Association of Paravalvular Regurgitation With 1-Year Outcomes After Transcatheter Aortic Valve Replacement With the SAPIEN 3 Valve

Question  What is the incidence, evolution, and effect on 1-year outcomes of paravalvular regurgitation assessed using a 5-class grading scheme following transcatheter aortic valve replacement with the new generation of balloon-expandable SAPIEN 3 valve?

Findings  In this secondary analysis of a randomized clinical trial, moderate paravalvular regurgitation (PVR) was observed in 3.5% of patients at 30 days and was associated with a 2.4- to 2.7-fold increase in the risk of mortality and rehospitalization at 1 year. Seventy-three percent of the patients with at least moderate PVR at 30 days showed a reduction in PVR severity at 1 year, and mild to moderate PVR (8.2% of patients) was associated with increased risk of aortic valve reintervention but had no significant effect on 1-year mortality or rehospitalization.

Meaning  In this series of patients with severe AS undergoing transcatheter aortic valve replacement with the SAPIEN 3, at least moderate PVR was rare but associated with increased risk of death and heart failure rehospitalization at 1 year; most patients with at least moderate PVR at 30 days showed a reduction in PVR grade at 1 year.

Importance  Moderate/severe and even mild paravalvular regurgitation (PVR) are associated with increased mortality following transcatheter aortic valve replacement (TAVR) with first and second generations of transcatheter valves.

Objective  To examine the incidence, evolution, and effect on 1-year outcomes of PVR following TAVR with a third-generation balloon-expandable transcatheter heart valve.

Design, Setting, and Participants  Prespecified analysis of PVR in the Placement of Aortic Transcatheter Valves (PARTNER) II SAPIEN 3 trial, conducted between October 1, 2013, and September 3, 2014. Multicenter, nonrandomized registry of 1661 patients at intermediate or high surgical risk undergoing TAVR with the SAPIEN 3. Patients with severe, symptomatic aortic stenosis and high/intermediate surgical risk were enrolled in the registry at 51 sites in the United States and Canada.

Interventions  Transcatheter aortic valve replacement with the SAPIEN 3 valve.

Main Outcomes and Measures  Paravalvular regurgitation was assessed in a core laboratory at 30 days and 1 year according to a 5-class scheme: 0, none or trace; 1, mild; 2, mild to moderate; 3, moderate; 4, moderate to severe; and 5, severe. We assessed the effect of PVR on 1-year mortality and heart failure rehospitalization.

Results  Among the 1661 included in the registry, 1592 received a SAPIEN 3 valve and had assessment of PVR. Of these patients, 55.7% had none-trace PVR, 32.6% had mild, 8.2% had mild to moderate, and 3.5% had at least moderate PVR at 30 days. At 1 year, 9.3% of patients had died and 14.2% had been rehospitalized. Only patients with at least moderate PVR had higher 1-year mortality (hazard ratio [HR], 2.40; 95% CI, 1.30-4.43; P = .005) and composite of mortality/rehospitalization (HR, 2.35; 95% CI, 1.52-3.62; P < .001). In a paired comparison including 1213 patients, 73% of the patients with at least moderate PVR at 30 days showed a reduction in PVR severity of at least 1 PVR class at 1 year.

Conclusions and Relevance  In this series of patients undergoing TAVR with the SAPIEN 3 valve, at least moderate PVR was rare but associated with increased risk of death and heart failure rehospitalization at 1 year. Even the upper range of the mild class in the 3-class grading scheme (ie, mild to moderate in the 5-class scheme) had no significant effect on short-term mortality or rehospitalization. Most patients with at least moderate PVR at 30 days showed a decrease of PVR severity grade at 1 year.

Trial Registration  clinicaltrials.gov Identifier: NCT01314313.

