID 9138403, 10 pages https://doi.org/10.1155/2022/9138403 Research Article Transcatheter Aortic Valve Implantation with ACURATE neo: Results from the PROGRESS PVL Registry 1 2 3 4 5 Won-Keun Kim , Holger Thiele, Axel Linke, Thomas Kuntze, Stephan Fichtlscherer, 6 7 8 9 10 John Webb, Michael W. A. Chu, Matti Adam, Gerhard Schymik, Tobias Geisler, 11 12 12 Rajesh Kharbanda, Thomas Christen, and Dominic Allocco Department of Cardiology and Cardiac Surgery, Kerckhoff Heart Center, Bad Nauheim, Germany Department of Cardiology, Heart Center Leipzig at University of Leipzig and Leipzig Heart Institute, Leipzig, Germany Department of Internal Medicine and Cardiology, Herzzentrum Dresden at Technische Universita¨t Dresden, Dresden, Germany Department of Cardiology, Heart Centre, Central Clinic in Bad Berka, Bad Berka, Germany Department of Internal Medicine, Division of Cardiology, Johann W. Goethe University, Frankfurt, Germany Centre for Heart Valve Innovation, St. Paul’s and Vancouver General Hospitals, University of British Columbia, Vancouver, British Columbia, Canada Division of Cardiac Surgery, Department of Surgery, Western University, London Health Sciences Centre, London, Ontario, Canada Clinic for Cardiology, University Hospital Cologne, Cologne, Germany Medical Clinic IV, Department of Cardiology, Municipal Hospital Karlsruhe, Karlsruhe, Baden-Wu¨rttemberg, Germany Department of Cardiology and Angiology, University Hospital Tu¨bingen, Tu¨bingen, Germany Oxford Heart Centre, John Radcliffe Hospital, Oxford, UK Boston Scientific, Marlborough, MA, USA Correspondence should be addressed to Won-Keun Kim; w.kim@kerckhoff-klinik.de Received 2 November 2021; Revised 18 March 2022; Accepted 3 May 2022; Published 25 June 2022 Academic Editor: Alessandro Sciahbasi Copyright © 2022 Won-Keun Kim et al. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objectives. +e PROGRESS PVL registry evaluated transcatheter aortic valve implantation (TAVI) in patients treated with ACURATE neo, a supra-annular self-expanding bioprosthetic aortic valve. Background. While clinical outcomes with TAVI are comparable with those achieved with surgery, residual aortic regurgitation (AR) and paravalvular leak (PVL) are common complications. +e ACURATE neo valve has a pericardial sealing skirt designed to minimize PVL. Methods. +e primary endpoint was the rate of total AR over time, as assessed by a core echocardiographic laboratory. +e study enrolled 500 patients (mean age: 81.8± 5.1 years; 61% female; mean baseline STS score: 6.0± 4.5%) from 22 centers in Europe and Canada; 498 patients were treated with ACURATE neo. Results. +e rate of≥ moderate AR was 4.6% at discharge and 3.1% at 12 months; the rate of≥ moderate PVL was 4.6% at discharge and 2.6% at 12 months. Paired analyses showed significant improvement in overall PVL between discharge and 12 months (P< 0.001); 64.6% of patients had no change in PVL grade, 24.9% improved, and 10.5% worsened. Patients also exhibited significant improvement in transvalvular gradient (P< 0.001) and effective orifice area (P � 0.01). +e mortality rate was 2.2% at 30 days and 11.3% at 12 months. +e permanent pacemaker implantation (PPI) rate was 10.2% at 30 days and 12.2% at 12 months. Conclusions. Results from PROGRESS PVL support the sustained safety and performance of TAVI with the ACURATE neo valve, showing excellent valve hemodynamics, good clinical outcomes, and significant interindividual im- provement in PVL from discharge to 12-month follow-up. 2 Journal of Interventional Cardiology followed by the upper and lower crown, allowing for he- 1. Introduction modynamic stability and uninterrupted aortic outflow. Transcatheter aortic valve implantation (TAVI) is an ACURATE neo is available in three sizes (S [small], M established, effective alternative treatment for patients with [medium], and L [large]) to treat native annulus diameters of symptomatic aortic stenosis who are considered high-risk 21 mm to 27 mm. Valve sizing was assessed by computerized for surgical valve replacement. While clinical outcomes with tomography (CT) and based on perimeter-derived annulus TAVI are comparable to those achieved with surgery, diameter; final size selection was at the operators’ discretion. concerns over complications such as residual aortic regur- gitation (AR) and paravalvular leak (PVL) persist. Moderate or greater PVL has been linked to less robust functional 2.3. Outcomes Measures and Statistical Methods. +e pri- mary endpoint was the rate of total aortic regurgitation (AR) improvement, increased rates of heart failure and hospi- talization, and increased long-term mortality [1–3]. at discharge/7 days, 30 days, and 12 months after TAVI. +e +e ACURATE neo valve, a self-expanding, supra-an- degree of paravalvular leak (PVL) was also examined, as this nular bioprosthetic aortic valve, has been commercially is the main driver of AR after TAVI and is typically of greater available for transfemoral TAVI in Europe since 2014. +e clinical interest. Per protocol, echocardiographic assess- largest study of ACURATE neo to date, the SAVI-TF study, ments were carried out according to local standard of care investigated clinical and echocardiographic outcomes in a for TAVI (if frequency or requirements were different from large high-risk patient population treated under real-world the study schedule) with all available data assessed by an conditions [4, 5]. +e study had a 98.7% procedural success independent core laboratory (Medical Research Develop- ment, Madrid, Spain). +e primary endpoint and all rate, a low rate of all-cause mortality (30 days: 1.4%; 1 year: 8.0%), and the pacemaker rate was <10% through 1 year. echocardiographic outcomes, including improvements in Patients exhibited a low rate of ≥ moderate PVL at 30 days mean transvalvular gradient and effective orifice area (EOA), (4.1%) and 1 year (3.8%). However, other studies of were measured in the per-protocol population (i.e., patients ACURATE neo have produced conflicting data regarding treated with the ACURATE neo valve). Clinical event rates PVL. Patients randomized to treatment with ACURATE neo were analyzed in the intent-to-treat (ITT) population, which in the SCOPE I and SCOPE II studies had a higher incidence includes all enrolled patients in whom valve implantation of ≥ moderate PVL at 30 days compared with Sapien 3 and was attempted. All VARC-2 safety events were evaluated by Evolut R/PRO, respectively, which contributed to ACU- an independent medical reviewer. A comprehensive list of RATE neo missing the noninferiority primary endpoints in secondary endpoints is presented in Supplementary Table 1. both studies [6, 7]. A post-hoc analysis was performed to compare the size of the implanted prosthetic valve with the native annulus di- Here, we report results from the PROGRESS PVL reg- istry, which evaluated the safety and performance of TAVI mensions (based on site-reported CT), expressed as cover with ACURATE neo in routine clinical practice. +e study index [CI � 100 x (nominal prosthesis diameter—annulus also included longitudinal assessment of echocardiographic diameter)/nominal prosthesis diameter]. data over time by an independent core laboratory. Baseline and outcome variables were summarized using descriptive statistics. For comparison of categorical variables, statistical differences were assessed using a chi-square test or a 2. Methods Fisher’s exact test, as appropriate. For comparison of con- tinuous variables, the Student’s t-test or analysis of variance 2.1. Study Design. PROGRESS PVL is a multicenter open- was used. Paired analysis of change in PVL over time was label single-arm study. Patients were considered eligible if performed according to Bhapkar’s test for marginal homo- they presented with severe aortic stenosis and were deter- geneity. All statistical analyses were two-sided with an alpha mined by a heart team to be at high risk for surgical valve level of 5%. Statistical analyses were performed with SAS replacement based on the patient’s Society of +oracic software (SAS Institute Inc., Cary, NC), version 9.3 or later. Surgeons (STS) score as well as the presence of other comorbidities. +e protocol was approved by locally appointed institutional review boards/ethics committees. 