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Echocardiographic Results of Transcatheter Versus Surgical Aortic Valve Replacement in Low-Risk Patients

The PARTNER 3 Trial
Originally publishedhttps://doi.org/10.1161/CIRCULATIONAHA.119.044574Circulation. 2020;141:1527–1537

Abstract

Background:

This study aimed to compare echocardiographic findings in low-risk patients with severe aortic stenosis after surgical aortic valve replacement (SAVR) or transcatheter aortic valve replacement (TAVR).

Methods:

The PARTNER 3 trial (Placement of Aortic Transcatheter Valves) randomized 1000 patients with severe aortic stenosis and low surgical risk to undergo either transfemoral TAVR with the balloon-expandable SAPIEN 3 valve or SAVR. Transthoracic echocardiograms obtained at baseline and at 30 days and 1 year after the procedure were analyzed by a consortium of 2 echocardiography core laboratories.

Results:

The percentage of moderate or severe aortic regurgitation (AR) was low and not statistically different between the TAVR and SAVR groups at 30 days (0.8% versus 0.2%; P=0.38). Mild AR was more frequent after TAVR than SAVR at 30 days (28.8% versus 4.2%; P<0.001). At 1 year, mean transvalvular gradient (13.7±5.6 versus 11.6±5.0 mm Hg; P=0.12) and aortic valve area (1.72±0.37 versus 1.76±0.42 cm2; P=0.12) were similar in TAVR and SAVR. The percentage of severe prosthesis–patient mismatch at 30 days was low and similar between TAVR and SAVR (4.6 versus 6.3%; P=0.30). Valvulo-arterial impedance (Zva), which reflects total left ventricular hemodynamic burden, was lower with TAVR than SAVR at 1 year (3.7±0.8 versus 3.9±0.9 mm Hg/mL/m2; P<0.001). Tricuspid annulus plane systolic excursion decreased and the percentage of moderate or severe tricuspid regurgitation increased from baseline to 1 year in SAVR but remained unchanged in TAVR. Irrespective of treatment arm, high Zva and low tricuspid annulus plane systolic excursion, but not moderate to severe AR or severe prosthesis–patient mismatch, were associated with increased risk of the composite end point of mortality, stroke, and rehospitalization at 1 year.

Conclusions:

In patients with severe aortic stenosis and low surgical risk, TAVR with the SAPIEN 3 valve was associated with similar percentage of moderate or severe AR compared with SAVR but higher percentage of mild AR. Transprosthetic gradients, valve areas, percentage of severe prosthesis–patient mismatch, and left ventricular mass regression were similar in TAVR and SAVR. SAVR was associated with significant deterioration of right ventricular systolic function and greater tricuspid regurgitation, which persisted at 1 year. High Zva and low tricuspid annulus plane systolic excursion were associated with worse outcome at 1 year whereas AR and severe prosthesis–patient mismatch were not.

Registration:

URL: https://www.clinicaltrials.gov; Unique identifier: NCT02675114.

Clinical Perspective

What Is New?

  • In patients with severe aortic stenosis and low surgical risk, transcatheter aortic valve replacement (TAVR) with the SAPIEN 3 valve is associated with similar and low percentage of moderate to severe aortic regurgitation, but higher percentage of mild aortic regurgitation, compared with surgical aortic valve replacement (SAVR).

  • Transprosthetic gradients, valve areas, percentage of severe prosthesis–patient mismatch, regression of left ventricular hypertrophy, and evolution of left ventricular systolic function are similar in TAVR and SAVR.

  • SAVR, but not TAVR, was associated with significant deterioration of right ventricular systolic function and tricuspid regurgitation, which persisted at 1 year.

What Are the Clinical Implications?

  • In the low surgical risk population with severe aortic stenosis, TAVR with the SAPIEN 3 valve achieves similar valve hemodynamic performance as with SAVR.

  • TAVR may be preferable to SAVR in patients with preexisting right ventricular dysfunction or significant tricuspid regurgitation, or both.

  • Longer follow-up is required to determine the durability of the SAPIEN 3 valve and the clinical effect of paravalvular aortic regurgitation and prosthesis–patient mismatch beyond 1 year.