Transcatheter aortic valve replacement (TAVR) is now well established in the treatment of high-risk and inoperable patients with severe aortic stenosis (AS).^1-4 Studies have shown that TAVR is equivalent to surgical aortic valve replacement in patients at intermediate surgical risk.^5,6 However, paravalvular regurgitation (PVR) is an important complication of TAVR that has been shown to be associated with increased mortality for both the balloon-expandable and the self-expanding transcatheter heart valves (THV).^2,7,8 Moderate or severe PVR occurs in 5% to 25% of patients undergoing TAVR and is associated with a 2- to 3-fold increase in mortality.^9,10 The studies on the effect of mild PVR on outcomes have yielded conflicting results.^2,7-9,11,12 New generations of THV, such as the SAPIEN 3 (Edwards Lifesciences), have been developed to reduce PVR.^6,13

Standardized and accurate measurement of PVR becomes an important means for establishing prognosis after TAVR and for determining the effectiveness of various THV iterations or designs. Several studies have used the 3-class grading scheme (mild, moderate, and severe) proposed in the most recent guidelines^14-16 to report the severity of PVR. To better understand the possible contribution to differences in grading attributable to the broad categories of mild, moderate, and severe and to align the regurgitation severity classifications with the commonly used clinical nomenclature that often uses more granular categories, we proposed using an expanded, 5-class grading scheme^10,17 (eTable in Supplement 1).

The objectives of this study were to (1) examine the effect of PVR graded using this 5-class scheme on 1-year mortality, rehospitalization for heart failure, and aortic valve reintervention and (2) assess the change in PVR severity between 30 days and 1 year in patients undergoing TAVR with the new-generation SAPIEN 3 THV.

The Placement of Aortic Transcatheter Valves (PARTNER) II SAPIEN 3 trial was a prospective, multicenter registry that enrolled patients with symptomatic severe AS. The Edwards SAPIEN 3 balloon-expandable THV consists of bovine pericardial leaflets sutured to a cobalt chromium frame. The lower portion of the frame is covered with a polyethylene terephthalate skirt to reduce PVR. The design, inclusion and exclusion criteria, and primary results of this trial have been reported.^6,13 The trial protocol is available in Supplement 2.The trial was approved by the institutional review boards of each participating site, and written informed consent was provided by all patients.

In total, 1661 patients were enrolled in the SAPIEN 3 registry at 51 hospitals in the United States, of whom 1651 received a SAPIEN 3 valve implantation (eFigure 1 in Supplement 1). Among these 1651 patients, 1592 had a transthoracic echocardiogram (TTE) available at 30-day follow-up or discharge and were included in this analysis (eFigure 1 in Supplement 1); 558 (35.1%) were considered inoperable or at high risk for surgical aortic valve replacement, whereas 1034 (64.9%) were considered at intermediate risk. Procedures were performed via transfemoral (n = 1384; 86.9%), transapical (n = 131; 8.2%), or transaortic (n = 77; 4.8%) access depending on preprocedural vascular assessment. Patients were required to have an aortic annular area between 273 mm² and 680 mm², appropriate for treatment with a 20-mm, 23-mm, 26-mm, or 29-mm SAPIEN 3 THV (eMethods in Supplement 1).

All baseline and follow-up TTEs were interpreted by a consortium of 3 echocardiography core laboratories based at Québec Heart and Lung Institute, Columbia University Medical Center, and MedStar Health Research Institute. The PVR was assessed at 30 days and 1 year after TAVR using a multiparameter integrative approach as previously described (eMethods and eTable in Supplement 1).¹⁰ Patients with missing 30-day TTE data were imputed using discharge echocardiographic results. Patients were assigned to a given core laboratory so that all echocardiograms from a given patient were assessed by the same laboratory.

The PVR was graded according to a 5-class scheme as follows (eTable in Supplement 1)¹⁰: 0, none or trace; 1, mild; 2, mild to moderate; 3, moderate; 4, moderate to severe; and 5, severe. These 5 classes of grading can easily be collapsed into the 3-class scheme recommended by the American Society of Echocardiography guidelines (eTable 1 in Supplement 1).^14-16

Prior to the start of core laboratory analyses in the SAPIEN 3 study, the 3 core laboratories read together a sample of 160 TTE examinations selected from the PARTNER II trial to standardize the methods for grading PVR among the 3 laboratories. During the course of the study, the intercore laboratory agreement in the grading of PVR severity was assessed in a subset of 64 echocardiographic examinations that were randomly selected and analyzed by the 3 laboratories.

The outcomes for this study were 1-year all-cause mortality, cardiovascular mortality, rehospitalization for heart failure, composite of death or rehospitalization, and need for valve reintervention after TAVR procedure. All events were adjudicated. We also assessed the change in the prevalence and severity of PVR between 30 days and 1 year in the subset of 1213 patients who had a TTE available at both 30 days and 1 year (eFigure 1 in Supplement 1). Patients with aortic valve reintervention between 30 days and 1 year were excluded from this analysis.