3. Results +e study was conducted in accordance with the Interna- 3.1. Study Cohort. PROGRESS PVL enrolled 500 patients at tional Conference for Harmonization Good Clinical Practice (ICH-GCP) regulations and guidelines and the ethical 22 centers in Europe and Canada between January 2017 and July 2018. A listing of investigators and sites can be found in principles outlined in the Declaration of Helsinki and registered with ClinicalTrials.gov (NCT02987894). All pa- Supplementary Table 2. Figure 2 depicts the disposition of enrolled patients. Two patients were not implanted with tients gave written informed consent. ACURATE neo and thus were not included in the per- protocol analysis set. In one patient, the femoral artery 2.2. Device Details. Figure 1 presents key elements of the anatomy was too small for the delivery system sheath, and in ACURATE neo valve (Boston Scientific, Marlborough, MA, another patient, the valve lost contact with the annulus and USA), which have been described in detail elsewhere [8]. +e embolized to the aortic root (valve was snared in the as- valve features controlled and predictable top-down de- cending aorta); these patients were treated with nonstudy ployment, with sequential release of the stabilization arches valves and assessed for safety through 30-day follow-up. Journal of Interventional Cardiology 3 Stabilization Arches Axial, self-aligning Upper Crown Porcine pericardium leaflets Captures native leaflets and provides coronary clearance Supra-annular positioning Lower Crown Pericardial Skirt Minimal protrusion into LVOT; low risk Integrated inner and outer skirts of conduction system interference designed to minimize paravalvular leak Figure 1: +e ACURATE neo valve. +e ACURATE neo valve is comprised of three porcine pericardial leaflets sewn into a self-expanding nitinol frame with three axial stabilization arches. +e supra-annular positioning contributes to low gradients. +e pericardial skirt is designed to minimize paravalvular leak. Enrolled Patients (Intent-to-treat population) N=500 Echocardiographic Assessment for Study valve not implanted: n=2* Primary Endpoint Implanted with ACURATE neo Discharge (Per-protocol population) n=380 (76.3%) N=498 Withdrew consent: n=6 30-day 30-day Clinical Follow-up or Death n=287 (57.6%) n=452 (90.4%) Withdrew consent: n=11 12-month Clinical Follow-up or Death 12-month n=462 (92.4%) n=237 (47.6%) *Femoral artery anatomy too small for sheath (n=1); embolization to aortic root (n=1); patients were treated with non-study valves and assessed for afety through 30-day follow-up. Echocardiography was performed per local standard of care if frequency or requirements were different from the study schedule. Figure 2: PROGRESS PVL study flow. +e mean age of enrolled patients was 81.8± 5.1 years, occurred in 493/500 patients (98.6%). In addition to the two and 61.2% were female. +e mean STS score in the study cases previously described, who were not treated with an population was 6.0± 4.5%, and 24.4% of patients had an STS ACURATE neo valve, there were four valve-in-valve pro- score ≥8%. At baseline, New York Heart Association cedures treated with a balloon-expandable nonstudy valve (NYHA) functional status was class III or IV in 75.2% of (two cases where the initial ACURATE bioprosthesis was patients. Based on site-reported assessment, calcification of placed in the aortic root but then lost contact with the the aortic leaflets was severe or extreme in approximately annulus, one case of dislocation to aortic root with in- one-third of patients. Additional baseline demographics, complete valve expansion, and one case of dislocation into the left ventricular outflow tract) and one case where the risk factors, and preexisting clinical conditions are detailed in Supplementary Table 3. initial valve was malpositioned with no further action noted. Patients treated with nonstudy valves in a valve-in-valve procedure were assessed for clinical safety events but were 3.2. Procedural Details. Procedural characteristics are not included in the per-protocol analysis set for echocar- summarized in Table 1. Preimplant balloon aortic valvu- diographic outcomes. In the case wherein the initially loplasty was performed in 91.4% of patients; postdilatation implanted ACURATE neo valve lost contact with the an- was performed in 45.1% of patients. Most patients were nulus, implantation with a nonstudy valve was attempted, implanted with either a M (38.8%) or L (41.6%) valve. +e but the patient subsequently experienced cardiogenic shock, median cover index in the as-treated population was 5.6%. resulting in death the same day as the index procedure, for a Correct positioning of a single valve in the proper location procedural mortality rate of 0.2%. +ere were no instances of 4 Journal of Interventional Cardiology Table 1: Procedural outcomes. Variable ITT population (N � 500) Total time from first puncture to time of transfemoral access site closure (min) 56.7± 26.8 (499) Total time from insertion of delivery system to removal of delivery system (min) 10.2± 11.6 (491) Valve size implanted S 19.6% (98) M 38.8% (194) L 41.6% (208) Balloon predilatation 91.4% (457) Postdilatation 45.2% (226) Correct positioning of a single valve in the proper location 98.6% (493) Procedural mortality 0.2% (1) Periprocedural myocardial infarction (≤72 h) 0.8% (4) Major vascular complications 2.8% (14) Life-threatening/disabling bleeding 0.8% (4) Valve-in-valve implant 0.8% (4/500) Surgical aortic valve replacement 0.0% (0/500) Unplanned use of cardiopulmonary bypass 0.0% (0/500) Coronary obstruction requiring intervention 0.0% (0/500) Ventricular septal perforation 0.0% (0/500) Cardiac tamponade 0.0% (0/500) Endocarditis 0.0% (0/500) Valve embolization 0.2% (1/500) Valve thrombosis 0.0% (0/500) Data are % (n) or mean± standard deviation (n). Two patients from the ITTpopulation were not implanted with ACURATE neo. ACURATE neo valve lost contact with the annulus; patient was treated valve-in-valve with a nonstudy valve, experienced cardiogenic shock, and died the same day as the index procedure. Intra-procedural myocardial infarction, n � 2 (STEMI, n � 1; NSTEMI, n � 1). conversion to surgery, annular rupture, or ventricular septal 3.4. Clinical Safety and Functional Improvement. Clinical perforation. One patient experienced dissection of the as- safety outcomes were analyzed for all enrolled patients in cending aorta, with subsequent endocarditis reported at whom valve implantation was attempted (i.e., the ITT three months after index procedure. population) and are presented in Table 2. +e VARC-2 composite endpoint for early safety at 30 days was met by 9.2% of patients, with low rates of all-cause mortality and 3.3. Echocardiographic Outcomes. In the overall pop- disabling stroke at 30 days. +e overall rate of permanent ulation, ≥ moderate AR was observed in 4.6% of patients at pacemaker implantation (PPI) was 10.2% at 30 days and discharge and 3.1% at 12 months (Figure 3(a)). Observed PVL 12.2% at 12 months (11.6% and 13.4%, respectively, in was very similar to total AR at all time points, with≥ moderate patients who did not have a pacemaker at baseline). +ere PVL in 4.6% of patients at discharge and 2.6% at 12 months were no instances of coronary obstruction during the study. (Figure 3(a)). +e median cover index was significantly higher +e rate of prosthetic valve thrombosis was very low, with in patients with no/trace PVL at discharge compared with only one case occurring within 12 months. patients with mild or greater PVL (6.7% vs 4.8%; P< 0.001) Figure 5 illustrates the functional status of patients (Supplementary Figure 1). A paired analysis performed treated with ACURATE neo (per-protocol population) among patients with core laboratory-adjudicated echo data based on NYHA functional class at baseline, discharge, available at discharge and 12 months (n � 209) demonstrated 30 days, and 12 months after the procedure. At discharge, significant overall improvement in PVL (P< 0.001; 86.6% of patients evaluated were class I or II, with 71.7% of Figure 3(b)). +e proportion of patients with improved PVL patients showing improvement from baseline of at least one between discharge and 12 months was greater than that with class, and 25.2% showing improvement of at least two worsening PVL (24.9% vs. 10.5%) (Figure 3(c)). classes. +is trend continued, with 87.6% of surviving pa- Patients treated with ACURATE neo demonstrated im- tients classified as class I or II at 12 months. One year after proved valve hemodynamics through 12 months of follow-up. TAVI, 76.4% and 33.8% of patients had improved at least In the per-protocol population, the mean aortic valve gradient one or two classes from baseline, respectively. declined and mean EOA increased substantially from baseline to discharge (Figure 4(a)). Improvements in gradient and 4. Discussion EOA were observed across valve sizes (Supplementary Fig- ure 2). Paired analyses performed in patients with hemo- PROGRESS PVL represents an extension of the body of dynamic data available at discharge, 30 days, and 12 months evidence supporting TAVI with ACURATE neo, providing demonstrate maintenance of significant improvement be- real-world data in an elderly high-risk patient population. tween discharge and 12 months in transvalvular gradient Importantly, the study includes longitudinal echocardio- (P< 0.001) and EOA (P � 0.01) (Figure 4(b)). graphic data adjudicated by an independent core laboratory. Journal of Interventional Cardiology 5 Total AR and PVL; per-protocol population 0.3 2.6 4.6 4.3 3.1 5.0 5.0 29.7 29.3 44.4 45.4 50.5 50.4 67.2 68.1 51.1 49.7 44.5 44.6 Total AR PVL Total AR PVL Total AR PVL (372) (372) (281) (280) (229) (229) Discharge 30 Days 12 Months Total AR / PVL Severe Mild Moderate None/Trace (a) PVL; paired analysis cohort (n=209) Directional change in PVL; paired analysis cohort P<0.001 4.3 2.9 10.5% Change in PVL from Discharge to 12m 42.1 29.2 (n=209) 24.9% 64.6% 67.9 53.6 Discharge 12 Months Improved Stayed the same PVL Worsened Severe Mild Moderate None/Trace (b) (c) Figure 3: Improvement in aortic regurgitation. (a) +e primary endpoint of PROGRESS PVL was the rate of total aortic regurgitation (AR), assessed by an independent echocardiography laboratory at discharge/7 days, 30 days, and 12 months in patients treated with ACURATE neo. Paravalvular leak (PVL) was very similar to total AR at all time points. (b, c) Paired analyses performed in patients with data available at both discharge and 12 months (N � 209) demonstrated significant overall improvement in PVL (P< 0.001; Bhapkar’s test for marginal homogeneity), with a greater proportion of patients showing interindividual improvement in PVL compared with worsening PVL. All echocardiographic data were assessed by a core laboratory. Patients maintained excellent valve hemodynamics, with time [10]. +e results with ACURATE neo are consistent large EOAs and low gradients, as expected for a supra- with data from the Italian CoreValve registry, in which all annular valve. Moderate or greater PVL was 2.6% at 1 year, patients with mild leak after procedure were either