Introduction

Editorial, see p 1538

Transcatheter aortic valve replacement (TAVR) is a valuable alternative to surgical aortic valve replacement (SAVR) in patients with symptomatic severe aortic stenosis (AS) across the spectrum of operative risk. Previous randomized trials, with both balloon-expandable valves1–3 and self-expandable valves,4–6 have demonstrated that in patients with high or intermediate risk for surgery, TAVR was either superior or noninferior to SAVR, resulting in an expansion of practice guideline recommendations for TAVR.7,8 However, the majority of patients with AS treated with surgery have low surgical risk profiles. Among patients with symptomatic severe AS who were at low surgical risk enrolled in the PARTNER 3 trial (Placement of Aortic Transcatheter Valves), the incidence of the primary end point of death, stroke, or rehospitalization at 1 year was significantly (P=0.0001) lower with TAVR (8.5%) than SAVR (15.1%).3 Concomitantly, the EVOLUT trial (Medtronic Evolut Transcatheter Aortic Valve Replacement in Low Risk Patients) reported that TAVR using self-expandable valves was noninferior to SAVR with respect to the primary end point of death and stroke at 2 years in the low-risk population.6 These data led to US Food and Drug Administration approval of TAVR for patients with symptomatic severe AS and low surgical risk in 2019. Echocardiography is key to assess the evolution of cardiac chamber geometry and function after aortic valve replacement and to determine prosthetic valve hemodynamic performance and stability during follow-up.

This article aimed to compare echocardiographic findings in low-risk patients with severe AS after SAVR or TAVR and determine association between echocardiographic parameters and clinical outcomes at 1 year.

Methods

Patient Selection, Study Design, and Management

Between March 2016 and October 2017, 1000 patients with severe AS and low surgical risk were enrolled at 71 centers and randomized to undergo either transfemoral TAVR with the balloon-expandable SAPIEN 3 valve or SAVR (Figure I in the Data Supplement). Details on study design, complete inclusion and exclusion criteria, procedures, and postprocedural antithrombotic regimen have been reported previously.3 The data, analytic methods, and study materials of the PARTNER 3 trial will not be made available to other researchers for purposes of reproducing the results or replicating the procedure. Patients were at low risk for SAVR on the basis of clinical and anatomic assessment including a Society of Thoracic Surgeons Predicted Risk of Operative Mortality score <4% and agreement by the site heart team and the case review committee. Patients had to be eligible for transfemoral access for the SAPIEN 3 transcatheter heart valve system. Patients with bicuspid aortic valves or anatomy deemed unsuitable for either TAVR or SAVR were excluded. All TAVR procedures were performed by the transfemoral approach. Balloon aortic valvuloplasty was performed at the operator’s discretion before TAVR (predilation) and after TAVR (postdilation). The trial was sponsored by Edwards Lifesciences (Irvine, CA), which funded all trial-related activities and participated in the selection of trial sites, monitoring, and collection and analysis of the data. The trial was approved by the individual site institutional review boards, and all patients provided written informed consent. The patient population for this study consists of all as-treated patients who survived at least 30 days and had a 30-day echocardiogram (Figure I in the Data Supplement).

Echocardiography Core Laboratory Analyses

Transthoracic echocardiograms of the as-treated population (Figure I in the Data Supplement) were obtained at baseline and at 30 days and 1 year after the procedure and were analyzed by a consortium of 2 echocardiography core laboratories based at Québec Heart & Lung Institute and Cardiovascular Research Foundation, Columbia University Medical Center. Patients were assigned to a given core laboratory so that all echocardiograms from a given patient were assessed by the same laboratory. Image acquisition and analysis were performed according to the American Society of Echocardiography standards for echocardiography core laboratories.9 Thirty echocardiograms were randomly selected and analyzed by the 2 core laboratories to assess interlaboratory measurement variability.

Aortic Valve Hemodynamics

Peak and mean transvalvular gradients were calculated with the use of the Bernoulli formula from the aortic velocity obtained by multiwindow continuous-wave Doppler interrogation. Aortic valve area (AVA) was calculated using the continuity equation as the stroke volume measured in the left ventricular outflow tract (LVOT) divided by the aortic velocity–time integral. LVOT stroke volume was calculated as the product of LVOT cross-sectional area and LVOT velocity–time integral measured by pulsed wave Doppler. At baseline, pulsed-wave Doppler sample volume was located just apical (≤5 mm) to the aortic annulus and the LVOT diameter was measured close (≤5 mm) to the aortic annulus (Figure II in the Data Supplement). After aortic valve replacement, the LVOT velocity and diameter were obtained just apical to the prosthetic valve stent or sewing ring (Figure II in the Data Supplement). The LVOT diameter was measured from the outer-to-outer border of the stent or sewing ring. Stroke volume was indexed for body surface area, and low flow state was defined as stroke volume index (SVi) <35 mL/m2 (moderate to severe low flow: SVi <30 mL/m2).7,8,10 Doppler velocity index (DVI) was calculated as the ratio of LVOT velocity–time integral to aortic velocity–time integral. The severity of prosthesis–patient mismatch (PPM) was graded using the AVA indexed to body surface area,11 with absence of PPM defined as >0.85 cm2/m2, moderate PPM as >0.65 and ≤0.85 cm2/m2, and severe PPM as ≤0.65 cm2/m2. If the patient was obese (body mass index ≥30 kg/m2), lower cutoff values of indexed AVA were used to define moderate (>0.55 and ≤0.70 cm2/m2) and severe (≤0.55 cm2/m2) PPM.12 The energy loss index was calculated to account for the pressure recovery phenomenon as [(AVA×AA)/(AA−AVA)]/body surface area, where AA is the cross-sectional area of the ascending aorta in systole.13 The valvulo-arterial impedance (Zva) was calculated to estimate the total left ventricular (LV) hemodynamic load as Zva = (systolic blood pressure + mean transvalvular gradient)/SVi.14,15