Continuous variables are presented as mean (SD) and compared with the use of the 1-way analysis of variance; pairwise comparisons are reported if the overall test was significant. Categorical variables were compared with the use of the χ² test or Fisher exact tests.

Survival curves for time-to-event variables were constructed on the basis of all available follow-up data with the use of Kaplan-Meier estimates and were compared with the use of the log-rank test. Multivariable analysis was performed with the Cox proportional hazards model. The PVR was entered into the models in binary (≥moderate vs <moderate PVR). Other variables entered into the multivariable models for adjustment were the Society of Thoracic Surgeons score and the variables that showed a statistically significant difference between the PVR groups. A paired comparison of the rate of PVR at 1 year vs at 30 days was performed using the McNemar test. Statistical significance was defined at 2-sided P value of less than .05. All statistical analyses were performed with the use of SAS software, version 9.4 (SAS Institute Inc).

The database for the study is maintained at the Cardiovascular Research Foundation, where independent analyses can be requested by investigators with statistical assistance provided. All of the analyses were performed with data from the as-implanted population. Data are based on an extract date of September 2, 2016, and December 10, 2015, for the inoperable/high-risk and intermediate-risk cohorts, respectively.

Of the 1592 patients included in this analysis, 887 patients (55.7%) had none (n = 462) or trace (n = 425) PVR, 519 (32.6%) had mild PVR, 131 (8.2%) had mild to moderate PVR, 7 (3.0%) had moderate PVR, and 8 (0.5%) had moderate to severe PVR at 30 days post-TAVR (Figure 1). There were no patients with severe PVR. We thus grouped together patients with moderate and those with moderate-to-severe PVR into 1 single group: ie, at least moderate PVR group (n = 55; 3.5%) (Figure 1 and Table 1). In the 3-class scheme, this would translate into: 55.7% with none or trace PVR (n = 887), 40.8% with mild PVR (n = 650), and 3.5% with moderate PVR (n = 55). The results of the intercore laboratory variability analysis are shown in the eResults in Supplement 1.

Patients with at least moderate PVR were older and had smaller body mass index, lower prevalence of diabetes, and higher prevalence of at least moderate aortic regurgitation and at least moderate mitral regurgitation at baseline compared with other PVR groups (Table 1). The proportion of patients in the inoperable/high-risk cohort was higher in the none/trace PVR group than in the mild PVR group. With regards to procedural characteristics (Table 1), patients with at least moderate PVR generally received smaller THVs and had smaller percentage of valve oversizing by area. There was a graded inverse relationship between the percentage of valve oversizing and the severity of PVR. Patients with at least moderate PVR also more frequently had balloon postdilation and more than 1 THV deployed during the TAVR procedure. Postdilation or implanting a second THV at the time of TAVR was not associated with increased risk of 1-year mortality or heart failure rehospitalization. Alternative access (transapical or transaortic) was more frequently used in patients with none/trace PVR compared with those with mild PVR. Factors associated with at least moderate PVR on multivariable logistic regression analysis were smaller THV size (odds ratio for THV size, 0.61; 95% CI, 0.37-0.99; P = .04) and smaller THV oversizing (odds ratio for percentage of oversizing, 0.89; 95% CI, 0.85-0.94; P < .001).

At 1 year, 147 patients (9.3%) had died (84 of cardiovascular cause [5.4%]), 220 (14.2%) had been rehospitalized, 319 (20.2%) had a composite of death or rehospitalization, and 10 (0.7%) had aortic valve reintervention after the TAVR procedure (4 valve-in-valve procedures, 4 surgical valve replacements, 1 balloon postdilation plus surgical valve replacement, and 1 closure of paravalvular leak with a vascular plug) (eFigure 1 in Supplement 1). Patients with at least moderate PVR had significantly higher 1-year rates of all-cause mortality (hazard ratio [HR], 2.40; 95% CI, 1.30-4.43; P = .005), cardiovascular mortality (HR, 2.68; 95% CI, 1.24-5.81; P = .01), rehospitalization (HR, 2.27; 95% CI, 1.34-3.83; P = .002), composite of death or rehospitalization (HR, 2.35; 95% CI, 1.52-3.62; P < .001), and valve reintervention (HR, 13.14; 95% CI, 3.39-50.85; P < .001) compared with patients in the 3 other PVR groups (Figure 2 and Table 2). Patients with mild PVR or mild to moderate PVR had similar incidence of all-cause mortality, cardiovascular mortality, and rehospitalization compared with patients with none/trace PVR. Patients with mild to moderate PVR (HR, 6.80; 95% CI, 1.37-33.7) but not those with mild PVR had higher rate of valve reintervention compared with patients with none or trace PVR (Figure 2).