un- which is lower than observed in earlier ACURATE neo changed or improved through three years of follow-up [11], studies (SAVI-TF: 3.6%, CE-mark cohort: 4.5%) [5, 9]. In the and the CoreValve U.S. Pivotal Trial, which noted im- provement in the severity of PVL grade in patients with paired analysis, patients showed significant overall im- provement in PVL from discharge to 12-month follow-up, paired discharge and one-year echocardiograms [12]. It is with 64.6% of patients showing no change and 24.9% less clear whether PVL also continues to improve following showing improvement in PVL grade over time. +ere is TAVI with a balloon-expandable valve. In the PARTNER some evidence that self-expanding prostheses have the study, PVL was unchanged through two-year follow-up in potential for continued frame expansion and adaptation to 46.2% of patients treated with a Sapien valve, improved in the annulus, thus contributing to a reduction in PVL over 31.5%, and worsened in 22.4% [13], while a paired analysis of Percentage of Percentage of Evaluable Echocardiograms Evaluable Echocardiograms 2 Mean Effective Orifice Area (cm ) 6 Journal of Interventional Cardiology 2.1 ± 0.8 100 2.4 1.9 ± 0.6 1.9 ± 0.7 (n=197) (n=233) (n=284) 2.0 1.6 40.6 ± 15.7 (n=324) 1.2 0.8 7.9 ± 4.1 6.7 ± 3.2 6.9 ± 3.6 0.8 ± 0.3 (n=358) (n=272) (n=222) 0.4 (n=267) 0.0 Baseline Discharge 30 Days 12 Months (a) Mean Aortic Valve Gradient (n=153) Mean Effective Orifice Area (n=118) 10 2.5 2.0 ± 0.8 2.0 ± 0.6 7.8 ± 4.2 1.8 ± 0.7 6.6 ± 3.4 2 6.4 ± 2.9 1.5 5 P=0.005 P=0.37 P<0.001 P=0.45 P=0.001 P<0.001 0.5 0 0 Discharge 30 Days 12 Months Discharge 30 Days 12 Months All echocardiographic data were assessed by a core laboratory. (b) Figure 4: Change in valve hemodynamics. (a) Patients treated with ACURATE neo demonstrated improvements in mean aortic valve gradient and mean effective orifice area through 12-month follow-up, as assessed by an independent echocardiography laboratory. (b) Paired analyses of core laboratory data at discharge, 30 days, and 12 months demonstrate early hemodynamic improvement on a per-subject basis, which was maintained through 12 months. Table 2: Clinical safety outcomes. Variable 30 days 12 months VARC-2 composite early safety 9.2% (46) — All-cause mortality 2.2% (11) 11.3% (54) Cardiovascular death 2.0% (10) 7.1% (34) Noncardiovascular death 0.2% (1) 4.2% (20) Stroke 2.6% (13) 3.6% (17) Disabling Stroke 2.4% (12) 3.1% (15) Nondisabling Stroke 0.2% (1) 0.4% (2) Major vascular complications 3.6% (18) 4.0% (19) Bleeding, life-threatening or disabling 1.4% (7) 3.4% (16) Myocardial infarction (>72 h postprocedure) 0.0% (0) 1.0% (5) Acute kidney injury (AKI stage 2/3) 0.8% (4) 1.0% (5) New permanent pacemaker implantation All patients 10.2% (51) 12.2% (58) Pacemaker-naive patients (n � 443) 11.6% (51) 13.4% (57) New onset of atrial fibrillation/flutter 5.2% (26) 7.5% (36) Valve malpositioning 1.4% (7) 1.5% (7) Coronary obstruction requiring intervention 0.0% (0) 0.0% (0) Ventricular septal perforation 0.0% (0) 0.0% (0) Cardiac tamponade 0.0% (0) 0.0% (0) ∗ ‡ Repeat procedure for valve-related dysfunction 1.2% (6) 1.7% (8) Prosthetic valve endocarditis 0.0% (0) 0.8% (4) Prosthetic valve thrombosis 0.0% (0) 0.2% (1) ∗ † Data are % (n), reported for the ITTpopulation (N � 500). Component of VARC-2 composite endpoint for early safety at 30 days. Includes valve migration, valve embolization, ectopic valve deployment; Two patients were treated with a repeat procedure after 30 days. In one patient, the 30-day follow-up TEE revealed reduced LVEF with persistent moderate PVL; balloon valvuloplasty was performed but did not improve aortic valve insufficiency, and patient underwent SAVR. One patient experienced endocarditis and associated dissection of the ascending aorta on day 89 post-TAVI; SAVR was performed to replace the ACURATE neo valve. mmHg Mean Aortic Valve Gradient (mmHg) cm II Journal of Interventional Cardiology 7 1.9 1.4 0.6 10.3 11.8 11.5 11.8 45.6 53.5 48.9 64.9 37.9 42.0 33.1 22.1 2.7 Baseline Discharge 30 Days 12 Months (N=476) (N=314) (N=356) (N=331) NYHA Class IV III Figure 5: Improvement in functional status. Improvement in functional status, based on New York heart association (NYHA) functional class, was evident at discharge and sustained through 12 months of follow-up. Analysis includes surviving subjects treated with ACURATE neo who had functional status recorded at a given time point. patients treated with Sapien 3 in the PARTNER 2A study did +e investigator-initiated SCOPE I and II studies have presented head-to-head comparisons of ACURATE neo not show any difference in PVL between 30-day and one- year follow-up [14]. with later generation competitor devices. In SCOPE I, ACURATE neo did not meet the noninferiority criteria vs. +e rate of procedural complications was low in PROGRESS PVL, with correct positioning of the valve in Sapien 3 for the 30-day composite endpoint, partially driven by a higher rate of PVL (9.4% vs. 2.8%; P< 0.001) [6]. 98.6% of patients, and there were no cases of coronary obstruction. Many of the participating centres and inves- However, at one-year follow-up, clinical and functional tigators in the current study had prior experience with outcomes did not differ significantly between the devices, ACURATE neo, which likely increased their comfort with and the mean AV gradient was significantly lower and using the valve, leading to fewer procedural complications. median EOA significantly larger in patients treated with +e 30-day PPI rate in the present study (10.2%) was in the ACURATE neo compared with those treated with Sapien 3 range of that observed in other studies of ACURATE neo [25]. ACURATE neo also missed the noninferiority com- posite endpoint of all-cause death or any stroke at 30 days vs. (SAVI-TF: 8.3%, SCOPE I: 10.0%, SCOPE II: 11.0%) [5–7]. It is possible that variations in PPI may be attributed to dif- Evolut R/PRO in SCOPE II [7], which was attributed to a higher rate of cardiac mortality (3% vs 1%, resp.; P � 0.03). ferences in positioning strategies. A recent publication comparing PPI rate in patients categorized by their con- +e rate of cardiovascular death among PROGRESS PVL secutive enrolment in a large European registry found that as patients was 2.0% at 30 days. More extensive operator ex- positioning strategy evolved from a low implantation depth perience with ACURATE neo in the current study compared to a deliberately higher position, PPI rate was reduced with SCOPE II may have played a factor in the differences in (quartile 1–3: 10.9% vs. quartile 4 : 7.4%) [15]. Prior expe- cardiac mortality between these studies. rience with implanting ACURATE neo, including consid- In the PROGRESS PVL study, the 30-day rate of ≥ eration of positioning, may have had an impact on the PPI moderate PVL (5.0%) was nearly half that observed with rate in PROGRESS PVL; however, collection of detailed ACURATE neo in SCOPE I (9.4%) and SCOPE II (9.6%) [6, 7]. +e lower PVL rates observed in PROGRESS PVL imaging data to allow for an in-depth analysis of positioning was outside the scope of the current study. may be partially explained by operators’ prior experience implanting ACURATE neo and more careful patient se- Early clinical outcomes with ACURATE neo were similar to or better than those observed with other first-generation lection. A similar “learning curve effect” has been observed valves. +e 30-day rates for all-cause mortality (2.2%) and in retrospective analyses of ACURATE neo, with substantial stroke (2.6%) are comparable to the ranges observed in studies improvement in PVL in later cases compared with earlier of Sapien/Sapien XT (3.5%–6.3% and 3.6%–5.8% , resp.) cases [26, 27]. +rough a combination of better patient [16–19] or CoreValve (2.1%–5.1% and 1.4%–4.9%, resp.) selection, careful sizing, consideration of aortic valve cal- [16, 20–22]. However, contextualizing the data from cification, and a modified implant technique, it was dem- PROGRESS PVL is difficult, due in part to differences in onstrated that the rate of≥ moderate PVL could be reduced patient risk assessments across studies. Also, as the practice of to<1% [27]. Additionally, a greater percentage of patients in the current study had size L valves implanted compared with TAVI has evolved and operators have become more experi- enced, implant technique and patient selection have become the SCOPE I and II studies (41.6% vs. 34.1% and 33.9%, more refined, leading to an overall decline in procedural resp.), indicating a tendency towards oversizing. +e median complications and improved early outcomes [23, 24]. cover index in the PROGRESS PVL as-treated population Percentage of Surviving Subjects 8 Journal of Interventional Cardiology the same, with a relatively low radial force, which can be was 5.6%, and patients with no/trace PVL were found to have a higher median cover index compared with patients expected to contribute to a low pacemaker rate. +is expec- tation is supported by data from the Early Neo2 Registry, in with ≥ mild PVL, suggesting oversizing may minimize leak risk. Previous studies have likewise noted an inverse cor- which the in-hospital rate of new PPI was 6.0% [33]. relation between cover index and annulus diameter and an association between low cover index and mild or greater 4.1. Study Limitations. Interpretation of data from the PVL [28, 29]. Finally, as ACURATE neo has a relatively low PROGRESS PVL study is limited by the lack of direct radial strength, postdilatation may have been used to achieve comparison with other devices. As an observational registry, optimal expansion of the valve and reduce leaks, particularly patient selection was not restricted; however, as this