Aortic regurgitation (AR) was assessed before and after the procedure using a multiparameter integrative approach as described previously16,17 and was graded according to a 5-class scheme as follows (Table I in the Data Supplement): 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 be collapsed into the 3-class scheme (Table I in the Data Supplement) recommended by the American Society of Echocardiography guidelines.16,18 We reported the incidence of both paravalvular and total (ie, paravalvular + transvalvular) AR.

Hemodynamic valve deterioration was defined as an increase in mean gradient ≥10 mm Hg with concomitant decrease in AVA ≥0.3 cm2 or in DVI ≥0.1 between 30 days and 1 year or a new onset or worsening of transvalvular AR by at least 1 class (3-class scheme) between 30 days and 1 year with ≥ moderate AR at 1 year.19,20

Left and Right Ventricular Geometry and Function

LV size and function were measured according to previously published guidelines.21 In the presence of a sigmoid septum, LV end-diastolic diameter and septal wall thickness were measured just distal (apical) to the septal bulge (Figure II in the Data Supplement). LV mass was calculated using the modified American Society of Echocardiography formula. LV hypertrophy was defined as an LV mass index ≥95 g/m2 in women and ≥115 g/m2 in men.21 Relative wall thickness was calculated as follows: (septal wall thickness + posterior wall thickness)/LV end-diastolic diameter. LV ejection fraction (LVEF) was measured by the biplane Simpson method. Tricuspid annulus plane systolic excursion (TAPSE) was measured on 2-dimensional images in the 4-chamber view to assess right ventricular (RV) function (Figure II in the Data Supplement). Tricuspid valve regurgitation peak gradient was obtained from the continuous-wave Doppler tricuspid regurgitation signal.

Statistical Analysis

Continuous variables are presented as means with SDs or medians with interquartile ranges and were compared using Student t test or the Wilcoxon rank-sum test. Categorical variables are presented as proportions and were compared using the Fisher exact test. Comparisons of continuous variables at 30 days and 1 year were performed with linear mixed models using baseline value, treatment, visit, and interaction between treatment and visit as predictors.

The primary clinical end point of the PARTNER 3 trial was the composite of death from any cause, stroke, and rehospitalization at 1 year after the procedure. Time to event outcomes was evaluated using Kaplan-Meier estimates and the log-rank test. Survival trend test was also provided for analysis with more than 3 groups. Association between 30-day echocardiographic findings and primary end point was analyzed using univariable and multivariable Cox regression analysis. Cox proportional hazards assumptions were verified with the Kolmogorov-type Supremum test. All statistical analyses were performed using SAS software, version 9.4 (SAS Institute, Cary, NC).

Results

Baseline, procedural, and hospital data are presented in Tables II and III in the Data Supplement. In the SAVR group, 4.6% of patients underwent root enlargement and 1.3% underwent concomitant mitral valve replacement (Table III in the Data Supplement). Figure III in the Data Supplement shows the distribution of valve size in the 2 groups.

Interlaboratory variability was <15% for all key echocardiographic measures including LVEF, SVi, effective AVA, and transvalvular gradients. For the grading of AR, there was perfect agreement in 83% of the cases and a difference of 1 class in 17%.

Prosthetic Valve Hemodynamics in TAVR Versus SAVR

Mean gradient, AVA, AVA index, and energy loss index were similar in SAVR and TAVR at 30 days and 1 year (Table 1 and Figure 1A and 1B). Peak aortic velocity, peak gradient, and percentage of mean gradient ≥20 mm Hg (5.5 versus 10.0%; P=0.021) were lower at 1 year and DVI was larger at 30 days and 1 year in SAVR (Table 1 and Figure IVA in the Data Supplement). The percentage of severe PPM at 30 days was low, with no evidence of a difference between SAVR and TAVR (6.3 and 4.6%; P=0.30; Figure 2A). Systolic blood pressure was not significantly different between treatment groups; however, the Zva was significantly lower in the TAVR than the SAVR group at both time points (Table 1 and Figure IVB in the Data Supplement).