In multivariable models adjusted for age, sex, Society of Thoracic Surgeons score, body mass index, diabetes, at least moderate aortic regurgitation, and at least moderate mitral regurgitation at baseline, the presence of at least moderate PVR at 30 days was independently associated with increased risk of all-cause mortality (HR, 2.59; 95% CI, 1.39-4.85; P = .003), cardiovascular mortality (HR, 2.87; 95% CI, 1.30-6.30; P = .009), rehospitalization (HR, 2.27; 95% CI, 1.31-3.94; P = .003), and composite of death and rehospitalization (HR, 2.36; 95% CI, 1.50-3.69; P < .001) (Table 2). The analysis of total, (ie, paravalvular and central) aortic regurgitation provided similar results in terms of prevalence (3.8% ≥moderate regurgitation at 30 days) and effect on 1-year outcomes (data not shown).

In multiple subgroups based on cohort assignment, clinical factors, and echocardiographic parameters, there was a consistent association between at least moderate PVR at 30 days and higher 1-year all-cause mortality and rehospitalization (eFigure 2 in Supplement 1). The effect of mild to moderate or mild PVR was also similar in the different subgroups (eFigure 3 in Supplement 1).

Among the 1213 patients who had an echocardiographic assessment of PVR available at 30 days and 1 year (eFigure 1 in Supplement 1), 33 (2.7%) had at least moderate PVR (31 moderate and 2 moderate to severe) at 30 days (Figure 3). Of these 33 patients, 9 (27%) remained at least moderate and 24 (73%) decreased to less than moderate PVR at 1 year, with improvement of 1 class in 14 patients, 2 classes in 7 patients, and 3 classes in 3 patients (Figure 3). On the other hand, among the 1180 patients with less than moderate PVR at 30 days, 11 (0.9%) increased to moderate PVR at 1 year. Overall, in the subset of 1213 patients with paired comparison, there were 33 patients (2.7%) with at least moderate PVR at 30 days vs 20 patients (1.6%) at 1 year (P < .001) (Figure 3). Additional results are provided in the eResults in Supplement 1.

The main findings of this study are (1) in this large, adjudicated prospective series of patients with severe AS undergoing TAVR with the new generation of balloon-expandable THV SAPIEN 3, the rate of at least moderate PVR at 30 days was low (3.5%); (2) the presence of at least moderate PVR at 30 days was associated with a 2.4- to 2.7-fold increase in the risk of mortality and rehospitalization, respectively; and (3) mild PVR and mild to moderate PVR were present in 32.6% and 8.2% of patients, respectively, and were not associated with increased risk of 1-year mortality or rehospitalization. As expected, at least moderate PVR was associated with markedly increased risk of aortic valve reintervention after TAVR procedure. Mild to moderate PVR but not mild PVR was associated with increased risk of reintervention. Given that mild PVR is frequent, even with the new generations of THVs, and that previous studies yielded to conflicting results with regards to its effect on outcomes,^2,7-9,11,12 these findings provide important new insights and have major clinical implications. Seventy-three percent of the patients with at least moderate PVR at 30 days showed a reduction in PVR severity at 1 year, whereas only 0.9% of those with less than moderate PVR at 30 days had a worsening of PVR at 1 year.