was a in annuli that were highly calcified or irregular in shape. postmarket study, it is likely that operators had some prior +e next iteration of the ACURATE valve, neo2, was experience with the valve and may have paid more careful designed to address concerns related to PVL while maintaining attention to patient selection in terms of optimized sizing the desirable features of the ACURATE platform. Design and avoiding unfavorable calcification patterns (e.g., heavy enhancements include radiopaque markers that help to facil- calcification in the device landing zone), which may have itate precise valve positioning, and an augmented pericardial contributed to the low PVL rates observed. +ere was no sealing skirt, which extends to the waist of the valve and is core laboratory for CT during initial patient assessment and approximately 60% larger than the prior skirt, to further valve sizing and no formal assessment of cerebrovascular minimize PVL. In the ACURATE neo AS study, 97% of pa- events by a neurological professional, which may have tients treated with ACURATE neo2 exhibited≤ mild PVL [30]. resulted in an underestimation of the stroke rate. As is often No patient had severe PVL, and the 30-day rate of moderate the case with patient registries, monitoring was limited, and PVL (3.0%) was comparable to that observed with Sapien 3 by the rates of clinical and echocardiographic follow-up were Mauri et al. (3.6%) and in SCOPE I (2.8%), and with Evolut in relatively low. Geographic variations in standards and fre- SCOPE II (2.9%) [6, 7, 31]. +ese results are corroborated by quency of data collection were likely compounded by dif- preliminary unpublished data from the Early Neo2 Registry, an ficulties in compelling patients to return to sites for investigator-initiated registry of >500 European patients scheduled follow-up assessments. treated with neo2. +e incidence of > mild PVL in the Early Neo2 Registry was 1.3% [32], and a separate core laboratory 5. Conclusions analysis found that mean aortic regurgitation fraction was significantly lower in patients treated with ACURATE neo2 Patients in the PROGRESS PVL registry demonstrated a versus ACURATE neo (4.4± 4.8% vs. 9.9± 8.2%; P< 0.001), as lower rate of moderate or greater PVL than has been ob- was the rate of moderate/severe aortic regurgitation (1.7% vs. served in earlier studies of the ACURATE neo valve, with 13.9%; P< 0.001) [33]. significant interindividual improvement in PVL from dis- +e impact of PVL on long-term prognosis is an im- charge to 12-month follow-up. Patients also maintained portant factor that must be considered, particularly as TAVI excellent valve hemodynamics and demonstrated good is extended to younger and lower-risk patients, for whom clinical outcomes overall. +e one-year results from this long-term valve performance is critical. While moderate-to- study support the safety and performance of TAVI with severe PVL has consistently been associated with increased ACURATE neo in patients with severe aortic valve stenosis mortality, data on the impact of mild PVL on survival is less and suggest that ACURATE neo can be used in any patient clear [3, 34, 35]. +e current study, which used the standard that meets the appropriate sizing range, absent in the 3-class grading scheme for PVL, may have overlooked presence of extreme, or very eccentric aortic valve calcifi- discrete differences between mild and mild-to-moderate cation. +e design of the next-generation ACURATE neo2 PVL, and although these subtle differences could potentially valve, which retains many of the desirable features of be associated with an adverse effect, the effect size may have ACURATE neo, allows for improved sealing and thus re- been small or masked by several covariates that affect sur- duced rates of PVL, conferring potential use in a wider range vival. It should also be considered that there are factors that of patients, including those with irregular or more calcified may affect patients’ susceptibility to residual PVL (e.g., re- anatomies. duced LV-function; mixed aortic valve disease). +us, it will be important to minimize even mild PVL, as there could be Data Availability an impact in some patient subgroups. While our analyses did not identify any factors strongly related to improvement or +e data and study protocol for this clinical trial may be worsening of PVL, there could be a signal that the presence made available to other researchers in accordance with of eccentric calcification plays a role regarding the potential Boston Scientific’s Data Sharing Policy (https://www. for improvement of PVL over time. +is is likely to be a topic bostonscientific.com/en-US/data-sharing-requests.html). of interest in future studies. +e ACURATE neo2 design incorporates improved sealing Conflicts of Interest to further reduce PVL, while preserving many desirable fea- tures of the ACURATE neo platform, including supra-annular Dr. Kim reports personal fees from Boston Scientific, valve positioning to allow for low gradients and a simplified Edwards Lifesciences, Abbott, Medtonic, and Meril, outside implant technique. +e stent configuration of the valve remains the submitted work. Dr. +iele has nothing to disclose. Dr. Journal of Interventional Cardiology 9 Eurointervention Journal, Eurointervention Journal, vol. 13, Linke reports grants from Novartis and Edwards Life- no. 15, 2018. sciences, personal fees from Medtronic, Abbott, Edwards [6] J. Lanz, W.-K. Kim, T. Walther et al., “Safety and efficacy of a Lifesciences, Boston Scientific, Astra Zeneca, Novartis, self-expanding versus a balloon-expandable bioprosthesis for Pfizer, Abiomed, Bayer, and Boehringer, and other from transcatheter aortic valve replacement in patients with Picardia, Transverse Medical, and Claret Medical, outside symptomatic severe aortic stenosis: a randomised non-infe- the submitted work. Dr. Kuntze reports grants from riority trial,” Lancet, vol. 394, no. 10209, 2019. Edwards, outside the submitted work. Dr. Fichtlscherer has [7] C. Tamburino, S. Bleiziffer, H. +iele et al., “Comparison of nothing to disclose. Dr. Webb reports personal fees from self-expanding bioprostheses for transcatheter aortic valve Edwards Lifesciences, outside the submitted work. Dr. Chu replacement in patients with symptomatic severe aortic ste- reports personal fees from Medtronic, Edwards Lifesciences, nosis: the SCOPE 2 randomized clinical trial,” Circulation, Boston Scientific, Abbott Vascular, Terumo Aortic, and vol. 142, 2020. Cryolife, outside the submitted work. Dr. Adam reports [8] H. Mollmann, ¨ P. Diemert, E. Grube, S. Baldus, J. Kempfert, grants and personal fees from Medtronic and personal fees and A. Alexandre, “Symetis ACURATE TF aortic bio- from Boston Scientific and Edwards Lifesciences, outside the prosthesis,” EuroIntervention, vol. 9, 2013. submitted work. Dr Schymik has nothing to disclose. Dr. [9] H. Mollmann, ¨ T. Walther, D. Siqueira et al., “Transfemoral Geisler reports grants from Edwards Lifesciences and TAVI using the self-expanding ACURATE neo prosthesis: one-year outcomes of the multicentre CE-approval cohort,” Medtronic, outside the submitted work. Dr. Kharbanda EuroIntervention, vol. 13, 2017. reports grants and personal fees from Boston Scientific, [10] T.-Y. Ko, H.-L. Kao, Y.-C. Chen et al., “Temporal change in outside the submitted work. Drs. Christen and Allocco are paravalvular leakage after transcatheter aortic valve replace- employees and shareholders of Boston Scientific. ment with a self-expanding valve: impact of aortic valve calcification,” Acta Cardiologica Sinica, vol. 36, no. 2, Acknowledgments pp. 140–47, 2020. [11] G. P. Ussia, M. Barbanti, A. S. Petronio et al., “Transcatheter +e authors thank Songtao Jiang, MS (Boston Scientific aortic valve implantation: 3-year outcomes of self-expanding Corporation), for statistical analysis and MaryEllen Carlile corevalve prosthesis,” European Heart Journal, vol. 33, 2012. Klusacek, PhD (Boston Scientific Corporation), for assis- [12] J. J. Popma, D. H. Adams, M. J. Reardon et al., “Transcatheter tance in manuscript preparation. aortic valve replacement using a self-expanding bioprosthesis in patients with severe aortic stenosis at extreme risk for surgery,” J Am Coll Cardiol, vol. 63, no. 19, pp. 1972–81, 2014. Supplementary Materials [13] S. K. Kodali, M. R. Williams, C. R. Smith et al., “Two-year outcomes after transcatheter or surgical aortic-valve re- Supplementary Table 1: primary and secondary endpoints. placement,” New England Journal of Medicine, vol. 366, no. 18, Supplementary Table 2: investigators and sites by enrolment. pp. 1686–95, 2012. 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Mehilli, C. Frerker et al., E. Guerra, vol. 97, no. 11, pp. 899–906, 2011. S. Massberg, U. Schafer, ¨ M. El-Mawardy, G. Richardt, and [2] S. Kodali, P. Pibarot, P. S. Douglas et al., “Paravalvular re- CHOICE investigators, Comparison of balloon-expandable vs gurgitation after transcatheter aortic valve replacement with self-expandable valves in patients undergoing transcatheter the edwards sapien valve in the PARTNER trial: character- aortic valve replacement: the CHOICE randomized clinical izing patients and impact on outcomes,” European Heart trial,” JAMA, vol. 311, no. 15, pp. 1503–1514, 2014. Journal, vol. 36, no. 7, pp. 449–56, 2015. [17] M. B. Leon, C. R. Smith, M. J. Mack et al., “Transcatheter or [3] P. Pibarot, R. T. Hahn, N. J. 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Wassef, J. Rodes-Cabau, Y. Liu et al., “+e learning curve and annual procedure volume standards for optimum outcomes of transcatheter aortic valve replacement: findings from an international registry,” JACC: Cardiovascular Inter- ventions, vol. 11, 2018. [25] T. Walther and On behalf of the SCOPE I investigators, “SCOPE I: one -year outcomes of a randomized trial com- paring a self-expanding to a balloon-expandable transcatheter aortic valve,” 2020, https://www.tctmd.com/TCT2020. [26] W.