Table 1. Echocardiographic Results: Aortic Valve Hemodynamics

VariableBaseline Echocardiogram*30-Day Echocardiogram1-Year Echocardiogram
TAVR (n=495)SAVR (n=453)TAVR (n=495)SAVR (n=453)P ValueTAVR (n=495)SAVR (n=453)P Value
Systolic blood pressure, mm Hg136.6±18.7 (495)136.4±18.0 (453)138.5±18.6 (492)133.0±20.2 (437)0.0008140.0±18.8 (481)139.6±19.3 (406)0.7700
Diastolic blood pressure, mm Hg73.8±10.0 (495)73.7±9.8 (453)72.3±10.0 (492)73.0±10.7 (437)0.391674.2±10.5 (481)75.9±9.5 (406)0.0076
Peak aortic velocity, m/s4.47±0.53 (483)4.44±0.52 (441)2.41±0.39 (490)2.25±0.43 (426)0.16392.46±0.46 (470)2.26±0.45 (390)0.0024
Peak gradient, mm Hg80.9±19.7 (483)79.9±18.9 (441)23.8±8.0 (490)21.0±8.0 (426)0.424225.0±10.1 (470)21.3±8.8 (390)0.0427
Mean gradient, mm Hg49.4±12.7 (483)48.3±11.8 (441)12.8±4.3 (490)11.2±4.3 (426)0.495813.7±5.6 (469)11.6±5.0 (390)0.1209
Mean gradient ≥20 mm Hg473/473 (100.0)427/428 (99.8)33/482 (6.8)17/413 (4.1)0.081246/460 (10.0)21/379 (5.5)0.0208
Aortic valve area, cm20.77±0.16 (458)0.77±0.15 (423)1.74±0.36 (470)1.79±0.41 (395)0.95671.72±0.37 (446)1.76±0.42 (371)0.1204
Indexed aortic valve area, cm2/m20.38±0.08 (458)0.38±0.08 (423)0.87±0.18 (470)0.89±0.21 (395)0.94490.85±0.18 (446)0.87±0.21 (371)0.1433
Doppler velocity index0.19±0.05 (463)0.20±0.04 (426)0.41±0.07 (448)0.45±0.08 (399)0.00320.40±0.07 (427)0.44±0.08 (369)<0.0001
Energy loss index, cm2/m20.42±0.10 (412)0.42±0.09 (380)1.17±0.64 (412)1.17±0.48 (315)0.35501.09±0.30 (364)1.15±0.43 (297)0.1189
Valvulo-arterial impedance, mm Hg/mL/m24.7±1.0 (458)4.8±1.0 (423)3.7±0.8 (471)3.9±0.9 (399)0.00053.7±0.8 (447)3.9±0.9 (372)<0.0001
≥ Moderate paravalvular aortic regurgitation4/487 (0.8)0/421 (0.0)0.12813/466 (0.6)2/381 (0.5)>0.9999
≥ Moderate total aortic regurgitation19/483 (3.9)11/445 (2.5)4/490 (0.8)1/428 (0.2)0.37935/470 (1.1)2/389 (0.5)0.4658

Data are mean±SD (number of patients in whom measure was available) or n/N (%). PPM indicates prosthesis–patient mismatch; SAVR, surgical aortic valve replacement; and TAVR, transcatheter aortic valve replacement.

*P>0.05 for all baseline variables.

P values for continuous variables are based on linear mixed models; P values for categorical and ordinal variables are based on Fisher exact test.

Figure 1.

Figure 1. Changes in echocardiographic measures of valve hemodynamic function from baseline to 30 days and 1 year in the surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) arms.A, Mean transvalvular gradient. B, Aortic valve area. Data are mean±SE. P values are based on linear mixed models.

Figure 2.

Figure 2. Percentage of severe prosthesis–patient mismatch (PPM) and paravalvular aortic regurgitation in the surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) arms.A, Percentage of moderate and severe PPM at 30 days in the TAVR and SAVR groups. Overall PPM includes moderate and severe PPM. B and C, Percentage of paravalvular aortic regurgitation (AR) using the 5-class (B) and 3-class (C) grading schemes (see Table I in the Data Supplement) in the TAVR and SAVR groups. P values are based on Fisher exact test. PVR indicates paravalvular regurgitation.