The advantages and limitations of the various imaging methods, parameters, and schemes to grade PVR severity have been discussed in details in previous articles (eTable in Supplement 1).^10,18 In this study, we used a 5-class grading scheme for the evaluation of PVR (eTable in Supplement 1).¹⁰ Although more grades would initially produce greater variability, using the 5-class scheme, which assigns in-between grades into a predetermined category, has been shown to reduce variability between echocardiography core laboratories in a substudy of the PARTNER IA trial.¹⁷ In this study, agreement between core laboratories was improved when the 5-class scheme was collapsed into the 3-class scheme. A 78% to 91% agreement between 3 different core laboratories for grading of PVR is exceptional when considering the inherent difficulties in assessing PVR following TAVR and the complexities of the multiparametric approach.^10,18

In this large series of patients with high or intermediate surgical risk, the rate of at least moderate PVR was close to 3%, which is about 3-fold lower compared with the rates with the previous generations of SAPIEN THVs. Among the procedural factors, valve undersizing appeared to be the main determinant of the occurrence of significant PVR in this series. The 1-year mortality HR (2.4) for at least moderate PVR in this study was actually similar to those reported in the PARTNER I trial (HR, 2.2)⁷ and in previous meta-analysis (HR, 2.3).⁹ This study thus confirms the poor outcome associated with at least moderate PVR.

However, the effect of mild PVR on outcomes is more controversial and debated. Several studies and meta-analyses indeed reported that mild PVR has a significant effect on clinical outcomes,^2,7,9 whereas others found no effect of mild PVR.^8,11,12 Several factors have been proposed to explain these discrepancies: (1) differences between sites or core laboratories in the grading of mild vs moderate PVR; (2) the mild PVR (in the 3-class scheme) represents a broad class, and the upper range of this mild class (ie, mild to moderate in the 5-class scheme) may have a significant effect on outcomes, whereas the lower range may not; and (3) some subsets of patients may tolerate a mild or moderate PVR, whereas others may be highly vulnerable to even a mild PVR. Using a more granular scale to grade PVR in this study, we were able to dissect out the effect of mild (ie, lower range of mild in 3-class) vs mild to moderate (ie, upper range of mild in 3-class). We found that even the upper range of mild (3 class) PVR, ie, mild to moderate (5-class), was not significantly associated with mortality or heart failure rehospitalization. Furthermore, in subgroup analyses, mild or mild to moderate PVR did not appear to have a detrimental effect on outcomes in some specific potentially more vulnerable subsets (eg, patients with no preexistent aortic regurgitation).

Some studies previously reported regression of PVR after TAVR with the self-expanding CoreValve.^8,19 In the CoreValve US pivotal trial,¹⁹ PVR was moderate or severe in 9.9% of patients at 30 days, and of the 36 patients with moderate PVR at discharge and paired data, 30 (83%) improved by at least 1 grade of regurgitation at 1 year. The regression in PVR after SAPIEN 3 TAVR reported in our study may be related to the continuing expansion of the valve skirt potentially owing to further radial deployment and/or thickening of the skirt as well as connective tissue overgrowth that may reduce the gaps between the THV and native annulus.²⁰

Given that patients with at least moderate PVR at 30 days harbor a 2.4-fold increase in 1-year mortality and that it is difficult to predict who among the survivors will exhibit a regression of PVR, it is essential to make every effort to avoid at least moderate PVR at the time of TAVR. This effort includes comprehensive periprocedural imaging to assess the presence and severity of PVR as well as the use of corrective procedures (ie, balloon postdilation) if at least moderate PVR is present. On the other hand, our results do not support the use of corrective procedure at the time of or after TAVR in the presence of mild PVR. Nonetheless, patients with mild to moderate PVR had increased rate of delayed aortic valve reintervention, and this factor may have contributed to the similar 1-year survival observed in patients with mild to moderate vs none/trace PVR at 30 days. Doppler echocardiography may underestimate the severity of PVR in some patients.^21,22 Additional imaging, including cardiac magnetic resonance, should thus be considered in patients with mild or mild to moderate PVR presenting with persistent or recurrent symptoms or signs of heart failure.

Inconsistent imaging may account for some differences in the grading of PVR between the 30-day and 1-year studies. The change in PVR severity during follow-up may also, at least in part, be related to a change in heart rate, blood pressure, or medications. Moreover, the data on PVR regression were based on a small subset of patients and may reflect a survivorship bias.

In this large, prospective series of patients undergoing TAVR with the SAPIEN 3 valve, at least moderate PVR was rare but associated with increased risk of death and rehospitalization at 1 year. Even the upper range of the mild class in the 3-class grading scheme, ie, the mild to moderate class in the 5-class scheme, had no significant effect on 1-year mortality or rehospitalization. However, mild to moderate PVR but not mild PVR was associated with a higher 1-year rate of aortic valve reinterventions. Longer follow-up is needed to determine the effect of mild to moderate PVR on outcomes beyond 1 year. Most patients with at least moderate PVR at 30 days, and surviving to 1 year showed a reduction in PVR grade at 1 year, which may be multifactorial.