-K. Kim, H. Mollmann, ¨ C. Liebetrau et al., “+e ACURATE neo transcatheter heart valve: a comprehensive analysis of predictors of procedural outcome,” JACC: Cardiovascular Interventions, vol. 11, no. 17, pp. 1721–29, 2018. [27] W.-K. Kim, H. Mollmann, ¨ C. Liebetrau, M. Renker, T. Walther, and C. W. Hamm, “Effectiveness and safety of the ACURATE neo prosthesis in 1,000 patients with aortic ste- nosis,” American Journal of Cardiology, vol. 20, 2020. [28] D. D´etaint, L. Lepage, D. 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Abumayyaleh et al., “Short-term outcome and hemodynamic performance of next-generation self-expanding versus balloon-expandable transcatheter aor- tic valves in patients with small aortic annulus: a multicenter propensity-matched comparison,” Circulation: Cardiovascu- lar Interventions, vol. 10, no. 10, Article ID e005013, 2017. [32] A. Ruck, ¨ “Results from the Early Neo2 Registry: ACURATE Neo2 TAVI Valve,” Presented at the EuroPCR eCourse, May 17, 2021. [33] A. Ruck, ¨ W.-K. Kim, H. Kawashima et al., “Paravalvular aortic regurgitation severity assessed by quantitative aortography: ACURATE neo2 versus ACURATE neo transcatheter aortic valve implantation,” Journal of Clinical Medicine, vol. 10, no. 20, 2021. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Interventional Cardiology Hindawi Publishing Corporation

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Copyright © 2022 Won-Keun Kim et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract

Hindawi Journal of Interventional Cardiology Volume 2022, Article ID 9138403, 10 pages https://doi.org/10.1155/2022/9138403 Research Article Transcatheter Aortic Valve Implantation with ACURATE neo: Results from the PROGRESS PVL Registry 1 2 3 4 5 Won-Keun Kim , Holger Thiele, Axel Linke, Thomas Kuntze, Stephan Fichtlscherer, 6 7 8 9 10 John Webb, Michael W. A. Chu, Matti Adam, Gerhard Schymik, Tobias Geisler, 11 12 12 Rajesh Kharbanda, Thomas Christen, and Dominic Allocco Department of Cardiology and Cardiac Surgery, Kerckhoff Heart Center, Bad Nauheim, Germany Department of Cardiology, Heart Center Leipzig at University of Leipzig and Leipzig Heart Institute, Leipzig, Germany Department of Internal Medicine and Cardiology, Herzzentrum Dresden at Technische Universita¨t Dresden, Dresden, Germany Department of Cardiology, Heart Centre, Central Clinic in Bad Berka, Bad Berka, Germany Department of Internal Medicine, Division of Cardiology, Johann W. Goethe University, Frankfurt, Germany Centre for Heart Valve Innovation, St. Paul’s and Vancouver General Hospitals, University of British Columbia, Vancouver, British Columbia, Canada Division of Cardiac Surgery, Department of Surgery, Western University, London Health Sciences Centre, London, Ontario, Canada Clinic for Cardiology, University Hospital Cologne, Cologne, Germany Medical Clinic IV, Department of Cardiology, Municipal Hospital Karlsruhe, Karlsruhe, Baden-Wu¨rttemberg, Germany Department of Cardiology and Angiology, University Hospital Tu¨bingen, Tu¨bingen, Germany Oxford Heart Centre, John Radcliffe Hospital, Oxford, UK Boston Scientific, Marlborough, MA, USA Correspondence should be addressed to Won-Keun Kim; w.kim@kerckhoff-klinik.de Received 2 November 2021; Revised 18 March 2022; Accepted 3 May 2022; Published 25 June 2022 Academic Editor: Alessandro Sciahbasi Copyright © 2022 Won-Keun Kim et al. +is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Objectives. +e PROGRESS PVL registry evaluated transcatheter aortic valve implantation (TAVI) in patients treated with ACURATE neo, a supra-annular self-expanding bioprosthetic aortic valve. Background. While clinical outcomes with TAVI are comparable with those achieved with surgery, residual aortic regurgitation (AR) and paravalvular leak (PVL) are common complications. +e ACURATE neo valve has a pericardial sealing skirt designed to minimize PVL. Methods. +e primary endpoint was the rate of total AR over time, as assessed by a core echocardiographic laboratory. +e study enrolled 500 patients (mean age: 81.8± 5.1 years; 61% female; mean baseline STS score: 6.0± 4.5%) from 22 centers in Europe and Canada; 498 patients were treated with ACURATE neo. Results. +e rate of≥ moderate AR was 4.6% at discharge and 3.1% at 12 months; the rate of≥ moderate PVL was 4.6% at discharge and 2.6% at 12 months. Paired analyses showed significant improvement in overall PVL between discharge and 12 months (P< 0.001); 64.6% of patients had no change in PVL grade, 24.9% improved, and 10.5% worsened. Patients also exhibited significant improvement in transvalvular gradient (P< 0.001) and effective orifice area (P � 0.01). +e mortality rate was 2.2% at 30 days and 11.3% at 12 months. +e permanent pacemaker implantation (PPI) rate was 10.2% at 30 days and 12.2% at 12 months. Conclusions. Results from PROGRESS PVL support the sustained safety and performance of TAVI with the ACURATE neo valve, showing excellent valve hemodynamics, good clinical outcomes, and significant interindividual im- provement in PVL from discharge to 12-month follow-up. 2 Journal of Interventional Cardiology followed by the upper and lower crown, allowing for he- 1. Introduction modynamic stability and uninterrupted aortic outflow. Transcatheter aortic valve implantation (TAVI) is an ACURATE neo is available in three sizes (S [small], M established, effective alternative treatment for patients with [medium], and L [large]) to treat native annulus diameters of symptomatic aortic stenosis who are considered high-risk 21 mm to 27 mm. Valve sizing was assessed by computerized for surgical valve replacement. While clinical outcomes with tomography (CT) and based on perimeter-derived annulus TAVI are comparable to those achieved with surgery, diameter; final size selection was at the operators’ discretion. concerns over complications such as residual aortic regur- gitation (AR) and paravalvular leak (PVL) persist. Moderate or greater PVL has been linked to less robust functional 2.3. Outcomes Measures and Statistical Methods. +e pri- mary endpoint was the rate of total aortic regurgitation (AR) improvement, increased rates of heart failure and hospi- talization, and increased long-term mortality [1–3]. at discharge/7 days, 30 days, and 12 months after TAVI. +e +e ACURATE neo valve, a self-expanding, supra-an- degree of paravalvular leak (PVL) was also examined, as this nular bioprosthetic aortic valve, has been commercially is the main driver of AR after TAVI and is typically of greater available for transfemoral TAVI in Europe since 2014. +e clinical interest. Per protocol, echocardiographic assess- largest study of ACURATE neo to date, the SAVI-TF study, ments were carried out according to local standard of care investigated clinical and echocardiographic outcomes in a for TAVI (if frequency or requirements were different from large high-risk patient population treated under real-world the study schedule) with all available data assessed by an conditions [4, 5]. +e study had a 98.7% procedural success independent core laboratory (Medical Research Develop- ment, Madrid, Spain). +e primary endpoint and all rate, a low rate of all-cause mortality (30 days: 1.4%; 1 year: 8.0%), and the pacemaker rate was <10% through 1 year. echocardiographic outcomes, including improvements in Patients exhibited a low rate of ≥ moderate PVL at 30 days mean transvalvular gradient and effective orifice area (EOA), (4.1%) and 1 year (3.8%). However, other studies of were measured in the per-protocol population (i.e., patients ACURATE neo have produced conflicting data regarding treated with the ACURATE neo valve). Clinical event rates PVL. Patients randomized to treatment with ACURATE neo were analyzed in the intent-to-treat (ITT) population, which in the SCOPE I and SCOPE II studies had a higher incidence includes all enrolled patients in whom valve implantation of ≥ moderate PVL at 30 days compared with Sapien 3 and was attempted. All VARC-2 safety events were evaluated by Evolut R/PRO, respectively, which contributed to ACU- an independent medical reviewer. A comprehensive list of RATE neo missing the noninferiority primary endpoints in secondary endpoints is presented in Supplementary Table 1. both studies [6, 7]. A post-hoc analysis was performed to compare the size of the implanted prosthetic valve with the native annulus di- Here, we report results from the PROGRESS PVL reg- istry, which evaluated the safety and performance of TAVI mensions (based on site-reported CT), expressed as cover with ACURATE neo in routine clinical practice. +e study index [CI � 100 x (nominal prosthesis diameter—annulus also included longitudinal assessment of echocardiographic diameter)/nominal prosthesis diameter]. data over time by an independent core laboratory. Baseline and outcome variables were summarized using descriptive statistics. For comparison of categorical variables, statistical differences were assessed using a chi-square test or a 2. Methods Fisher’s exact test, as appropriate. For comparison of con- tinuous variables, the Student’s t-test or analysis of variance 2.1. Study Design. PROGRESS PVL is a multicenter open- was used. Paired analysis of change in PVL over time was label single-arm study. Patients were considered eligible if performed according to Bhapkar’s test for marginal homo- they presented with severe aortic stenosis and were deter- geneity. All statistical analyses were two-sided with an alpha mined by a heart team to be at high risk for surgical valve level of 5%. Statistical analyses were performed with SAS replacement based on the patient’s Society of +oracic software (SAS Institute Inc., Cary, NC), version 9.3 or later. Surgeons (STS) score as well as the presence of other comorbidities. +e protocol was approved by locally appointed institutional review boards/ethics committees. 