The percentage of ≥ moderate paravalvular and total AR was very low and not different between TAVR and SAVR at 30 days and 1 year (≥ moderate total AR at 1 year, 1.1 versus 0.5%; P=0.47; Figure 2B and 2C and Figure V in the Data Supplement). Mild and mild to moderate (with the 5-class scheme) or mild (with the 3-class scheme) paravalvular AR was more prevalent in TAVR than in SAVR (Figure 2B and 2C).

Hemodynamic valve deterioration between 30 days and 1 year occurred in 7 of 421 (1.66%) patients of the TAVR group and 3 of 322 (0.93%) patients of the SAVR group (P=0.527). The cause of valve hemodynamic deterioration was valve leaflet thrombosis in 7 patients (5 in TAVR and 2 in SAVR), structural valve deterioration in 1 patient (SAVR), and undetermined in 2 patients (TAVR).

LV and RV Function in TAVR Versus SAVR

The regression of LV mass index from baseline to 30 days (−5.3±16.17 versus −7.6±19.76 g/m2, P=0.283) and from baseline to 1 year (−11.9±21.10 versus −12.0±27.09 g/m2, P=0.843) was similar after TAVR or SAVR (Table 2 and Figure 3A). The percentage of patients with LV hypertrophy decreased by ≈2-fold from baseline to 1 year in both groups but was significantly higher in TAVR compared with SAVR at baseline (41.7 versus 31.8%; P=0.003). This difference persisted at 30 days (31.8 versus 23.3%; P=0.005) but was no longer significant at 1 year (20.3 versus 15.7%; P=0.089). The degree of LV concentric remodeling, as reflected by the relative wall thickness ratio, decreased to a larger extent and was significantly lower in TAVR than in SAVR at 1 year (Figure VIA in the Data Supplement). LVEF did not change significantly after valve replacement and was similar between groups at all time points (Figure 3B). The SVi increased and thus the percentage of low-flow state decreased from baseline to 30 days and 1 year after TAVR (Table 2 and Figure VIB in the Data Supplement). After SAVR, the SVi decreased from baseline to 30 days and then increased from 30 days to 1 year but remained significantly lower than with TAVR at 1 year. Hence, the percentage of low-flow state was higher in SAVR than in TAVR at 30 days and 1 year (29.3% versus 17.0%; P<0.001; Table 2). The percentage of moderate to severe mitral regurgitation was significantly higher with SAVR than with TAVR at 30 days (3.5% versus 0.6%; P=0.002; Table 2).

Table 2. Echocardiographic Results: LV and RV Geometry and Function

End PointBaseline Echocardiogram*30-Day Echocardiogram1-Year Echocardiogram
TAVR (n=495)SAVR (n=453)TAVR (n=495)SAVR (n=453)P ValueTAVR (n=495)SAVR (n=453)P Value
LV end diastolic diameter, cm4.9±0.52 (480)4.9±0.51 (440)4.9±0.50 (484)4.8±0.51 (414)<0.00014.9±0.53 (466)4.8±0.51 (385)<0.0001
LV end systolic diameter, cm3.0±0.62 (477)3.0±0.63 (431)3.0±0.59 (480)3.0±0.59 (412)0.20112.9±0.59 (460)2.9±0.56 (382)0.9827
LV mass index, g/m2104.6±25.7 (475)101.6±25.4 (434)99.0±23.7 (478)94.1±25.9 (407)0.068491.9±22.6 (462)89.0±28.0 (382)0.5610
LV hypertrophy198/475 (41.7)138/434 (31.8)152/478 (31.8)95/407 (23.3)0.005494/462 (20.3)60/382 (15.7)0.0892
Relative wall thickness0.46±0.09 (475)0.45±0.08 (434)0.45±0.08 (478)0.45±0.09 (407)0.14070.43±0.08 (462)0.44±0.09 (382)0.0005
LV ejection fraction, %65.7±9.0 (471)66.2±8.6 (435)65.7±8.2 (479)65.5±8.9 (408)0.265766.4±7.9 (449)66.5±7.8 (365)0.2267
LV ejection fraction <50%21/462 (4.5)21/422 (5.0)19/471 (4.0)19/395 (4.8)0.619513/441 (2.9)12/354 (3.4)0.8386
LV stroke volume, mL81.7±15.3 (458)80.9±15.5 (423)84.2±15.4 (472)76.6±16.2 (400)<0.000187.0±16.5 (450)80.6±16.3 (373)<0.0001
LV stroke volume index, mL/m240.7±7.65 (458)40.1±7.68 (423)41.9±7.55 (472)38.0±7.97 (400)<0.000143.2±8.14 (450)40.1±8.09 (373)<0.0001
LV stroke volume index <35 mL/m2106/449 (23.6)110/411 (26.8)99/464 (21.3)142/390 (36.4)<0.000175/441 (17.0)106/362 (29.3)<0.0001
≥ Mild mitral regurgitation174/476 (36.6)154/436 (35.3)128/490 (26.1)142/424 (33.5)0.0164141/467 (30.2)141/386 (36.5)0.0572
≥ Moderate mitral regurgitation6/476 (1.3)14/436 (3.2)3/490 (0.6)15/424 (3.5)0.00154/467 (0.9)10/386 (2.6)0.0587
RV TAPSE, cm2.1±0.4 (460)2.1±0.4 (419)2.1±0.4 (477)1.4±0.4 (395)<0.00012.1±0.5 (446)1.6±0.4 (361)<0.0001
≥ Mild tricuspid regurgitation152/472 (32.2)140/430 (32.6)135/483 (28.0)179/427 (41.9)<0.0001144/460 (31.3)178/381 (46.7)<0.0001
≥ Moderate tricuspid regurgitation8/472 (1.7)10/430 (2.3)4/483 (0.8)22/427 (5.2)<0.00018/460 (1.7)21/381 (5.5)0.0038
Tricuspid regurgitation peak gradient, mm Hg27.4±10.0 (318)28.6±9.7 (280)25.4±7.35 (328)24.9±7.1 (310)0.852825.6±7.7 (328)24.5±7.6 (306)0.5467