Corresponding Author: Philippe Pibarot, DVM, PhD, Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec, QC G1V-4G5, Canada (philippe.pibarot@med.ulaval.ca).

Accepted for Publication: August 8, 2017.

Published Online: September 27, 2017. doi:10.1001/jamacardio.2017.3425

Author Contributions: Dr Pibarot had full access to all data in the study and takes full responsibility for integrity of the data.

Concept and design: Pibarot, Hahn, Asch, Herrmann, Mack, Thourani, Kodali.

Acquisition, analysis, or interpretation of data: Pibarot, Hahn, Weissman, Arsenault, Beaudoin, Bernier, Dahou, Khalique, Asch, Toubal, Leipsic, Blanke, Zhang, Alu, Herrmann, Makkar, Mack, Smalling, Leon, Kodali.

Drafting of the manuscript: Pibarot, Hahn, Toubal, Zhang.

Critical revision of the manuscript for important intellectual content: Pibarot, Hahn, Weissman, Arsenault, Beaudoin, Bernier, Dahou, Khalique, Asch, Leipsic, Blanke, Alu, Herrmann, Makkar, Mack, Smalling, Leon, Thourani, Kodali.

Statistical analysis: Pibarot, Zhang, Makkar.

Obtained funding: Weissman.

Administrative, technical, or material support: Weissman, Beaudoin, Asch, Blanke, Alu, Leon.

Supervision: Pibarot, Khalique, Mack, Leon, Thourani.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Pibarot holds the Canada Research Chair in Valvular Heart Disease and his research program is funded by grant FDN-143225 from the Canadian Institutes of Health Research. Dr Pibarot has Core Lab contracts with Edwards Lifesciences for which he receives no direct compensation. Dr Hahn has Core Lab contracts with Edwards Lifesciences for which she receives no direct compensation and has speaker honoraria for Philips Healthcare, St Jude Medical, Boston Scientific, and Abbott Structural. Drs Weissman and Asch have Core Lab contracts with Edwards Lifesciences, St Jude Medical, Boston Scientific, Medtronic, Biostable, Sorin/Livanova, Symetis, Biotronik, JenaValve, Abbott Vascular, Direct Flow, GDS, MValve, Xeltis, and Mitralign, for which they receive no direct compensation. Dr Dahou is a reader for a Core Lab, which has contracts with Edwards Lifesciences, for which he receives no direct compensation. Dr Khalique receives speaker honoraria from Edwards Lifesciences, Boston Scientific, and is a reader for a Core Lab which has contracts with Edwards Lifesciences, for which he receives no direct compensation. Drs Leipsic and Blanke are consultants for Edwards Lifesciences and provide CT Core Lab services for Edwards Lifesciences, Medtronic, Neovasc, GDS, and Tendyne Holdings, for which they receive no direct compensation. Drs Leon and Mack are members of the PARTNER Trial Executive Committee, with no compensation. Dr Herrmann has received research funding from Edwards Lifesciences, Medtronic, St Jude, Boston Scientific, and Abbott Vascular and is a consultant for Edwards Lifesciences. Dr Makkar has received grants from Edwards Lifesciences and St Jude Medical; is a consultant for Abbott Vascular, Cordis, and Medtronic; and holds equity in Entourage Medical. Dr Herrmann has received grants from Edwards Lifesciences, St Jude Medical, Medtronic, Boston Scientific, Abbott Vascular, Gore, Siemens, Cardiokinetix, and Mitraspan; is a consultant for Edwards Lifesciences and Siemens; and holds equity in Microinterventional Devices. Dr Thourani is a member of the PARTNER Trial Steering Committee and is a consultant for Edwards Lifesciences, Sorin Medical, St Jude Medical, and DirectFlow. Dr Kodali consults with Edwards Lifesciences and Medtronic, and has ownership interest in Thubrikar Aortic Valve Inc. No other disclosures were supported.

Funding/Support: The Placement of Aortic Transcatheter Valves II Trial was funded by Edwards Lifesciences.

Role of the Funder/Sponsor: The funding source had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.