3. Results +e study was conducted in accordance with the Interna- 3.1. Study Cohort. PROGRESS PVL enrolled 500 patients at tional Conference for Harmonization Good Clinical Practice (ICH-GCP) regulations and guidelines and the ethical 22 centers in Europe and Canada between January 2017 and July 2018. A listing of investigators and sites can be found in principles outlined in the Declaration of Helsinki and registered with ClinicalTrials.gov (NCT02987894). All pa- Supplementary Table 2. Figure 2 depicts the disposition of enrolled patients. Two patients were not implanted with tients gave written informed consent. ACURATE neo and thus were not included in the per- protocol analysis set. In one patient, the femoral artery 2.2. Device Details. Figure 1 presents key elements of the anatomy was too small for the delivery system sheath, and in ACURATE neo valve (Boston Scientific, Marlborough, MA, another patient, the valve lost contact with the annulus and USA), which have been described in detail elsewhere [8]. +e embolized to the aortic root (valve was snared in the as- valve features controlled and predictable top-down de- cending aorta); these patients were treated with nonstudy ployment, with sequential release of the stabilization arches valves and assessed for safety through 30-day follow-up. Journal of Interventional Cardiology 3 Stabilization Arches Axial, self-aligning Upper Crown Porcine pericardium leaflets Captures native leaflets and provides coronary clearance Supra-annular positioning Lower Crown Pericardial Skirt Minimal protrusion into LVOT; low risk Integrated inner and outer skirts of conduction system interference designed to minimize paravalvular leak Figure 1: +e ACURATE neo valve. +e ACURATE neo valve is comprised of three porcine pericardial leaflets sewn into a self-expanding nitinol frame with three axial stabilization arches. +e supra-annular positioning contributes to low gradients. +e pericardial skirt is designed to minimize paravalvular leak. Enrolled Patients (Intent-to-treat population) N=500 Echocardiographic Assessment for Study valve not implanted: n=2* Primary Endpoint Implanted with ACURATE neo Discharge (Per-protocol population) n=380 (76.3%) N=498 Withdrew consent: n=6 30-day 30-day Clinical Follow-up or Death n=287 (57.6%) n=452 (90.4%) Withdrew consent: n=11 12-month Clinical Follow-up or Death 12-month n=462 (92.4%) n=237 (47.6%) *Femoral artery anatomy too small for sheath (n=1); embolization to aortic root (n=1); patients were treated with non-study valves and assessed for afety through 30-day follow-up. Echocardiography was performed per local standard of care if frequency or requirements were different from the study schedule. Figure 2: PROGRESS PVL study flow. +e mean age of enrolled patients was 81.8± 5.1 years, occurred in 493/500 patients (98.6%). In addition to the two and 61.2% were female. +e mean STS score in the study cases previously described, who were not treated with an population was 6.0± 4.5%, and 24.4% of patients had an STS ACURATE neo valve, there were four valve-in-valve pro- score ≥8%. At baseline, New York Heart Association cedures treated with a balloon-expandable nonstudy valve (NYHA) functional status was class III or IV in 75.2% of (two cases where the initial ACURATE bioprosthesis was patients. Based on site-reported assessment, calcification of placed in the aortic root but then lost contact with the the aortic leaflets was severe or extreme in approximately annulus, one case of dislocation to aortic root with in- one-third of patients. Additional baseline demographics, complete valve expansion, and one case of dislocation into the left ventricular outflow tract) and one case where the risk factors, and preexisting clinical conditions are detailed in Supplementary Table 3. initial valve was malpositioned with no further action noted. Patients treated with nonstudy valves in a valve-in-valve procedure were assessed for clinical safety events but were 3.2. Procedural Details. Procedural characteristics are not included in the per-protocol analysis set for echocar- summarized in Table 1. Preimplant balloon aortic valvu- diographic outcomes. In the case wherein the initially loplasty was performed in 91.4% of patients; postdilatation implanted ACURATE neo valve lost contact with the an- was performed in 45.1% of patients. Most patients were nulus, implantation with a nonstudy valve was attempted, implanted with either a M (38.8%) or L (41.6%) valve. +e but the patient subsequently experienced cardiogenic shock, median cover index in the as-treated population was 5.6%. resulting in death the same day as the index procedure, for a Correct positioning of a single valve in the proper location procedural mortality rate of 0.2%. +ere were no instances of 4 Journal of Interventional Cardiology Table 1: Procedural outcomes. Variable ITT population (N � 500) Total time from first puncture to time of transfemoral access site closure (min) 56.7± 26.8 (499) Total time from insertion of delivery system to removal of delivery system (min) 10.2± 11.6 (491) Valve size implanted S 19.6% (98) M 38.8% (194) L 41.6% (208) Balloon predilatation 91.4% (457) Postdilatation 45.2% (226) Correct positioning of a single valve in the proper location 98.6% (493) Procedural mortality 0.2% (1) Periprocedural myocardial infarction (≤72 h) 0.8% (4) Major vascular complications 2.8% (14) Life-threatening/disabling bleeding 0.8% (4) Valve-in-valve implant 0.8% (4/500) Surgical aortic valve replacement 0.0% (0/500) Unplanned use of cardiopulmonary bypass 0.0% (0/500) Coronary obstruction requiring intervention 0.0% (0/500) Ventricular septal perforation 0.0% (0/500) Cardiac tamponade 0.0% (0/500) Endocarditis 0.0% (0/500) Valve embolization 0.2% (1/500) Valve thrombosis 0.0% (0/500) Data are % (n) or mean± standard deviation (n). Two patients from the ITTpopulation were not implanted with ACURATE neo. ACURATE neo valve lost contact with the annulus; patient was treated valve-in-valve with a nonstudy valve, experienced cardiogenic shock, and died the same day as the index procedure. Intra-procedural myocardial infarction, n � 2 (STEMI, n � 1; NSTEMI, n � 1). conversion to surgery, annular rupture, or ventricular septal 3.4. Clinical Safety and Functional Improvement. Clinical perforation. One patient experienced dissection of the as- safety outcomes were analyzed for all enrolled patients in cending aorta, with subsequent endocarditis reported at whom valve implantation was attempted (i.e., the ITT three months after index procedure. population) and are presented in Table 2. +e VARC-2 composite endpoint for early safety at 30 days was met by 9.2% of patients, with low rates of all-cause mortality and 3.3. Echocardiographic Outcomes. In the overall pop- disabling stroke at 30 days. +e overall rate of permanent ulation, ≥ moderate AR was observed in 4.6% of patients at pacemaker implantation (PPI) was 10.2% at 30 days and discharge and 3.1% at 12 months (Figure 3(a)). Observed PVL 12.2% at 12 months (11.6% and 13.4%, respectively, in was very similar to total AR at all time points, with≥ moderate patients who did not have a pacemaker at baseline). +ere PVL in 4.6% of patients at discharge and 2.6% at 12 months were no instances of coronary obstruction during the study. (Figure 3(a)). +e median cover index was significantly higher +e rate of prosthetic valve thrombosis was very low, with in patients with no/trace PVL at discharge compared with only one case occurring within 12 months. patients with mild or greater PVL (6.7% vs 4.8%; P< 0.001) Figure 5 illustrates the functional status of patients (Supplementary Figure 1). A paired analysis performed treated with ACURATE neo (per-protocol population) among patients with core laboratory-adjudicated echo data based on NYHA functional class at baseline, discharge, available at discharge and 12 months (n � 209) demonstrated 30 days, and 12 months after the procedure. At discharge, significant overall improvement in PVL (P< 0.001; 86.6% of patients evaluated were class I or II, with 71.7% of Figure 3(b)). +e proportion of patients with improved PVL patients showing improvement from baseline of at least one between discharge and 12 months was greater than that with class, and 25.2% showing improvement of at least two worsening PVL (24.9% vs. 10.5%) (Figure 3(c)). classes. +is trend continued, with 87.6% of surviving pa- Patients treated with ACURATE neo demonstrated im- tients classified as class I or II at 12 months. One year after proved valve hemodynamics through 12 months of follow-up. TAVI, 76.4% and 33.8% of patients had improved at least In the per-protocol population, the mean aortic valve gradient one or two classes from baseline, respectively. declined and mean EOA increased substantially from baseline to discharge (Figure 4(a)). Improvements in gradient and 4. Discussion EOA were observed across valve sizes (Supplementary Fig- ure 2). Paired analyses performed in patients with hemo- PROGRESS PVL represents an extension of the body of dynamic data available at discharge, 30 days, and 12 months evidence supporting TAVI with ACURATE neo, providing demonstrate maintenance of significant improvement be- real-world data in an elderly high-risk patient population. tween discharge and 12 months in transvalvular