Data are mean±SD (number of patients in whom measure was available) or n/N (%). LV indicates left ventricular; PPM, prosthesis–patient mismatch; RV, right ventricular; SAVR, surgical aortic valve replacement; TAPSE, tricuspid annulus plane systolic excursion; and TAVR, transcatheter aortic valve replacement.

*P>0.05 for all baseline variables.

P values for continuous variables are based on linear mixed models; P values for categorical and ordinal variables are based on Fisher exact test.

Figure 3.

Figure 3. Changes in echocardiographic measures of left ventricular (LV) and right ventricular (RV) function from baseline to 30 days and 1 year in the surgical aortic valve replacement (SAVR) and transcatheter aortic valve replacement (TAVR) arms.A, LV mass index. B, LV ejection fraction. C, Tricuspid annulus systolic plane excursion (TAPSE). D, Percentage of ≥ moderate RV dysfunction, defined as TAPSE <1.6 cm. Data are mean±SE. P values are based on linear mixed models for A, B, and C and on Fisher exact test for D.

RV TAPSE did not change significantly after TAVR but declined markedly from baseline to 30 days after SAVR and remained significantly lower compared with values after TAVR at 1 year (Table 2 and Figure 3C). The percentage of patients with ≥ moderate RV dysfunction defined as TAPSE <1.6 cm was markedly higher in SAVR than TAVR at 1 year (51.0% versus 14.3%; P<0.001; Figure 3D). The percentage of ≥ mild and ≥ moderate tricuspid regurgitation remained unchanged after TAVR but increased after SAVR (Table 2).

Association of Echocardiographic Measures and 1-Year Outcomes

Severe PPM or high residual gradient (mean gradient ≥20 mm Hg) at 30 days were not associated with higher rates of mortality, stroke, or cardiac rehospitalization at 1 year in the whole cohort (Figure VIIA and VIIB in the Data Supplement). The rate of the primary end point was 25%, 16.7%, 6.6%, and 7.6% in patients who underwent TAVR with ≥ moderate, mild to moderate, mild, or no or trace paravalvular AR, respectively (P=0.14; Figure VIIIA in the Data Supplement). With the 3-class grading scheme, the end point rate was 25%, 7.9%, and 7.6% for moderate or severe, mild, and no or trace paravalvular AR, respectively (Figure VIIIB in the Data Supplement). Similar results were obtained for total AR in the whole (TAVR and SAVR) cohort (Figure VIIIC and VIIID in the Data Supplement). High Zva (>4 mm Hg/mL/m2) and reduced TAPSE (<1.6 cm) at 30 days were significantly (P=0.04) associated with higher risk of the primary end point (Figure IXA and IXB in the Data Supplement). There was a trend (P=0.06) for association between moderate to severe low-flow state at 30 days and 1-year outcomes (hazard ratio, 1.74 [95% CI, 0.99–3.07]; P=0.06; Figure IXC in the Data Supplement). After adjustment for age, Society of Thoracic Surgeons Predicted Risk of Operative Mortality score, baseline mitral regurgitation (at least mild), baseline LVEF (<50%), baseline SVi (<35 mL/m2), and baseline and 30-day AR (at least mild), high Zva (>4 mm Hg/mL/m2; hazard ratio, 1.84 [95% CI, 1.13–3.00]; P=0.014), but not reduced TAPSE (<1.6 cm; hazard ratio, 1.33 [95% CI, 0.83–2.12]; P=0.23) at 30 days, remained independently associated with higher risk of the primary end point. Similar results were obtained when using moderate to severe in lieu of at least mild for severity threshold of AR and mitral regurgitation.