gradient Importantly, the study includes longitudinal echocardio- (P< 0.001) and EOA (P � 0.01) (Figure 4(b)). graphic data adjudicated by an independent core laboratory. Journal of Interventional Cardiology 5 Total AR and PVL; per-protocol population 0.3 2.6 4.6 4.3 3.1 5.0 5.0 29.7 29.3 44.4 45.4 50.5 50.4 67.2 68.1 51.1 49.7 44.5 44.6 Total AR PVL Total AR PVL Total AR PVL (372) (372) (281) (280) (229) (229) Discharge 30 Days 12 Months Total AR / PVL Severe Mild Moderate None/Trace (a) PVL; paired analysis cohort (n=209) Directional change in PVL; paired analysis cohort P<0.001 4.3 2.9 10.5% Change in PVL from Discharge to 12m 42.1 29.2 (n=209) 24.9% 64.6% 67.9 53.6 Discharge 12 Months Improved Stayed the same PVL Worsened Severe Mild Moderate None/Trace (b) (c) Figure 3: Improvement in aortic regurgitation. (a) +e primary endpoint of PROGRESS PVL was the rate of total aortic regurgitation (AR), assessed by an independent echocardiography laboratory at discharge/7 days, 30 days, and 12 months in patients treated with ACURATE neo. Paravalvular leak (PVL) was very similar to total AR at all time points. (b, c) Paired analyses performed in patients with data available at both discharge and 12 months (N � 209) demonstrated significant overall improvement in PVL (P< 0.001; Bhapkar’s test for marginal homogeneity), with a greater proportion of patients showing interindividual improvement in PVL compared with worsening PVL. All echocardiographic data were assessed by a core laboratory. Patients maintained excellent valve hemodynamics, with time [10]. +e results with ACURATE neo are consistent large EOAs and low gradients, as expected for a supra- with data from the Italian CoreValve registry, in which all annular valve. Moderate or greater PVL was 2.6% at 1 year, patients with mild leak after procedure were either un- which is lower than observed in earlier ACURATE neo changed or improved through three years of follow-up [11], studies (SAVI-TF: 3.6%, CE-mark cohort: 4.5%) [5, 9]. In the and the CoreValve U.S. Pivotal Trial, which noted im- provement in the severity of PVL grade in patients with paired analysis, patients showed significant overall im- provement in PVL from discharge to 12-month follow-up, paired discharge and one-year echocardiograms [12]. It is with 64.6% of patients showing no change and 24.9% less clear whether PVL also continues to improve following showing improvement in PVL grade over time. +ere is TAVI with a balloon-expandable valve. In the PARTNER some evidence that self-expanding prostheses have the study, PVL was unchanged through two-year follow-up in potential for continued frame expansion and adaptation to 46.2% of patients treated with a Sapien valve, improved in the annulus, thus contributing to a reduction in PVL over 31.5%, and worsened in 22.4% [13], while a paired analysis of Percentage of Percentage of Evaluable Echocardiograms Evaluable Echocardiograms 2 Mean Effective Orifice Area (cm ) 6 Journal of Interventional Cardiology 2.1 ± 0.8 100 2.4 1.9 ± 0.6 1.9 ± 0.7 (n=197) (n=233) (n=284) 2.0 1.6 40.6 ± 15.7 (n=324) 1.2 0.8 7.9 ± 4.1 6.7 ± 3.2 6.9 ± 3.6 0.8 ± 0.3 (n=358) (n=272) (n=222) 0.4 (n=267) 0.0 Baseline Discharge 30 Days 12 Months (a) Mean Aortic Valve Gradient (n=153) Mean Effective Orifice Area (n=118) 10 2.5 2.0 ± 0.8 2.0 ± 0.6 7.8 ± 4.2 1.8 ± 0.7 6.6 ± 3.4 2 6.4 ± 2.9 1.5 5 P=0.005 P=0.37 P<0.001 P=0.45 P=0.001 P<0.001 0.5 0 0 Discharge 30 Days 12 Months Discharge 30 Days 12 Months All echocardiographic data were assessed by a core laboratory. (b) Figure 4: Change in valve hemodynamics. (a) Patients treated with ACURATE neo demonstrated improvements in mean aortic valve gradient and mean effective orifice area through 12-month follow-up, as assessed by an independent echocardiography laboratory. (b) Paired analyses of core laboratory data at discharge, 30 days, and 12 months demonstrate early hemodynamic improvement on a per-subject basis, which was maintained through 12 months. Table 2: Clinical safety outcomes. Variable 30 days 12 months VARC-2 composite early safety 9.2% (46) — All-cause mortality 2.2% (11) 11.3% (54) Cardiovascular death 2.0% (10) 7.1% (34) Noncardiovascular death 0.2% (1) 4.2% (20) Stroke 2.6% (13) 3.6% (17) Disabling Stroke 2.4% (12) 3.1% (15) Nondisabling Stroke 0.2% (1) 0.4% (2) Major vascular complications 3.6% (18) 4.0% (19) Bleeding, life-threatening or disabling 1.4% (7) 3.4% (16) Myocardial infarction (>72 h postprocedure) 0.0% (0) 1.0% (5) Acute kidney injury (AKI stage 2/3) 0.8% (4) 1.0% (5) New permanent pacemaker implantation All patients 10.2% (51) 12.2% (58) Pacemaker-naive patients (n � 443) 11.6% (51) 13.4% (57) New onset of atrial fibrillation/flutter 5.2% (26) 7.5% (36) Valve malpositioning 1.4% (7) 1.5% (7) Coronary obstruction requiring intervention 0.0% (0) 0.0% (0) Ventricular septal perforation 0.0% (0) 0.0% (0) Cardiac tamponade 0.0% (0) 0.0% (0) ∗ ‡ Repeat procedure for valve-related dysfunction 1.2% (6) 1.7% (8) Prosthetic valve endocarditis 0.0% (0) 0.8% (4) Prosthetic valve thrombosis 0.0% (0) 0.2% (1) ∗ † Data are % (n), reported for the ITTpopulation (N � 500). Component of VARC-2 composite endpoint for early safety at 30 days. Includes valve migration, valve embolization, ectopic valve deployment; Two patients were treated with a repeat procedure after 30 days. In one patient, the 30-day follow-up TEE revealed reduced LVEF with persistent moderate PVL; balloon valvuloplasty was performed but did not improve aortic valve insufficiency, and patient underwent SAVR. One patient experienced endocarditis and associated dissection of the ascending aorta on day 89 post-TAVI; SAVR was performed to replace the ACURATE neo valve. mmHg Mean Aortic Valve Gradient (mmHg) cm II Journal of Interventional Cardiology 7 1.9 1.4 0.6 10.3 11.8 11.5 11.8 45.6 53.5 48.9 64.9 37.9 42.0 33.1 22.1 2.7 Baseline Discharge 30 Days 12 Months (N=476) (N=314) (N=356) (N=331) NYHA Class IV III Figure 5: Improvement in functional status. Improvement in functional status, based on New York heart association (NYHA) functional class, was evident at discharge and sustained through 12 months of follow-up. Analysis includes surviving subjects treated with ACURATE neo who had functional status recorded at a given time point. patients treated with Sapien 3 in the PARTNER 2A study did +e investigator-initiated SCOPE I and II studies have presented head-to-head comparisons of ACURATE neo not show any difference in PVL between 30-day and one- year follow-up [14]. with later generation competitor devices. In SCOPE I, ACURATE neo did not meet the noninferiority criteria vs. +e rate of procedural complications was low in PROGRESS PVL, with correct positioning of the valve in Sapien 3 for the 30-day composite endpoint, partially driven by a higher rate of PVL (9.4% vs. 2.8%; P< 0.001) [6]. 98.6% of patients, and there were no cases of coronary obstruction. Many of the participating centres and inves- However, at one-year follow-up, clinical and functional tigators in the current study had prior experience with outcomes did not differ significantly between the devices, ACURATE neo, which likely increased their comfort with and the mean AV gradient was significantly lower and using the valve, leading to fewer procedural complications. median EOA significantly larger in patients treated with +e 30-day PPI rate in the present study (10.2%) was in the ACURATE neo compared with those treated with Sapien 3 range of that observed in other studies of ACURATE neo [25]. ACURATE neo also missed the noninferiority com- posite endpoint of all-cause death or any stroke at 30 days vs. (SAVI-TF: 8.3%, SCOPE I: 10.0%, SCOPE II: 11.0%) [5–7]. It is possible that variations in PPI may be attributed to dif- Evolut R/PRO in SCOPE II [7], which was attributed to a higher rate of cardiac mortality (3% vs 1%, resp.; P � 0.03). ferences in positioning strategies. A recent publication comparing PPI rate in patients categorized by their con- +e rate of cardiovascular death among PROGRESS PVL secutive enrolment in a large European registry found that as patients was 2.0% at 30 days. More extensive operator ex- positioning strategy evolved from a low implantation depth perience with ACURATE neo in the current study compared to a deliberately higher position, PPI rate was reduced with SCOPE II may have played a factor in the differences in (quartile 1–3: 10.9% vs. quartile 4 : 7.4%) [15]. Prior expe- cardiac mortality between these studies. rience with implanting ACURATE neo, including consid- In the PROGRESS PVL study, the 30-day rate of ≥ eration of positioning, may have had an impact on the PPI moderate PVL (5.0%) was nearly half that observed with rate in PROGRESS PVL; however, collection of detailed ACURATE neo in SCOPE I (9.4%) and SCOPE II (9.6%) [6, 7]. +e lower PVL rates observed in PROGRESS PVL imaging data to allow for an in-depth analysis of positioning was outside the scope of the current study. may be partially explained by operators’ prior experience implanting ACURATE neo and more careful patient se- Early clinical outcomes with ACURATE neo were similar to or better than those observed with other first-generation lection. A similar “learning curve effect” has been observed valves. +e 30-day rates for all-cause mortality (2.2%) and in retrospective analyses of ACURATE neo, with substantial stroke (2.6%) are comparable to the ranges observed in studies improvement in PVL in later cases compared with earlier of Sapien/Sapien XT (3.5%–6.3% and 3.6%–5.8% , resp.) cases [26, 27]. +rough a combination of better patient [16–19] or CoreValve (2.1%–5.1% and 1.4%–4.9%, resp.) selection, careful sizing, consideration of aortic valve cal- [16, 