Figure X in the Data Supplement presents subgroup analyses of the effect of echocardiographic measures at 30 days on 1-year outcomes. Severe PPM was significantly associated with increased risk of 1-year mortality, stroke, or rehospitalization in women but not in men (Figures X and XI in the Data Supplement). Severe PPM and high Zva were associated with increased risk of 1-year outcomes in patients older than 75 years but not in younger patients (Figure X in the Data Supplement). The association of 30-day echocardiographic measures and 1-year outcomes was similar in other subgroups and, in particular, in TAVR versus SAVR.

Figure XII in the Data Supplement shows the effect of the type of aortic valve replacement on 1-year outcomes in different subgroups of patients dichotomized according to their baseline (preprocedure) echocardiographic measures. The effect of TAVR versus SAVR was not significantly different between different subgroups. However, there was a trend (P=0.13) for greater benefit of TAVR versus SAVR in patients with baseline TAPSE <1.6 cm.

Discussion

In the PARTNER 3 trial, which included patients with symptomatic severe AS and low surgical risk, compared with SAVR, TAVR (using the SAPIEN 3 valve) was associated with similar and low percentage of moderate or severe AR but higher percentage of mild AR; similar mean transprosthetic gradients and AVAs but smaller DVI; lower valvulo-arterial impedance; similar and low percentage of severe PPM; similar LV mass regression and evolution of LVEF but higher SVi at 30 days and 1 year; and better RV function (TAPSE) with less tricuspid regurgitation at 30 days and 1 year.

In the PARTNER 3 population (both TAVR and SAVR), ≥ moderate paravalvular AR, severe PPM, or high residual gradient at 30 days were not associated with higher rate of mortality, stroke, or cardiac rehospitalization at 1 year, whereas higher Zva and reduced TAPSE at 30 days were associated with higher rate of the primary end point.

Prosthetic Valve Hemodynamic Performance in TAVR Versus SAVR

This is the first randomized trial in which the percentage of ≥ moderate paravalvular AR in the TAVR arm was <1% and not statistically different from that in the SAVR arm. Such results may be related, in part, to the use of a third-generation balloon-expandable transcatheter valve, the SAPIEN 3, and the systematic use of preoperative computed tomography for appropriate valve sizing. Mild paravalvular AR was more frequent in TAVR than in SAVR, although without clinical impact at 1 year.

In the PARTNER 1A and 2A trials, the mean transprosthetic gradients and AVAs were better and percentage of severe PPM lower in TAVR than in SAVR, whereas in PARTNER 3, they were similar in SAVR and TAVR. The valve size distribution and valve hemodynamics of TAVR with the SAPIEN 3 are comparable in the PARTNER 3 trial and in the PARTNER 2 SAPIEN 3 registry, whereas those of SAVR were substantially better in the PARTNER 3 than the PARTNER 2A trial. The label size of the surgical valves was ≤21 mm in 44.3% of the patients in the PARTNER 2A trial versus only 20.1% in the PARTNER 3 trial, whereas the distribution of valve size in the TAVR cohorts was similar in the PARTNER 2 and the PARTNER 3 trials (Figure III in the Data Supplement). Hence, in the low-risk population of the PARTNER 3 trial, the surgeons implanted larger valves in part because of more aggressive root enlargement, which has led to improved hemodynamics in the SAVR group of the PARTNER 3 trial versus that of the PARTNER 2A trial.

Zva was lower (ie, better) in TAVR than in SAVR at 30 days and 1 year. The Zva represents the sum of the valvular load (mean gradient) plus the arterial load (systolic blood pressure) and is standardized for flow (SVi). Hence, Zva may be better than the mean gradient, AVA, or DVI for assessing the residual LV hemodynamic burden related to the valvulo-arterial system after aortic valve replacement. Consistently, Zva at 30 days was one of the sole echocardiographic measures associated with 1-year outcomes in the present study.

LV and RV Function in TAVR Versus SAVR

There was no significant difference between TAVR and SAVR in the regression of LV hypertrophy or changes in LVEF in this low-risk population. RV longitudinal systolic function as reflected by the TAPSE and the prevalence of ≥ moderate tricuspid regurgitation remained stable in TAVR, whereas these measures worsened after SAVR. Mechanisms that may explain the deterioration of RV function with SAVR include suboptimal myocardial protection of the right ventricle during aortic cross clamp, episodes of perioperative pulmonary hypertension, and uncoupling of the right ventricle and pericardial sac attributable to pericardiectomy.22–24 A recent analysis of the PARTNER 2A trial showed that the worsening of RV function was 4-fold more frequent after SAVR than TAVR and was associated with a 2-fold increase in the risk of 2-year mortality.24 Altogether, these results suggest that TAVR may be preferable to SAVR in patients with preexisting RV dysfunction.

Worsening RV function, in combination with greater tricuspid regurgitation, may be one of the reasons that patients undergoing SAVR had significantly lower SVi during follow-up compared with patients undergoing TAVR. The lesser regression of LV concentric remodeling and of mitral regurgitation in SAVR versus TAVR may also have contributed to the lower SVi at 30 days and 1 year in SAVR. These factors may explain why the SVi increased during follow-up in the TAVR group despite no significant change in LVEF.

Association of Echocardiographic Measures and Outcomes

In contrast with previous PARTNER trials, ≥ moderate paravalvular or total AR at 30 days was not associated with increased risk of mortality, stroke, or rehospitalization at 1 year in PARTNER 3. This may be related to the fact that only 5 patients had moderate AR (4 in TAVR and 1 in SAVR) at 30 days and none had severe AR in this trial. In the PARTNER 1 TAVR randomized and nonrandomized continued access registry cohorts, even mild AR was significantly associated with increased risk of mortality.25,26 In PARTNER 3, which included low-risk patients, mild AR at 30 days was not associated with 1-year outcomes.

The lack of association between severe PPM or high residual gradient at 30 days and 1-year outcomes in the PARTNER 3 population may be related to the fact that there were few patients with these risk factors in both treatment arms. Recent studies suggest that transprosthetic pressure gradients and PPM may be overestimated by Doppler echocardiography, particularly in balloon-expandable transcatheter valves, because of significant pressure recovery downstream of the valve.27 Longer follow-up is required to determine whether PPM or paravalvular AR are associated with clinical outcomes beyond 1 year. Our results also show that the effect of PPM on outcomes differs in women versus men and in older versus younger patients. Indeed, severe PPM was associated with a marked increase in the risk of 1-year events in women, whereas it had no significant effect in men. These findings emphasize the existence of sex-related differences in the pathophysiology of AS and the response to therapy. In the PARTNER 3 trial, women were underrepresented (31% of the total cohort), and there is thus a need for randomized trials (eg, the RHEIA trial [Randomized Research in Women All Comers With Aortic Stenosis]; URL: https://www.clinicaltrials.gov; Unique identifier: NCT04160130) or registries dedicated to women with low surgical risk.

High Zva and reduced TAPSE at 30 days were the sole echocardiographic measures associated with higher risk of death, stroke, or rehospitalization at 1 year, and these risk markers were more prevalent after SAVR than after TAVR. Hence, the better preservation of RV function achieved with TAVR may have contributed to the superiority of TAVR versus SAVR observed in PARTNER 3 with respect to the primary clinical end point.

Study Limitations

The present results reflect only 1-year outcomes; long-term assessment of structural and hemodynamic valve deterioration is required. Ten-year clinical and echocardiographic follow-up is planned in all patients with adjudication in echocardiography core laboratories. The results of this study apply only to the enrolled AS population for this study and may not be generalizable to subgroups of patients who were excluded from the trial (eg, those with bicuspid aortic valves, severe LVOT calcification, or complex coronary artery disease, or who were not suitable for transfemoral TAVR).

Conclusions

In patients with severe AS and low surgical risk, TAVR with the SAPIEN 3 valve was associated with similar and low percentage of moderate or severe AR but higher percentage of mild AR, compared with SAVR, with no association between AR and outcomes. Transprosthetic gradients, valve areas, percentage of severe PPM, regression of LV hypertrophy, and evolution of LV systolic function were also similar in TAVR and SAVR during 1 year of follow-up. SAVR, but not TAVR, was associated with significant deterioration of RV systolic function and tricuspid regurgitation, which persisted at 1 year.

Supplemental Materials

Data Supplement Figures I–XII

Data Supplement Tables I–III

Footnotes

Sources of Funding, see page 1535

https://www.ahajournals.org/journal/circ

The Data Supplement is available with this article at https://www.ahajournals.org/doi/suppl/10.1161/CIRCULATIONAHA.119.044574.

Philippe Pibarot, DVM, PhD, Institut Universitaire de Cardiologie et de Pneumologie de Québec, 2725 Chemin Sainte-Foy, Québec, Canada. Email

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