20–22]. However, contextualizing the data from cification, and a modified implant technique, it was dem- PROGRESS PVL is difficult, due in part to differences in onstrated that the rate of≥ moderate PVL could be reduced patient risk assessments across studies. Also, as the practice of to<1% [27]. Additionally, a greater percentage of patients in the current study had size L valves implanted compared with TAVI has evolved and operators have become more experi- enced, implant technique and patient selection have become the SCOPE I and II studies (41.6% vs. 34.1% and 33.9%, more refined, leading to an overall decline in procedural resp.), indicating a tendency towards oversizing. +e median complications and improved early outcomes [23, 24]. cover index in the PROGRESS PVL as-treated population Percentage of Surviving Subjects 8 Journal of Interventional Cardiology the same, with a relatively low radial force, which can be was 5.6%, and patients with no/trace PVL were found to have a higher median cover index compared with patients expected to contribute to a low pacemaker rate. +is expec- tation is supported by data from the Early Neo2 Registry, in with ≥ mild PVL, suggesting oversizing may minimize leak risk. Previous studies have likewise noted an inverse cor- which the in-hospital rate of new PPI was 6.0% [33]. relation between cover index and annulus diameter and an association between low cover index and mild or greater 4.1. Study Limitations. Interpretation of data from the PVL [28, 29]. Finally, as ACURATE neo has a relatively low PROGRESS PVL study is limited by the lack of direct radial strength, postdilatation may have been used to achieve comparison with other devices. As an observational registry, optimal expansion of the valve and reduce leaks, particularly patient selection was not restricted; however, as this was a in annuli that were highly calcified or irregular in shape. postmarket study, it is likely that operators had some prior +e next iteration of the ACURATE valve, neo2, was experience with the valve and may have paid more careful designed to address concerns related to PVL while maintaining attention to patient selection in terms of optimized sizing the desirable features of the ACURATE platform. Design and avoiding unfavorable calcification patterns (e.g., heavy enhancements include radiopaque markers that help to facil- calcification in the device landing zone), which may have itate precise valve positioning, and an augmented pericardial contributed to the low PVL rates observed. +ere was no sealing skirt, which extends to the waist of the valve and is core laboratory for CT during initial patient assessment and approximately 60% larger than the prior skirt, to further valve sizing and no formal assessment of cerebrovascular minimize PVL. In the ACURATE neo AS study, 97% of pa- events by a neurological professional, which may have tients treated with ACURATE neo2 exhibited≤ mild PVL [30]. resulted in an underestimation of the stroke rate. As is often No patient had severe PVL, and the 30-day rate of moderate the case with patient registries, monitoring was limited, and PVL (3.0%) was comparable to that observed with Sapien 3 by the rates of clinical and echocardiographic follow-up were Mauri et al. (3.6%) and in SCOPE I (2.8%), and with Evolut in relatively low. Geographic variations in standards and fre- SCOPE II (2.9%) [6, 7, 31]. +ese results are corroborated by quency of data collection were likely compounded by dif- preliminary unpublished data from the Early Neo2 Registry, an ficulties in compelling patients to return to sites for investigator-initiated registry of >500 European patients scheduled follow-up assessments. treated with neo2. +e incidence of > mild PVL in the Early Neo2 Registry was 1.3% [32], and a separate core laboratory 5. Conclusions analysis found that mean aortic regurgitation fraction was significantly lower in patients treated with ACURATE neo2 Patients in the PROGRESS PVL registry demonstrated a versus ACURATE neo (4.4± 4.8% vs. 9.9± 8.2%; P< 0.001), as lower rate of moderate or greater PVL than has been ob- was the rate of moderate/severe aortic regurgitation (1.7% vs. served in earlier studies of the ACURATE neo valve, with 13.9%; P< 0.001) [33]. significant interindividual improvement in PVL from dis- +e impact of PVL on long-term prognosis is an im- charge to 12-month follow-up. Patients also maintained portant factor that must be considered, particularly as TAVI excellent valve hemodynamics and demonstrated good is extended to younger and lower-risk patients, for whom clinical outcomes overall. +e one-year results from this long-term valve performance is critical. While moderate-to- study support the safety and performance of TAVI with severe PVL has consistently been associated with increased ACURATE neo in patients with severe aortic valve stenosis mortality, data on the impact of mild PVL on survival is less and suggest that ACURATE neo can be used in any patient clear [3, 34, 35]. +e current study, which used the standard that meets the appropriate sizing range, absent in the 3-class grading scheme for PVL, may have overlooked presence of extreme, or very eccentric aortic valve calcifi- discrete differences between mild and mild-to-moderate cation. +e design of the next-generation ACURATE neo2 PVL, and although these subtle differences could potentially valve, which retains many of the desirable features of be associated with an adverse effect, the effect size may have ACURATE neo, allows for improved sealing and thus re- been small or masked by several covariates that affect sur- duced rates of PVL, conferring potential use in a wider range vival. It should also be considered that there are factors that of patients, including those with irregular or more calcified may affect patients’ susceptibility to residual PVL (e.g., re- anatomies. duced LV-function; mixed aortic valve disease). +us, it will be important to minimize even mild PVL, as there could be Data Availability an impact in some patient subgroups. While our analyses did not identify any factors strongly related to improvement or +e data and study protocol for this clinical trial may be worsening of PVL, there could be a signal that the presence made available to other researchers in accordance with of eccentric calcification plays a role regarding the potential Boston Scientific’s Data Sharing Policy (https://www. for improvement of PVL over time. +is is likely to be a topic bostonscientific.com/en-US/data-sharing-requests.html). of interest in future studies. +e ACURATE neo2 design incorporates improved sealing Conflicts of Interest to further reduce PVL, while preserving many desirable fea- tures of the ACURATE neo platform, including supra-annular Dr. Kim reports personal fees from Boston Scientific, valve positioning to allow for low gradients and a simplified Edwards Lifesciences, Abbott, Medtonic, and Meril, outside implant technique. +e stent configuration of the valve remains the submitted work. Dr. +iele has nothing to disclose. Dr. Journal of Interventional Cardiology 9 Eurointervention Journal, Eurointervention Journal, vol. 13, Linke reports grants from Novartis and Edwards Life- no. 15, 2018. sciences, personal fees from Medtronic, Abbott, Edwards [6] J. Lanz, W.-K. Kim, T. Walther et al., “Safety and efficacy of a Lifesciences, Boston Scientific, Astra Zeneca, Novartis, self-expanding versus a balloon-expandable bioprosthesis for Pfizer, Abiomed, Bayer, and Boehringer, and other from transcatheter aortic valve replacement in patients with Picardia, Transverse Medical, and Claret Medical, outside symptomatic severe aortic stenosis: a randomised non-infe- the submitted work. Dr. Kuntze reports grants from riority trial,” Lancet, vol. 394, no. 10209, 2019. Edwards, outside the submitted work. Dr. Fichtlscherer has [7] C. Tamburino, S. Bleiziffer, H. +iele et al., “Comparison of nothing to disclose. Dr. Webb reports personal fees from self-expanding bioprostheses for transcatheter aortic valve Edwards Lifesciences, outside the submitted work. Dr. Chu replacement in patients with symptomatic severe aortic ste- reports personal fees from Medtronic, Edwards Lifesciences, nosis: the SCOPE 2 randomized clinical trial,” Circulation, Boston Scientific, Abbott Vascular, Terumo Aortic, and vol. 142, 2020. Cryolife, outside the submitted work. Dr. Adam reports [8] H. Mollmann, ¨ P. Diemert, E. Grube, S. Baldus, J. Kempfert, grants and personal fees from Medtronic and personal fees and A. Alexandre, “Symetis ACURATE TF aortic bio- from Boston Scientific and Edwards Lifesciences, outside the prosthesis,” EuroIntervention, vol. 9, 2013. submitted work. Dr Schymik has nothing to disclose. Dr. [9] H. Mollmann, ¨ T. Walther, D. Siqueira et al., “Transfemoral Geisler reports grants from Edwards Lifesciences and TAVI using the self-expanding ACURATE neo prosthesis: one-year outcomes of the multicentre CE-approval cohort,” Medtronic, outside the submitted work. Dr. Kharbanda EuroIntervention, vol. 13, 2017. reports grants and personal fees from Boston Scientific, [10] T.-Y. Ko, H.-L. Kao, Y.-C. Chen et al., “Temporal change in outside the submitted work. Drs. Christen and Allocco are paravalvular leakage after transcatheter aortic valve replace- employees and shareholders of Boston Scientific. ment with a self-expanding valve: impact of aortic valve calcification,” Acta Cardiologica Sinica, vol. 36, no. 2, Acknowledgments pp. 140–47, 2020. [11] G. P. Ussia, M. Barbanti, A. S. 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Journal of Interventional CardiologyHindawi Publishing Corporation

Published: Jun 25, 2022

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